Research Reference Guide
A Comprehensive Handbook of Clinical Research
Compiled by Health RAB & Medical Department PharmEvo Pvt. Ltd.
[email protected] www.HealthRAB.org 402,Business Avenue,Block-6,P.E.CH.S Shahrah-e-Faisal ,Karachi-75400,Pakistan.
2
Message from the Chairman
Dr. Abdul Gaffar Billoo Chairman, Health Research Advisory Board Aga Khan University Hospital, Karachi Professor, Department of Paediatrics and child Health
I feel honored to chair the Health Research Advisory Board, a unique & visionary program, which is developed to promote & establish clinical research in Pakistan.
Clinical research has always been very close to my heart simply because it allows us to help our patients effectively through evidence based knowledge and information.
The importance of conducting indigenous clinical research cannot be over emphasized. Depending only upon research from western world does not allow us to treat our local population having local illnesses with a local solution.
One of the objectives of Health RAB is to educate our clinicians and build their capacity in the field of clinical research. For this very purpose, Health RAB compiled this Research Reference Guide to help our physicians, mainly the younger generation, in understanding and then conducting clinical research in Pakistan.
This guide takes us through the subject of clinical research in a simple and categorical manner covering nearly all its various aspects in a concise way.
I am very optimistic that this initiative will go a long way not only in serving our patients better, but in creating visionary healthcare leaders in healthcare in Pakistan InshaAllah.
3
Message from the Vice Chairman
Prof. Dr. Abdul Basit Vice Chairman, Health Research Advisory Board Director & Professor of Medicine Baqai Institute of Diabetes & Endocrinology, Karachi
I feel honored to write about the Research Reference Guide which is a humble effort by Health RAB to assist our clinicians remain abreast with the various academic as well as procedural aspects of clinical trials and research in Pakistan.
As a clinician who has been committed to clinical research throughout my career, I realize the significance of local research and its impact on clinical practice and health outcomes.
This RRG is a comprehensive booklet which is developed keeping in mind the needs of all those who wish to be involved in clinical research. It is a one stop resource which includes an overview of some concepts & terminologies, a helpful check list, relevant SoPs & guidelines, a useful glossary and fundamentals of research, epidemiology, statistics & trials.
I am confident that this RRG will contribute immensely in promoting research culture which in turn gives rise to research projects & activities in Pakistan InshaAllah.
I hope and pray that this effort of ours helps you in your journey of clinical research and that our patients receive the real benefit of this endeavor InshaAllah.
4
Message from the General Secretary
Dr. Zakiuddin Ahmed General Secretary, Health Research Advisory Board Medical Director PharmEvo (Pvt.) Ltd.
As the general secretary of RAB, I feel privileged to present to you the Research Reference Guide, a handbook which comprises of valuable reference material required by clinicians, researchers and students alike.
We realized that there wasn’t any single resource available for our Doctors which could provide most, if not all, the information about clinical trials, registration process, IRBs, proposal writing, etc. Therefore, in order to facilitate our Doctors in their need for finding relevant information from a single reference point, the leadership at Health RAB decided to compile a quick reference booklet.
Health RAB, as you all know, is established by PharmEvo through a research grant, to promote clinical research in Pakistan through various value added activities and projects for the medical community at large. The RRG is yet another step towards building the clinical research ecosystem of our country and supporting those who are involved in clinical research in some capacity.
I am hopeful that this resource will provide you most of the information which you seek in undertaking your research projects.
I would like to thank the Health RAB leadership which provided the necessary guidance as well as the team at PharmEvo which helped develop this reference guide.
5
About Health Research Advisory Board (RAB)
Health Research Advisory Board (RAB) is a “think tank” of senior clinicians, researchers & academicians who are committed to the mission of Health RAB which is to “Develop the Research Ecosystem of Pakistan”.
The members of Health RAB represent major clinical specialties, medical institutions and associations and possess relevant expertise and experience to spearhead such a significant component of our health system.
Objectives of Health RAB
Provide leadership for developing the medical research ecosystem of Pakistan.
Create synergy among the existing stake holders and bring them together.
Build capacity of the human resource involved in conducting research.
Collaborate & network locally as well as globally to initiate research activities in the country.
Facilitate the development of a national research policy & strategy.
6
Advisory Council
1 Dr. Abdul Gaffar Billoo Professor, Department of Paediatrics and Child Health Aga Khan University Hospital, Karachi
2 Dr. Abdul Basit Professor of Medicine & Director Baqai Institute of Diabetes & Endocrinology, Karachi
3 Dr. Zakiuddin Ahmed Medical Director PharmEvo (Pvt.) Ltd.
4 Dr. Ejaz Ahmed Vohra Dean, Postgraduate Clinical Studies Chairman & Professor, Department of Medicine Ziauddin Medical University & Hospital, Karachi
5 Dr. Syed Shahid Noor Head, Department of Orthopaedic Surgery Liaquat National Hospital, Karachi
6 Dr. Kamran Hameed Consultant Rheumatologist & Dean Ziauddin Medical University & Hospital, Karachi
7 Dr. Tahir Shamsi Consultant Haematologist & Transplant Physician Medical Director National Institute Of Blood Disease & Bone Marrow Transplantation, Karachi
8 Dr. Bashir Hanif Consultant Cardiologist Medical Director TABBA Heart Institute, Karachi
9 Dr. Rufina Soomro Consultant Surgeon Liaquat National Hospital, Karachi
10 Dr. Naila Zahid Consultant Oncologist Liaquat National Hospital, Karachi
11 Dr. Shabeen Naz Masood Consultant Gynaecologist & Obstetrician Aga Khan University Hospital, Karachi
12 Dr. Tashfeen Ahmed Orthopaedic Surgeon & Researcher Aga Khan University Hospital, Karachi
13 Dr. Mohammad Saeed Consultant Rheumatologist & Head of Medical Research Liaquat National Hospital & Medical College, Karachi
7
Table of Contents
Chapter 1 – Research and Research Methodology………………………………………………………………………………….13
Chapter 2 – Epidemiology Basics……………………………………………………………………………………………...... 19
Chapter 3 – Clinical Trial Step by Step Overview……………………………………………………………….…………………..30
Chapter 4 – Types of Clinical Trials (Phase I – IV)…………………………………………………………………………………...52
Chapter 5 – International Conference on Harmonization – Good Clinical Practice (E6-R1)…………………….62
INTRODUCTION...... 64
1 GLOSSARY ...... 65
2 THE PRINCIPLES OF ICH GCP...... 72
3 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)...... 72
3.1 Responsibilities...... 72
3.2 Composition, Functions and Operations ...... 74
3.3 Procedures ...... 74
3.4 Records ...... 75
4 INVESTIGATOR ...... 75
4.1 Investigator's Qualifications and Agreements...... 75
4.2 Adequate Resources ...... 76
4.3 Medical Care of Trial Subjects...... 76
4.4 Communication with IRB/IEC...... 76
4.5 Compliance with Protocol ...... 77
4.6 Investigational Product(s)...... 77
4.7 Randomization Procedures and Unblinding ...... 78
4.8 Informed Consent of Trial Subjects...... 78
4.9 Records and Reports...... 81
4.10 Progress Reports...... 82
4.11 Safety Reporting ...... 82
4.12 Premature Termination or Suspension of a Trial ...... 82.
4.13 Final Report(s) by Investigator...... 83
5 SPONSOR...... 83
5.1 Quality Assurance and Quality Control...... 83
5.2 Contract Research Organization (CRO) ...... 83
5.3 Medical Expertise ...... 83
5.4 Trial Design ...... 83
5.5 Trial Management, Data Handling, and Record Keeping...... 84
8
5.6 Investigator Selection ...... 85
5.7 Allocation of Responsibilities ...... 85
5.8 Compensation to Subjects and Investigators ...... 85.
5.9 Financing ...... 86
5.10 Notification/Submission to Regulatory Authority(ies) ...... 86
5.11 Confirmation of Review by IRB/IEC ...... 86
5.12 Information on Investigational Product(s) ...... 86
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) ...... 87
5.14 Supplying and Handling Investigational Product(s)...... 87
5.15 Record Access ...... 88
5.16 Safety Information ...... 88
5.17 Adverse Drug Reaction Reporting...... 88
5.18 Monitoring ...... 88
5.18.1 Purpose ...... 88
5.18.2 Selection and Qualifications of Monitors ...... 89
5.18.3 Extent and Nature of Monitoring ...... 89
5.18.4 Monitor's Responsibilities ...... 89
5.18.5 Monitoring Procedures ...... 91
5.18.6 Monitoring Report ...... 91
5.19 Audit ...... 91
5.19.1 Purpose ...... 91
5.19.2 Selection and Qualification of Auditors ...... 91
5.19.3 Auditing Procedures ...... 91
5.20 Noncompliance ...... 92
5.21 Premature Termination or Suspension of a Trial ...... 92
5.22 Clinical Trial/Study Reports...... 92
5.23 Multicenter Trials ...... 92
6 CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)...... 93.
6.1 General Information ...... 93
6.2 Background Information ...... 93
6.3 Trial Objectives and Purpose ...... 93
6.4 Trial Design ...... 94
6.5 Selection and Withdrawal of Subjects ...... 94
6.6 Treatment of Subjects ...... 95
9
6.7 Assessment of Efficacy...... 95
6.8 Assessment of Safety ...... 95
6.9 Statistics ...... 95
6.10 Direct Access to Source Data/Documents ...... 96
6.11 Quality Control and Quality Assurance...... 96
6.12 Ethics...... 96
6.13 Data Handling and Record Keeping...... 96
6.14 Financing and Insurance ...... 96
6.15 Publication Policy ...... 96
6.16 Supplements ...... 96
7 NVESTIGATOR’S BROCHURE...... 97
7.1 Introduction ...... 97
7.2 General Considerations...... 98
7.2.1 Title Page ...... 98
7.2.2 Confidentiality Statement...... 98
7.3 Contents of the Investigator’s Brochure ...... 98
7.3.1 Table of Contents ...... 98
7.3,2 Summary ...... 98
7.3.3 Introduction ...... 98
7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation ...... 98
7.3.5 Nonclinical Studies ...... 99
7.3.6 Effects in Humans ...... 100
7.3.7 Summary of Data and Guidance for the Investigator ...... 101
7.4 APPENDIX 1: ...... 102
7.5 APPENDIX 2: ...... 103
8 ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL ...... 104
8.1 Introduction ...... 104
8.2 Before the Clinical Phase of the Trial Commences ...... 105
8.3 During the Clinical Conduct of the Trial ...... 109
8.4 After Completion or Termination of the Trial ...... 115
Chapter 6 – Pakistan Clinical Trial Application Submission Process……………………………………………………….117
Chapter 7 – Institutional Review Boards and Ethics Committees in Pakistan………………………………………….130
Chapter 8 – Elements of Informed Consent (with sample forms)……………………………………………………………134
Chapter 9 – Safety Reporting – Adverse Events and Serious Adverse Events ………………….……………………156
10
Chapter 10 – Biostatistics Fundamentally Speaking………………………………………………….…………………………..178
Chapter 11 – How to Write an Effective Proposal………………………………………………………………………………...196
REFERENCES
Appendix I – Clinical Research Information Resources – (Links, Associations, Journals,…)
Appendix II – Clinical Research Glossary (CDISC)
Appendix III – Abbreviations, Acronyms and Initials (CDISC)
11
Preamble
The aim of this pocket guide is to provide a ready reference tool containing some key pertinent information relevant to clinical research and research methodologies intended for physicians, life sciences graduates and those pursuing clinical research or interested in becoming clinical research professionals. Contents on several clinical research related topics are abridged In order to limit size focusing on an easy and clear comprehension of research focused topics.
Promoting clinical research and research methodology trainings is in line with PharmEvo’s core CSR initiatives by making a meaningful contribution toward the medical community in particular and society in general by developing the clinical research ecosystem spearheading indigenous research and trials. PharmEvo engages in the following training & development workshops among others such as customized ad hoc programs tailored to medical professional and institutional requirements:
Research Methodology
Biostatistics Workshops
Clinical Research Training (ICH-GCP)
Epidemiology
Medical Literature Search
Patient First
We hope that this pocket guide will be substantial reference tool by adding value to the clinical research professional in general and across the board for those participating or aiming to be engaged in clinical research studies and trials in Pakistan and abroad.
Editor
12
Chapter 1 – What is Research and Research Methodology?
Introduction
Research and in particular clinical research offers us an opportunity to better understand the mechanism of disease onset and in turn enables us develop new innovative drugs, products and devices with PATIENT as the ultimate beneficiary.
In order to understand research holistically we have attempted to offer an explanation by posing questions for easy remembrance:
What is Research?
Simply put: An art of scientific investigation
Systematic, controlled, empirical and critical investigation of hypothetical propositions about the presumed relationship among natural phenomena, i.e.
Systematic & controlled Empirical Self-correcting
Research is a combination of both experience and reasoning and must be regarded as the most successful approach to the discovery of truth.
A process of arriving at dependable solutions to problems through the planned and systematic collection, analysis and interpretation of data
Why do Research?
To serve society – by increasing standard of living in case of standard of treatment, and by showing right path to society in case of social and behavioral sciences
What is a Research Technique?
Behavior and instruments used in research operations such as scales, recording techniques, content analysis, moving average, longitudinal / cross-sectional collection of data, etc.
What is a Research Method?
Behavior and instruments used in selecting and constructing technique (a range of approaches used to gather data)
Examples: Observation, questionnaire, interview, analysis of records, case study, etc.
13
Methods are more general than techniques. These are used in performing research operations, i.e., collection of data, statistical processing and analyses (tests). To evaluate the accuracy of the results obtained.
What is Research Methodology?
It is the science of studying how research is done scientifically.
A way to systematically solve the research problem by logically adopting various steps
Methodology helps to understand not only the products of scientific inquiry but the process itself
Aims to describe and analyze methods, throw light on their limitations and resources, clarify their presuppositions and consequences.
What are the Benefits of Research Methodology?
Develops a critical and scientific attitude, disciplined thinking to observe objectively (scientific deduction and inductive reasoning)
Provides opportunity to study a subject in depth
Enables us to make intelligent decisions
Ability to evaluate and use results of earlier research (retrospective data) with reasonable confidence and take rational decisions
14
The Levels of Evidence Pyramid diagram above represents the quality of research designs by levels well as the quantity of each study design in the body of published literature. Systematic reviews (higher quality), for instance, are the most time-intensive articles to write and are therefore rarer (lower quantity) than other types of studies.
What are the Qualities of Good Research?
Most importantly good research is possible only through competency, expertise, experience; specialized training, honesty and integrity of researcher
The purpose and objectives are clearly delineated in a proposal or protocol
Procedures enumerated to justify study design
Carefully planned study design leading to objective results and outcomes
Research and data integrity where errors are reported and their effect estimated
Data analysis with appropriate methods/tools for analysis
Confirm and validate data for accuracy
Conclusions drawn based on data evaluation, clarification and statistical analysis
What are the Steps Involved in Research Process?
First we need to formulate the research question
Defining the Objective(s)
Perform extensive medical literature research
Prepare the research design including sample design/sampling
Describe how data will be collected
Define how data will be analyzed
15
Perform statistical analysis for outcome
Prepare study report
The diagram below illustrates the process:
Planning Stage
First of all you need to know what you want to know. So, you need clearly stated research questions.
Then you have to figure out, what kind of data is needed to answer the research questions. Furthermore you have to find a feasible way to collect such data. All this can be called a research design. The research design provides a plan or a framework for data collection and analysis. You refine your research design by planning details related to measurement and sampling.
'Well planned is half done' means that planning should take a considerable amount of time in the total work. Planning might not actually take half of the time; in fact, it might take a lot more than half.
Before entering the implementation stage, think once more whether your research design is able to give answers to your research questions and is it possible to accomplish the planned procedures. It is crucial to go as far as thinking about data analysis:
What are the variables you are going to generate from the data you are going to collect?
What kind of tables, descriptive statistics and charts are you going to create to summarize variables?
What kind of methods are you going to use to analyze relationships between variables?
Do you need statistical inference (error margins, hypothesis testing)?
Implementation Stage
After collecting the data according to your plan you need to get it to an analysis software like SPSS or Excel.
If you have collected data by yourself then you have to enter it to SPSS or Excel.
If you use data from somewhere else then you need to transform it to an appropriate format.
16
If you have used an online survey tool (like Webropol or Digium) then you can get data in an Excel format.
To display, summarize and analyze your data you may use SPSS or Excel. Despite analysis tools you use you must master the basics of statistics.
Why do We Need Good Quality Research?
38% papers published in Nature and 25% of papers in BMJ contain one or more statistical errors; 4% of errors are caused by non-significant findings evaluated as significant by researchers (The Economist, 5 June 2004, p 70- 71).
Information (data, registries, papers, etc.) is power and in this global village where information generated is increasingly being exchanged, additional research planned based on previous research, having a unified clinical research standard and harmonization across continents is increasingly necessary to design and plan high quality research and added benefit of avoiding duplication and a more economical use of resources among others as will be shared in the next chapter on ICH GCP.
“Every honest researcher I know admits he's just a professional amateur. He's doing whatever he's doing for the first time. That makes him an amateur. He has sense enough to know that he's going to have a lot of trouble, so that makes him a professional.”
-- Charles Franklin Kettering (1876 – 1958)
American inventor, engineer, businessman, and the holder of 186 patents
17
Research Flowchart:
18
Chapter 2 - Epidemiology Basics
“The study of the distribution and determinants of health related states or events in specified populations and the application of this study to control health problems” (James Last)
The aim is to obtain, interpret and use health information and reduce disease burden.
The purpose is to provide a basis for developing disease control and prevention measures for groups at risk and this translates into developing measures to prevent or control disease.
7 Uses of Epidemiology:
1. To study the natural history of disease: Trends of a disease for the prediction of trends/periodicity Result are useful in planning for health services and public health 2. Community diagnosis: What are the diseases, conditions, injuries, disorders and disabilities, defects causing illness, health problems or death in a community or region? 3. Look at risks to individuals as they affect groups or population What are the risk factors, problems, behavior that affect groups? Risk factor assessment done: health screening, medical exams, disease assessments. 4. Assessments, evaluating prevention/intervention programs, research How well do public health and health services meet the problems and needs of the population or group? 5. Completing the clinical picture: Identification and diagnosis process to establish that a condition exists or that a person has a specific disease (i.e., who gets the disease, who dies from it and what is the outcome) 6. Identification of syndromes and precursors: Help to establish and set criteria to define syndromes (e.g., the relationship of high blood pressure to stroke, kidney disease and heart disease) 7. Determine the causes and sources of disease (including epidemics and disease of unknown etiology): Findings allow for control, prevention and elimination of the causes of disease, conditions, injury, and disability
What is Epidemiology?
Epidemiology is the study of health and illness (study of diseases, most common diseases and epidemics) in human populations. It is primarily concerned with identifying the important factors or variables that influence a health outcome of interest.
John Snow is the father of modern Epidemiology who in 1854 made a determined effort by employing statistical mapping methods to study how cholera was spread in London.
Example: A randomized clinical trial conducted by Epidemiologists at the Harvard School of Public Health showed that taking aspirin reduces heart attack risk by 20 to 30 percent. It describes the relationship between a health outcome (heart attack status) and an explanation of that outcome (Aspirin intake). We
19 must choose an appropriate study design that must be careful to avoid bias, and must use appropriate statistical methods to analyze the data. Epidemiology deals with each of these three challenges.
Issues to consider when planning an epidemiologic research study:
Question Define a question of interest and key variables Variables What to measure: exposure (E), disease (D), and control (C) variables Design: What study design and sampling frame? Frequency: Measures of disease frequency o A measure of disease frequency quantifies how often the health outcome has occurred in a subgroup of interest. Effect: Measures of effect o A measure of effect quantifies a comparison of measures of disease frequency for two or more subgroups. Bias: Flaws in study design, collection, or analysis Bias is a flaw in the study design, the methods of data collection, or the methods of data analysis that may lead to spurious conclusions about the exposure-disease relationship. o Three general sources of bias occur in: Selection of study subjects Incorrect information gathered on study subjects Failure to adjust for variables other than the exposure variable (confounding) Analysis: Perform appropriate analyses The choice of measure of disease frequency and measure of effect depends on the type of study design used and the goal of the research study.
What is Study Design?
This is defined to be the process of planning an empirical investigation to assess a conceptual hypothesis about the relationship between one or more exposures and a health outcome. The purpose of the study design is to transform the conceptual hypothesis into an operational hypothesis that can be empirically tested. Since all study designs are potentially flawed, it is therefore important to understand the specific strengths and limitations of each design. Most serious problems or mistakes at this stage cannot be rectified in subsequent stages of the study.
What are the Types of Epidemiological Research?
There are two broad types of epidemiologic studies, experimental and observational.
Experimental studies in epidemiology usually take the form of clinical trials and community intervention trials and use randomization of exposures.
The objective of most clinical trials is to test the possible effect, that is, the efficacy, of a therapeutic or preventive treatment such as a new drug, physical therapy or dietary regimen for either treating or preventing the occurrence of a disease. The objective of most community intervention trials is to assess the effectiveness of a prevention program. For example, one might study the effectiveness of fluoridation, of sex education, or of needle exchange.
Observational studies are broadly identified as two types: descriptive and analytic. Descriptive studies are performed to describe the natural history of a disease, to determine the allocation of health care resources, and to suggest hypotheses about disease causation. Analytic studies are performed to test hypotheses about the determinants of a disease or other health condition, with the ideal goal of assessing causation.
20
Most epidemiological studies are observational. Observational studies do not use randomization of exposures.
Experimental/Interventional and Randomized Clinical Trials
Intervention studies are considered to provide the most reliable evidence in epidemiological research. Intervention studies can generally be considered as either preventative or therapeutic.
The randomized controlled trial is considered as the most rigorous method of determining whether a cause- effect relationship exists between an intervention and outcome. The strength of the RCT lies in the process of randomization that is unique to this type of epidemiological study design.
21
Generally, in a randomized controlled trial, study participants are randomly assigned to one of two groups: the experimental group receiving the intervention that is being tested and a comparison group (controls) which receives a conventional treatment or placebo. These groups are then followed prospectively to assess the effectiveness of the intervention compared with the standard or placebo treatment.
The random allocation of subjects is used to ensure that the intervention and control groups are similar in all respects (distribution of potential confounding factors) with the exception of the therapeutic or preventative measure being tested. The choice of comparison treatments may include an existing standard treatment or a placebo (a treatment which resembles the intervention treatment in all respects except that it contains no active ingredients).
Note that ethical constraints limit the choice of comparison treatments.
Quasi Experimental Study Design
Quasi-experimental research designs share many similarities with the traditional experimental design or randomized controlled trial, but they specifically lack the element of random assignment to treatment or control.
A quasi-experiment is a study that includes a manipulated independent variable but lacks important controls (e.g., random assignment), or a study that lacks a manipulated independent variable but includes important controls. So a quasi-experiment has some features of a well conducted experiment but not others.
There are many types of quasi-experiments. Here we discuss just a few of the more common ones:
A non-equivalent groups design includes an existing group of participants who receive a treatment and another existing group of participants to serve as a control or comparison group. Participants are not randomly assigned to conditions, but rather are assigned to the treatment or control conditions along with all the others in their existing group. Example: Imagine that we wanted to do a study to compare student performance in a cooperative learning section of Psych 144 with student performance in a standard lecture section. Imagine further that we scheduled two sections of the course, let students sign up for which one they wanted, and then taught one using cooperative learning and the other using standard lecture. Note
22
that this study includes a manipulated independent variable, but it lacks random assignment of participants to conditions. In a pretest-posttest design, a single group of participants is measured on the dependent variable both before and after the manipulation of the independent variable. Example: Imagine that a group of 100 sixth graders is given a test of their attitudes toward drugs. This is the pretest. Then, a week later, a police officer comes to school and presents an anti-drug program (complete with “cool” decorated car and performing police dog). This is the treatment. Then, in another week, the students are given another test of their attitudes toward drugs. This is the posttest. Obviously, the substantive question here is whether the students’ attitudes toward drugs change after being presented with the anti-drug program. Interrupted Time-Series Designs A time series is simply a set of measurements of a variable taken at various points in time. For example, we could measure the moods of the students in our class each day throughout the semester, and we could see how people’s moods changed (or did not change) over time. In an interrupted time-series design, a time series like this (the dependent variable) is interrupted (usually near the middle) by the manipulation of the independent variable. For example, if we were interested in the effect of the color of the classroom on students’ moods, we could start measuring your moods each day from the beginning of September through Halloween. Then we could paint the room yellow (hoping to raise your moods) and continue measuring your moods each day from the beginning of November to the end of the semester. In analyzing the data, we would want to see whether there was an increase in your moods shortly after the painting of the room that continued to the end of the semester.
Quasi-experiments have somewhat less internal validity (Internal validity is how much we can say the experiment is free from flaws that could have influenced our results. Since quasi-experiments lack important control mechanisms they generally have less internal validity then a true experiment but more than a purely correlation study. To the extent that a study allows one to conclude that the independent variable affected the dependent variable, we say that it has good internal validity. So an ideal experiment has perfect internal validity, experiments usually have good internal validity).
Observational Study Designs
There are three general categories of observational designs:
Basic Designs: Cohort, Case-Control, Cross-Section Hybrid Designs: Nested Case-Control, Case-Cohort Incomplete Designs: Ecologic, Proportional
23
What is a COHORT Study?
A cohort design starts with subjects who do not have a health outcome of interest and are followed forward to determine health outcome status. A key feature of a cohort study is that subjects are grouped on the basis of their exposure characteristics prior to observing the health outcome, that is, the directionality of the study is always forward.
In summary:
The Framingham Heart Study is a classic example of a cohort study. The cohort design is always a follow-up study with forward directionality. A cohort study can be prospective or retrospective. The Framingham study is a prospective cohort study because the study began before the health outcome occurred.
Summary: Cohort Study +’s (advantages) and –’s (disadvantages)
(+) Prospective cohort study: least prone to bias compared with other observational study designs. (+) Can address several diseases in the same study. (+) Retrospective cohort study: can be relatively low-cost and quick; frequently used in occupational studies. (-) Loss to follow-up is a potential source of bias (-) Prospective cohort study: quite costly and time-consuming; may not find enough cases if disease is rare. (-) If exposed are followed more closely than unexposed, the outcome is more likely to be diagnosed in exposed.
24
What is a CASE CONTROL Study?
In case control studies, subjects are selected based on their disease status. The investigator first selects cases of a particular disease and then chooses controls from persons without the disease
Ideally, cases are selected from a clearly defined population, often called the source population, and controls are selected from the same population that yielded the cases. The prior exposure histories of cases and controls are then determined. Thus, in contrast to a cohort study, a case-control study works backwards from disease status to prior exposure status. While case-control studies are always backward in directionality, they can be either prospective or retrospective in timing.
In summary:
Start with cases and non-cases of a disease or other health outcome and proceed backwards to determine prior exposure history. Popular primarily because cheaper and less time-consuming than cohort studies. Other advantages include providing sufficient numbers of cases for rare diseases with long latencies and allowing several exposures to be evaluated. Disadvantages include being susceptible to selection and information bias, not allowing estimation of risk, not considering more than one disease, and not feasible for rare exposures.
What is a CROSS-SECTIONAL study?
In a cross-sectional study, subjects are sampled at a fixed point or within a short period of time. All participating subjects are examined, observed, and questioned about their disease status, their current or past exposures, and other relevant variables. A cross-sectional study provides a snapshot of the health experience of a population at a specified time and is therefore often used to describe patterns of disease
25 occurrence. A cross-sectional sample is usually more representative of the general population being studied than are other study designs.
Summary: Cross-Sectional Studies
Subjects are sampled at a fixed point or short period of time: a snapshot.
Advantages:
Convenient and inexpensive. Can consider several exposures and several diseases. Can generate hypotheses. Usually represents the general population.
Disadvantages:
Cannot establish whether the exposure preceded disease or disease influence exposure. Possible bias since only survivors are available for study. May under-represent diseases with short duration.
What is an Ecological Study?
These examine relationship between exposure and disease with population-level rather than individual-level data. Population-level factors include summaries of individual population members, environmental measures, and global measures. Study groups are usually identified by place, time, or a combination of the two.
For example, researchers conducted an ecologic study with groups identified by place to determine the association between air pollution and mortality rates. The study authors obtained 1978–1981 air pollution levels from monitoring stations throughout the United States and 1980 mortality rates for 305 Standard Metropolitan Statistical Areas (SMSAs). SMSAs are geographic areas that typically include a city and its surrounding areas. The investigators examined correlations between the air pollution variables (such as total suspended particulates and sulfates) and mortality. They observed a positive association between annual mean sulfate concentration and total mortality. That is, SMSAs with high sulfate concentrations tended to have high mortality rates (for example, Scranton, Pennsylvania), while those with low sulfate concentrations tended to have low mortality rates (for example, Salt Lake City, Utah)
What is VALIDITY?
The primary objective of most epidemiologic research is to obtain a valid estimate of an effect measure of interest. Validity in epidemiologic studies concerns methodological flaws that might distort the conclusions made about an exposure-disease relationship.
The validity of an epidemiologic study concerns whether or not there are imperfections in the study design, the methods of data collection, or the methods of data analysis that might distort the conclusions made about an exposure-disease relationship.
If there are imperfections, then the extent of the distortion of the results from the correct conclusions is called bias.
26
What is Bias?
Bias may be defined as any systematic error in an epidemiological study that results in an incorrect estimate of the association between exposure and risk of disease.
Bias results from systematic errors in the research methodology.
Limited scope exists for the adjustment of most forms of bias at the analysis stage. As a result careful consideration and control of the ways in which bias may be introduced during the design and conduct of the study is essential in order to limit the effects on the validity of the study results.
What is Selection Bias?
Selection bias occurs when the two groups being compared differ systematically. That is, there are differences in the characteristics between those who are selected for a study and those who are not selected, and where those characteristics are related to either the exposure or outcome under investigation.
Case-control studies carried out exclusively in hospital settings are subject to a type of "selection" bias. Patients with two disease conditions (Berkson bias) or high-risk behaviors are more likely to be hospitalized than those with a single condition. Such patients will tend to be over-represented in the study population when compared to the community population
What is Information Bias?
In the 1980's and 1990's, US Air Force researchers assessed the health effects among Vietnam War veterans associated with exposure to the herbicide Agent Orange. Agent Orange contained a highly toxic trace contaminant known as TCDD. Initially, exposure to TCDD was classified according to job descriptions of the veterans selected for study. It was later determined that this produced substantial misclassification of TCDD. The validity problem here is called information bias. Bias could be avoided using laboratory techniques that were developed to measure TCDD from blood serum. The use of such biologic markers in epidemiologic research is rapidly increasing as a way to reduce misclassification and, more generally, to improve accuracy of study measurements.
What is Recall Bias?
In a case-control study, data on exposure are collected retrospectively. The quality of the data, therefore, is determined to a large extent by the patient's ability to accurately recall past exposure(s). Recall bias may occur when the information provided on exposure is different between the cases and controls. For example, an individual with the outcome under investigation (case) may report their exposure experience differently than an individual without the outcome (control) under investigation. That is, cases may tend to have a better recall on past exposures than controls.
Recall bias may result in either an underestimate or overestimate of the association between exposure and outcome.
Methods to minimize recall bias include: the collection of exposure data from work or medical records or to blind the study participants as to the hypothesis under investigation.
27
What is Confounding Bias?
Confounding involves the possibility that an observed association is due, totally or in part, to the effects of differences between the study groups (other than the exposure under investigation) that could affect their risk of developing the outcome being studied.
Confounding occurs when the effects of two associated exposures have not been separated, resulting in the interpretation that the effect is due to one variable rather than the other. The consequence of confounding is that the estimated association is not the same as the true effect.
Example:
A study found alcohol consumption to be associated with the risk of Coronary Heart Disease. However, smoking may have confounded the association between alcohol and CHD. For example smoking is independently associated with CHD (is a risk factor) and is also associated with alcohol consumption (smokers tend to drink more than non-smokers).
Controlling for the potential confounding effect of smoking may in fact show no association between alcohol consumption and CHD.
What is Observer Bias?
Observer bias occurs when there are systematic differences in the way information is collected for the groups being studied. Observer bias may occur as a result of the investigator's prior knowledge of the hypothesis under investigation or knowledge of an individual's exposure or disease status. Such information may result in differences in the way information is collected, measured or interpretation by the investigator for each of the study groups.
Losses to Follow-up
Loss to follow-up is a particular problem associated with cohort studies. Bias may be introduced if the individuals lost to follow-up differ with respect to the exposure and outcome from those persons who remain in the study.
28
Validity versus Precision
Validity and precision concern two different sources of inaccuracy that can occur when estimating an exposure-disease relationship: systematic error (a validity problem) and random error (a precision problem). Systematic and random error can be distinguished in terms of shots at a target. These two types of error can be distinguished by viewing an epidemiologic study as a shot at a target. The blue dot in the middle of the target symbolizes the true measure of effect being estimated in a population of interest.
Systematic error is illustrated by comparing Target A with Target B. The shots at Target A are aimed at the blue dot, whereas the shots at Target B are not aimed at the blue dot, but rather centered on the red dot. The distance between the blue dot and the red dot measures the systematic error associated with Target B. In contrast, there is no systematic error associated with Target A.
Problems of precision generally concern statistical inference about the parameters of the population actually being aimed at. In contrast, problems of validity concern methodological imperfections of the study design or the analysis that may influence whether or not the correct population parameter, as represented by the blue dot in each target, is being aimed at by the study.
Reference:
Pocket Guide to Epidemiology by D. Kleinbaum, K. M. Sullivan and N.D. Barker
29
Chapter 3 - Clinical Trial Steps Overview
An attempt has been made to provide a step-by-step overview of the clinical trial process in some detail.
The Division of Biological Evaluation and Research (DBER) of the Drug Regulatory Authority of Pakistan (DRAP) is now the national authority with the regulatory function of clinical trials in Pakistan. This change is relatively new as DRAP itself was formed recently on Nov 12, 2012 upon signing the DRAP Act 2012. Previously it was the Ministry of Health (MoH) that responsible authority for clinical trials in Pakistan.
Clinical trials in Pakistan are still relatively new and need for regulatory guidance; directives and vigilance are necessary prerequisites for successful implementation. Ministerial oversight, institutional capacity building, educational programs on clinical research as a discipline, ethics and safety monitoring will offer those interested in research some much needed support in the right direction. We can learn from the examples of the developed world such as United States, EU and Japan on successful implementation of clinical trials as processes have been streamlined considering thousands of clinical trials they have successfully conducted and improved upon over the years through application of good clinical practices, stringent ethical committees reviews, data monitoring committees and adaptive designs to name some.
The guidance below will assist the researcher appreciate the various steps involved in a typical clinical trial life cycle.
Please refer to Chapter 5 for references to ICH-GCP E6 made in the text.
Legend: CTA submission: Clinical trial application submission (to DBER in Pakistan, US FDA, MHRA in UK or any national regulatory body) DBER: Division of Biological Evaluation Research in Pakistan is responsible for reviewing clinical trial applications R&D: Research and Development R&D submission: Institutional R&D department approval as needed PI: Principal Investigator
30
# TABLE OF CONTENTS
1 Trial Planning & Design 23 Ethics Submission
2. Within the scope of the Clinical Trial 24 CT Dossier Submission Regulations?
3 Risk Assessment 25 Permissions & Approvals Obtained
4 Sponsorship 26 Final Trial Management Documentation
5 Protocol Development 27 Trial is Abandoned
6 GCP & Serious Breach Reporting 28 Trial Begins
7 Trial Management & Monitoring 29 Informed Consent
8 Trial Documentation 30 Safety Reporting
9 Trial Supplies 31 Progress Reporting
10 Pharmacovigilance 32 Ongoing Management & Monitoring
11 R&D Consultation 33 Regulatory Inspection
12 Funding Proposal 34 Audit
13 Peer Review 35 Addition of New Sites & Investigators
14 Funding Secured 36 Substantial Amendments
15 Trial Master File 37 Urgent Safety Measures
16 Unique Trial Number 38 Temporary Halt or Early Termination
17 Confirm Sponsor 39 Trial does not Recommence
18 Feasibility & Investigator Selection 40 End of Trial Declaration
19 Contracts & Agreements 41 Statistical Data Analysis
20 Final Protocol 42 Clinical Trial Summary Report
21 PI Checklist Before Seeking Approval 43 Dissemination of Results
22 R&D Submission 44 Archiving
31
1. Trial Planning & Design
A robust trial design is essential to ensure a successful outcome. The trial design should be considered before developing the protocol. This will help ensure that all necessary practical requirements are identified early so that adequate funds are requested.
A well-documented study plan will facilitate the process of developing funding applications, ethics committee and R&D approvals/institutional permissions, and any necessary regulatory approvals (such as DBER of Pakistan.
Successful trials often share similar characteristics. They are:
Conceptually simple and tailored to the patient group
Address questions of clinical relevance where genuine uncertainties exist
Avoid unnecessarily complex/restrictive entry criteria to ensure generalizability, where appropriate
Avoid unnecessarily complex data requirements (resulting from a careful justification of each data point to be collected)
Ensure the most appropriate choice of control arm (where appropriate)
Ensure robust allocation concealment (where possible)
Ensure robust blinding of intervention or appropriately blinded outcome assessments (where appropriate).
It is important to collaborate with a statistician who can help with:
Designing your trial
Choosing an appropriate outcome
Providing justification of the sample size
Advising on appropriate randomization methodology
Drawing up a statistical analysis plan
Handling and structuring collected data
Preparing and presenting interim reports to Data Monitoring Committees (DMCs), if applicable.
It is important to consult with several patients who have personal experience or understanding of the condition or intervention that forms the basis of the trial. They can help with:
Designing your trial
Identifying patient factors that might affect the likelihood of recruiting
Planning the ways in which patients could contribute to the conduct of the trial.
You may wish to approach charities or patient-led organizations to secure the involvement of these people or you may recruit directly from the current patients and carers using local services.
32
2. Within the scope of the Clinical Trial Regulations?
There are a number of steps to follow before a trial can commence. The first step is to confirm whether it falls within the scope of the DBER regulatory and Pakistan GCP requirements.
The Clinical Trials Regulations cover only investigations/studies which are undertaken to ascertain the efficacy or safety of a medicine in human subjects. Non-interventional trials are excluded from the Regulations. To classify a trial as non-interventional, it must meet all of the following criteria:
involves products with a marketing authorization that are prescribed in the usual manner and used in accordance with the authorization; when the patient is assigned to a therapeutic strategy within current practice and not according to a protocol; the diagnostic or monitoring procedures are only those ordinarily applied to the therapeutic strategy; and epidemiological methods are used to analyze the data.
If a study is not for the purpose of ascertaining the effects of or reactions to a product and the product is simply being used as an aid or tool in the study, it is not a clinical trial covered by the Regulations. For example, in the case of the study of blood flow involving the infusion of vasoactive substances, if the purpose of the study is to monitor the effects of a particular substance to see if it is effective in achieving a particular physiological effect, then it is not a clinical trial. If the infusion is for the purpose of modifying the rate of flow for a therapeutic indication such as claudication, it would be deemed a trial under the Directive as the purpose of the study is to establish the efficacy of a particular medicine.
3. Risk Assessment
Some host organizations may not be in a position to undertake the role of sponsor for Clinical Trials of Investigational Medicinal Products (CTIMPs) or may only sponsor trials of a certain risk level. It is essential therefore that they are involved at an early stage and that a risk assessment is undertaken at the very start. The process could be defined such that the risk assessment is undertaken on the research proposal and then further refined once the protocol has been drafted.
Risk Adaptation
Any important factor to consider in an emergent market economy like Pakistan are patient safety, rights and welfare in particular as the regulatory and ethical landscape is still in its infancy. It is easy to breach GCP guidelines as the necessary trained clinical researcher and associated staff is also lacking aside from negligible clinical research overview through audits and inspections locally and federally.
The MHRA (regulatory body of the UK) have implemented a scheme for defining the risks associated with each clinical trial by adopting a dual strategy:
1. Defining the risks of the IMP using a simple IMP risk categorization (Type A,B and C) based on marketing status and standard medical care:
Type A = No higher than the risk of standard medical care Type B = Somewhat higher than the risk of standard medical care Type C = Markedly higher than the risk of standard medical care
2. Defining the risks associated with trial conduct by examining the trial design, population and procedures to identify specific areas of vulnerability and to determine how any risks can be mitigated.
33
4. Sponsorship
Sponsorship is required for studies. It may take some time to secure a sponsor(s), so identification of the sponsor must be considered early in the planning process.
Definition of Sponsor: An individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial.
The sponsor therefore is not simply responsible for ensuring there are adequate funds for the trial and for CTIMPs; the ICH-GCP guidelines define responsibilities that the sponsor must arrange to carry out. These legal responsibilities should not be confused with liability for the harm of a subject
Before initiating a trial, the sponsor should define, establish and allocate all trial-related duties and functions (as various models of sponsorship are possible and the allocation of responsibilities, duties or functions).
5. Protocol Development
A protocol is defined as: “A document that describes the objectives, design, methodology, statistical considerations, and organization of a clinical trial”
The protocol also provides information on the background and rationale for a trial and outlines the study plan for that trial. The plan must be carefully designed to safeguard the health and safety of the participants, as well as answer specific research question(s). The protocol describes:
the type of participant the schedule of tests procedures medications and dosages the duration of the trial and should include a definition of the ‘end of the trial’
Protocols (and many other documents produced as part of a trial) should be controlled documents; version numbered and dated using a formalized convention.
For Clinical Trials of Investigational Medicinal Products (CTIMPs), the content and format of the protocol can be found in guidance references Section 6 of the ICH GCP E6 Guidelines which lists the topics/sections to include in the protocol. A consideration of section 6 is useful when preparing funding applications and will facilitate the development of the protocol if funding is awarded. It is also worth noting that many research funders have specific requirements for protocol content and presentation that should be considered.
(See Final Protocol section)
6. GCP and Serious Breach Reporting
The Clinical Trials Regulations require all clinical trials of investigational medicinal products (CTIMPs) to be run to the conditions and principles of Good Clinical Practice (GCP). These regulations define GCP as:
“.... a set of internationally recognized ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects.”
Compliance with GCP provides assurance that the rights, safety and well-being of subjects are protected and that the results of CTIMPs (and other clinical research) are credible.
34
It is recognized however, that there is some flexibility in the interpretation GCP and where appropriate, a risk adapted approach should be considered.
For trials run by commercial sponsors where data are intended to be submitted to regulatory authorities, the ICH (GCP) E6 Guideline is the internationally recognized GCP standard and should be adhered to.
For non-CTIMP research, serious breaches/ deviations of GCP or the protocol should be reported to the relevant ethics committee. However, non-CTIMPs don’t fall within the scope of regulatory department.
Participating Sites Responsibilities:
For a multicenter trial, the person with overall responsibility for the trial at each site is defined as the Principal Investigator (also known as site PI). Guidelines for GCP, from the perspective of the Principal Investigator, are detailed in ICH (GCP) E6 section 4.
The sponsor should ensure that each site is aware of all regulations and quality standards that apply to CTIMPs by:
1. Specifying the standards that must be adhered to in any site agreements 2. Ensuring that site staff has received GCP and Clinical Trials Regulation training commensurate to their role.
Serious Breach of GCP/Protocol:
The Clinical Trials Regulations (US FDA and MHRA) require the reporting of serious breaches of/or deviations from GCP or the protocol. The Pakistan GCP requirement is to report any serious deviations to the IRB/IEC. Sponsors of CTIMPs should ensure the requirement to report serious breaches to the IRB/ IEC in Pakistan and the ethics committee is incorporated into their standard operating procedures to ensure all relevant staff are aware of this legal requirement. This should include detail of how site staffs are made aware of requirements (via training or protocol procedures). Host organizations and other parties working with the trial sponsor may also need to consider their own mechanisms for reporting serious breaches (including arrangements for reporting serious breaches directly to the IRB/IEC if the sponsor is in breach).
For non-CTIMP research, serious breaches of GCP or the protocol should be reported to the relevant ethics committee in accordance with the institutional requirements.
7. Trial Management & Monitoring
Appropriate planning before the trial and adequate oversight and monitoring during the trial will help ensure that trial subject safety is maintained throughout the trial and that there is accurate reporting of results at its conclusion.
The sponsor is responsible for ensuring that robust trial management systems are put in place. The monitoring of a trial is one of the key activities undertaken as part of the trial’s management.
Where trial management activities are contracted out to third parties (i.e., CROs) the sponsor must implement procedures to ensure appropriate oversight of all delegated functions. This can be achieved by:
a) Assessing that individuals or organizations delegated trial management functions are appropriately qualified and competent to perform those functions.
b) Ensuring all parties are aware of their roles and responsibilities (for example by clearly defining them in contracts and agreements).
35
c) Maintaining lines of communication to ensure the obligations of all parties are being met (for example by receiving progress reports).
Documentation should be in place to describe all key processes. This ensures that those performing tasks have a clear plan of what, when and how trial activities are undertaken and also enables auditors/inspectors to historically reconstruct all trial management activities.
8. Trial Documentation
Good Clinical Practice (GCP) requires that all clinical trial information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified.
Essential documents are:
"...those which enable both the conduct of the clinical trial and the quality of the data produced to be evaluated; and show whether the trial is, or has been, conducted in accordance with the applicable regulatory requirements"
Many essential documents are filed in a Trial Master File / Investigator Site File. Some, essential documents may also be source documents, which are often generated as part of the subject’s medical care and therefore documented and archived in medical records and other service departments.
Information on essential documents can be found in ICH GCP E6 Section 8. This document includes an explanation of the purpose of each essential document and whether it should be retained by the sponsor, the investigational site or both.
Source data and other essential documents may be kept in either paper or electronic format (eTMF would ideally have the following attributes: where there is approval of documents via a workflow system, there should be use of digital signatures; role based permissions for activities being undertaken; audit trail in place to identify date/time/user details for creation, uploading, approval and changes to a document).
9. Trial Supplies
To ensure all regulatory and ICH GCP E6 Sections 5.13 and 5.14 requirements are met, it is essential that investigators obtain advice and support from those with specialist knowledge relating to Investigational Medicinal product (IMP) supplies (for example from a Clinical Trial Pharmacist, Clinical Trials Unit (CTU) or Contract Research Organization (CRO)).
Advice should be sought early in the trial planning process as requirements may impact on trial design and any funding application.
Trial Supplies cover the following:
Introduce Principal Investigators (and others involved in organizing IMP supplies) and complexities surrounding these activities (including a Trial Supplies Checklist). To provide Pharmacy staff with a comprehensive guide covering all aspects relating to the manufacture, supply, assembly, labeling, blinding and costing of trial supplies, as well as consideration for the pharmacy documentation required for clinical trials.
Where an Investigator's Brochure (IB) is required for a non-commercial trial, it may be supplied by the Marketing Authorization Holder of the IMP under trial. If it cannot be obtained from the Marketing Authorization Holder or the IMP is being developed ‘in house’, the sponsor must ensure that an IB is produced.
36
10. Pharmacovigilance
Pharmacovigilance (PV) is the science relating to the detection, assessment, understanding and prevention of the adverse effects of medicines. Systems must be in place to enable the identification, recording, reporting and analysis of safety information so that any safety signals that arise during a trial are quickly identified and acted upon.
Notification of serious adverse events, notification of suspected unexpected serious adverse reactions (see ICH GCP E6 4.11.2) and annual list of suspected serious adverse reactions and safety reports are areas covered under PV.
The Investigational Site
For all trials, the investigator should make all staff aware of any safety reporting requirements and have systems to ensure all relevant events are detected, recorded and notified in accordance with the protocol.
Staff should be made aware of these requirements through GCP training and/or knowledge of local procedures or policies.
11. R&D Consultation
Within higher education institutions there are Research and Development (R&D) Departments or Clinical Research Offices. Organizations that work closely together, for example clinical trials unit/office and a local university/institution act on behalf of the organization(s) to facilitate the local management of all research within that organization.
An R&D Office must give formal permission before a research project can take place within their organization:
It will be involved in the oversight of the trial by guiding the Principal Investigator and managing the risks associated with any trial initiated. It will facilitate the timely risk management and set up of sponsored trials and support the Principal Investigators participating in those trials.
Whichever scenario applies, R&D office needs to ensure that:
Appropriate negotiations are initiated with relevant university or departments (and other third parties) Appropriate arrangements are put in place to support the research Risk management measures are in place, in particular appropriate insurance or indemnity provision.
Researchers are advised to contact their local R&D Office in the early stages of study development so that they can help identify facilities that can provide valuable support.
It will be important when consulting R&D to define how costs are allocated by differentiating between research costs, support costs and treatment costs in relation to activities specified in the protocol.
It is mandatory for all research (CTIMPs and other studies) in the organization to be conducted in line with the regulatory requirements and the R&D Office is responsible for ensuring that all research meets these requirements.
37
12. Funding Proposal
Trials are typically a major financial investment, and as a result securing funding can be a lengthy process. Major Funders will need to be assured that the proposed research is important and addresses a clear need, well designed, feasible and scientifically valid, and offers value for money.
The time required to secure funding should be considered in wider development and planning activity, and many Funders publish timetables for funding opportunities to assist with this task.
It is recommended that the eligibility requirements of the precise funding scheme are checked before submitting an application, and many Funders offer resources to enable researchers to confirm suitability ‘in principle’ at an early stage.
In addition, several Funders offer key documents and resources to explain ‘tips’ to applicants which address key aspects required for success.
13. Peer Review
Peer review is where a number of 'experts' examine the proposed trial to consider aspects such as design quality, feasibility, acceptability and importance of the topic etc. ‘Experts’ in this context will usually include views from relevant clinicians, allied health professionals and other professional groups, methodologists, patients and members of the public.
If an application for external funding has been submitted, then peer review will be undertaken as part of this process.
If external funding is not required, and therefore peer review has not been conducted as part of the funding process, the sponsoring organization will be able to assist with this matter.
It is important to note that both ethical and regulatory approval will require sufficient demonstration of appropriate peer review.
14. Funding Secured
If funding for a trial is required, it is important to consider that the process of applying and securing funding may take some time. This time should be factored into planning and related activities.
Once you have received confirmation of a funding award from your Funder, they will require you to complete a number of requirements and activities before the trial can formally start. It is important to stay in contact with the Funder at this stage, and provide a timely response to requests and keep them informed of developments and issues.
15. Trial Master File
A Trial Master File (TMF) should be set up at the beginning of a trial. The essential documents that make up the file should be kept in a secure but accessible manner. A well-kept TMF can help with efficient trial management and can facilitate the reconstruction of the conduct of the trial during the audit/inspection process.
The TMF should be held at the coordinating site (usually the Principal Investigator’s office or Coordinating Centre) and for multi-site trials, copies of relevant documents should be kept at each participating site in an
38
Investigator Site File (ISF). Most sponsors will provide guidance on the content and set up of the TMF/ISF based on their local policies/procedures.
The TMF/ISF should be maintained throughout the course of the trial and it should be clear who has been given the task of maintaining it, for example by indicating this role on the delegation log.
Some documents must be in place before a trial is opened, some are generated as the trial progresses and others are added to the file only at the end (e.g. analysis codes and Data Monitoring Committee (DMC) closed reports and minutes). In addition to the guidance above, researchers may also be required to file any trial documentation specific to local policies/procedures.
For non-CTIMP research, it would be good practice to file any document that meets the definition of an essential document. Sponsors and host organizations may provide specific guidance on content of files in their policies/procedures.
16. Unique Trial Number
Trial Registration: Each clinical trial must have a unique trial number. This requirement is cited in a number of publications including:
1. The Declaration of Helsinki of the World Medical Association (revised 18 October 2008 at Seoul) states: "19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject." 2. The International Committee of Medical Journal Editors (ICMJE) stipulated that from July 1st 2005, no trial will be considered for publication unless it is included on a clinical trials registry so it can be tracked from initial protocol through to publication.
The World Health Organisation (WHO) regards trial registration as the publication of an internationally agreed standard dataset about a clinical trial on a publicly accessible database managed by a registry conforming to WHO standards. The standard dataset is published by the WHO International Clinical Trials Registry Platform (ICTRP).
The International Standard Randomised Controlled Trial Number (ISRCTN) is a simple numeric system for the unique identification of clinical trials worldwide. It will simplify the identification of trials and provide a unique number that can be used to track all publications and reports resulting from each trial.
Alternatively, trials may be registered at ClinicalTrials.gov.
The EudraCT number is an additional mandatory reference number allocated by the European Medicines Agency (EMEA) for CTIMPs authorized on or after 1 May 2004. Further details are available from the EMEA website.
For other randomized controlled trials and other forms of studies designed to assess the efficacy of healthcare interventions, it is still good practice to register the trial on a database such as ISRCTN.
17. Confirm Sponsor
Principal Investigators normally will approach a potential sponsor (often through a formal registration process) who will assess the operational risk the trial poses before confirming sponsorship. Sponsorship will only be granted once any issues raised by the risk assessment have been addressed. The sponsorship letter should be retained in the Trial Master File
The sponsor’s name is required on both the application for ethical approval and for DBER regulatory authorization in Pakistan.
39
Other parties, including trial funders and host organizations conducting the trial will also require documented assurance that an organization has accepted the role of sponsor and the obligations and responsibilities of this role.
18. Feasibility & Investigator Selection
Non-commercial trials which fail to meet their targets often result in a request for further funding, or may fail to achieve a statistically significant result. It is important that a proper feasibility assessment is undertaken for any proposed trial.
For larger trials, the sponsor should consider, during the funding process, whether a feasibility or pilot study should be undertaken.
In all cases the sponsor should ensure that any barriers to recruitment have been identified and resolved including:
Are protocol requirements aligned with current clinical/medical practice? Are inclusion/exclusion criteria too restrictive? Is the proposed patient recruitment rate realistic?
Other factors will affect a researcher's ability to deliver a trial effectively. For multi-site trials, the careful selection and evaluation of investigator sites is critical for the successful completion of a trial within budget, timelines and to ensure the generation of high quality data. Factors that should influence investigator site selection include:
Interest in the research question Experience and qualifications of the investigator Sufficient staff to conduct the study and their experience and qualifications Availability of suitable patient population: o Anticipated rate of patient recruitment (determined through feasibility assessments) o Conflicting studies (competing for the patient population and potentially introducing recruitment bias) Adequate time to conduct and oversee the trial Adequate facilities: o Availability of any specialized diagnostic or therapeutic equipment required by the protocol o Adequate space and storage conditions (including archive) Track record with similar trials previously Geographic location Contractual and budgetary negotiations and arrangements.
When undertaking site selection, the preparation of ‘reserve’ investigator sites (so that the trial may be extended to these sites if recruitment issues arise) should be considered as part of proactive trial planning.
19. Contracts & Agreements
Many parties may be involved in the conduct and management of a clinical trial and it is important that each party has a clear reference of what is expected of them.
Contracts and agreements should be in place prior to the initiation of any trial and should be subject to periodic review to ensure that they remain up to date and relevant.
The content of contracts and agreements should include:
40
The standards that are applicable (for Clinical Trials of Investigational Medicinal Product (CTIMPs) this would include the regulatory requirements) The roles and responsibilities of various parties The procedures to be undertaken The lines of communication
Contracts and agreements can be formed at many levels; internal or external and both legal or non- legal. Examples include but are not limited to:
Co-Sponsorship Agreements (defining the legal responsibilities taken on by parties under the Clinical Trials Regulations) Funding Agreements (terms and conditions related to any funding granted) Clinical Trial Agreement/Site Agreements Collaboration Agreements Intellectual property Agreements Commercialization Agreements Service Level Agreements (with external suppliers such as central laboratories, external statisticians) Material Transfer Agreements (handling requirements for material, such as tissue samples, transferred from one organization to another) Pharmacy Technical Agreements (to cover processes applied to the IMP such as packaging, manufacture and radiolabelling)
At the site level, the roles and responsibilities of the Principal investigator, particularly if they are delegated sponsor tasks, should be documented and agreed.
For multi-center trials, the Principal Investigator at each site should understand and accept their particular responsibilities and should document the allocation of all trial tasks, to members of their trial team, using a staff signature and delegation log.
20. Final Protocol
Before seeking approvals to start a trial, the protocol must be finalized, as this constitutes part of the application. Please refer to the Protocol Development station for details of protocol content.
The final protocol should be signed off by the Principal Investigator as a minimum, but usually other signatures may be required such as those from the sponsor and trial statistician. The sponsor should specify (usually in their policies/procedures) which signatures are required and the Principal Investigator should be aware of their local requirements.
In multi-center trials, it is good practice to ensure the Principal Investigator signs a protocol signature page to confirm receipt and also their agreement to work to the current version of the protocol.
In addition the Funder should be informed of any changes to a protocol and their agreement to these obtained.
21. Principal Investigator Checklist Before Seeking Approval
The following checklist for Principal Investigators has been designed as a means of checking that the necessary documentation required for the permissions and approvals process are in place.
41
Principal Investigator Checklist (before seeking approvals)
Sponsor(s) identified and agreements for allocation / delegation of responsibilities (if necessary) are in place Arrangements for appropriate Patient and Public Involvement Input from a statistician secured Peer review complete Arrangements for a data monitoring committee, steering group and/or management group in place (with consent from members) Trial risk assessment carried out, trial management systems and monitoring plan/arrangements in place Funding secured Unique trial number obtained R&D and support departments (e.g. pharmacy, labs, radiology etc) consulted and capacity available Contracts and agreements in place including third party agreements where outsourcing of any trial specific test/services is required Insurance and indemnity arrangements in place CVs of investigators (signed and dated) Arrangements for trial supplies in place Arrangements for pharmacovigilance considered Systems in place to ensure trial will be conducted the principles of GCP and Clinical Trials Regulations Trial Master File established Protocol and associated documents (see relevant stations): o CT number on all documentation o End of trial defined o Safety reporting section of the protocol outlining definitions and reporting requirements o All written information provided to/viewed by subjects (e.g. Participant information sheets, consent forms, patient diaries, recruitment advertisements) finalized and version controlled o All other relevant trial documentation finalized and version controlled e.g. questionnaires, case report forms, trial specific SOPs o Investigator’s brochure/SMPC (summary of product characteristics)/package inserts/ package leaflets developed/identified
22. R&D Submission
Researchers wishing to conduct research at their institution must obtain permission for each site. R&D management approval is required from relevant authorities and other institutional authorities taking part in a trial. Without approval in writing (permission letter), indemnity and insurance cannot be assumed to be in place to cover the proposed research activity.
The R&D permission process is two-fold with general trial information captured and local site information. For multi-center trials, relevant information needs to be separately assessed for suitability of the research site(s) and site investigator(s).
23. Ethics Submission
Application for Ethical Review: The institutional Review Board (IRB)/IEC or ERB at the institution exists to protect the rights, safety, dignity and well-being of research participants whilst facilitating ethical research that is of potential benefit to participants, science and society. This is achieved through the review of research taking place IRBs give their opinion about the proposed participant involvement and whether the research is ethical.
IRBs meeting frequency varies from weekly, bi-weekly to monthly meetings according to their SOP where research protocols are discussed and evaluated. If trial appropriately addresses patient’s rights, safety and welfare concerns it is approved.
42
24. CT Dossier Submission
CT dossier submission is required for a Clinical Trial of an Investigational Medicinal Product (CTIMP).
Prior to submission to the DBER, a fee is also payable to DBER (currently PKR 5,000).
Note: For some first in human trials where certain risk factors are present, the regulatory body will seek advice from an Expert Advisory Group before a CTA application can be made. Sponsors should consult the regulatory body before making an application. The regulatory body may refer other applications for expert advice, if particular issues are identified during the assessment process.
The Clinical Trial Notification Scheme: The regulatory body will process the application based on the type of the trial, Phase I – IV.
Pages of the DBER/DRAP website (under development) describe the process and timelines for the CTA application. Once the application is sent to the DBER, it will be acknowledged. An approval letter will be sent to say that the trial may go ahead if no objections have been raised.
For non-CTIMP research, a Clinical Trials Authorization is not required.
25. Permissions & Approvals Obtained
A trial cannot begin until all the relevant permissions and approvals have been obtained and reviewed by the relevant parties (including the funder where appropriate).
Clear evidence of the documents submitted to the approval bodies (the submission package/dossier) and the documents that were approved (approval letters referencing the submission package) need to be retained in the Trial Master File. This will allow auditors / inspectors to confirm that all legal and good practice requirements have been followed.
26. Final Trial Management Documentation
A trial cannot begin until all the relevant permissions and approvals have been obtained. For Clinical Trials of Investigational Medicinal Products (CTIMPs), GCP requires specific documentation to be in place before an Investigational Medicinal Product (IMP) can be released.
Before commencing the trial, the Principal Investigator in conjunction with the sponsor, will ensure that all trial documentation has been prepared and version controlled. For multi-center trials, the Principal Investigator will ensure that each site Investigator is provided with all relevant, version-controlled documents before commencing recruitment.
Final Documentation Checklist
The following list is a suggested guide for Principal Investigators relating to documentation that should be in place at the main site before a trial begins. This list is not exhaustive and local documents may also be applicable.
Confirmation of Sponsorship letter
Final approved trial protocol signed by all parties according to local requirements
43
Final approved participant information sheet(s) and consent form(s)
Final approved other written participant information e.g. diary card(s)
Final approved participant recruitment advertisement (if relevant)
Research ethics committee (IRB, IEC, ERB) approval
Institutional R&D (or clinical trial unit) permission
Clinical Trial Authorization (CTA ) or approval letter with any stated conditions addressed (if appropriate)
Final approved risk assessment document and any monitoring plan
Sign off from a statistician (if required)
Signed off/finalized case report forms (CRFs)
Signed off/finalized clinical database (if required by local policy)
Systems for managing safety data (e.g. in pharmacovigilance database) agreed and finalized
Details of any data monitoring committee or trial steering or management group (if not in protocol)
Access to all relevant standard operating procedures (SOPs)
Investigator’s Brochure or Summary of Product Characteristics (SMPC)/ Package Inserts
Signed agreements including operational and financial arrangements
Statement of insurance to document compensation to participants for trial-related
CVs and other evidence of relevant training (e.g. GCP/Regulation/protocol) and qualifications for the investigator(s) and local study team members
Normal values/ranges for laboratory/medical/technical tests/procedures
Laboratory accreditation(s)
Pharmacy documentation/file
Decoding procedures for blinded trials
All records for Investigational Medicinal Products(s) procurement/supply (e.g. shipping)
Template logs including delegation logs, screening/enrolment logs, participant identification log, randomization logs (where applicable)
Trial start-up/initiation report (or confirmation that site initiation activities have been completed.
During the review process, regulatory body may request alterations to trial documentation before final approval is given. The Principal Investigator should ensure that once the approval process is complete, the same version of each document has been approved by all relevant bodies.
44
27. Trial is Abandoned
The trial is generally considered to have ‘commenced’ when any of the trial procedures (such as patient screening/consent) that are set out in the protocol, are initiated.
If the sponsor decides to abandon the trial before it commences, the Principal Investigator or sponsor should notify the ethics committee by letter, giving reasons. Other bodies, such as local R&D Offices (or clinical trials unit or clinical research office) and funders will also require notification.
*Please note that a trial funder may have a different view on when a trial ‘commences’ e.g. when payments are released, and this can be several months before any consent or screening processes are undertaken. A funder should be kept informed of all developments and will advise on appropriate processes and requirements.
28. Trial Begins
Once all of the relevant approvals are in place, all documentation has been finalized, and all participating sites have the information they need, the trial can begin.
This process is often achieved by a holding start-up meeting (or Site Initiation Visit) at each. The Principal Investigator is then able to satisfy him/herself that all technical aspects of a trial and protocol requirements are fully understood by all relevant site staff. Trial specific training (protocol and trial-specific procedures) as well as training on aspects of trial conduct such as Case Report Form (CRF) completion and safety reporting requirements is often undertaken at this stage. The site also has an opportunity to ask questions and clarify misunderstandings.
For Clinical Trials of Investigational Medicinal Products (CTIMPs), this communication should also include pharmacy (where applicable) so that they can confirm that all requirements are in place before dispensing Investigational Medicinal Products (IMPs) to subjects.
Generally, there is an expectation that a trial should start (recruitment activities) within a specified time period. For example, the ethics committee will assume that the research will commence within 12 months of the date of favorable ethical opinion and may review its opinion if the trial does not start within 24 months of receipt of the final opinion letter.
29. Informed Consent
Subjects must give their informed consent before being entered into a trial. Consent should be obtained before the first trial-specific activity is undertaken with the exception of certain emergency trials involving vulnerable subjects (minors or incapacitated adults – please see below).
For each trial, specific consent documentation consisting of a participant information sheet and consent form must be developed and approved by the ethics committee. It should be noted that involvement of patient groups when developing the consent process/documentation is looked upon favorably by ethics committees.
Throughout the trial, the subject’s willingness to continue participation should be reaffirmed periodically. However, if significant new information becomes available, subjects are provided with revised (and re- approved) consent documentation so that written consent can be formally documented if the subject is willing to continue.
CTIMPs involving minors or incapacitated adults (including the emergency setting): ICH GCP E6 4.8.12 and ICH GCP E6 1.61 describes the conditions and principles that must be in place before trials involving a minor
45 or incapacitated adult can be undertaken. ICH GCP E6 1.37 defines the ‘legal representative’ who, for CTIMPs only, must give written informed consent on behalf of the minor** or incapacitated adult.
**A legal representative would only give consent on behalf of a minor in the rare circumstance that a person with parental responsibility is not available prior to their proposed inclusion by reason of the emergency nature of the treatment.
ICH GCP E6 4.8.9 document outlines the hierarchy for consent using personal or professional legal representatives.
30. Safety Reporting
The sponsor is responsible for the on-going safety evaluation of the Investigational Medicinal Product(s) used in a Clinical Trial of Investigational Medicinal Products (CTIMPs).
ICH GCP E6 3.3.8 and ICH GCP E6 5.17.1 define the responsibilities for safety reporting of both the sponsor and the investigational site.
The sponsor should develop formal, written processes for the management of adverse events and safety reports including the handling of both (1) expedited and (2) annual safety reporting:
The annual safety report for CTIMPs should be in the format of a Development Safety Update Report (DSUR) set out in the ICH E2F guideline. Any researcher who has been assigned the task of completing a DSUR should also follow their local policies/procedures.
The Principal Investigator should make all investigational site staff aware of the trial’s safety reporting requirements and have systems to ensure all relevant events are detected, recorded and notified in accordance with the protocol and Clinical Trials Regulations.
31. Progress Reporting
There is a requirement to send progress reports to a number of interested parties throughout a trial. For example, Trial Steering Committees and Funders will require regular updates and routine reports.
An annual progress report is also sent to the ethics committee. In addition, progress reports are usually required by the trial sponsor and the R&D Office (clinical trials unit or clinical research office) where the trial is conducted.
Quarterly reports about study progress are required by the DBER of Pakistan.
32. Ongoing Management & Monitoring
The expectation of the sponsor to develop appropriate trial management plans is outlined in the Trial Management and Monitoring section (Section 7).
As the trial progresses, the sponsor must oversee its management and ensure that management strategies are adhered to. It is important, for example, to ensure that the monitoring performed for a particular trial, is in accordance with its monitoring plan. In addition, investigators must comply with the sponsor’s instructions and study procedures.
The sponsor will re-appraise trial management strategies, clinical monitoring plans and quality assurance measures at necessary intervals and in response to events such a serious breach of GCP/protocol or a
46 substantial amendment to the protocol. The sponsor will ensure that any changes are implemented in a timely fashion and where applicable, are communicated to all investigators.
33. Regulatory Inspection
The regulatory bodies (i.e., US FDA, MHRA in the UK and DBER in Pakistan) are required under GCP to inspect Clinical Trials of Investigational Medicinal Products (CTIMPs) conducted by both commercial and non- commercial organizations. GCP Inspectors assess compliance with all relevant legislation and guidance. In particular, the regulatory bodies assess whether organization sponsoring and/or conducting CTIMPs have systems in place to meet the requirements of the Clinical Trials Regulations.
The regulatory bodies conduct a risk based approach to inspection which now takes into account number and type (Phase I-IV) trials sponsored by an organization.
The following checklist for inspectors serves to illustrate what would be evaluated during an inspection of a clinical trial:
1. LEGAL AND ADMINISTRATIVE ASPECTS a. Communication with the IEC (Independent Ethics Committee) b. Communication with the regulatory authorities 2. ORGANIZATIONAL ASPECTS a. Implementation of the trial at the site i. Organization and Personnel Organization charts (facility management and scientific organization charts). Documentation of delegation of responsibilities by the principal investigator. Systems for QA and QC, if available. SOP system where available. Disaster plans, e.g. handling of defective equipment and consequences. Staff–qualification, responsibilities, experience, availability, training programs, training records, CV. Numbers of clinical trials performed and their nature. Proportion of time allocated to clinical trial work b. Check the conditions of implementation of the study at the site: Contracts between the sponsor and the investigator. Qualifications and experience of the investigator's team in the considered clinical area. Documentation describing the distribution of duties and functions for the conduct of the trial. Compatibility of the workload of the investigator and the staff with the requirements of the study. Organization of the site for the study: organization chart, GCP training, trial specific training, specific equipment, specific procedures. Compliance with the planned time schedule for the study. Correct implementation of the correct versions of the protocol and its amendments. c. The inspector should also check the dates of the first inclusion/selection of a patient at the site inspected and the last visit of the last patient.
47
3. Facilities and equipment The aim is to verify the proper use, adequacy and validation status of procedures and equipment used during the performance of the trial. The inspection may include a review of the following: a. Equipment used. b. Facilities. c. Their suitability for the protocol requirements and the characteristics of the study being inspected for the conduct of the inspection at a laboratory site see Annex II 4. Management of biological samples a. The aim is to examine conditions and documentation regarding the management of biological samples, if applicable b. Collection: person in charge of this task, dates and handling procedures, including labeling. c. Storage of the samples before analysis or shipping. d. Shipping conditions 5. Organization of the documentation a. The aim is to determine whether the general documentation, is available, dated, signed and if applicable how it is archived at the trial site. b. Also it should be determined if the following trial subjects’ documents are available, completed and archived at the trial site: i. Source documents (patient’s charts, X-ray, etc.). ii. Informed consent documents. iii. Case Report Form (CRF) c. A sample of data should be verified from the study report and or CRF to the source documents. 6. Monitoring and auditing The following points should be examined, if available: a. Monitoring and follow-up by the sponsor. Number of visits at the site, scope and dates of the visits, content of the monitoring visit reports, where these have been requested from the sponsor. b. Actions required by the monitor. Monitoring visits log. Monitoring plan and Standard Operating Procedures. c. Audit certificates (from sponsor file) 7. Use of computerized systems If computerized systems have been used for the trial, it will be necessary to ascertain their validation status. The elements to be evaluated during an inspection of computerized systems used in clinical trials are established in a separate document. Computers may be study specific and supplied by the sponsor (e-CRFs, e-patient diaries, IVRS.). They may be site specific and part of the routine equipment of the site (medical records, on-line laboratory data, ECG recording, etc.) 8. INFORMED CONSENT OF TRIAL SUBJECTS The aim is to determine whether informed consent was obtained in accordance with GCP requirements as set out in ICH GCP E6.4.8 and local regulatory requirements from an appropriate sample of subjects (patients) (including the subjects/patients whose medical records are reviewed), or the subjects' legally acceptable representative, prior to their entry into the study. This needs to include patients whose medical records are reviewed. a. The signed and self-dated (by the subject and by the person who conducted the informed consent discussion) consent form actually used and approved by the IRB/IEC at the time of inclusion of the subjects.
48
b. The information sheet actually used and approved by the IRB/IEC, in order to determine whether it includes all the elements per ICH GCP E6.4.4.1 and any local regulatory requirements. c. The center practice for giving a copy of the informed consent to the patient d. Consent for access to medical records by the authorities. 9. REVIEW OF THE TRIAL SUBJECT DATA The aim is to check whether the investigator team conducted the clinical trial according to the approved protocol and its amendments by source data verification. In the source data verification it will be necessary to evaluate the source records taking into account their organization, completeness and legibility. The description of the source data inspected should be reported by the inspector. It will be necessary to evaluate whether corrections of the data recorded in the CRF was done according to ICH GCP E6.4.9.3 and the local regulatory requirements (signed and dated by the authorized person and providing justification, if necessary). 10. MANAGEMENT OF THE INVESTIGATIONAL MEDICINAL PRODUCT(S) The aim is to verify whether all the activities related to the Investigational Medicinal Product(s) have been conducted according to the protocol and other study documents. It will be necessary to review the following documents: a. Instructions for handling of Investigational Medicinal Product(s) and trial related materials (if not included in protocol or investigator’s brochure). b. Shipping records for Investigational Medicinal Product(s) and trial related material. Receipt date(s) of product delivery and quantity. This record should also contain batch numbers (check correspondence with the information kept at the sponsor site), expiration dates and codes assigned to the product and the trial subject. c. Documentation regarding allocation of treatment, randomization and code breaking. d. Investigational Medicinal Product(s) accountability at site (pharmacy or investigator):- Date and quantity dispensed or returned, identification of recipients (patients’ code or authorized person’s). This record should contain also batch numbers, expiration dates and codes assigned to the product and the trial subject. e. Documentation about re-labeling, if applicable. f. Date and quantity returned to the sponsor. Return receipt: this record should also contain batch numbers, expiration dates and codes assigned to the product and the trial subject. g. Documentation of destruction of the Investigational Medicinal Product (if destroyed at the site) dates and quantity. Documentation or receipt. h. Treatment compliance
The inspectors should check that where required these documents have been signed and dated by the responsible persons according to the site and/or sponsor SOP and/or applicable requirements related to the management of the Investigational Medicinal Products
Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization. A response to this report (describing any corrective and preventative actions) must be produced.
34. Audit
The sponsor of a clinical trial is responsible for implementing quality systems including the development of an audit plan for the trials they manage. Audit is designed to assess and assure the reliability and integrity of sponsor’s trial systems against all relevant written standards.
49
Activities and system checks which may be undertaken during an audit include:
Staff interview: To assess whether staff working on the trial are appropriately trained, are clear of their role and are working to all relevant standards, the protocol and standard operating procedures (SOPs)
Facility Tour: To assess whether there are adequate resources and that any equipment is fit for its intended use
Document Review: To assess whether data reported is verifiable from source data and that written records confirm that the trial was conducted appropriately.
Auditors should be independent of the trial team / process and should be appropriately trained for their role. Findings and observations from any audit conducted should be documented in a formal audit report. Any deficiencies identified during an audit should be followed up with appropriate corrective and preventative actions wherever possible.
Audits that are conducted by regulatory authorities (such as the US FDA, MHRA and DBER in Pakistan) are termed inspections.
35. Addition of New Sites and Investigators
For Clinical Trials of Investigational Medicinal Products (CTIMPs), adding a new trial site* or a change of Principal Investigator at a site constitutes a substantial amendment (a change to the protocol or any other document submitted with the applications) requiring notification to the ethics committee.
One of the standard conditions for ethics committee approval (for all research) is that the sponsor must obtain regulatory body permission and R&D Management (clinical trials unit/ clinical research office approval) from the relevant host organizations prior to the start of the study at each site.
For non-CTIMP research, the addition of a new site or Principal Investigator is not considered a substantial amendment.
All changes to sites and / or investigators should be communicated to the Funder at the earliest opportunity.
*Sites that were listed as potential sites on the original ethics application do not need to be submitted as a substantial amendment.
36. Substantial Amendments
For Clinical Trials of Investigational Medicinal Products (CTIMPs), a substantial amendment is defined as a change to the terms of the approval given by either:
the regulatory authority or the Research Ethics Committee (REC) or;
a change to the protocol or any other document submitted with the applications, which significantly affects one of the following:
o The safety or physical or mental integrity of trial subjects
o The conduct or management of the trial
o The scientific value of the trial
o The quality or safety of any Investigational Medicinal Product (IMP) used in the trial
50
The decisions on whether an amendment is substantial or non-substantial should be made by the sponsor
*It is the responsibility of the sponsor to decide whether a substantial amendment requires authorization, or an ethical opinion, or both.
R&D offices that sponsor or host research, are notified of all amendments (whether substantial or non- substantial) in accordance with their local policies. This allows the organization to assess whether the amendment has any impact on governance arrangements or resources.
All amendments should be reported to the Funder as soon as possible.
37. Urgent Safety Measures
The Clinical Trials Regulations make provision for the sponsor and investigator to take appropriate Urgent Safety Measures (USMs) to protect a research participant from an immediate hazard to their health and safety. This measure can be taken before seeking approval from the regulatory authorities and ethics committees of all member states concerned.
Any urgent safety measure relating to a Clinical Trial of an Investigational Medicinal Product (CTIMP) should be communicated to the regulatory body immediately. In the UK, they advise that sponsors phone the MHRA Clinical Trial Unit and discuss the event with a safety scientist. The sponsor must then follow-up with notification in writing within three days (or ASAP) of the action being taken. The notification should be in the form of a substantial amendment and should describe the event, the measures taken and justification for the measures taken.
The main research ethics committee (IRB/REC) must be notified immediately and in any event within three days, that such measures have been taken and the reasons why. R&D offices will require notification in accordance with local policies/procedures.
Where applicable, oversight committees (such as the Data Monitoring Committee) should review information relating to urgent safety measures and report any recommendations to all relevant parties.
If the Principal Investigator (and not the sponsor) has instigated the USM, the sponsor should be notified immediately so that they can assess and report the USM within the timelines required.
For non-CTIMP research, the Principal Investigator must notify the main REC immediately of any USMs and in any event within three days. R&D offices will also require notification in accordance with local policies/procedures.
The funder should be updated on all developments and actions as soon as possible.
38. Temporary Halt or Early Termination
There are four major reasons for stopping a randomized clinical trial (RCT) early.
First, the trial may show serious adverse effects and may be stopped for unacceptable safety.
Second, investigators may stop the trial if interim differences in outcomes between the intervention and control groups are so unimpressive that any prospect of a positive result with the planned sample size is extremely unlikely so-called ‘‘futility.’’ In this case, the argument goes continuing the trial may not be justifiable in terms of time, money, and effort.
51
Third, new external information may arise during the conduct of the study that either convincingly answers the primary study question or that raises serious safety issues.
Finally, investigators may terminate an RCT for apparent benefit
A temporary halt of a trial is a stoppage of the trial which is not envisaged in the approved protocol and where there is an intention to resume it.
When a trial is temporarily halted, the competent authorities (such as MHRA in the UK) and ethics committees of all member states concerned must be informed within 15 days of the halt. This notification should be in the form of a substantial amendment.
If a trial is terminated early; before the date specified for its conclusion*, the sponsor should notify the competent authorities (MHRA in the UK) and the relevant ethics committees within 15 days of the date of termination by submitting a ‘Declaration of the End of a Clinical Trial’ form.
In the United States under US FDA: A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND (Investigational New Drug application). When a proposed study is placed on clinical hold, subjects may not be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety.
An investigation may only resume after FDA (usually the Division Director, or the Director's designee, with responsibility for review of the IND) has notified the sponsor that the investigation may proceed. Resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfies the agency that the investigation(s) can proceed. FDA may notify a sponsor of its determination regarding the clinical hold by telephone or other means of rapid communication. If a sponsor of an IND that has been placed on clinical hold requests in writing that the clinical hold be removed and submits a complete response to the issue(s) identified in the clinical hold order, FDA shall respond in writing to the sponsor within 30-calendar days of receipt of the request and the complete response. FDA's response will either remove or maintain the clinical hold, and will state the reasons for such determination. Notwithstanding the 30-calendar day response time, a sponsor may not proceed with a clinical trial on which a clinical hold has been imposed until the sponsor has been notified by FDA that the hold has been lifted.
*Note: an earlier end of the clinical trial, which is not based on grounds of safety, but on other grounds, such as faster recruitment than anticipated, is not considered an ‘early termination’.
The sponsor should clearly explain the reasons for the temporary halt or early termination, and describe follow-up measures, if any, that are taken for safety reasons. A notification of substantial amendment should be submitted alongside declaration of early termination where necessary, to seek ethical review of related actions e.g. informing participants, continuity of care and follow-up.
It is also important that there is clear documentation in the Trial Master File (TMF) about the decision to temporarily halt or terminate a trial early. This documentation should include a clear justification and rationale for the decision, made by the appropriate personnel, which provides the evidence basis for the relevant submissions.
R&D offices and any participating sites will also require notification in accordance with local policies/procedures.
52
For non-CTIMP research, the Principal Investigator should notify the ethics committee as per the requirements.
The Funder should be informed of any such developments as soon as possible.
39. Trial does not Recommence
If the sponsor decides not to recommence the trial after halting it, they should notify the competent authorities ( such as MHRA in the UK) and ethics committees of all member states concerned.
The letter should provide a brief explanation of the reasons for not recommencing the trial. This notification must be provided within 15 days of the decision not to recommence.
R&D offices and any participating sites will also require notification in accordance with local policies/procedures.
The Funder should be informed of all developments and decisions as soon as possible.
For non-CTIMP research, the Principal Investigator should notify the ethics committee using the end of study form.
40. End of Trial Declaration
There is no specific end of trial notification form, however, the US Food and Drug Administration (US FDA) regulations for the conduct of clinical investigations require sponsors to submit this information in their annual reports in accordance with 21 CFR 312.33.
The Clinical Trials Regulations require the sponsor to notify the end of a trial to competent authorities (MHRA in the UK) and ethics committees of all member states concerned, within 90 days.
In Pakistan, end of trial will be shared as part of end of study activities in the final study report and also quarterly report to the regulatory authority and ethics committee.
The definition of the end of the trial should be provided in the protocol. In most cases this should be the date of the last visit of the last patient (LPLV) undergoing the trial.
However trials where follow-up monitoring is required to meet endpoints, the end of trial should be the final data capture rather than the last treatment visit. Once the end of trial has been declared, no further substantial amendments are possible and a Clinical Trial Summary Report must be produced within set timeframes.
The regulatory body, ethics committee and R&D offices will require notification in accordance with local policies/procedures.
For multi-national trials, the end of trial should only be reported when the trial has ended in all countries (except UK where this should be reported once trial ends in UK signalling the suspension of the annual service fee for maintaining the Clinical Trial Authorization.
For non-CTIMP research, notification to the relevant ethics committee is required.
It is important to note that funders will not regard this as the end of the project and will require additional reporting and requirements. However it is important to update them on developments and activities such as those listed above.
53
41. Statistical Data Analysis
In the majority of trials, funders and sponsors will require appropriate arrangements to be specified during the trial design phase and the services of an appropriately trained statistician to be secured.
One of the main components of the analysis is the statistical analysis plan (SAP). This plan ensures that the analyses to evaluate all planned study hypotheses are conducted in a scientifically valid manner and that all decisions are documented. It also provides detail on how the results will be presented and reported. The statistician should refer to The CONSORT Statement (and any extensions) and also ICH E9 Statistical Principles for Clinical Trials (PDF, 325 KB).
The following should be described and agreed in the SAP:
Any primary and key secondary outcome measures stated in the protocol to be analyzed
Methods for handling missing data and multiplicity of data
Justification for any non-standard statistical techniques
In addition, any subsequent post hoc analysis should be justified and reported in any publication.
Other important considerations relating to statistical analysis include:
Practicalities relating to the blinding of the trial statistician
Documentation to ensure that all data manipulations and analyses performed on the original data extracted from the data entry system, can be replicated
Procedures to ensure that all relevant documentation in the possession of the statistician is filed at trial completion, in the Trial Master File.
The trial results should be discussed by the Principal Investigator and all relevant oversight groups (such as Data Monitoring Committee and Trial Steering Committee) to assist interpretation and to discuss the implications of the findings.
42. Clinical Trial Summary Report
The sponsor must provide a clinical trial summary report to regulatory authorities (such as DBER of Pakistan, US FDA and MHRA in the UK) and ethics committees of any countries concerned (in case of multi-center trials).
For non-pediatric trials, this is due within one year of the ‘end of trial’. The format of the summary report should take into account ICH E3 guidelines for structure and content of a clinical study report as much as possible.
It is important to consider that content from the summary report will be accessible to the wider public.
Randomized controlled trials should be reported in compliance with the CONSORT Statement (and any extensions). This initiative was developed to improve the reporting of randomized controlled trials (RCTs), enabling readers to understand a trial's design, conduct, analysis and interpretation, and to assess the validity of its results.
Similar initiatives have been developed for other study designs:
STARD (reporting of diagnostic accuracy studies)
54
STROBE(reporting of observational studies in epidemiology) PRISMA (reporting of systematic reviews), which replaced QUOROM MOOSE (reporting of meta-analyses of observational studies).
Others are under development and information can be accessed from the Equator Network
43. Dissemination of Results
It is important to disseminate the results of clinical research to the research community, trial participants and the general public. The obvious route to inform the research community is through publication in peer- reviewed scientific journals.
Funders may also wish to be informed of any outputs and publications during the trial and after it has been completed. Specific funders should be consulted to determine precise requirements.
Information concerning publication policy should be included in the protocol and funders will be interested to consider plans in place. The ethics application form requires the applicant to confirm how they intend to report and disseminate their results.
It is the responsibility of the Principal Investigator to ensure that the outcomes of a trial are communicated effectively: The EQUATOR Network is a resource center for good reporting of health research.
Different organizations have different strategies for informing the public. For example, the findings from trials published on websites, leaflets in hospital/clinical research center waiting rooms. The dissemination of research findings promotes research participation and demonstrates that findings have improved current clinical practice and many funders are committed to open access of study results.
Informing participants of results acknowledges their contribution, shows respect and sees them not simply as a means to the researchers’ ends. It is important to establish whether a participant will want to be actively informed of trial results, or whether they would like the onus to be left with them to obtain the results. Patient and public involvement may help to guide this process.
44. Archiving
The archiving requirements for Clinical Trials of Investigational Medicinal Products (CTIMPs for all essential documents should be archived and this includes essential documents held by investigators, sponsors and others involved in the conduct of a clinical trial (including services departments such as pharmacy, laboratories and radiology).
The ICH GCP E6 4.9.5, 5.5.6, 5.5.7, 5.5.8, 5.5.11 and 5.6.3 guidelines offers further information on the storage and destruction of essential documents and the duration/timelines appropriate for archiving.
Funders, journals, sponsors and host organizations will also have local policies/procedures covering archive requirements, which must also be followed.
Consideration should be given for the archive of both paper and electronic data (such as databases) as original records are transferred to electronic media for the purpose of archive).
The Clinical Trials Regulations require the sponsor to appoint ‘named individuals’ for archiving to ensure all requirements are met and systems are in place to track and retrieve archived documents. Named individuals should ensure that archive facilities are secure with appropriate environmental control and adequate protection from physical damage.
55
In multi-center trials, it is common practice for trial documents held by the Principal Investigator to be archived by their host organization and responsibilities should be defined in any relevant agreements. Researchers should be aware of the specific arrangements for their trials.
For non-CTIMP research, the archive time period is usually stipulated by the sponsor and/or local SOPs/policies.
------
References:
1. National Institutes of Health Research 2. International Conference for Harmonization
56
Chapter 4 - Types of Clinical Trials
The most commonly performed clinical trials evaluate new drugs, medical devices, biologics, or other interventions on patients in strictly scientifically controlled settings, and are required for regulatory authority (in Pakistan, Division of Biological Evaluation and Research (DBER); in the USA, the Food and Drug Administration (US FDA); in Canada, Health Canada; in the EU, the European Medicines Agency (EMA); in Japan, the Ministry of Health, Labor and Welfare (MHLW) approval of new therapies. Trials may be designed to assess the safety and efficacy of an experimental therapy, to assess whether the new intervention is better than standard therapy, or to compare the efficacy of two standard or marketed interventions. The trial objectives and design are usually documented in a clinical trial protocol.
To be ethical, they must involve the full and informed consent of participating human subjects. They are closely supervised by appropriate regulatory authorities. All interventional studies must be approved by an ethics committee (in Pakistan, this body is the Institutional/Ethics Review Board) before permission is granted to run the trial.
The study design that provides the most compelling evidence of a causal relationship between the treatment and the effect, is the randomized controlled trial. Observational studies in epidemiology such as the cohort study and the case-control study are clinical studies in that they involve human participants, but provide less compelling evidence than the randomized controlled trial. The major difference between clinical trials and observational studies is that, in clinical trials, the investigators manipulate the administration of a new intervention and measure the effect of that manipulation, whereas observational studies only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. These are fundamental distinctions in evidence-based medicine.
Currently some Phase II and most Phase III drug trials are designed to be randomized, double-blind, and placebo-controlled. This means that each study subject is randomly assigned to receive one of the treatments, which might be the placebo. Neither the subjects nor scientists involved in the study know which study treatment is being administered to any given subject; and, in particular, none of those involved in the study know which subjects are being administered a placebo. This is to prevent biases in the administration of the drugs, since a physician may feel more useful to give the drug to a patient who could more easily benefit of it, and the placebo to a more advanced case. Moreover, it has been assessed how there can be a "placebo effect" that can cause tumor responses in the order of roughly 10%. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" trials (also known as "active control" trials) - in other words, when a treatment exists that is clearly better than doing nothing (i.e. the placebo) for the subject, the alternate treatment would be a standard-of-care therapy.
While the term clinical trials is most commonly associated with large randomized studies, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. Other clinical trials require large numbers of participants followed over long periods of time, and the trial sponsor is more likely to be a commercial company or a government, or other academic, research body. It is sometimes necessary to organize multicenter trials. Often the centers taking part in such trials are in different countries (in which case they may be termed international clinical trials).
The number of patients enrolled in the study has a large bearing on the ability of the trial to reliably detect an effect of a treatment. This is described as the "power" of the trial. It is usually expressed as the probability that, if the treatments differ in their effect on the outcome of interest, the statistical analysis of the trial data will detect that difference. The larger the sample size or number of participants, the greater the statistical power. The number of patients required to give a statistically significant result relates also to the question the trial wants to answer: to show the efficacy of a new drug in a non-curable disease as metastatic kidney cancer requires much less patients than in a highly curable disease as seminoma. However, in designing a clinical trial, this consideration must be balanced with the greater costs associated with larger studies. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated and control groups. For example, a trial of a lipid-lowering drug
57 with 100 patients per group, might have a power of .90 to detect a difference between active and placebo of 10 mg/dL or more, but only have a power of .70 to detect a difference of 5 mg/dL.
Phases
Pharmaceutical clinical trials are commonly classified into four phases, and the drug-development process will normally proceed through all four stages over many years. If the drug successfully passes through the first three phases, it will usually be successfully approved for use in the general population.
Before pharmaceutical companies start clinical trials on drugs, extensive pre-clinical studies are conducted.
Phase I
Phase I trials are the first-stage of testing in human subjects. Normally a small (20-80) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety (Pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a therapy. These trials are almost always conducted in an inpatient clinic, where the subject can be observed by full-time medical staff. The subject is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging studies so that doses for clinical use can be refined. The tested range of doses will usually be a small fraction of the dose that causes harm in animal testing. Phase I trials most often include healthy volunteers, however there are some circumstances when patients are used, such as with oncology (cancer) and HIV drug trials. In Phase I trials of new cancer drugs, for example, patients with advanced (metastatic) cancer are used. These trials are usually offered to patients who have had other types of therapy and who have few, if any, other treatment choices.
There are two specific kinds of Phase I trials - SAD studies, and MAD studies.
SAD - Single Ascending Dose studies are those in which groups of three or six patients are given a small dose of the drug and observed for a specific period of time. If they do not exhibit any adverse side effects, a new group of patients is then given a higher dose. This is continued until intolerable side effects start showing up, at which point the drug is said to have reached the Maximum tolerated dose (MTD).
MAD - Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics/pharmacodynamics of the drug. In these studies, a group of patients receives a low dose of the drug and the dose is subsequently escalated up to a predetermined level. Samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body.
Phase II
Once the initial safety of the therapy has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess clinical efficacy of the therapy; as well as to continue Phase I assessments in a larger group of volunteers and patients. The development process for a new drug commonly fails during Phase II trials due to the discovery of poor efficacy or toxic effects.
Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements, whereas Phase IIB is specifically designed to study efficacy.
Some trials combine Phase I and Phase II into a single trial, monitoring both efficacy and toxicity.
Phase III
Phase III studies are randomized controlled trials on large patient groups (300–3,000 or more depending upon the condition) and are aimed at being the definitive assessment of the efficacy of the new therapy, in
58 comparison with current 'Gold Standard' treatment. Phase III trials are the most expensive, time-consuming and difficult trials to design and run; especially in therapies for chronic conditions. Once a drug has proven satisfactory over Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to various regulatory authorities in different countries, such as the Therapeutic Goods Administration (TGA) in Australia, the European Medicines Agency (EMEA) or the Food and Drug Administration (FDA) in the United States for marketing approval.
It is also common practice with many drugs whose approval is pending, that certain Phase III trials will continue in an attempt at "label expansion”. In other words, proving additional efficacy for uses beyond the original use for which the drug was designed. Other reasons for performing trials at this stage are to support marketing claims. Studies in this phase are by some companies categorized as "Phase IIIB studies".
Phase 3b studies
These studies are called peri-approval studies. Conducted in numerous centers on several thousand patients. Numbers of patients per center is usually small The aim of the studies is Method of use, to see how well the proposed presentation (dosage form, palatability) works in the general target population and to gather preliminary safety data while the NDA is being reviewed.
While not required in all studies, it is typically expected that there be at least two successful phase III trials, proving a drug's safety and efficacy, for approval from the standard regulatory agencies (FDA, TGA, EMEA, etc.). Though the current trend in recent months seems to be a move toward adaptive (live, changing) studies to expedite the process, there are no formal regulations for these trials in the pharmaceutical industry as of yet.
Phase IV
Phase IV trials involve the post-launch safety surveillance and ongoing technical support of a drug. Phase IV studies may be mandated by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons. Post-launch safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the initial clinical trials. Such adverse effects detected by Phase IV trials may result in the withdrawal or restriction of a drug - recent examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
Pharmacodynamics is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect. It is often summarily stated that pharmacodynamics is the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug.
59
Notes:
Pharmacodynamics : what a drug does to a body
Pharmacokinetics : What the body does to a drug
Please see table below for a comparison of the different types of trials.
References:
1. Kriger Research International 2. US FDA
60
NIH=National Institute of Health in the US DSMB=Data Safety Monitoring Board
61
Chapter 5 - INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
ICH HARMONISED TRIPARTITE GUIDELINE
GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R1)
Current Step 4 version dated 10 June 1996
(including the Post Step 4 corrections)
This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.
62
E6(R1) Document History
New
First History Date Codification Codification November 2005
E6 Approval by the Steering Committee under Step 2 27 E6 and release for public consultation. April 1995
E6 Approval by the Steering Committee under Step 4 and 1 E6 recommended for adoption to the three ICH regulatory May bodies. 1996
Current Step 4 version
E6 Approval by the Steering Committee of Post-Step 4 10 E6(R1) editorial corrections. June 1996
63
GUIDELINE FOR GOOD CLINICAL PRACTICE ICH Harmonized Tripartite Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 1 May 1996, this guideline is recommended for
adoption to the three regulatory parties to ICH (This document includes the Post Step 4 corrections agreed by the Steering Committee on 10 June 1996)
GUIDELINE FOR GOOD CLINICAL PRACTICE
INTRODUCTION
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO).
This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities.
The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects.
64
Guideline for Good Clinical Practice
1. GLOSSARY
1.1 Adverse Drug Reaction (ADR) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
1.2 Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
1.3 Amendment (to the protocol) See Protocol Amendment.
1.4 Applicable Regulatory Requirement(s) Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
1.5 Approval (in relation to Institutional Review Boards) The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.
1.6 Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
1.7 Audit Certificate A declaration of confirmation by the auditor that an audit has taken place.
1.8 Audit Report A written evaluation by the sponsor's auditor of the results of the audit.
65
Guideline for Good Clinical Practice
1.9 Audit Trail Documentation that allows reconstruction of the course of events.
1.10 Blinding/Masking A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double- blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).
1.11 Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.
1.12 Clinical Trial/Study Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
1.13 Clinical Trial/Study Report A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).
1.14 Comparator (Product) An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.
1.15 Compliance (in relation to trials) Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.
1.16 Confidentiality Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.
1.17 Contract A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.
1.18 Coordinating Committee A committee that a sponsor may organize to coordinate the conduct of a multicenter trial.
66
Guideline for Good Clinical Practice
1.19 Coordinating Investigator An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicenter trial.
1.20 Contract Research Organization (CRO) A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions.
1.21 Direct Access Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.
1.22 Documentation All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.
1.23 Essential Documents Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial).
1.24 Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee) An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.
1.26 Impartial Witness A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.
1.27 Independent Ethics Committee (IEC) An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favorable
67
Guideline for Good Clinical Practice
opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.
1.28 Informed Consent A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.
1.29 Inspection The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).
1.30 Institution (medical) Any public or private entity or agency or medical or dental facility where clinical trials are conducted.
1.31 Institutional Review Board (IRB) An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
1.32 Interim Clinical Trial/Study Report A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
1.33 Investigational Product A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.
1.34 Investigator A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Sub-investigator.
68
Guideline for Good Clinical Practice
1.35 Investigator / Institution An expression meaning "the investigator and/or institution, where required by the applicable regulatory requirements".
1.36 Investigator's Brochure A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
1.37 Legally Acceptable Representative An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.
1.38 Monitoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
1.39 Monitoring Report A written report from the monitor to the sponsor after each site visit and/or other trial- related communication according to the sponsor’s SOPs.
1.40 Multicenter Trial A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.
1.41 Nonclinical Study Biomedical studies not performed on human subjects.
1.42 Opinion (in relation to Independent Ethics Committee) The judgment and/or the advice provided by an Independent Ethics Committee (IEC).
1.43 Original Medical Record See Source Documents.
1.44 Protocol A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments.
1.45 Protocol Amendment A written description of a change(s) to or formal clarification of a protocol.
1.46 Quality Assurance (QA) All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).
69
Guideline for Good Clinical Practice
1.47 Quality Control (QC) The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.
1.48 Randomization The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.
1.49 Regulatory Authorities Bodies having the power to regulate. In the ICH GCP guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are sometimes referred to as competent authorities.
1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) Any untoward medical occurrence that at any dose:
- results in death,
- is life-threatening,
- requires inpatient hospitalization or prolongation of existing hospitalization,
- results in persistent or significant disability/incapacity, or - is a congenital anomaly/birth defect
(see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
1.51 Source Data All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).
1.52 Source Documents Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).
1.53 Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.
70
Guideline for Good Clinical Practice
1.54 Sponsor-Investigator An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
1.55 Standard Operating Procedures (SOPs) Detailed, written instructions to achieve uniformity of the performance of a specific function.
1.56 Subinvestigator Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.
1.57 Subject/Trial Subject An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.
1.58 Subject Identification Code A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data.
1.59 Trial Site The location(s) where trial-related activities are actually conducted.
1.60 Unexpected Adverse Drug Reaction An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
1.61 Vulnerable Subjects Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
1.62 Well-being (of the trial subjects) The physical and mental integrity of the subjects participating in a clinical trial.
71
Guideline for Good Clinical Practice
2. THE PRINCIPLES OF ICH GCP
2.1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).
2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
2.3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.
2.4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
2.6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion.
2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation.
2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.
2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.
3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
3.1 Responsibilities 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.
72
Guideline for Good Clinical Practice
3.1.2 The IRB/IEC should obtain the following documents:
Trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g. advertisements), written information to be provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities.
The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following:
- approval/favorable opinion;
- modifications required prior to its approval/favorable opinion;
- disapproval / negative opinion; and
- termination/suspension of any prior approval/favorable opinion.
3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.
3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well- being of the subjects.
3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.
3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e. in emergency situations).
3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.
3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the
73
Guideline for Good Clinical Practice
written informed consent form and any other written information to be provided to subjects. The way payment will be prorated should be specified.
3.2 Composition, Functions and Operations
3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include:
(a) At least five members.
(b) At least one member whose primary area of interest is in a nonscientific area.
(c) At least one member who is independent of the institution/trial site.
Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.
A list of IRB/IEC members and their qualifications should be maintained.
3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s).
3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present.
3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.
3.2.5 The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
3.3 Procedures The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is established.
3.3.2 Scheduling, notifying its members of, and conducting its meetings.
3.3.3 Conducting initial and continuing review of trials.
3.3.4 Determining the frequency of continuing review, as appropriate.
3.3.5 Providing, according to the applicable regulatory requirements, expedited review and approval/favorable opinion of minor change(s) in ongoing trials that have the approval/favorable opinion of the IRB/IEC.
3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favorable opinion of the trial.
3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favorable opinion of an appropriate 74
Guideline for Good Clinical Practice
amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or
administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
(c) All adverse drug reactions (ADRs) that are both serious and unexpected.
(d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4 Records The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authority(ies).
The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists.
4. INVESTIGATOR
4.1 Investigator's Qualifications and Agreements 4.1.1 The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
4.1.2 The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the product information and in other information sources provided by the sponsor.
4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).
75
Guideline for Good Clinical Practice
4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.
4.2 Adequate Resources
4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period.
4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.
4.2.3 The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
4.2.4 The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.
4.3 Medical Care of Trial Subjects 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub- investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
4.3.2 During and following a subject's participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.
4.3.3 It is recommended that the investigator inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
4.4 Communication with IRB/IEC 4.4.1 Before initiating a trial, the investigator/institution should have written and dated approval/favorable opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects.
4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the Investigator's Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
76
Guideline for Good Clinical Practice
4.5 Compliance with Protocol
4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favorable opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.
4.5.2 The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).
4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.
4.5.4 The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favorable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
(a) to the IRB/IEC for review and approval/favorable opinion, (b) to the sponsor for agreement and, if required, (c) to the regulatory authority(ies).
4.6 Investigational Product(s) 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.
4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution..
4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.
4.6.4 The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s).
4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.
77
Guideline for Good Clinical Practice
4.6.6 The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.
4.7 Randomization Procedures and Unblinding The investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).
4.8 Informed Consent of Trial Subjects 4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favorable opinion of the written informed consent form and any other written information to be provided to subjects.
4.8.2 The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favorable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.
4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
4.8.4 None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.
4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favorable opinion by the IRB/IEC.
4.8.6 The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable.
4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative.
78
Guideline for Good Clinical Practice
4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.
4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.
4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:
(a) That the trial involves research. (b) The purpose of the trial. (c) The trial treatment(s) and the probability for random assignment to each treatment.
(d) The trial procedures to be followed, including all invasive procedures. (e) The subject's responsibilities. (f) Those aspects of the trial that are experimental.
(g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.
(h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the event of trial- related injury.
(k) The anticipated prorated payment, if any, to the subject for participating in the trial.
(l) The anticipated expenses, if any, to the subject for participating in the trial.
(m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access.
79
Guideline for Good Clinical Practice
(o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.
(p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial.
(q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury.
(r) The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated.
(s) The expected duration of the subject's participation in the trial. (t) The approximate number of subjects involved in the trial. 4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.
4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.
4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.
4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:
(a) The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally.
(b) The foreseeable risks to the subjects are low.
(c) The negative impact on the subject’s well-being is minimized and low. (d) The trial is not prohibited by law. (e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favorable opinion covers this aspect.
80
Guideline for Good Clinical Practice
Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.
4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be requested.
4.9 Records and Reports 4.9.1 The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports.
4.9.2 Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.
4.9.3 Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic changes or corrections (see 5.18.4 (n)). Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.
4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.
4.9.5 Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (see 5.5.12).
4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records
81
Guideline for Good Clinical Practice
4.10 Progress Reports 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.
4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.
4.11 Safety Reporting 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.
4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.
4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).
4.12 Premature Termination or Suspension of a Trial If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.
4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension.
4.12.3 If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial (see 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the
82
Guideline for Good Clinical Practice
investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
4.13 Final Report(s) by Investigator Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.
5. SPONSOR
5.1 Quality Assurance and Quality Control 5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.
5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.
5.2 Contract Research Organization (CRO) 5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.
5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.
5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.
5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor.
5.3 Medical Expertise The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.
5.4 Trial Design 5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.
83
Guideline for Good Clinical Practice
5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct.
5.5 Trial Management, Data Handling, and Record Keeping 5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.
5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all its meetings.
5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
(a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
(b) Maintains SOPs for using these systems.
(c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail). (d) Maintain a security system that prevents unauthorized access to the data. (e) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).
5.5.4 If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.
5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all the data reported for each subject.
5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor- specific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).
5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s).
5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e. for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).
5.5.9 If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities.
84
Guideline for Good Clinical Practice
5.5.10 Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).
5.5.11 The sponsor specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.
5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.
5.6 Investigator Selection 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicenter trials, their organization and/or selection are the sponsor's responsibility.
5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.
5.6.3 The sponsor should obtain the investigator's/institution's agreement:
(a) to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the IRB/IEC (see 4.5.1);
(b) to comply with procedures for data recording/reporting;
(c) to permit monitoring, auditing and inspection (see 4.1.4) and
(d) to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).
The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.
5.7 Allocation of Responsibilities Prior to initiating a trial, the sponsor should define, establish, and allocate all trial- related duties and functions.
5.8 Compensation to Subjects and Investigators 5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.
85
Guideline for Good Clinical Practice
5.8.2 The sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).
5.9 Financing The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
5.10 Notification/Submission to Regulatory Authority(ies) Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol.
5.11 Confirmation of Review by IRB/IEC 5.11.1 The sponsor should obtain from the investigator/institution:
(a) The name and address of the investigator's/institution’s IRB/IEC.
(b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.
(c) Documented IRB/IEC approval/favorable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested.
5.11.2 If the IRB/IEC conditions its approval/favorable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favorable opinion was given by the IRB/IEC.
5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favorable opinion, and of any withdrawals or suspensions of approval/favorable opinion.
5.12 Information on Investigational Product(s) 5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.
5.12.2 The sponsor should update the Investigator's Brochure as significant new information becomes available (see 7. Investigator's Brochure).
86
Guideline for Good Clinical Practice
5.13 Manufacturing, P a c k a g i n g , L a b e l i n g , and Coding Investigational Product(s) 5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labeled in a manner that protects the blinding, if applicable. In addition, the labeling should comply with applicable regulatory requirement(s).
5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.
5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.
5.13.5 If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.
5.14 Supplying and Handling Investigational Product(s) 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).
5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g. approval/favorable opinion from IRB/IEC and regulatory authority(ies)).
5.14.3 The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).
5.14.4 The sponsor should:
(a) Ensure timely delivery of investigational product(s) to the investigator(s). (b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
(c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim).
87
Guideline for Good Clinical Practice
(d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition.
5.14.5 The sponsor should:
(a) Take steps to ensure that the investigational product(s) are stable over the period of use.
(b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.
5.15 Record Access 5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.
5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
5.16 Safety Information 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favorable opinion to continue the trial.
5.17 Adverse Drug Reaction Reporting 5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s).
5.18 Monitoring
5.18.1 Purpose The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
88
Guideline for Good Clinical Practice
(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
5.18.2 Selection and Qualifications of Monitors (a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
5.18.3 Extent and Nature of Monitoring The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.
5.18.4 Monitor's Responsibilities
The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:
(a) Acting as the main line of communication between the sponsor and the investigator.
(b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
89
Guideline for Good Clinical Practice
(v) That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor. (d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
(e) Verifying that written informed consent was obtained before each subject's participation in the trial.
(f) Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial.
(h) Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enroling only eligible subjects. (j) Reporting the subject recruitment rate. (k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
(l) Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
(m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:
(i) The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
(ii) Any dose and/or therapy modifications are well documented for each of the trial subjects.
(iii) Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.
(n) Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.
90
Guideline for Good Clinical Practice
(o) Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).
(p) Determining whether the investigator is maintaining the essential documents (see 8. Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.
5.18.5 Monitoring Procedures The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.
5.18.6 Monitoring Report (a) The monitor should submit a written report to the sponsor after each trial- site visit or trial-related communication.
(b) Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
(c) Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.
(d) The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.
5.19 Audit
If or when sponsors perform audits, as part of implementing quality assurance, they should consider:
5.19.1 Purpose The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.
5.19.2 Selection and Qualification of Auditors (a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.
5.19.3 Auditing Procedures (a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
(b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
91
Guideline for Good Clinical Practice
(c) The observations and findings of the auditor(s) should be documented.
(d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
(e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
5.20 Noncompliance 5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.
5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial. When an investigator's/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).
5.21 Premature Termination or Suspension of a Trial If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).
5.22 Clinical Trial/Study Reports Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases.)
5.23 Multicenter Trials For multicenter trials, the sponsor should ensure that:
5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favorable opinion by the IRB/IEC.
5.23.2 The CRFs are designed to capture the required data at all multicenter trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.
5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.
92
Guideline for Good Clinical Practice
5.23.4 All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.
5.23.5 Communication between investigators is facilitated.
6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) The contents of a trial protocol should generally include the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.
6.1 General Information 6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).
6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
6.1.3 Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
6.1.4 Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial. 6.1.5 Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
6.1.6 Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
6.1.7 Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.
6.2 Background Information 6.2.1 Name and description of the investigational product(s).
6.2.2 A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
6.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
6.2.4 Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
6.2.6 Description of the population to be studied.
6.2.7 References to literature and data that are relevant to the trial, and that provide background for the trial.
6.3 Trial Objectives and Purpose A detailed description of the objectives and the purpose of the trial.
93
Guideline for Good Clinical Practice
6.4 Trial Design The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design, should include:
6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
6.4.2 A description of the type/design of trial to be conducted (e.g. double-blind, placebo- controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
6.4.3 A description of the measures taken to minimize/avoid bias, including: (a)
Randomization. (b) Blinding.
6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
6.4.5 The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
6.4.6 A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.
6.4.7 Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
6.4.8 Maintenance of trial treatment randomization codes and procedures for breaking codes.
6.4.9 The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data
6.5 Selection and Withdrawal of Subjects 6.5.1 Subject inclusion criteria.
6.5.2 Subject exclusion criteria.
6.5.3 Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
(a) When and how to withdraw subjects from the trial/ investigational product treatment.
(b) The type and timing of the data to be collected for withdrawn subjects. (c) Whether and how subjects are to be replaced. (d) The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
94
Guideline for Good Clinical Practice
6.6 Treatment of Subjects 6.6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s),the dosing schedule(s),the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
6.6.2 Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
6.6.3 Procedures for monitoring subject compliance.
6.7 Assessment of Efficacy 6.7.1 Specification of the efficacy parameters.
6.7.2 Methods and timing for assessing, recording, and analysing of efficacy parameters.
6.8 Assessment of Safety 6.8.1 Specification of safety parameters.
6.8.2 The methods and timing for assessing, recording, and analysing safety parameters.
6.8.3 Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
6.8.4 The type and duration of the follow-up of subjects after adverse events.
6.9 Statistics
6.9.1 A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
6.9.2 The number of subjects planned to be enrolled. In multicenter trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
6.9.3 The level of significance to be used.
6.9.4 Criteria for the termination of the trial.
6.9.5 Procedure for accounting for missing, unused, and spurious data.
6.9.6 Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).
6.9.7 The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).
95
Guideline for Good Clinical Practice
6.10 Direct Access to Source Data/Documents The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.
6.11 Quality Control and Quality Assurance
6.12 Ethics Description of ethical considerations relating to the trial.
6.13 Data Handling and Record Keeping
6.14 Financing and Insurance Financing and insurance if not addressed in a separate agreement.
6.15 Publication Policy Publication policy, if not addressed in a separate agreement.
6.16 Supplements (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)
96
Guideline for Good Clinical Practice
7. INVESTIGATOR’S BROCHURE
7.1 Introduction The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data.
This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout. It is expected that the type and extent of information available will vary with the stage of development of the investigational product. If the investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the investigator. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is included in a revised IB.
Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators are responsible for providing the up- to-date IB to the responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational product is provided by the sponsor- investigator, then he or she should provide the necessary information to the trial personnel. In cases where preparation of a formal IB is impractical, the sponsor- investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in this guideline.
97
Guideline for Good Clinical Practice
7.2 General Considerations The IB should include:
7.2.1 Title Page This should provide the sponsor's name, the identity of each investigational product (i.e., research number, chemical or approved generic name, and trade name(s) where legally permissible and desired by the sponsor), and the release date. It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided. An example is given in Appendix 1.
7.2.2 Confidentiality Statement The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator's team and the IRB/IEC.
7.3 Contents of the Investigator’s Brochure The IB should contain the following sections, each with literature references where appropriate:
7.3.1 Table of Contents An example of the Table of Contents is given in Appendix 2
7.3.2 Summary A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product.
7.3.3 Introduction A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s), all active ingredients, the investigational product (s ) pharmacological class and its expected position within this class (e.g. advantages), the rationale for performing research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product.
7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation A description should be provided of the investigational product substance(s) (including the chemical and/or structural formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties.
To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given.
Any structural similarities to other known compounds should be mentioned.
98
Guideline for Good Clinical Practice
7.3.5 Nonclinical Studies
Introduction: The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavorable and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
• Species tested • Number and sex of animals in each group • Unit dose (e.g., milligram/kilogram (mg/kg)) • Dose interval • Route of administration • Duration of dosing • Information on systemic distribution • Duration of post-exposure follow-up • Results, including the following aspects: − Nature and frequency of pharmacological or toxic effects − Severity or intensity of pharmacological or toxic effects − Time to onset of effects − Reversibility of effects − Duration of effects − Dose response Tabular format/listings should be used whenever possible to enhance the clarity of the presentation.
The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis.
(a) Nonclinical Pharmacology A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g. efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).
99
Guideline for Good Clinical Practice
(b) Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species.
(c) Toxicology
A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:
− Single dose − Repeated dose − Carcinogenicity − Special studies (e.g. irritancy and sensitization) − Reproductive toxicity − Genotoxicity (mutagenicity)
7.3.6 Effects in Humans
Introduction: A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use of the investigational product(s) other than from in clinical trials, such as from experience during marketing.
(a) Pharmacokinetics and Product Metabolism in Humans − A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available: − Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination). − Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form. − Population subgroups (e.g., gender, age, and impaired organ function). − Interactions (e.g., product-product interactions and effects of food). − Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s). (b) Safety and Efficacy A summary of information should be provided about the investigational product's/products' (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials
100
Guideline for Good Clinical Practice
(including those for all the studied indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
(c) Marketing Experience The IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reactions). The IB should also identify all the countries where the investigational product did not receive approval/registrationfor marketing or was withdrawn from marketing/registration.
7.3.7 Summary of Data and Guidance for the Investigator This section should provide an overall discussion of the nonclinical and clinical data, and should summarize the information from various sources on different aspects of the investigational product(s), wherever possible. In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials.
Where appropriate, the published reports on related products should be discussed. This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials.
The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the investigational product.
101
Guideline for Good Clinical Practice
7.4 APPENDIX 1:
TITLE PAGE (Example)
SPONSOR'S NAME
Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR'S BROCHURE
Edition Number: Release Date:
Replaces Previous Edition Number: Date:
102
Guideline for Good Clinical Practice
7.5 APPENDIX 2:
TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example)
- Confidentiality Statement (optional) - Signature Page (optional)
1 Table of Contents
2 Summary
3 Introduction
4 Physical, Chemical, and Pharmaceutical Properties and Formulation
5 Nonclinical Studies
5.1 Nonclinical Pharmacology
5.2 Pharmacokinetics and Product Metabolism in Animals
5.3 Toxicology 6 Effects in Humans
6.1 Pharmacokinetics and Product Metabolism in Humans
6.2 Safety and Efficacy
6.3 Marketing Experience
7 Summary of Data and Guidance for the Investigator
NB: References on 1. Publications
2. Reports
These references should be found at the end of each chapter
Appendices (if any)
103
Guideline for Good Clinical Practice
8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
8.1 Introduction Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected.
The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable.
Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files.
Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).
104
Guideline for Good Clinical Practice
8.2 Before the Clinical Phase of the Trial Commences During this planning stage the following documents should be generated and should be on file before the trial formally starts
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.1 INVESTIGATOR’S BROCHURE To document that relevant and current scientific X X information about the investigational product has been provided to the investigator
8.2.2 SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND To document investigator and sponsor X X SAMPLE CASE REPORT FORM (CRF) agreement to the protocol/amendment(s) and CRF
8.2.3 INFORMATION GIVEN TO TRIAL SUBJECT X X
- INFORMED CONSENT FORM (including all applicable translations) To document the informed consent
- ANY OTHER WRITTEN INFORMATION To document that subjects will be given X X appropriate written information (content and wording) to support their ability to give fully informed consent
- ADVERTISEMENT FOR SUBJECT To document that recruitment measures are X RECRUITMENT (if used) appropriate and not coercive
8.2.4 FINANCIAL ASPECTS OF THE TRIAL To document the financial agreement between the X X investigator/institution and the sponsor for the trial
105
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution
8.2.5 INSURANCE STATEMENT To document that compensation to subject(s) for X X (where required) trial-related injury will be available
8.2.6 SIGNED AGREEMENT BETWEEN INVOLVED To document agreements PARTIES, e.g.: - investigator/institution and sponsor X X - investigator/institution and CRO X X (where required) - sponsor and CRO X - investigator/institution and authority(ies) X X (where required)
8.2.7 DATED, DOCUMENTED APPROVAL/FAVORABLE To document that the trial has been subject to X X OPINION OF INSTITUTIONAL REVIEW BOARD (IRB) IRB/IEC review and given approval/favorable /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE opinion. To identify the version number and date FOLLOWING: of the document(s) - protocol and any amendments - CRF (if applicable) - informed consent form(s) - any other written information to be provided to the subject(s) - advertisement for subject recruitment (if used) - subject compensation (if any) - any other documents given approval/ favorable opinion
106
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.8 INSTITUTIONAL REVIEW To document that the IRB/IEC is constituted in X X BOARD/INDEPENDENT ETHICS agreement with GCP (where COMMITTEE COMPOSITION required)
8.2.9 REGULATORY AUTHORITY(IES) To document appropriate X X AUTHORISATION/APPROVAL/ authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to initiation of the (where (where NOTIFICATION OF PROTOCOL (where required) required) required) trial in compliance with the applicable regulatory requirement(s)
8.2.10 CURRICULUM VITAE AND/OR OTHER RELEVANT To document qualifications and eligibility to conduct X X DOCUMENTS EVIDENCING QUALIFICATIONS OF trial and/or provide medical supervision of subjects INVESTIGATOR(S) AND SUB-INVESTIGATOR(S)
X X 8.2.11 NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ To document normal values and/or ranges of the tests LABORATORY/TECHNICAL PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOL
8.2.12 MEDICAL/LABORATORY/TECHNICAL To document competence of facility to perform X X PROCEDURES /TESTS required test(s) , and support reliability of results (where - certification or required) - accreditation or - established quality control and/or external quality assessment or - other validation (where required) 107
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.2.13 SAMPLE OF LABEL(S) ATTACHED TO To document compliance with applicable X INVESTIGATIONAL PRODUCT CONTAINER(S) labelling regulations and appropriateness of instructions provided to the subjects
8.2.14 INSTRUCTIONS FOR HANDLING OF To document instructions needed to ensure X X INVESTIGATIONAL PRODUCT(S) AND TRIAL- proper storage, packaging, dispensing and RELATED MATERIALS disposition of investigational products and trial- related (if not included in protocol or Investigator’s materials Brochure)
8.2.15 SHIPPING RECORDS FOR INVESTIGATIONAL To document shipment dates, batch numbers X X PRODUCT(S) AND TRIAL-RELATED MATERIALS and method of shipment of investigational product(s) and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability
8.2.16 CERTIFICATE(S) OF ANALYSIS OF To document identity, purity, and strength of X INVESTIGATIONAL PRODUCT(S) SHIPPED investigational product(s) to be used in the trial
8.2.17 DECODING PROCEDURES FOR BLINDED TRIALS To document how, in case of an emergency, X X identity of blinded investigational product can be (third party if revealed without breaking the blind for the remaining applicable) subjects' treatment
108
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.2.18 MASTER RANDOMISATION LIST To document method for randomisation of trial X population (third party if applicable)
8.2.19 PRE-TRIAL MONITORING REPORT To document that the site is suitable for the X trial (may be combined with 8.2.20)
8.2.20 TRIAL INITIATION MONITORING REPORT To document that trial procedures were X X reviewed with the investigator and the investigator’s trial staff ( may be combined with 8.2.19)
8.3 During the Clinical Conduct of the Trial In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant information is documented as it becomes available
8.3.1 INVESTIGATOR’S BROCHURE UPDATES To document that investigator is informed in a X X timely manner of relevant information as it becomes available
109
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.2 ANY REVISION TO: To document revisions of these trial related X X - protocol/amendment(s) and CRF documents that take effect during trial - informed consent form - any other written information provided to subjects - advertisement for subject recruitment (if used)
8.3.3 DATED, DOCUMENTED APPROVAL/FAVORABLE To document that the amendment(s) and/or X X
OPINION OF INSTITUTIONAL REVIEW BOARD (IRB) revision(s) have been subject to IRB/IEC review and /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE were given approval/favorable opinion. To identify FOLLOWING: the version number and date of the document(s).
- protocol amendment(s) - revision(s) of: - informed consent form - any other written information to be provided to the subject - advertisement for subject recruitment (if used) - any other documents given approval/favorable opinion - continuing review of trial (where required)
110
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution 8.3.4 REGULATORY AUTHORITY(IES) To document compliance with applicable X (where X AUTHORISATIONS/APPROVALS/NOTIFICATI ONS WHERE regulatory requirements required) REQUIRED FOR: - protocol amendment(s) and other documents 8.3.5 CURRICULUM VITAE FOR NEW (see 8.2.10) X X INVESTIGATOR(S) AND/OR SUB- INVESTIGATOR(S)
8.3.6 UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR To document normal values and ranges that are X X MEDICAL/ LABORATORY/ TECHNICAL revised during the trial (see 8.2.11) PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL
8.3.7 UPDATES OF MEDICAL/LABORATORY/ TECHNICAL To document that tests remain adequate X (where X PROCEDURES/TESTS throughout the trial period (see 8.2.12) required)
- certification or - accreditation or - established quality control and/or external quality assessment or - other validation (where required) 8.3.8 DOCUMENTATION OF INVESTIGATIONAL PRODUCT(S) (see 8.2.15.) X X AND TRIAL-RELATED MATERIALS SHIPMENT
111
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.9 CERTIFICATE(S) OF ANALYSIS FOR NEW BATCHES OF (see 8.2.16) X INVESTIGATIONAL PRODUCTS
8.3.10 MONITORING VISIT REPORTS To document site visits by, and findings of, the X monitor
8.3.11 RELEVANT COMMUNICATIONS OTHER THAN SITE To document any agreements or significant discussions X X VISITS regarding trial administration, protocol violations, trial conduct, adverse event (AE) - letters reporting - meeting notes - notes of telephone calls
8.3.12 SIGNED INFORMED CONSENT FORMS To document that consent is obtained in X accordance with GCP and protocol and dated prior to participation of each subject in trial. Also to document direct access permission (see 8.2.3) 8.3.13 SOURCE DOCUMENTS To document the existence of the subject and X substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject
112
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.14 SIGNED, DATED AND COMPLETED CASE To document that the investigator or authorised X X REPORT FORMS (CRF) member of the investigator’s staff confirms the (copy) (original) observations recorded
8.3.15 DOCUMENTATION OF CRF To document all changes/additions or X X CORRECTIONS corrections made to CRF after initial data were (copy) (original) recorded
8.3.16 NOTIFICATION BY ORIGINATING Notification by originating investigator to X X INVESTIGATOR TO SPONSOR OF SERIOUS sponsor of serious adverse events and related ADVERSE EVENTS AND RELATED REPORTS reports in accordance with 4.11
8.3.17 NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, Notification by sponsor and/or investigator, where X (where X WHERE APPLICABLE, TO REGULATORY applicable, to regulatory authorities and IRB(s)/IEC(s) required) AUTHORITY(IES) AND IRB(S)/IEC(S) OF UNEXPECTED of unexpected serious adverse drug reactions in SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER accordance with 5.17 and SAFETY INFORMATION 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2
8.3.18 NOTIFICATION BY SPONSOR TO Notification by sponsor to investigators of safety X X INVESTIGATORS OF SAFETY INFORMATION information in accordance with 5.16.2
8.3.19 INTERIM OR ANNUAL REPORTS TO IRB/IEC AND Interim or annual reports provided to IRB/IEC in X X (where AUTHORITY(IES) accordance with 4.10 and to authority(ies) in required) accordance with 5.17.3
113
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution
8.3.20 SUBJECT SCREENING LOG To document identification of subjects who X X entered pre-trial screening (where required)
8.3.21 SUBJECT IDENTIFICATION CODE LIST To document that investigator/institution keeps X a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject
8.3.22 SUBJECT ENROLMENT LOG To document chronological enrolment of X subjects by trial number
8.3.23 INVESTIGATIONAL PRODUCTS To document that investigational product(s) X X ACCOUNTABILITY AT THE SITE have been used according to the protocol
8.3.24 SIGNATURE SHEET To document signatures and initials of all X X persons authorised to make entries and/or corrections on CRFs
8.3.25 RECORD OF RETAINED BODY FLUIDS/ TISSUE To document location and identification of X X SAMPLES (IF ANY) retained samples if assays need to be repeated
114
Guideline for Good Clinical Practice
8.4 After Completion or Termination of the Trial After completion or termination of the trial, all of the documents identified in sections 8.2 and 8.3 should be in the file together with the following
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.4.1 INVESTIGATIONAL PRODUCT(S) To document that the investigational product(s) have X X ACCOUNTABILITY AT SITE been used according to the protocol. To documents the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor
8.4.2 DOCUMENTATION OF To document destruction of unused X X INVESTIGATIONAL PRODUCT investigational products by sponsor or at site (if destroyed at DESTRUCTION site)
8.4.3 COMPLETED SUBJECT IDENTIFICATION CODE LIST To permit identification of all subjects enrolled in the X trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time
8.4.4 AUDIT CERTIFICATE (if available) To document that audit was performed X
8.4.5 FINAL TRIAL CLOSE-OUT MONITORING REPORT To document that all activities required for trial close- X out are completed, and copies of essential documents are held in the appropriate files
8.4.6 TREATMENT ALLOCATION AND DECODING Returned to sponsor to document any decoding that X DOCUMENTATION may have occurred
115
Guideline for Good Clinical Practice
Title of Document Purpose Located in Files of Investigator/ Sponsor Institution
8.4.7 FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE To document completion of the trial X REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)
8.4.8 CLINICAL STUDY REPORT To document results and interpretation of trial X X (if applicable)
116
Chapter 6 - Clinical Trials Regulatory Approval Process – Division of Biological Evaluation and Research (DBER)
In 2006, draft legislation was put forward for the establishment of a body to be called the Drug Regulatory Authority of Pakistan. As part of its function, this body will oversee areas such as R&D, pharmacovigilance and drug information. The new authority will also liaise and interact with counterpart regulatory agencies and organizations in other countries for capacity building and exchange of information. Regulations concerning the conduct of clinical trials should appear as part of these new developments. DRAP was recently formed on November 12, 2012 with the passing of DRAP Act 2012. The office of the Division of Biological Evaluation and Research (DBER) of the Drug Regulatory Authority of Pakistan (DRAP) was formed to act as the national control authority for biologicals with 6 functions among which included clinical trials.
Objectives
To provide a unified standard for managing clinical trials across Pakistan and to facilitate mutual acceptance of clinical trial data by regulatory bodies of Pakistan and abroad To ensure that only adequately designed studies are conducted thereby safeguarding the subject, investigator, sponsor and general community interests
Pakistan Good Clinical Practice (PGCP) came into effect in 2002. It is the national ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected; consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. These guidelines were basically adopted from ICH-GCP Guidelines which were developed with consideration of the current Good Clinical Practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health organization (WHO).
Checklist for Clinical Trials Application
1. CVs of Investigators
2. Ethics committee approval for sites (members[name& designation] list included)
3. GMP certificate along with the CPP/FSC of COO in case of Phase IV trials
4. Pre-clinical, clinical data and safety studies available on Investigational Medicinal Product (IMP)
5. Investigator Brochure (IB)
117
6. Final Protocol
7. Informed consent form (English & Urdu)
8. List of participating countries
9. Phase of trial
10. Quantity of drugs to be imported on Form-4 of Drug import & Export rules 1976
11. Site(s) where trial will be conducted
12. GMP certificate along with Free Sale Certificate/Certificate of Pharmaceutical Product
13. Preclinical and clinical data and safety studies
14. Summary of the protocol
15. Summary of the Investigator Brochure
16. Adverse Event Reporting form
17. Number of patients to be enrolled at each center
18. Name of monitors/clinical research associates
19. Evidence of registration in country of origin
20. Copy of registration letter (if registered in Pakistan)
21. Copy of Drug label sample
22. Study duration
23. Clinical Trial fee Rs.5000/-
Approvals Process
Lack of infrastructure and necessary facilities
The process for approval has been initiated but hasn’t been finalized yet. National and international assistance has been sought.
118
Phase II and III Approval Process
See diagram below (New flow diagram under development by DBER)
119
Phase IV Approval Process
(New flow diagram under development by DBER)
Timelines for Processing of Clinical Trial Application
120
121
RESEARCH RULES
All functions of NCLB are now under DRAP Act, 2012 (Act No. XXI of 2012) under this law all previous actions and SROs are protected. Lot Release is now under Schedule I, and NCLB is part of DRAP under Section 3 of this Act.
S.R.O. 1047(I)/78, dated 15th July, 1978:
In exercise of the powers conferred by Section 43 of the Drugs Act, 1976 (XXXI of 1976), the Federal Government is pleased to make the following rules, the same having been previously published as required by sub-section (3) of the said section, namely :-
1. Short title and commencement:
1) These rules may be called the Drugs (Research) Rules, 1978. 2) They shall come into force at once.
2. Definitions:
In these rules, unless there is anything repugnant in the subject or context,-
a. "Committee" means the Committee of Experts constituted under rule 8; (aa) "Form" means form appended to these rules; b. "Fund" means the Central Research Fund maintained by the Federal Government under sub-rule (14) of rule 19 of the Drugs (Licensing, Registering and Advertising), Rules, 1976; c. "investigator" means a person engaged in the investigation, research, development or evaluation of a drug on his own initiative or under the sponsorship of any other person or an institution; d. "recipient" means a person or an institution who or which receives aid from the Fund; and e. "Sponsor" means a person, firm, an establishment or institution promoting research on a drug.
3. Utilization of Fund:
The Federal Government may utilize the Fund for conducting research, development or evaluation of a drug either itself or through a research institution working under its control or disburse it among investigators or institutions for such purposes subject to such conditions as may be specified and for that matter, it may also utilize the fund to upgrade and establish Drugs Research and testing laboratories and a unit in the Drugs Control Section, Ministry of Health, for evaluation and monitoring of the research proposals and projects and management of the fund.
4. Research in drugs: The research in drugs shall be conducted at such place or places and by such person or persons as may be approved by the Federal Government and shall be categorized as under:--
122
i. other than clinical trials; and ii. clinical trials
5. Application for grant of aid:
1) An application for the grant of aid from the Fund for conducting research on a drug on aspects other than the clinical trials and for clinical trials shall be made in Form 'A' and Form 'B', respectively, and addressed to the Secretary of the Committee. 2) The Federal Government may, before granting any aid from the Fund, cause inspection of the premises concerned end technical evaluation of the project by the Committee or any expert appointed by it for this purpose. 3) The Federal Government may, after obtaining the advice of the Committee and subject to such conditions as it may specify in this behalf, grant such aid from the Fund to a person or an institution as it may deem fit.
6. Conditions for conducting research on aspects of other than clinical trials:
1) The research on any aspect of drugs other than clinical trial shall be conducted under the supervision of an investigator who possesses post-graduate qualification and experience in the relevant field and has sufficient background knowledge to conduct scientific investigation. 2) The recipient shall, at regular intervals not exceeding six months, submit the progress report to the Federal Government in respect of the investigation being conducted. 3) No change of an investigator or in the plan for investigation shall be made without prior approval of the Federal Government. 4) The recipient shall allow an expert or a panel of experts authorized by the Federal Government to visit the premises at which the research is being conducted and to see that the Fund is being utilized in accordance with the approved plan.
7. Conditions for research in clinical trials:
1) In addition to the conditions laid down in rule 6, research in drugs on aspect of clinical trials shall be conducted in the following stages:- i. Stage 1 of investigation on human beings shall consist of studies to determine single and short term multiple dosing for tolerance, side effects, toxicity, metabolism, preferred routes of administration, safe dosage range and other pharmacological actions of the drug: Provided that these studies shall be conducted under carefully controlled circumstances on comparatively small number of subjects to prevent any serious deleterious effect on health. ii. Stage II of investigation shall consist of studies to determine safety and effectiveness including an effective dose range, the common side effects of the drug on both clinical and laboratory parameters and where possible the level of drug in biological fluids in relation to therapeutic response: Provided that these studies shall be undertaken if studies in Stage I of investigation demonstrate satisfactory results and shall involve initial and limited use of the drug in the treatment or prevention of the
123
disease for which the drug is intended and shall be administered to carefully supervised patients: Provided further that the Federal Government may require additional pharmacological studies to be conducted concurrently on animals to indicate safety for stage II of the investigation. iii. Stage III of investigation shall consist of studies under controlled conditions in order to expand knowledge of potential use and hazards and shall be undertaken if the data obtained in stages I and II provide reasonable assurance of safety and effectiveness or suggest that the drug may have a potential value of conducting several trials outweighing its hazards: Provided that these studies shall be carefully monitored and all possible precautions shall be taken to prevent unnecessary exposure of the patient to the risk. 2) If at any stage there appears to be an unwarranted hazard in the continuation of the ongoing clinical trials, the sponsor and recipient may be asked by the Federal Government to modify or discontinue clinical trials until further pre-clinical work has been done and the investigator conducting such research shall discontinue further tests under intimation to the sponsor and the recipient in writing, a copy of which be sent to the Federal Government. 3) Studies on children shall not be undertaken unless there is a possibility of benefit to them and adequate studies of safety and efficacy are available in adults. 4) When any dangerous or adverse effects are observed, emergency reports shall be sent immediately by the recipient to the Federal Government so that the other investigators are informed and the studies are stopped if the hazard so warrants. 5) The consent for use of all investigational new drugs in clinical trials for stages I and II shall be obtained in writing by the investigator but for stage III it is the responsibility of the investigator to take into consideration the physical and mental state of the patient to decide when it is necessary or preferable to obtain consent other than in writing and if written consent is not obtained, the investigator, must obtain oral consent and record the fact in the medical record of the person receiving the drug. 6) The recipient shall keep the record of his studies carefully in respect of every drug, retain it for at least ten years after registration of that drug and produce it before the Federal Government whenever required.
8. Committee of Experts on Drug Research:
The Federal Government shall set up a Committee of Experts on Drug Research to determine the priorities, to give directions in drug research, to evaluate the applications received for the grant and make allocations from the Fund and to take or propose such actions and measures as may be necessary for ensuring effective and proper use of the Fund:
1. The Federal Government shall constitute a Committee of Experts to advise it on the utilization of the Fund and for such other purposes as may be necessary for the proper utilization of the Fund. 2. The Committee shall consist of the following members namely :- (a) Director-General Health who shall be its ex-officio Chairman.
124
(b) Executive Director, National Institute of Health, Islamabad. (c) Chairman of the Pharmacy Department who shall hold office for three years by rotation. Chairman, Pharmacy Department, Peshawar University shall be the member for the first term. (d) Chairman of the Pakistan Council of Scientific and industrial Research or his nominee who may be directly responsible for drugs research activities in the Council. (e) Chairman of the Pakistan Medical Research Council, or his nominee who may be directly responsible for drugs research activities in the Council. (f) A Dean of the Pharmacy Faculty who shall hold office for three years by rotation. Dean of the Pharmacy Faculty, University of Karachi, shall be the member for the first term. (g) A Professor of Pharmacology who shall hold office for three years by rotation. Professor of Pharmacology Allama Iqbal Medical College, Lahore, shall be the member for the first term. (h) One representative of the Pakistan Pharmaceutical Manufacturers' Association (PPMA) who may be well-versed with the subject and actively engaged in the planning or conducting of research on drugs. (i) Drugs Controller, Ministry of Health, Islamabad. (j) Deputy Director General Health (Research and Development), Ministry of Health, Islamabad, who shall be its ex-officio Secretary. 3. The Federal Government may appoint a Secretary of the Committee from amongst its members.
9. Withdrawal of Fund and termination of an investigation:
The Federal Government may, at any stage of an investigation, withdraw the aid from the recipient and direct him and the sponsor to terminate a clinical trial under any of the following conditions, namely:-
i. evidence of significant hazard; ii. convincing evidence that the drug is ineffective; iii. submission of false data; iv. omission of material information pertaining to safety or efficiency of the drug; v. unsatisfactory manufacturing practices; vi. failure to conduct the investigation in accordance with plan submitted and approved by the Federal Government; vii. commercialization of the drug before completing clinical trial; viii. failure to report serious or potentially serious adverse reaction; ix. failure to meet the requirement of patient's consent; and x. evidence of misuse of the Fund:
Provided that the Federal Government may, before withdrawing the aid, require the recipient and the sponsor of any drug to comply with any of the above conditions which he has failed to comply within a specified period and may, after it is satisfied that the said conditions have been compiled with, allow resumption of the investigation.
125
FORM 'A'
[See rule 5 (1)] Application for grant of aid for conducting research in drugs other than clinical trials
1. Name and address of the applicant 2. Name and address of the sponsor if he is other than the applicant 3. Title of Research project 4. Financial implications of the project (i) Total Financial implications (ii) Present investment (iii) Other sources of finance. if any (iv) Amount required from the Drugs Research Fund and details of its proposed utilization 5. Details of the Research project as follows :-- (i) Purpose (ii) Outline (iii) Progress already made (if any) (iv) Comprehensive future Plan (v) Benefits 6. Bio-data of all investigators including In-charge of the Research project giving the name, qualifications with years and experience.
FORM 'B'
[See rule S (l)] Application for grant of aid for conducting clinical trials
1. Name and address of the applicant 2. Name and address of the sponsor if he is other than applicant 3. Title of Research project 4. Financial implications of the project: (i) Total Financial implications (ii) Present Investment (iii) Other sources of finance, if any (iv) Amount required from the Central Research Fund and details of its proposed utilization 5. Enclose herewith- (i) Outline of the Research Project, its purpose, benefits, description of the comprehensive plans. and progress already made, if any : (ii) Information and data about the drug to be investigated including its exact composition, chemistry. pharmacology, toxicity, conditions for use in man, and pharmacy with special reference to the method of manufacture and quality control to show that adequate standards exist and a meaningful assessment can be made of the safety of the material for use in man (copies
126
of all informational material to be supplied to the investigator should be enclosed); (iii) results of pre-clinical investigation including animal studies directed towards defining its safety and efficacy; and (iv) An agreement from the sponsor and the applicant that they shall notify the Federal Government and all investigators if they become aware of any adverse effect arising during the course of investigation. Note: When an investigator himself wishes to act as sponsor conducting an investigation, the amount of information required under item 4 (ii) and (iii) may vary but should be sufficient to identify the compound under investigation together with the facts which satisfy that the substance may be justifiably administered to human beings with reasonable margin of safety. 6. Bio-data of all investigators including In-charge of the Research project giving the name, qualifications and experience.
Clinical Trials in Pakistan and the Subcontinent
The data noted below does not represent active ongoing trials alone rather includes those completed, active not recruiting, not yet recruiting, and those whose status is unknown as information has not been updated.
127
A number of diseases as noted below have been studied or some of the indications were part of a global multi-center trial. The avenues for collaboration in clinical research are enormous considering Pakistan is fertile territory for various diseases with a sizeable treatment naïve patient pool.
Indications: Atherosclerosis, Breast Ca, Hep C chronic, Bronchitis, Menorrhagia, TB pulmonary, Hyperlipidemia, Nausea, Vomiting, Glaucoma, Infertility, IBS, Polio, ITP, RCC, Schizophrenia, TIA, Glaucoma, Anemia, Malnutrition, Diarrhea, Pneumonia, Growth, Blood stream infection, Malaria falciparum, osteoporosis, skin diseases, epilepsy, VTE, Psychosis first episode, Gastric Ulcer, H&N ca, Central neuropathic pain, Liver ca, Febrile neutropenia, NSCLC, Cervical ca, Hemorrhage postpartum, Retinitis pigmentosa, Diabetes mellitus, Depression, Asthma, Hemophilia….
Spearheading research as in most countries are the multinational global pharmaceutical companies who are striving to market and license the next blockbuster drug considering that this decade experienced the largest number of patent expirations. Despite the economic slowdown pharmaceutical industry expenditure in R&D is growing unabated.
Global Pharma Sponsors: Bayer, GSK, Eli Lilly, Pfizer, Roche, Sanofi, Novartis Vaccines Institute for Global Health, Abbott …
Institutional and Others: Aga Khan University (John Snow Inc, Wellcome Trust, Ferozsons Laboratories Ltd.…), Mark Eisenberg (Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Quebec), ARI Research Cell (WHO), Pakistan Institute of Learning and Living(Hincks Dellcrest Toronto), Takeda (Pfizer), Public Health Foundation of India (National Heart, Lung, and Blood Institute (NHLBI), United Health Group, USA, All India Institute of Medical Sciences, New Delhi, Madras Diabetes Research Foundation, Chennai, Aga Khan University, IAEA, USAID, Gynuity Health Projects, Pakistan Association of Cognitive Therapists, Liaquat National Hospital & Medical College, Universal Research Group (UNIQUIP INTERNATIONAL, Pakistan), Dow University of Health Sciences, National Eye Institute (NEI), Hamilton Health Sciences Corporation (McMaster University), National Institute on Deafness and other Communication Disorders (NIDCD), Combined Military Hospital, Pakistan, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Johns Hopkins Bloomberg School of Public Health, MTI Medical Private Limited, Pakistan, Cubist Pharmaceuticals (GSK), Conor Medsystems (Getz Pharma), Ascension Orthopedics, Inc., Services Institute of Medical Sciences, Pakistan, PharmEvo, ….
Opportunity begging at the doorstep of Pakistan
For several years now the international clinical research communities have expressed its keenness in exploring Pakistan as a clinical research destination and is awaiting special measures to be taken by the relevant regulatory body of Pakistan to facilitate and equip institutions through capacity building and human resources development, introduce regulations
128 and offer specific clinical research training programs such as ICH GCP and ethics for the clinical professionals interested in pursuing a career in clinical research.
We hope that in not too far in the future Pakistan and especially its talented human resources hailing from the medical and life sciences can benefit by working on breakthrough new therapeutics and improve the healthcare of its citizens and that of the world.
Reference: www.clinicaltrials.gov
129
Chapter 7 - Institutional Review Boards (IRB/IEC) and Ethical Review of Clinical Research
Pakistan is increasingly attracting foreign clinical research sponsors; however this is obvious only on their radar screen projections as the Pakistan regulatory and ethical framework falls short of international norms.
Sections 3.1.1 to 3.1.9 of ICH GCP E6 guidelines detail the responsibilities of an IRB/IEC which essentially highlight the importance of safeguarding the rights, safety, and well-being of all trial subjects with special attention to be paid to trials that may include vulnerable subjects. With a high rate of illiteracy and low socioeconomic status of a majority of patients in Pakistan it becomes increasingly important that study participants are properly informed about all aspects of the trial and their right to withdraw at any time is appropriately shared by the investigator to avoid any charges of coercion or neglectful/irresponsible recruitment.
A properly constituted IRB can review the protocol, study design and informed consent in particular for scientific credibility and assure patient safety and risks are addressed and sample size are appropriate and will pose questions and request for modifications as necessary.
The IRB/IEC conducts continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.
Challenges Facing IRBs based in Pakistan
There are a numbers of active IRBs in Pakistan at local hospitals in particular. The major concern is that there is no regulatory guidance, directive or registry of active IRBs in Pakistan. IRBs are not registered or accredited with the important concern regarding IRB membership, members’ credibility such as qualifications, training and experience on ethical review of clinical trials.
Conflict of interest issues persist within board leadership and membership which could be attributed to lack of oversight and IRB SOPs among others.
IRB opinions are not based on thorough evaluations (due to lack of training in ethics or IRB SOPs)
External influence affects IRB opinion leading to quick approvals
Lack of uniformity and consistency in operations and meeting frequency
However, there are an increasing number of programs and workshops conducted by the Centre of Biomedical Ethics and Culture (CBEC) of the Sindh Institute of Urology and Transplantation (SIUT) and Aga Khan University in Karachi to address this shortfall in trained ethicists.
130
A number of institutional IRBs have sprung up in the country some of which are also registered with the US government Office of Human Research Protection (OHRP) as listed toward the end of this chapter. The need for ministerial guidance is necessary for fostering a unified standard through regulation. But, a lot of credit goes to Pakistan based clinical researchers and expats, local institutions such as SIUT and AKU along with international collaborators that have helped in moving this process forward.
The National Bioethics Committee (NBC) Pakistan was established under the Ministry of Health with the mandate to "promote and facilitate ethical health services delivery, health research and to be an umbrella body linked with the Ethics Review Committee in various organizations/institutions". However, IRBs are still operating independently without NBC vigilance or guidance.
While there are no national human subjects regulations or guidelines per se, PMDC has issued a Code of Ethics that is intended to govern the conduct of all medical practitioners and institutions. Registered practitioners are obligated to follow the Code of Ethics, which includes a section on research ethics. According to the Code of Ethics, any research project involving human subjects should be reviewed by an ethics committee at the institution hosting the research. The document also addresses issues such as informed consent, compensation for research participants and the use of placebos.
Conclusion
Realizing the significant role Pakistan can play in clinical trials globally we can hope that hospitals and institutions will select appropriately qualified members with proper training in ethics and clinical research and who can make independent decision without external influence and are honest and sincere in their efforts to make best decisions in favor of the Pakistani patient. There is also a need for SOPs for each established IRB, comprehensive training in research ethics for reviewers, researchers and administrators.
Lastly, it is only through regulation by an appropriate government authority such as Ministry of National Regulation and Services of DRA to come up with proper guidance and directives to streamline processes and have mandatory oversight over all IRB or enable NBC to fulfill that role.
A list of IRBs in Pakistan (next page)
131
IRB Number Institutional Review Board City IRB Type Status Faisalabad, IRB00006912 Punjab Medical College IRB #1 - Biomedical Pakistan OHRP Only Deactivated IRB00002993 ARI Rsch CELL IRB #1 Islamabad OHRP Only Deactivated IRB00005335 Human Development Rsch Foundation IRB #1 Islamabad OHRP Only Deactivated IRB00007034 International Islamic U IRB #1 Islamabad OHRP Only Deactivated IRB00002510 Nai Zindagi IRB #1 Islamabad OHRP Only Deactivated IRB00003532 Quaid-I-Azam U IRB #1 - Biomedical Islamabad OHRP Only Active IRB00001234 AGA Khan U IRB #1 Karachi OHRP Only Active IRB00008427 Bahria University Medical and Dental College IRB #1 Karachi OHRP Only Active IRB00003157 Bridge IRB #1 Karachi OHRP Only Active IRB00007048 Center for Non-Communicable Diseases (CNCD) IRB #1 - ERC Karachi OHRP Only Active IRB00002208 Health Oriented Prev Education (HOPE) IRB #1 Karachi OHRP Only Active IRB00005148 Interactive Rsch & Development. IRB #1 Karachi OHRP Only Active IRB00003084 Sindh AIDS Control Program IRB #1 Karachi OHRP Only Deactivated IRB00006708 Sindh Inst of Urology & Transplantation IRB #1 Karachi OHRP Only Active IRB00009043 Lahore University of Management Sciences (LUMS) IRB #1 Lahore OHRP Only Active IRB00001794 National Ctr Excellence in Molecular Biology U IRB #1 Lahore OHRP Only Active IRB00005281 School of Biological Sciences IRB #1 Lahore OHRP Only Deactivated Shaukat Khanum Mem Cancer Hosp & Rsch Centre IRB #1 - IRB00005898 SKMCH & RC Lahore OHRP Only Active IRB00007307 Sheikh Zayed Medical Complex IRB #1 Lahore OHRP/FDA Deactivated IRB00006436 Bahauddin Zakariya U IRB #1 - Genetic Studies Multan OHRP Only Active IRB00007509 Postgraduate Medical Institute Peshawar IRB #1 Peshawar OHRP Only Active IRB00007510 Postgraduate Medical Institute Peshawar IRB #2 Peshawar OHRP Only Active Department of Biotechnology and Informatics, BUITEMS, Quetta, IRB00007818 Pakistan IRB #1 Quetta OHRP Only Active IRB00005556 Faculty of Biotechnology &Informatics IRB #1 Quetta OHRP Only Deactivated IRB00008882 University of Balochistan, Quetta IRB #1 Quetta OHRP/FDA Active
132
Institute of Psychiatry, Rawalpindi Medical College and Allied IRB00008416 Hospitals IRB #1 Rawalpindi OHRP Only Active Not listed National Institute for Blood Diseases Karachi Active Not listed Liaquat National Hospital Ethics Committee Karachi Active Not listed Ziauddin University Hospital Ethics Committee Karachi Active Not listed Liaquat Univ of Medical and Health Sciences Jamshoro Active Not listed Dow University of Health Sciences IRB Karachi Active Not listed Shifa International Hospital Islamabad Active Not listed King Edward Medical University Lahore Active
The above table is not a comprehensive list, but an IRB listing based on data available.
Reference:
Office for Human Research Protections (OHRP)
133
Chapter 8 - INFORMED CONSENT PROCESS
Informed consent and informed consent process are major burning topics of concern in the international clinical trials arena especially due to vulnerability of susceptible populations in the emerging market economies such as Pakistan. Pakistan’s agrarian based economy with a large population poses several challenges, lack of healthcare, clean water, education, low per capita income with a significant number 48% being illiterate, unemployed and majority belonging to the rural and suburban areas. Breaches, deviations or violations are more likely due the low socioeconomic status and literacy profile of the patient pool. To boot limited or lack of proper regulatory and ethical oversight of clinical trials adds to the bane of clinical research conduct in Pakistan. It behooves the government of Pakistan to take proactive measures to enhance the healthcare infrastructure by expending more of the GDP on public health and hospitals. The government also needs to promote clinical research culture and invest in grooming of future clinical researchers who are adequately trained and qualified. A lot depends on the Pakistani clinical researcher to take necessary steps for quality assurance, upholding patient rights, welfare and safety. Participants to be adequately informed about their rights and about the trial and procedures involved ensuring patients are not coerced rather well-informed. The following chapter will help the investigator appreciate the design and contents of an ethically acceptable informed consent form.
What is Informed Consent?
Informed Consent is the process of communication between a patient and physician that results in the patient’s authorization or agreement to undergo a specific medical intervention. …It’s more than a signature on a piece of paper!
The informed consent process is just one part of a larger system in place to safeguard participants who voluntarily participate in research projects to study new practices that may improve treatment, supportive care, screening, and disease prevention. It ensures that clinical research studies are conducted ethically, and without undue risk to participants.
The informed consent process provides the participant with ongoing explanations that will help them make educated decisions about whether to begin or continue participating in a trial.
Obtaining informed consent is the provider’s legal responsibility. Failure to obtain informed consent renders any physician liable for negligence or battery and constitutes medical malpractice. Granting informed consent is the patient’s exclusive right.
134
Steps of the Informed Consent Process include:
A clear discussion of the information in the Informed Consent Form A signed and dated Informed Consent Form Source document containing a progress note/chart note
Rather than an endpoint, the consent document should be the basis for a meaningful exchange between the investigator and the subject.
Informed consent is required if the study involves:
human participation greater than minimal risk use of human organs, tissue or biological fluids clinical data or other sensitive personal information
Informed Consent is not required, if the study involves:
Observation of legal public behavior Study of existing publicly available data/records Normal educational practices Where the researcher does not manipulate the subjects’ behavior and the study does not involve more than minimal risk. Surveys and questionnaires involving perception, cognition, or game theory and do NOT involve gathering personal information, invasion of privacy or potential for emotional distress.
Waver of Informed Consent may be given if:
The research involves no more than minimal risk to the subjects The waiver or alteration will not adversely affect the rights and welfare of the subjects The research could not practicably be carried out without the waiver or alteration Whenever appropriate, the subjects will be provided with additional pertinent information after participation
Subjects should be consented prior to:
• Screening procedures performed solely for eligibility determination
• Altering the subject’s care for the purposes of research
Eight Required Elements of the ICF:
1. A clear statement that the study involves “research”;
135
a. An explanation of the purposes of the research; b. The expected duration of the subject’s participation; c. A complete description of the procedures to be followed, and identification of procedures that are performed as standard of care and identification of procedures that are performed solely for the purposes of research; 2. A description of the reasonably foreseeable risks and discomforts; 3. A description of any benefits to the participant or others that may reasonably be expected from the research; 4. A disclosure of appropriate alternative procedures or courses of treatment that might be advantageous to the participant; 5. A description of the extent to which confidentiality of records identifying the participant and privacy will be maintained; 6. An explanation as to whether any compensation, as well as whether any medical treatments are available, if injury occurs and, if so, what they consist of, or where further information may be obtained; 7. An explanation of whom to contact for answers to pertinent questions and to voice comment or concerns about the research (e.g., Investigator or the IRB, or the IRB Administration) and research participants’ rights (e.g., information available from IRB Administration Office, or on IRB Administration website), and whom to contact (as well as an alternate contact information) in the event of a research-related injury to the participant; and 8. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant may discontinue participation at any time without penalty or loss of benefits to which the participant is otherwise entitled, and without being required to provide any reason for their decisions.
Additional Elements of the ICF (required if applicable):
1. Whenever the research involves investigational articles or interventions whose risk profile is not well known: a statement that the particular treatment or procedure may involve risks to the participant, which are currently unforeseeable; 2. Whenever the research involves pregnant women or women of child bearing potential and involves interventions whose effects on fetuses are not well known: a statement that if the participant is or becomes pregnant, the particular treatment or procedure may involve risks to the embryo or fetus, which are currently unforeseeable; 3. Whenever there are anticipated circumstances under which the participant’s participation may be terminated by the investigator without regard to the participant’s consent: List anticipated circumstances under which the subject’s participation may be terminated by the Investigator without regard to the participant’s consent;
136
4. If there is the potential that costs of research procedures will not be paid by the sponsor or the participant’s insurance, a description of any additional costs to the participant that may result from participation in the research should be in the consent document; 5. Whenever there are adverse consequences to a decision to withdraw from the research: the consequences of a participant’s decision to withdraw from the research should be included; 6. Procedures for orderly termination of participation by the participants should be included whenever such procedures are included in the research; 7. A statement that significant new findings developed during the course of the research which may relate to the participant’s willingness to continue participation will be provided to the participant should be included whenever such information is likely to be developed during the course of the research; 8. The approximate number of participants involved in the study should be included whenever such information may affect a participant’s willingness to take part in the research; 9. The probability of random assignment to placebo or to each treatment should be included for all randomized trials; and 10. The IRB may require that information, in addition to that required in Federal regulations, be given to research participants when in its judgment the information would meaningfully add to the protection of the rights and welfare of participants.
Readability of Informed Consent
Basic Principles of Readability:
1. Write at 6th grade level or below 2. Use common, everyday words 3. Define complex words using “Alternative word suggestions” or Glossary of Human Subject Terminology: http://research.ucdavis.edu/gt/g 4. Use short sentences < 15 words 5. Use active language/verb tense 6. Use formatting (Bullets, white spaces, shaded boxes) to improve the visual understanding. 7. Use visual aids, examples, analogs
Non-English Speaking Subjects
In the case of a non-English speaking subject, the regulatory/ethical body fully expects that a translated version of the ICF will be provided to the study subject. IRB assures that translation of the ICF is accurate.
A person who reads and speaks this language should administer the consent.
137
Alternatively, a translator could be called in; however, while a translator may be helpful in facilitating conversation with a non-English speaking subject, routine ad hoc translation of the consent document should not be substituted for a written translation.
If a non-English speaking subject is unexpectedly encountered, and investigators do not have a written translation of the consent document, the investigators must rely on oral translation. Investigators should carefully consider the ethical/legal ramifications of enrolling subjects when a language barrier exists. If the subject does not clearly understand the information presented, the subject’s consent will not truly be informed and may not be legally effective. If investigators enroll subjects without an IRB approved written translation. A witness is required to attest to the adequacy of the consent process and to the subject’s voluntary consent. Therefore, the witness must be present during the entire consent interview, not just for signing the documents. The subject or the subject’s legally authorized representative must sign and date the form.
Illiterate English-Speaking Subjects
A person who speaks and understands English, but does not read and write, can be enrolled in a study by “making their mark” on the consent document, when consistent with applicable federal or provincial law.
Physical disabilities preventing reading or writing
A person who can understand and comprehend spoken English, but is physically unable to talk or write, can be entered into a study if they are competent and able to indicate approval or disapproval by other means. The subject may be entered into the study if:
1. The person retains the ability to understand the concepts of the study and evaluate the risk and benefit of being in the study when it is explained verbally (still competent), and 2. is able to indicate approval or disapproval to study entry.
The consent form should document the method used for communication with such subject and the specific means by which the subject communicated agreement to participate in the study. An impartial third party should witness the entire consent process and sign the consent document. A video tape recording of the consent interview is recommended.
Vulnerable Populations
The regulations require that IRBs give special consideration to protecting the welfare of particularly vulnerable subjects, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons. In general, these regulations allow IRBs to approve research that is of minimal risk or that will benefit the subjects directly. Investigations involving these subjects that present significantly greater than minimal risk
138
without direct benefit to them must be reviewed and approved by the IRB in consultation with appropriate experts.
Special considerations and procedures are required to be employed when obtaining consent from a legally authorized representative.
Consent and Assent of children
Where the research subject is a minor, special attention should be given to the informed consent process, because, as a general rule, minors lack the legal capacity to consent to the treatments or procedures involved in the research.
Therefore, for research with children two documents are developed:
• For obtaining the parents’ permission (consent)
• For obtaining permission of children who can understand the concepts involved (assent).
Parental consent. For subjects who are children, their parents or guardians are the legally authorized representatives who may grant permission for their participation in research. In such instances, satisfactory evidence of the person’s authority to consent on behalf of a child to general medical care is required and a determination is required to be made as to the scope of the authority under applicable state or local law. Grandparents and other relatives or caregivers may not grant permission unless they have been authorized under applicable state or local law (e.g. by a court) to consent on behalf of a child. When enrolling a child into research using the permission of someone other than the child’s parent, the Principal Investigator (PI) is required to obtain a copy of the court order or other evidence of that person’s authority to grant permission for participation in research on the child’s behalf.
This may be because of the minor’s status (e.g., emancipated minors and self-sufficient minors), or the nature of the procedures (e.g., pregnancy care, mental health treatment, drug or alcohol treatment). In such instances, satisfactory evidence of the minor’s legal status is required to be documented and a determination made as to the scope of the participant’s legal capacity to consent to the treatments or procedures involved in the research under the laws of the jurisdiction in which the research is conducted.
Financial responsibilities of subjects
Financial responsibilities of the subjects should be clearly explained in the consent documents. Generally, there are three options.
1) the study is fully paid for by the sponsor, and no billing to the patient insurance occurs;
139
2) the study is fully paid for by insurance and no billing to the study occurs;
3) some study costs are billed to the insurance and some are covered by the study sponsor. This delineation should be reflected in the consent documents.
Subject Compensation for Participation
It is not uncommon for subjects to be paid for their participation in research, especially in the early phases of investigational drug, biologic, or device development. Payment to research subjects for participation in studies is not considered a benefit; it is compensation for their time and effort for participation.
Financial incentives are often used when health benefits to subjects are remote or non-existent, such as in cases when healthy subjects are recruited. The amount and schedule of all payments should be presented to the IRB at the time of initial review.
The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that neither is coercive or present undue influence. It is not advisable to pay a financial incentive to a subject when the patient is seen for research related services and insurance is going to be billed.
All information concerning payment, including the amount and schedule of payment(s), should be set forth in the informed consent document.
Subject injury
Compensation for injury resulting from participation from research must be mentioned.
The current regulations for consent forms for research involving more than minimal risk indicate that the following must be included:
An explanation as to whether any compensation and whether any medical treatments are available if injury occurs and, If so, what they consist of, or where further information may be obtained
While clinical sites typically provide medical treatment to the subjects sustaining injury/complication on the study, who will cover the costs may not always be a clear decision. Industry sponsor, insurance or even self-pay options may be considered.
For privately sponsored studies (industry), the sponsor of the study is required to pay for injuries/complications directly resulting from the study material or research procedures performed in connection with the study protocol, granted that the injuries/complications were not a result of negligence, willful misconduct or failure to reasonably act on the part of the study
140
personnel. The treatment of complications that are typical for this type of disease may be billed to the insurance.
Documentation of Informed Consent
A signed and dated consent form is not sufficient in documenting the informed consent process. A written note (i.e. progress report, clinic note, etc.) should be created at each encounter documenting the communication between investigator and subject about the research. This note should include what was discussed; the fact that the subject’s questions were answered, if the subject received a copy of the consent form to take home, or if the subject signed the consent form. The accumulation of these notes over a period of time will document the consenting process. In addition to signing the consent, the subject/representative should enter the date of signature on the consent document, to permit verification that consent was actually obtained before the subject began participation in the study. If consent is obtained the same day that the subject’s involvement in the study begins, the subject’s medical records/case report form should document that consent was obtained prior to participation in the research. A copy of the consent document must be provided to the subject and the original signed consent document should be retained in the study records.
A copy of the signed and dated consent form shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject’s legally authorized representative. A copy shall be given to the person signing the form.” However, the ICH GCP Guidelines (E6 4.8.11), Informed Consent, do require that it does have to be a copy of the signed and dated consent form.
141
Please see SAMPLE Consent Form below and also the ASSENT FORM
RESEARCH SUBJECT INFORMATION AND CONSENT FORM
TITLE:
PROTOCOL NO.:
SPONSOR: Insert company name
City, State
INVESTIGATOR:
SITE(S):
STUDY-RELATED PHONE NUMBER(S):
This consent form may contain words that you do not understand. Please ask the study doctor or the study staff to explain any words or information that you do not clearly understand. You may take home an unsigned copy of this consent form to think about or discuss with family or friends before making your decision.
SUMMARY
You are being asked to be in a research study. Your decision to be in this study is voluntary. If you decide to be in this study and then change your mind, you can leave the study at any time. The drug in this study is experimental. Not all risks or side effects are known. Some of the side effects may be life threatening. The most common side effects of this drug are: You may receive placebo during this study. The placebo looks like ______but has no medication in it.
142
The care (treatment) you receive in this study is not standard medical care and should not replace your usual medical care from your doctor. OR This is not a treatment study. You will be in this study for about (time period) and have (number) study visits If you agree to be in this research study, your medical records will become part of this research. They may be looked at or copied by the sponsor of this study or government agencies or other groups associated with the study. If you are injured in this study, your medical insurance may be billed for any treatment you need, or for standard medical care that you receive as a part of this study. Your insurance would then have access to the research records and would know that you were in this study. Your insurance company may not pay for treatment associated with a research study, and your participation could affect your insurance coverage.
More detailed information about this study is in this consent form. Please read it carefully.
PURPOSE OF THE STUDY:
The purpose of this research study is to test an experimental drug called ______. You are being asked to be in this study because you have ______.
An experimental drug is also “investigational.” This means the drug has not been approved by the Ministry of Health/DRAP.
In this study, the safety of _(drug)__, its effects on (disease), and how well people tolerate it will be looked at. It will be compared to placebo. The placebo will look just like ______, but has no medication in it. Both ______and the placebo will be called “study drugs.”
You cannot choose if you will be on ______or placebo. This is decided by chance. You will have an equal chance of getting ______or placebo. You will not know which study drug you get and your study doctor will not know, but your study doctor can find this out if it needs to be known in an emergency.
You will be in this study about (length of time). Approximately (how many) subjects will participate in this study.
143
PROCEDURES
The following tests and procedures will be done at some or all of the study visits.
Physical exam (all visits) Blood and urine sample collection for routine tests (visits 1, 2, 4, and 6) Pregnancy test for all female subjects (visits 1 and 6) Electrocardiogram (ECG - tracing of the electrical activity of the heart) (visits 1 and 6) Blood collection for viral load (visits 1, 3, and 6) etc.
The procedures listed below are experimental and are only done for the research:
(angiogram) (burr hole through your skull) etc.
RISKS AND DISCOMFORTS
The most serious possible side effects of [drug name] are:
Allergic reaction to [drug name] is possible. Serious allergic reactions that can be life- threatening may occur etc.
The most common side effects of [drug name] are
Less common side effects are: Rare side effects are:
There may be side effects which are unknown at this time.
[YOU WILL NEED TO INCLUDE RISKS AND SIDE EFFECTS FOR EACH COMPARATOR DRUG, IF ANY.]
Women who are pregnant or nursing a child may not participate in this study. You must confirm that, to the best of your knowledge, you are not now pregnant, and that you do not intend to become pregnant during the study. Before entering the study, you and the study doctor must agree on the method of birth control you will use during the entire study. If you suspect that you have become pregnant during the study, you must notify the study doctor immediately. Pregnant women will be withdrawn from the
144 study because the risks to the unborn fetus from the study drug are not known. [OR OTHER PREGNANCY LANGUAGE SUPPLIED BY SPONSOR]
Drawing blood from your arm may cause pain, bruising, lightheadedness, and, on rare occasions, infection.
[RISKS OF OTHER PROCEDURES IF NEEDED ESPECIALLY ANY INVASIVE PROCEDURE. FOR EXAMPLE endoscopy or tympanocentesis procedures.]
[IF A TREATMENT STUDY]
Your [disease, condition, symptoms] may not get better or may become worse while you are in this study.
[IF STUDY DRUG IS TAKEN HOME]
Only you can take the study drug. It must be kept out of the reach of children and persons who may not be able to read or understand the label.
NEW FINDINGS
You will be told about any new information that might change your decision to be in this study.
BENEFITS
Your [disease, condition, symptoms] may improve as a result of your participation in this study. However, there is no guarantee of this.
[IF NOT A TREATMENT STUDY]
This is not a treatment study. You are not expected to receive any direct medical benefits from your participation in the study.
The information from this research study may lead to a better treatment in the future for people with [disease, condition, symptoms].
145
COSTS
Study drug will be provided by the sponsor. There are no charges for the study visits. [OR OTHER LISTING FURNISHED BY AUTHOR. IF WILL BE BILLED FOR ANYTHING, NEED TO TELL SUBJECT. ALSO TELL SUBJECT IF INSURANCE WILL BE BILLED AND WHO WILL BE RESPONSIBLE IF INSURANCE DOESN’T PAY.]
PAYMENT FOR PARTICIPATION
[ONLY IF ARE PAYING, OR THE PROTOCOL SAYS MUST INFORM ARE NOT PAYING.]
You will be paid $____ for each completed study visit. If you do not complete the study, you will be paid for the visits you have completed.
ALTERNATIVE TREATMENT
If you decide not to enter this study, there are other choices available. These include: [list of major drugs and/or therapies]. Ask the study doctor to discuss these alternatives with you. You do not need to be in this study to receive treatment for your condition.
[IF NOT A TREATMENT STUDY - REMOVE “TREATMENT”: FROM SECTION TITLE AND ADD:]
This is not a treatment study. Your alternative is to not participate in this study.
CA sites: This next HIPAA entire section plus authorization statement and signature must be in a separate section (e.g., following a page break) at the end of the form. The revocation must have a specific date … suggest December 31, 2050 or some other long term date.
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH PURPOSES
Federal regulations give you certain rights related to your health information. These include the right to know who will be able to get the information and why they may be able to get it. The study doctor must get your authorization (permission) to use or give out any health information that might identify you.
146
What information may be used and given to others?
If you choose to be in this study, the study doctor will get personal information about you. This may include information that might identify you. The study doctor may also get information about your health including:
Past and present medical records Research records Records about phone calls made as part of this research Records about your study visits Information obtained during this research about [select additional from below as appropriate] HIV / AIDS
Hepatitis infection
Sexually transmitted diseases
Other reportable infectious diseases
Physical exams
Laboratory, x-ray, and other test results
Diaries and questionnaires
The diagnosis and treatment of a mental health condition
Records about any study drug you received Records about the study device
Who may use and give out information about you?
Information about your health may be used and given to others by the study doctor and staff [add any SMO here: XXXXXX, an agent for the study doctor] or by the sponsor.
“Sponsor” includes any persons or companies that are contracted by the sponsor. They might see the research information during and after the study. For this study, “sponsor” includes [insert CRO here].
147
Who might get this information?
Information about you and your health which might identify you may be given to:
The U.S. Food and Drug Administration (FDA) if this is a US FDA study Governmental agencies in other countries Governmental agencies to whom certain diseases (reportable diseases) must be reported [Add any institution names here]
Why will this information be used and/or given to others?
Information about you and your health that might identify you may be given to others to carry out the research study. The sponsor will analyze and evaluate the results of the study. In addition, people from the sponsor and its consultants will be visiting the research site. They will follow how the study is done, and they will be reviewing your information for this purpose.
The information may be given to the FDA. It may also be given to governmental agencies in other countries. This is done so the sponsor can receive marketing approval for a new product resulting from this research. The information may also be used to meet the reporting requirements of governmental agencies.
The results of this research may be published in scientific journals or presented at medical meetings, but your identity will not be disclosed.
What if I decide not to give permission to use and give out my health information?
By signing this consent form, you are giving permission to use and give out the health information listed above for the purposes described above. If you refuse to give permission, you will not be able to be in this research.
May I review or copy the information obtained from me or created about me?
You have the right to review and copy your health information. However, if you decide to be in this study and sign this permission form, you will not be allowed to look at or copy your information until after the research is completed.
148
May I withdraw or revoke (cancel) my permission?
Yes, but this permission will be good until [usually “end of research study” or “this permission will not stop automatically”].
You may withdraw or take away your permission to use and disclose your health information at any time. You do this by sending written notice to the study doctor. If you withdraw your permission, you will not be able to continue being in this study.
When you withdraw your permission, no new health information which might identify you will be gathered after that date. Information that has already been gathered may still be used and given to others. This would be done if it were necessary for the research to be reliable.
Is my health information protected after it has been given to others?
If you give permission to give your identifiable health information to a person or business, the information may no longer be protected. There is a risk that your information will be released to others without your permission.
COMPENSATION FOR INJURY
[EXAMPLE
If you are injured or become ill as a result of participation in this study, contact the study doctor immediately. Emergency medical treatment will be provided by the study doctor. Your insurance will be billed for such treatment. The sponsor will pay any charges that your insurance does not cover. No other compensation is routinely available from the study doctor or sponsor.]
[OR OTHER LANGUAGE SUPPLIED BY SPONSOR. CHECK THIS LANGUAGE AGAINST THE LANGUAGE IN THE CLINICAL TRIALS AGREEMENT TO BE SURE THE PLANS MATCH.]
By signing this consent form, you will not give up any legal rights.
149
VOLUNTARY PARTICIPATION AND WITHDRAWAL
Your participation in this study is voluntary. You may decide not to participate or you may leave the study at any time. Your decision will not result in any penalty or loss of benefits to which you are entitled.
Your participation in this study may be stopped at any time by the study doctor or the sponsor without your consent for any of the following reasons:
if it is in your best interest; [if the protocol lists specific reasons, insert the specific reasons for discontinuation listed in protocol] or for any other reason.
If you leave the study before the final regularly-scheduled visit, you may be asked by the study doctor to make a final visit for some of the end of study procedures.
SOURCE OF FUNDING FOR THE STUDY
The study doctor (investigator) is being paid by [the sponsor, or other wording, as appropriate] to conduct this research. QUESTIONS Contact at for any of the following reasons:
if you have any questions concerning your participation in this study, if at any time you feel you have experienced a research-related injury or a reaction to the study drug, or if you have questions, concerns or complaints about the research
If you have questions about your rights as a research subject or if you have questions, concerns or complaints about the research, you may contact:
Institutional Review Board
XXXX
XXXX
Telephone: XXXXX
E-mail: XXXX
150
IRB will not be able to answer some study-specific questions, such as questions about appointment times. However, you may contact IRB if the research staff cannot be reached or if you wish to talk to someone other than the research staff.
IRB is a group of people who perform independent review of research.
Do not sign this consent form unless you have had a chance to ask questions and have received satisfactory answers to all of your questions.
If you agree to participate in this study, you will receive a signed and dated copy of this consent form for your records.
CONSENT
I have read the information in this consent form (or it has been read to me). All my questions about the study and my participation in it have been answered. I freely consent to be in this research study.
I authorize the use and disclosure of my health information to the parties listed in the authorization section of this consent for the purposes described above.
By signing this consent form, I have not given up any of my legal rights.
______
Subject Name
CONSENT SIGNATURE:
______
Signature of Subject Date
______
Signature of Legally Authorized Representative Date
(when applicable)
______
Authority of Subject’s Legally Authorized Representative or Relationship to Subject (when applicable)
______
Signature of Person Conducting Informed Date
151
Consent Discussion
------Use the following only if applicable ------
If this consent form [OR ADDENDUM] is read to the subject because the subject (or legally authorized representative) is unable to read the form, an impartial witness not affiliated with the research or investigator must be present for the consent and sign the following statement:
I confirm that the information in the consent form [OR ADDENDUM] and any other written information was accurately explained to, and apparently understood by, the subject (or the subject’s legally authorized representative). The subject (or the subject’s legally authorized representative) freely consented to be in the research study.
Signature of Impartial Witness Date
Note: This signature block cannot be used for translations into another language. A translated consent form is necessary for enrolling subjects who do not speak English.
152
RESEARCH SUBJECT ASSENT FORM Use for Subjects 7 through 12 years
TITLE:
PROTOCOL NO.: Protocol #
SPONSOR: Insert company name
INVESTIGATOR:
SITE(S):
STUDY-RELATED
PHONE NUMBER(S):
ABOUT THE STUDY
You are being asked to be in a research study. This is because you have [disease or condition].
This study will look at a new (experimental) [drug, device]. We want to see how well it works and if it is safe.
If you say yes, you will have to do certain things, like:
Visit the study doctor when you are told to.
Take the study medicine [or other as applicable].
This may make you feel different, or [important risk symptoms might experience].
153
Tell the study doctor or nurse how you are feeling.
Have some tests done, like listening to your heart and checking how you breathe or [other
significant procedures].
Have some blood drawn for tests using a needle. This will hurt a little when they do it. [take
out if no blood draws]
[if appropriate] For Girls: The study drug could cause bad birth defects in babies. If you have
started your periods you will have pregnancy tests done during the study. If at any time you
think you might be pregnant, you must tell the study doctor right away.
The study [medicine, device, etc.] may not help … you feel better … or … your [disease or symptoms].
You can choose if you want to be in this study or not. If you decide not to be in the study, no one will be mad at you. Your doctor will still take care of you.
Also, you can change your mind at any time. You can stop being in the study at any time. All you have to do is tell someone you don't want to be in the study any more.
ASSENT This research study has been explained to me and I agree to be in this study.
______
Subject’s Signature for Assent Date
154
Check which applies (to be completed by person conducting assent discussion):
The subject is capable of reading and understanding the assent form and has signed above as documentation of assent to take part in this study.
The subject is not capable of reading the assent form, however, the information was explained verbally to the subject who signed above to acknowledge the verbal explanation and his/her assent to take part in this study.
Name of Person Conducting Assent Discussion (Print)
Signature of Person Date
Conducting Assent Discussion
References:
1. Kriger Research Center 2. University of California Davis
155
CHAPTER 9 - SAFETY REPORTING IN CLINICAL TRIALS
Many agencies across the world have pharmacovigilance requirements. Investigators, have an ethical and scientific obligation to ensure optimum safety reporting. The regulations/ requirements cover:
Definitions of adverse events, the responsibilities of investigators for recording of adverse events and the notification of adverse events to sponsors, the responsibilities of sponsors for reporting to regulatory authorities and ethical committees including expedited reports of SUSARs and regular Safety Reports.
Most agencies (sponsors, country regulators) accept in principle that a risk-based approach to trial management and monitoring is appropriate. This includes the management of pharmacovigilance. For each clinical trial a risk assessment should generally be undertaken at the protocol development stage. This may be used to plan the details of the approach to pharmacovigilance taken for the trial.
Definitions and Terminology associated with Clinical Safety Experience
A. Basic Terms
Definitions for the terms adverse event (or experience), adverse reaction, and unexpected adverse reaction have previously been agreed to by consensus of the more than 30 Collaborating Centers of the WHO International Drug Monitoring Centre (Uppsala, Sweden). [Edwards, I.R., et al, Harmonization in Pharmacovigilance. Drug Safety 10(2): 93-102, 1994.] Although those definitions can pertain to situations involving clinical investigations, some minor modifications are necessary, especially to accommodate the pre-approval, development environment.
The following definitions, with input from the WHO Collaborative Centre, have been agreed:
156
1. ADVERSE EVENT (OR ADVERSE EXPERIENCE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Types of Adverse Events:
Serious: Any adverse event occurring that results in any of the following outcomes: Death, a life-threatening adverse event*, requires inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in the previous outcomes may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
*Life-threatening: An experience that in the opinion of the Investigator places the subject at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.
Other: Any adverse experience that does not meet the definition of serious. Non- serious adverse experiences can be classified as: Severe: an experience that requires therapeutic intervention. The experience interrupts usual daily activities. If hospitalization is required for treatment it becomes a serious adverse event. Moderate: an experience that is alleviated with simple therapeutic treatments. The experience impacts usual daily activities. Includes laboratory test alterations indicating injury, but without long-term risk. Mild: an experience that is usually transient and requires no special treatment or intervention. The experience does not generally interfere with usual daily activities. Includes transient laboratory test alterations
Correlation with NCI’s Common Toxicity Criteria Scale: Mild and Moderate adverse events are usually equivalent to grade 1 and 2 toxicities respectively. Severe adverse events usually
157 correlate with Grade 3 toxicities and may be considered serious adverse events if they require hospitalization or if they jeopardize the subject and require medical or surgical intervention to prevent one of the outcomes listed in this definition as noted above. Life-threatening adverse events correlate with grade 4-5 events by CTC criteria (CTCAE ver. 4.03, 2010-06-14)
2. ADVERSE DRUG REACTION (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established:
All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.
The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
Regarding marketed medicinal products, a well-accepted definition of an adverse drug reaction in the post-marketing setting is found in WHO Technical Report 498[1972] and reads as follows:
A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function
The old term “side effect” has been used in various ways in the past, usually to describe negative (unfavourable) effects, but also positive (favourable) effects. It is recommended that this term no longer be used and particularly should not be regarded as synonymous with adverse event or adverse reaction.
3. UNEXPECTED ADVERSE DRUG REACTION
An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigator’s Brochure for an unapproved investigational medicinal product). (See section III.C.)
B. Serious Adverse Event or Adverse Drug Reaction
During clinical investigations, adverse events may occur which, if suspected to be medicinal product-related (adverse drug reactions), might be significant enough to lead to important changes in the way the medicinal product is developed (e.g. change in dose, population, needed
158 monitoring, consent forms). This is particularly true for reactions which, in their most severe forms, threaten life or function. Such reactions should be reported promptly to regulators.
Therefore, special medical or administrative criteria are needed to define reactions that, either due to their nature (“serious”) or due to the significant, unexpected information they provide, justify expedited reporting.
To ensure no confusion or misunderstanding of the difference between the terms “serious” and “severe”, which are not synonymous, the following note of clarification is provided:
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache).
This is not the same as “serious”, which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.
After reviewing the various regulatory and other definitions in use or under discussion elsewhere, the following definition is believed to encompass the spirit and meaning of them all:
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:
– results in death,
– is life-threatening,
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe
– requires inpatient hospitalization or prolongation of existing hospitalization,
– results in persistent or significant disability/incapacity, or
– is a congenital anomaly/birth defect
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.
159
Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse
C. Expectedness of an Adverse Drug Reaction
The purpose of expedited reporting is to make regulators, investigators, and other appropriate people aware of new, important information on serious reactions.
Therefore, such reporting will generally involve events previously unobserved or undocumented, and a guideline is needed on how to define an event as “unexpected” or “expected” (expected/unexpected from the perspective of previously observed, not on the basis of what might be anticipated from the pharmacological properties of a medicinal product).
As stated in the definition (II.A.3.), an “unexpected” adverse reaction is one, the nature or severity of which is not consistent with information in the relevant source document(s). Until source documents are amended, expedited reporting is required for additional occurrences of the reaction.
The following documents or circumstances will be used to determine whether an adverse event/reaction is expected:
1. For a medicinal product not yet approved for marketing in a country, a company’s Investigator’s Brochure will serve as the source document in that country. (See section III.F. and ICH Guideline for the Investigator’s Brochure.) 2. Reports which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events. For example, an event more specific or more severe than described in the Investigator’s Brochure would be considered “unexpected”. Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis
III. STANDARDS FOR EXPEDITED REPORTING
A. What Should be Reported?
1. SINGLE CASES OF SERIOUS, UNEXPECTED ADRS
All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting. This applies to reports from spontaneous sources and from any type of clinical or epidemiological investigation, independent of design or purpose.
160
It also applies to cases not reported directly to a sponsor or manufacturer (for example, those found in regulatory authority-generated ADR registries or in publications).
The source of a report (investigation, spontaneous, other) should always be specified.
Expedited reporting of reactions which are serious but expected will ordinarily be inappropriate. Expedited reporting is also inappropriate for serious events from clinical investigations that are considered not related to study product, whether the event is expected or not. Similarly, non- serious adverse reactions, whether expected or not, will ordinarily not be subject to expedited reporting.
Information obtained by a sponsor or manufacturer on serious, unexpected reports from any source should be submitted on an expedited basis to appropriate regulatory authorities if the minimum criteria for expedited reporting can be met. See section III.B.
Causality assessment is required for clinical investigation cases. All cases judged by either the reporting health care professional or the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as ADRs. For purposes of reporting, adverse event reports associated with marketed drugs (spontaneous reports) usually imply causality.
Many terms and scales are in use to describe the degree of causality (attributability) between a medicinal product and an event, such as certainly, definitely, probably, possibly or likely related or not related. Phrases such as “plausible relationship”, “suspected causality”, or “causal relationship cannot be ruled out” are also invoked to describe cause and effect. However, there is currently no standard international nomenclature. The expression “reasonable causal relationship” is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship
2. OTHER OBSERVATIONS
There are situations in addition to single case reports of “serious” adverse events or reactions that may necessitate rapid communication to regulatory authorities; appropriate medical and scientific judgement should be applied for each situation.
In general, information that might materially influence the benefit-risk assessment of a medicinal product or that would be sufficient to consider changes in medicinal product administration or in the overall conduct of a clinical investigation represents such situations. Examples include:
a. For an “expected”, serious ADR, an increase in the rate of occurrence which is judged to be clinically important. b. A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease.
161
c. A major safety finding from a newly completed animal study (such as carcinogenicity).
B. Reporting Time Frames
1. FATAL OR LIFE-THREATENING UNEXPECTED ADRs
Certain ADRs may be sufficiently alarming so as to require very rapid notification to regulators in countries where the medicinal product or indication, formulation, or population for the medicinal product are still not approved for marketing, because such reports may lead to consideration of suspension of, or other limitations to, a clinical investigations program. Fatal or life-threatening, unexpected ADRs occurring in clinical investigations qualify for very rapid reporting. Regulatory agencies should be notified (e.g. by telephone, facsimile transmission, or in writing) as soon as possible but no later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8 additional calendar days. This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products.
2. ALL OTHER SERIOUS, UNEXPECTED ADRs
Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting.
3. MINIMUM CRITERIA FOR REPORTING
Information for final description and evaluation of a case report may not be available within the required time frames for reporting outlined above. Nevertheless, for regulatory purposes, initial reports should be submitted within the prescribed time as long as the following minimum criteria are met: an identifiable patient; a suspect medicinal product; an identifiable reporting source; and an event or outcome that can be identified as serious and unexpected, and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. Follow- up information should be actively sought and submitted as it becomes available.
162
D. How to Report
The CIOMS-I form has been a widely accepted standard for expedited adverse event reporting. However, no matter what the form or format used, it is important that certain basic information/data elements, when available, be included with any expedited report, whether in a tabular or narrative presentation. The listing in Attachment 1 addresses those data elements regarded as desirable; if all are not available at the time of expedited reporting, efforts should be made to obtain them. (See section III.B.)
All reports must be sent to those regulators or other official parties requiring them (as appropriate for the local situation) in countries where the drug is under development.
E. Managing Blinded Therapy Cases
When the sponsor and investigator are blinded to individual patient treatment (as in a double- blind study), the occurrence of a serious event requires a decision on whether to open (break) the code for the specific patient. If the investigator breaks the blind, then it is assumed the sponsor will also know the assigned treatment for that patient. Although it is advantageous to retain the blind for all patients prior to final study analysis, when a serious adverse reaction is judged reportable on an expedited basis, it is recommended that the blind be broken only for that specific patient by the sponsor even if the investigator has not broken the blind. It is also recommended that, when possible and appropriate, the blind be maintained for those persons, such as biometrics personnel, responsible for analysis and interpretation of results at the study’s conclusion.
There are several disadvantages to maintaining the blind under the circumstances described which outweigh the advantages. By retaining the blind, placebo and comparator (usually a marketed product) cases are filed unnecessarily. When the blind is eventually opened, which may be many weeks or months after reporting to regulators, it must be ensured that company and regulatory data bases are revised. If the event is serious, new, and possibly related to the medicinal product, then if the Investigator’s Brochure is updated, notifying relevant parties of the new information in a blinded fashion is inappropriate and possibly misleading. Moreover, breaking the blind for a single patient usually has little or no significant implications for the conduct of the clinical investigation or on the analysis of the final clinical investigation data.
However, when a fatal or other “serious” outcome is the primary efficacy endpoint in a clinical investigation, the integrity of the clinical investigation may be compromised if the blind is broken. Under these and similar circumstances, it may be appropriate to reach agreement with
163
regulatory authorities in advance concerning serious events that would be treated as disease- related and not subject to routine expedited reporting.
E. Miscellaneous Issues
1. REACTIONS ASSOCIATED WITH ACTIVE COMPARATOR OR PLACEBO TREATMENT
It is the sponsor’s responsibility to decide whether active comparator drug reactions should be reported to the other manufacturer and/or directly to appropriate regulatory agencies. Sponsors must report such events to either the manufacturer of the active control or to appropriate regulatory agencies. Events associated with placebo will usually not satisfy the criteria for an ADR and, therefore, for expedited reporting.
2. PRODUCTS WITH MORE THAN ONE PRESENTATION OR USE
To avoid ambiguities and uncertainties, an ADR that qualifies for expedited reporting with one presentation of a product (e.g. a dosage form, formulation, delivery system) or product use (e.g. for an indication or population), should be reported or referenced to regulatory filings across other product presentations and uses.
It is not uncommon that more than one dosage form, formulation, or delivery system (oral, IM, IV, topical, etc.) of the pharmacologically active compound(s) is under study or marketed; for these different presentations there may be some marked differences in the clinical safety profile. The same may apply for a given product used in different indications or populations (single dose vs. chronic administration, for example). Thus, “expectedness” may be product or product-use specific, and separate Investigator’s Brochures may be used accordingly. However, such documents are expected to cover ADR information that applies to all affected product presentations and uses. When relevant, separate discussions of pertinent product-specific or use-specific safety information will also be included.
It is recommended that any adverse drug reactions that qualify for expedited reporting observed with one product dosage form or use be cross referenced to regulatory records for all other dosage forms and uses for that product. This may result in a certain amount of over- reporting or unnecessary reporting in obvious situations (for example, a report of phlebitis on IV injection sent to authorities in a country where only an oral dosage form is studied or marketed). However, underreporting is completely avoided.
164
3. POST-STUDY EVENTS
Although such information is not routinely sought or collected by the sponsor, serious adverse events that occurred after the patient had completed a clinical study (including any protocol- required post-treatment follow-up) will possibly be reported by an investigator to the sponsor.
Such cases should be regarded for expedited reporting purposes as though they were study reports. Therefore, a causality assessment and determination of expectedness are needed for a decision on whether or not expedited reporting is required.
F. Informing Investigators and Ethics Committees/ Institutional Review Boards of New Safety Information
International standards regarding such communication are discussed within the ICH GCP Guidelines, including the addendum on “Guideline for the Investigator’s Brochure”. In general, the sponsor of a study should amend the Investigator’s Brochure as needed, and in accord with any local regulatory requirements, so as to keep the description of safety information updated.
Attachment 1
KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OF SERIOUS ADVERSE DRUG REACTIONS
The following list of items has its foundation in several established precedents, including those of CIOMS-I, the WHO International Drug Monitoring Centre, and various regulatory authority forms and guidelines. Some items may not be relevant depending on the circumstances. The minimum information required for expedited reporting purposes is: an identifiable patient, the name of a suspect medicinal product, an identifiable reporting source, and an event or outcome that can be identified as serious and unexpected and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. Attempts should be made to obtain follow- up information on as many other listed items pertinent to the case.
165
1. Patient Details
• Initials • Other relevant identifier (clinical investigation number, for example) • Gender • Age and/or date of birth • Weight • Height
2. Suspected Medicinal Product(s)
• Brand name as reported • International Non-Proprietary Name (INN) • Batch number • Indication(s) for which suspect medicinal product was prescribed or tested • Dosage form and strength • Daily dose and regimen (specify units – e.g., mg, ml, mg/kg) • Route of administration • Starting date and time of day • Stopping date and time, or duration of treatment
3. Other Treatment(s)
For concomitant medicinal products (including non-prescription/OTC medicinal products) and non-medicinal product therapies, provide the same information as for the suspected product.
4. Details of Suspected Adverse Drug Reaction(s)
Full description of reaction(s) including body site and severity, as well as the criterion (or criteria) for regarding the report as serious should be given. In addition to a description of the reported signs and symptoms, whenever possible, attempts should be made to establish a specific diagnosis for the reaction.
• Start date (and time) of onset of reaction • Stop date (and time) or duration of reaction • Dechallenge and rechallenge information • Setting (e.g. hospital, out-patient clinic, home, nursing home)
166
Outcome: information on recovery and any sequelae; what specific tests and/or treatment may have been required and their results; for a fatal outcome, cause of death and a comment on its possible relationship to the suspected reaction should be provided. Any autopsy or other post-mortem findings (including a coroner’s report) should also be provided when available. Other information: anything relevant to facilitate assessment of the case, such as medical history including allergy, drug or alcohol abuse; family history; findings from special investigations.
5. Details on Reporter of Event (Suspected ADR)
• Name • Address • Telephone number • Profession (speciality)
6. Administrative and Sponsor/Company Details
Source of report: was it spontaneous, from a clinical investigation (provide details), from the literature (provide copy), other?
• Date event report was first received by sponsor/manufacturer • Country in which event occurred • Type of report filed to authorities: initial or follow-up (first, second, etc.) • Name and address of sponsor/manufacturer/company • Name, address, telephone number, and FAX number of contact person in reporting company or institution • Identifying regulatory code or number for marketing authorization dossier or clinical investigation process for the suspected product (for example IND or CTX number, NDA number) • Sponsor/manufacturer’s identification number for the case (this number must be the same for the initial and follow-up reports on the same case).
167
UNEXPECTED EVENT EXPECTED EVENT
GRADES 2 - 3 GRADES 4 - 5 GRADES 1 - 3 GRADES 4 - 5 Attribution of Regardless of Regardless of Possible, Attribution Attribution Probable or Definite
Grade 2 - Report by Adverse Event Report by phone to Expedited phone to IDB Expedited IDB within 24 hrs. report within within 24 hrs. Reporting Expedited report to 10 working Expedited NOT required. follow within 10 days report to working days. follow within Grade 3 - 10 working This includes all Report by days. deaths within 30 days phone to IDB of the last dose of within 24 hrs. This includes treatment with an Expedited all deaths investigational agent report to within 30 days regardless of follow within of the last attribution. 10 working dose of days. treatment with Any late death an attributed to the (Grade 1 - investigational agent (possible, Adverse Event agent probable, or definite) Expedited regardless of should be reported Reporting attribution. within 10 working NOT days. required.) Any late death attributed to the agent (possible, probable, or definite) should be reported within 10 working days.
168
TABLE A: Expedited Reporting for Phase I Studies (including hospitalization )
TABLE B: Expedited Reporting for Phase II and III Studies (including hospitalization) UNEXPECTED EVENT EXPECTED EVENT
GRADES 2 - 3 GRADES 4 - 5 GRADES 1 - 3 GRADES 4 - 5 Attribution of Regardless of Regardless of Possible, Attribution Attribution Probable or Definite
Expedited Report by phone Adverse Event Expedited report, report within to IDB within 24 Expedited including Grade 5 10 working hrs. Expedited Reporting Aplasia in leukemia days report to follow NOT required. patients, within 10 within 10 working working days. Grade 1 - days. Adverse Event This includes all deaths Expedited This includes all within 30 days of the Reporting deaths within 30 last dose of treatment NOT days of the last with an investigational required.) dose of agent regardless of treatment with attribution. an investigational agent regardless Any late death of attribution. attributed to the agent (possible, probable, or Any late death definite) should be attributed to the reported within 10 agent (possible, working days. probable, or definite) should Grade 4 be reported Myelosuppression or within 10 working other Grade 4 events days. that do not require expedited reporting will be specified in the protocol.
*For Hospitalization Only — Any medical event equivalent to CTC Grade 3, 4, 5 which precipitated hospitalization (or prolongation of existing hospitalization) must be reported regardless of requirements for Phase of study, expected or unexpected and attribution.
169
Expedited reporting may not be appropriate for specific expected adverse events for certain later Phase II and Phase III protocols. In those situations the adverse events that will not have expedited reporting must be specified in the text of the approved protocol. An expected Grade 3 event that is definitely related to the investigational agent is only to be reported if the patient is hospitalized using the generic reporting criteria, for instance. In a trial of an investigational agent where Grade 3 diarrhea requiring hospitalization is expected, only diarrhea requiring ICU care (Grade 4) might be designated for expedited reporting.
170
171
172
173
174
175
CIOMS FORM
SUSPECT ADVERSE REACTION REPORT
I. REACTION INFORMATION
1. PATIENT INITIALS 1a. COUNTRY 2. DATE OF BIRTH 2a. AGE 3. SEX 4-6 REACTION ONSET 8-12 CHECK ALL (first, last) Day Month Year Years Day Month Year APPROPRIATE TO ADVERSE REACTION
7 + 13 DESCRIBE REACTION(S) (including relevant tests/lab data) PATIENT DIED
INVOLVED OR PROLONGED INPATIENT HOSPITALISATION
INVOLVED PERSISTENT OR SIGNIFICANT DISABILITY OR INCAPACITY
LIFE THREATENING
CONGENITAL ANOMALY
OTHER MEDICALLY IMPORTANT CONDITION II. SUSPECT DRUG(S) INFORMATION
14. SUSPECT DRUG(S) (include generic name) 20. DID REACTION ABATE AFTER STOPPING DRUG?
YES NO NA 15. DAILY DOSE(S) 16. ROUTE(S) OF ADMINISTRATION 21. DID REACTION REAPPEAR AFTER REINTRO- 17. INDICATION(S) FOR USE DUCTION?
YES NO NA 18. THERAPY DATES (from/to) 19. THERAPY DURATION
176
III. CONCOMITANT DRUG(S) AND HISTORY
22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION (exclude those used to treat reaction)
23. OTHER RELEVANT HISTORY (e.g. diagnoses, allergies, pregnancy with last menstrual period, etc.)
IV. MANUFACTURER INFORMATION
24a. NAME AND ADDRESS OF MANUFACTURER 26-26a. NAME AND ADRESS OF REPORTER (INCLUDE ZIP CODE)
ORIGINAL REPORT NO. 24b. MFR CONTROL NO. 24c. DATE RECEIVED 24d. REPORT SOURCE BY MANUFACTURER STUDY LITERATURE HEALTH PROFESSIONAL REGULATORY AUTHORITY OTHER DATE OF THIS REPORT 25a. REPORT TYPE INITIAL FOLLOW-UP
Note:
Serious adverse reactions are serious adverse events judged to be related to drug therapy.
A SUSAR (suspected unexpected serious adverse reaction) should be reported to a drug regulatory authority under an investigational license by using the CIOMS form (or in some countries an equivalent form). "Unexpected" means that for an authorized (approved) medicinal product that the event is not described in the product's labeling, or in the case of an investigational (unapproved) product that the event is not listed in the Investigator’s Brochure.
References:
1. Council for Inter- national Organizations of Medical Sciences 2. National Institute for Health Research 3. Common Terminology Criterion for Adverse Events. Standard terminology 4. Drug Regulatory Authority of Pakistan
177
Chapter 10: Statistics: Fundamentally Speaking
One thing that a healthcare professional needs to do if critically appraising a paper is check that the right statistical technique has been used. This part explains which statistical method should be used for what scenario.
In this chapter we have included some fundamental statistical information that will help in understanding statistical terms and their applications.
What is MEAN?
Also known as arithmetic mean or average
When is it used?
It is used when the spread of the data is fairly similar on each side of the midpoint, for example when the data are “normally distributed”.
The “normal distribution” is referred to a lot in statistics. It’s the symmetrical, bell-shaped distribution of data shown in Fig. 1.
What does it mean?
The mean is the sum of all values, divided by the number of values
What is MEDIAN?
Also known as midpoint
When is it used?
It is used to represent the average when data are not symmetrical, for instance the ‘skewed distribution in Fig 2
178
What does it mean?
It is the point which has half the values above, half below
Imagine there are six patients 53, 55,56,58,59 and 92. Here there are two ‘middle’ ages 56 and 58. The median is half-way between these, i.e. 57 years. This gives a better idea of the mid-point of this skewed data than the mean of 62.
What is MODE?
The mode is the most common of a set of events (when we want to put a label to the most frequently occurring event).
Example:
In this example mode in brown as it is most common eye color among the 4 noted.
What is STANDARD DEVIATION?
SD indicates how much a set of values is spread around the mean. SD is used for data which are “normally distributed”.
A range of one SD above and below the mean (abbreviated to ± 1 SD) includes 68.2% of the values. ±2 SD includes 95.4% of the data. ±3 SD includes 99.7%.
179
What are CONFIDENCE INTERVALS (CIs)?
Statisticians can calculate a range (interval) in which we can be fairly sure (confident) that the “true value” lies.
CIs are typically used when, instead of simply wanting the mean value of a sample, we want a range that is likely to contain the true population value.
This “true value” is another tough concept – it is the mean value that we would get if we had data for the whole population.
Example:
180
The size of a CI is related to the sample size of the study. Larger studies usually have a narrower CI.
What is DIFFERENCE between SD and CI?
Standard deviation tells us about the variability (spread) in a sample.
The CI tells us the range in which the true value (the mean if the sample were infinitely large) is likely to be.
What is P Value?
The P value gives the probability of any observed difference having happened by chance. The P value is used when we wish to see how likely it is that a hypothesis is true. The hypothesis is usually that there is no difference between two treatments, known as the “null hypothesis”.
P = 0.5 means that the probability of the difference having happened by chance is 0.5 in 1, or 50:50.
P = 0.05 means that the probability of the difference having happened by chance is 0.05 in 1, i.e. 1 in 20.
It is the figure frequently quoted as being “statistically significant”, i.e. unlikely to have happened by chance and therefore important. However, this is an arbitrary figure.
If we look at 20 studies, even if none of the treatments work, one of the studies is likely to have a P value of 0.05 and so appear significant!
The lower the P value, the less likely it is that the difference happened by chance and so the higher the significance of the finding.
P = 0.01 is often considered to be “highly significant”. It means that the difference will only have happened by chance 1 in 100 times. This is unlikely, but still possible.
181
P = 0.001 means the difference will have happened by chance 1 in 1000 times, even less likely, but still just possible. It is usually considered to be “very highly significant”.
EXAMPLE: Out of 50 new babies on average 25 will be girls, sometimes more, sometimes less. Say there is a new fertility treatment and we want to know whether it affects the chance of having a boy or a girl. Therefore we set up a null hypothesis – that the treatment does not alter the chance of having a girl. Out of the first 50 babies resulting from the treatment, 15 are girls. We then need to know the probability that this just happened by chance, i.e. did this happen by chance or has the treatment had an effect on the sex of the babies?
The P value gives the probability that the null hypothesis is true.
The P value in this example is 0.007. Do not worry about how it was calculated, concentrate on what it means. It means the result would only have happened by chance in 0.007 in 1 (or 1 in 140) times if the treatment did not actually affect the sex of the baby. This is highly unlikely, so we can reject our hypothesis and conclude that the treatment probably does alter the chance of having a girl. t Tests and other Parametric Tests
What are these tests?
Parametric statistics are used to compare samples of ”normally distributed” data.
A parametric test is any test which requires the data to follow a specific distribution, usually a normal distribution. Common parametric tests you will come across are the t test and the χ2 test (Chi squared). If the data do not follow a normal distribution, these tests should not be used.
Analysis of variance (ANOVA):
This is a group of statistical techniques used to compare the means of two or more samples to see whether they come from the same population – the “null hypothesis”. These techniques can also allow for independent variables which may have an effect on the outcome.
Again check out the P value. t test (also known as Student’s t):
182 t tests are typically used to compare just two samples. They test the probability that the samples come from a population with the same mean value.
Example:
Two hundred adults seeing an asthma nurse specialist were randomly assigned to either a new type of bronchodilator or placebo.
After 3 months the peak flow rates in the treatment group had increased by a mean of 96 l/min (SD 58), and in the placebo group by 70 l/min (SD 52). The null hypothesis is that there is no difference between the bronchodilator and the placebo.
The t statistic is 11.14, resulting in a P value of 0.001. It is therefore very unlikely (1 in 1000 chance) that the null hypothesis is correct so we reject the hypothesis and conclude that the new bronchodilator is significantly better than the placebo.
CHI-SQUARED
What is Chi-squared test?
It is a measure of the difference between actual and expected frequencies.
The “expected frequency” is that there is no difference between the sets of results (the null hypothesis). In that case, the Χ2 value would be zero.
The larger the actual difference between the sets of results, the greater the Χ2 value. However, it is difficult to interpret the Χ2 value by itself as it depends on the number of factors studied.
Statisticians make it easier for you by giving the P value, giving you the likelihood there is no real difference between the groups.
A group of patients with bronchopneumonia were treated with either amoxicillin or erythromycin. The results are shown in Table 3.
183
First, look at the table to get an idea of the differences between the effects of the two treatments.
Remember, do not worry about the Χ2 value itself, but see whether it is significant. In this case P is 0.13, so the difference in treatments is not statistically significant.
The χ2 test is simpler for statisticians to calculate but gives only an approximate P value and is inappropriate for small samples.
WHAT IS RISK RATIO?
Also known as Relative Risk
Risk is the probability that an event will happen. It is calculated by dividing the number of events by the number of people at risk. One boy is born for every two births, so the probability (risk) of giving birth to a boy is 1⁄2 = 0.5. If one in every 100 patients suffers a side-effect from a treatment, the risk is 1⁄100 = 0.01
Relative risk is used in “cohort studies”, prospective studies that follow a group (cohort) over a period of time and investigate the effect of a treatment or risk factor.
Risk Ratio These are calculated by dividing the risk in the treated or exposed group by the risk in the control or unexposed group.
A risk ratio of one indicates no difference in risk between the groups. If the risk ratio of an event is >1, the rate of that event is increased compared to controls. If <1, the rate of that event is reduced.
Risk ratios are frequently given with their 95% CIs – if the CI for a risk ratio does not include one (no difference in risk), it is statistically significant.
Example:
A cohort of 1000 regular football players and 1000 non-footballers were followed to see if playing football was significant in the injuries that they received.
After 1 year of follow-up there had been 12 broken legs in the football players and only four in the non-footballers.
The risk of a footballer breaking a leg was therefore 12/1000 or 0.012. The risk of a non- footballer breaking a leg was 4/1000 or 0.004.
The risk ratio of breaking a leg was therefore 0.012/0.004 which equals three. The 95% CI was calculated to be 0.97 to 9.41. As the CI includes the value 1 we cannot exclude the possibility that there was no difference in the risk of footballers and non-footballers
184 breaking a leg. However, given these results further investigation would clearly be warranted.
What is ODDS Ratio?
Used by epidemiologists in studies looking for factors which do harm, it is a way of comparing patients who already have a certain condition (cases) with patients who do not (controls) – a “case–control study”.
Odds ratios are calculated by dividing the odds of having been exposed to a risk factor by the odds in the control group.
An odds ratio of 1 indicates no difference in risk between the groups, i.e. the odds in each group are the same.
If the odds ratio of an event is >1, the rate of that event is increased in patients who have been exposed to the risk factor.
If <1, the rate of that event is reduced.
Odds ratios are frequently given with their 95% CI - if the CI for an odds ratio does not include 1 (no difference in odds), it is statistically significant.
Example:
A group of 100 patients with knee injuries, “cases”, was matched for age and sex to 100 patients who did not have injured knees, “controls”.
In the cases, 40 skied and 60 did not, giving the odds of being a skier for this group of 40:60 or 0.66.
In the controls, 20 patients skied and 80 did not, giving the odds of being a skier for the control group of 20:80 or 0.25.
We can therefore calculate the odds ratio as 0.66/0.25 = 2.64. The 95% CI is 1.41 to 5.02.
If you cannot follow the math, do not worry! The odds ratio of 2.64 means that the number of skiers in the cases is higher than the number of skiers in the controls, and as the CI does not include 1 (no difference in risk) this is statistically significant. Therefore, we can conclude that skiers are more likely to get a knee injury than non-skiers.
What is Hazard Ratio?
A rate ratio is a ratio of two average rates. It is sometimes called an incidence density ratio or a hazard ratio.
It is an expression of hazard or chance of event occurring in the treatment arm as a ratio of the hazard of the events occurring in the control arm outcome.
185
HR = 1: No Difference between the two groups.
HR > 1: Event of interest is happening faster for the treatment group than for the control group.
HR< 1: Event of interest is happening slower for the treatment group than for the control group.
Note: Rate is a measure of disease frequency that describes how rapidly health events such as new diagnoses of cases or deaths are occurring in a population of interest.
Synonyms: hazard, incidence density.
What are RELATIVE RISK REDUCTION and ABSOLUTE RISK REDUCTION?
They are used when an author wants to know how often a treatment works, rather than just whether it works. RRR is the proportion by which the intervention reduces the event rate.
ARR is the difference between the event rate in the intervention group and that in the control group. It is also the reciprocal of the NNT and is usually given as a percentage, i.e. ARR = 100/NNT where NNT is the number of patients who need to be treated for one to get benefit.
Example:
One hundred women with vaginal candida were given an oral antifungal, 100 were given placebo. They were reviewed 3 days later. The results are given in Table 4.
Table 4: Results of placebo-controlled trial of oral antifungal agent
ARR = improvement rate in the intervention group – improvement rate in the control group = 80% – 60% = 20%
NNT=100/ARR =100/20 = 5
So five women have to be treated for one to get benefit.
The incidence of candidiasis was reduced from 40% with placebo to 20% with treatment, i.e. by half.
Thus, the RRR is 50%.
What is CORRELATION?
186
A linear relationship between two variables there is said to be a correlation between them. Examples are height and weight in children, or socio-economic class and mortality.
The strength of that relationship is given by the “correlation coefficient”.
A positive correlation coefficient means that as one variable is increasing the value for the other variable is also increasing – the line on the graph slopes up from left to right. Height and weight have a positive correlation: children get heavier as they grow taller.
A negative correlation coefficient means that as the value of one variable goes up the value for the other variable goes down – the graph slopes down from left to right.
Higher socio-economic class is associated with a lower mortality, giving a negative correlation between the two variables.
If there is a perfect relationship between the two variables then r = 1 (if a positive correlation) or r = -1 (if a negative correlation).
If there is no correlation at all (the points on the graph are completely randomly scattered) then r = 0.
The following is a good rule of thumb when considering the size of a correlation: r = 0–0.2: very low and probably meaningless. r = 0.2–0.4: a low correlation that might warrant further investigation. r = 0.4–0.6: a reasonable correlation. r = 0.6–0.8: a high correlation. r = 0.8–1.0: a very high correlation. Possibly too high! Check for errors or other reasons for such a high correlation.
Example:
A nurse wanted to be able to predict the laboratory HbA1c result (a measure of blood glucose control) from the fasting blood glucoses which she measured in her clinic. On 12 consecutive diabetic patients she noted the fasting glucose and simultaneously drew blood for HbA1c. She compared the pairs of measurements and drew the graph in Fig. 10.
187
Correlation tells us how strong the association between the variables is, but does not tell us about cause and effect in that relationship.
Where the author shows the graph, you can get a good idea from the scatter as to how strong the relationship is without needing to know the r value.
Authors often give P values with correlations; however take care when interpreting them. Although a correlation needs to be significant, we need also to consider the size of the correlation. If a study is sufficiently large, even a small clinically unimportant correlation will be highly significant.
In Fig. 10, r = -0.88. R2 = -0.88 × -0.88 = 0.77. This means that 77% of the variation in HbA1c is related to the variation in fasting glucose.
What is REGRESSION Analysis?
Regression analysis is used to find how one set of data relates to another.
This can be particularly helpful where we want to use one measure as a proxy for another – for example, a near-patient test as a proxy for a lab test.
A regression line is the “best fit” line through the data points on a graph.
The regression coefficient gives the “slope” of the graph, in that it gives the change in value of one outcome, per unit change in the other.
Example:
188
Consider the graph shown in Fig. 10 (page 50). A statistician calculated the line that gave the “best fit” through the scatter of points, shown in Fig. 12.
Fig. 12: Plot with linear regression line of fasting glucose and HbA1c in 12 patients with diabetes.
The line is called a “regression line”.
To predict the HbA1c for a given blood glucose the nurse could simply plot it on the graph, as here where a fasting glucose of 15 predicts an HbA1c of 9.95.
This can also be done mathematically. The slope and position of the regression line can be represented by the “regression equation”:
HbA1c = 3.2 + (0.45 × blood glucose).
The 0.45 figure gives the slope of the graph and is called the “regression coefficient”.
The “regression constant” that gives the position of the line on the graph is 3.2: it is the point where the line crosses the vertical axis.
Try this with glucose of 15: HbA1c = 3.2 + (0.45 x 15) = 3.2 + 6.75 = 9.95
The R2 value may also be given. This represents the amount of the variation in the data that is explained by the regression. In our example the R2 value is 0.77. This is stating that 77% of the variation in the HbA1c result is accounted for by variation in the blood glucose.
What is the Difference between Regression and Correlation?
Correlation measures the strength of the association between variables. Regression quantifies the association. It should only be used if one of the variables is thought to precede or cause the other.
What is SURVIVAL ANALYSIS: LIFE TABLES AND KAPLAN–MEIER PLOTS
189
Survival analysis techniques are concerned with representing the time until a single event occurs. That event is often death, but it could be any other single event, for example time until discharge from hospital.
Survival analysis techniques are able to deal with situations in which the end event has not happened in every patient or when information on a case is only known for a limited duration – known as “censored” observations.
Life table: A life table is a table of the proportion of patients surviving over time.
Life table methods look at the data at a number of fixed time points and calculate the survival rate at those times. The most commonly used method is Kaplan–Meier.
The Kaplan–Meier approach recalculates the survival rate when an end event (e.g. death) occurs in the data set, i.e. when a change happens rather than at fixed intervals.
This is usually represented as a “survival plot”. Fig.13 shows a fictitious example.
The dashed line shows that at 20 years, 36% of this group of patients is still alive. Life tables and Kaplan–Meier survival estimates are also used to compare survival between groups. The plots make any difference between survival in two groups beautifully clear. Fig. 14 shows the same group of patients as above, but compares survival for men and women.
190
In this example 46% of women were still alive at 20 years but only 18% of men. The test to compare the survival between these two groups is called the “log rank test”. Its P value will tell you how significant the result of the test is.
What are SENSITIVITY, SPECIFICITY and PREDICTIVE VALUE?
They are used to analyze the value of screening or tests.
Think of any screening test for a disease. For each patient:
the disease itself may be present or absent the test result may be positive or negative
We need to know how useful the test is.
The results can be put in the “two-way table” shown in Table 7. Try working through it.
Sensitivity: If a patient has the disease, we need to know how often the test will be positive, i.e.
“Positive in disease”, this is calculated from: A/A+C.
This is the rate of pick-up of the disease in a test, and is called the Sensitivity.
Specificity: If the patient is in fact healthy, we want to know how often the test will be negative, i.e. “negative in health”.
191
This is given by: D/D+B
This is the rate at which a test can exclude the possibility of the disease, and is known as the Specificity.
Positive Predictive Value: If the test result is positive, what is the likelihood that the patient will have the condition?
Look at: A/A+B
This is known as the Positive Predictive Value (PPV).
Negative Predictive Value: If the test result is negative, what is the likelihood that the patient will be healthy?
Here we use: D/D+C
This is known as the Negative Predictive Value (NPV).
In a perfect test, the sensitivity, specificity, PPV and NPV would each have a value of 1. The lower the value (the nearer to zero), the less useful the test is in that respect.
Example:
Imagine a blood test for gastric cancer, tried out on 100 patients admitted with hematemesis. The actual presence or absence of gastric cancers was diagnosed from endoscopic findings and biopsy. The results are shown in Table 8.
Sensitivity = 20/20 + 5 = 20/25 = 0.8
If the gastric cancer is present, there is an 80% (0.8) chance of the test picking it up.
Specificity = 45/30+45 = 45/75 =0.6
If there is no gastric cancer there is a 60% (0.6) chance of the test being negative – but 40% will have a false positive result.
PPV = 20/20+30 = 20/50 = 0.4
There is a 40% (0.4) chance, if the test is positive, that the patient actually has gastric cancer.
NPV = 45/45+5 = 45/50 =0.9
192
There is a 90% (0.9) chance, if the test is negative, that the patient does not have gastric cancer. However, there is still a 10% chance of a false negative, i.e. that the patient does have gastric cancer.
The “Likelihood Ratio” (LR) is the likelihood that the test result would be expected in a patient with the condition compared to the likelihood that that same result would be expected in a patient without the condition.
To calculate the LR, divide the sensitivity by (1 – specificity).
Try using the example above to calculate the LR for a positive result.
LR = sensitivity/(1 - specificity = 0.8/1 - 0.6 = 0.8/0.4 = 2
In this example, LR for a positive result = 2. This means that if the test is positive in a patient, that patient is twice as likely to have gastric cancer as not have it.
Summary:
Sensitivity: how often the test is positive if the patient has the disease. Specificity: if the patient is healthy, how often the test will be negative. PPV: If the test is positive, the likelihood that the patient has the condition. NPV: If the test is negative, the likelihood that the patient will be healthy. LR: If the test is positive, how much more likely the patient is to have the disease than not have it.
What are 1- and 2- tailed tests?
When trying to reject a “null hypothesis” we are generally interested in two possibilities: either we can reject it because the new treatment is better than the current one, or because it is worse. By allowing the null hypothesis to be rejected from either direction we are performing a “two-tailed test” – we are rejecting it when the result is in either “tail” of the test distribution.
Occasionally there are situations where we are only interested in rejecting a hypothesis if the new treatment is worse than the current one but not if it is better. This would be better analyzed with a one-tailed test. However, be very skeptical of one-tailed tests. A P value that is not quite significant on a two-tailed test may become significant if a one-tailed test is used.
What is INCIDENCE?
The number of new cases of a condition over a given time is given as a percentage of the population.
Example: Each year 15 people in a practice of 1000 patients develop Brett’s palsy.
193
15/1000 x 100 = yearly incidence of 1.5%
What is PREVALENCE?
The existing number of cases of a condition at a single point in time is given as a percentage of the population.
Example: At the time of a study 90 people in a practice of 1000 patients were suffering from Brett’s palsy (15 diagnosed in the last year plus 75 diagnosed in previous years).
90/1000 x 100 = a prevalence of 9%
With chronic diseases like the fictitious Brett’s palsy, the incidence will be lower than the prevalence – each year’s new diagnoses swell the number of existing cases.
With short-term illnesses the opposite may be true. 75% of a population may have a cold each year (incidence), but at any moment only 2% are actually suffering (prevalence).
What is POWER?
The power of a study is the probability that it would detect a statistically significant difference.
If the difference expected is 100% cure compared with 0% cure with previous treatments, a very small study would have sufficient power to detect that. However if the expected difference is much smaller, e.g. 1%, then a small study would be unlikely to have enough power to produce a result with statistical significance.
ERRORS
Error Type I (alpha error):
The error of wrongly rejecting a null hypothesis, i.e., declaring that a difference exists when there isn’t a difference (False Positive).
Error Type II (Beta error):
The error of failing to reject a false null hypothesis, i.e., declaring that a difference does not exist when in fact a difference exists (False Negative).
Decision Ho False Ho True
Reject Ho Correct Decision Type I Error (Alpha)
Retain Ho Type II Error (Beta) Correct Decision
194
What is Bayesian Statistics?
Bayesian analysis is not often used. It is a totally different statistical approach to the classical,
“frequentist” statistics explained here. In Bayesian statistics, rather than considering the sample of data on its own, a “prior distribution” is set up using information that is already available. For instance, the researcher may give a numerical value and weighting to previous opinion and experience as well as previous research findings.
The new sample data are then used to adjust this prior information to form a “posterior distribution”. Thus these resulting figures have taken both the disparate old data and the new data into account. Bayesian methodology is intuitively appealing because it reflects how we think. When we read about a new study we do not consider its results in isolation, we factor it in to our pre-existing opinions, knowledge and experience of dealing with patients.
Reference:
Medical Statistics made easy by M Harris and G Taylor
195
Chapter 11: How to Write an Effective Proposal
The aim is to help researchers translate their research plans into an effective research proposal. A well-written proposal will ease the process of obtaining institutional and ethical approval and will increase one’s chances of obtaining funding for their project.
ELEMENTS OF A RESEARCH PROPOSAL
1. Title 2. Abstract 3. Study Problem 4. Rationale/Relevance of the Project 5. Literature Review 6. Specific Study Objectives 7. Research Methods a. Study design b. Subjects i. Inclusion/exclusion criteria ii. Sampling iii. Recruitment plans iv. Method of assignment to study groups c. Data collection i. Variables: outcomes, predictors, confounders ii. Measures/instruments iii. Procedures d. Intervention e. Statistical considerations i. Sample size ii. Data analysis 8. Ethical Considerations i. Consent form ii. Privacy of information 9. Work Plan 10. Budget 11. Research team 12. Dissemination Plan
KEYS TO SUCCESSFUL PROPOSAL WRITING
196
Overall Quality of the Study i. Good research question ii. Appropriate research design iii. Rigorous and feasible methods iv. Qualified research team v. Research questions matches’ data collection/data analysis
Quality of the Proposal
i. Informative title ii. Self-sufficient and convincing abstract iii. Clear research questions iv. Scholarly and pertinent background and rationale v. Relevant previous work vi. Appropriate population and sample vii. Appropriate measurement and intervention methods viii. Quality control ix. Adequate sample size x. Sound analysis plan xi. Ethical issues well addressed xii. Tight budget xiii. Realistic timetable xiv. Identify strengths and limitations
Quality of the Presentation
i. Clear, concise, well-organized ii. Helpful table of contents and subheadings iii. Good schematic diagrams and tables iv. Neat and free of errors
TYPE OF SHORTCOMINGS
A. Research problem a. Hypothesis: ill-defined, lacking, faulty, diffuse, unwarranted b. Significance: unimportant, unimaginative, unlikely to provide new info B. Experimental Design a. Study group or control: inappropriate composition, number, characteristics b. Technical methodology: questionable, unsuited, defective c. Data collection procedures: confused, inappropriate d. Data management & analysis: vague, unsophisticated C. Investigator Inadequate expertise or unfamiliarity with literature, insufficient time D. Resources
197
Inadequate setting, support staff, lab, equipment. Restricted access to patient population
BEFORE YOU START
Remember developing a research proposal takes time. The process starts by identifying a general area of research and then developing a focused research question to be answered. Next a research protocol is created. The protocol needs to be appropriate to the research question, but also feasible in terms of time, resources and ethical considerations. The research proposal is the formal description of this process. The first part of the proposal will include the research question to be answered along with a statement of why the area of research is important and what is known already. The second part of the proposal is the methods section, where the plan for answering the research question is given. Depending on why the research proposal is being written (ethical approval, submission to funding agency), other sections may need to be included in the proposal.
When you are ready to start writing the research proposal, the first step is to carefully read over the guidelines of whatever agency you are submitting it to. These guidelines will give the deadlines for submission and instructions for the length, structure and format of the proposal. Proposals that are late or do not meet the agency’s guidelines will usually be returned without being reviewed. Therefore, it is well worth the effort to obtain and carefully read the guidelines prior to writing your research proposal.
STUDY PROBLEM AND GENERAL PURPOSES OF RESEARCH
Study Problem: Health care issue that is a concern or a problem.
Research Purpose: Broad statement indicating the goals of the project.
Different types of purposes include:
A. Exploration B. Description C. Explanation D. Prediction/Control
Some agencies want to know what are the overall objectives of the research program (i.e. long-term goals) and what are the specific aims of the current project (i.e. what is hoped to be accomplished with this project). Some agencies require that research address specific areas or goals set by the agency.
KEYS TO SUCCESS
A. Relevant B. Clear
198
C. Logically argued
STUDY RATIONALE - WHY SHOULD THIS RESEARCH BE DONE?
In this section, you are arguing why your study should be done. Granting agencies may have specific high priority areas. Be sure to explain how you study fits into those areas.
Ask yourself:
A. Will this study generate new knowledge? B. Will the study benefit patients, advance understanding or influence policy? C. Will the study fill gaps in existing knowledge or resolve current controversies?
Generally a study should do more than just generate new knowledge. The knowledge should in some way be useful, either by leading to a tangible benefit such as improved patient care, or a less tangible one such as addressing an area of controversy.
LITERATURE SEARCH and REVIEW
A critical summary of research on a topic of interest, generally prepared to put a research problem in context OR to identify gaps and weaknesses in prior studies so as to justify a new investigation.
Research tends to be a cyclical process – research findings lead to theory development, theory leads to further research. As a researcher, you can jump into this cycle at many places. In the literature review, you should show that you are jumping in at the appropriate place. If little is known in an area, then very basic descriptive studies designed to give a preliminary understanding about a phenomenon are appropriate. However, if the area is well advanced, that type of study will be inappropriate. When reading the literature review section, a reviewer will be looking to see whether you are sufficiently knowledgeable about the area and whether your proposed work is appropriate for the level of knowledge currently existing in that area.
Thorough, complete and up to date, but not a recitation of every study ever conducted
A. Logical B. Original research C. Primary sources Focus on original research and systematic reviews D. Well organized/synthesized E. Critical appraisal F. Build a case for a new study a. Describe any controversial areas objectively i. Include evidence for and against your position b. Identify any gaps in existing knowledge
199
RESEARCH QUESTION – OBJECTIVE(S) – HYPOTHESIS
Identifying the research problem and developing a question to be answered are the first steps in the research process. The research question will guide the remainder of the design process.
Research Objectives
A clear statement of the specific purpose(s) of the study, which identifies the key study variables and their possible inter-relationship(s) and the nature of the population of interest.
Research Question
The specific purpose stated in the form of a question (descriptive/exploratory research).
Hypotheses
The specific purpose stated in terms of a tentative prediction or explanation of the relationship between two or more variables. A prediction of the answer to the research question (explanatory research).
Example: The objective of this study is to determine which operative method of treating a fractured pelvis is associated with a lower risk of postoperative infection—the Morgan procedure or the Miller procedure?
Functions
1. Provide reviewers with a clear picture of what you plan to accomplish. 2. Show the reviewers that you have a clear picture of what you want to accomplish. 3. Form the foundation for the rest of the proposal. 4. Will be used to assess the adequacy/appropriateness of the study’s proposed methods.
KEYS FOR SUCCESS
1. Only one or two primary research questions or hypotheses: focus on the important question. 2. Clear and consistent. 3. Key concepts/constructs identified. 4. Includes the independent and dependent variables (if applicable). 5. Measurable. 6. Hypotheses clearly predict a relationship between variables. 7. Relevant or novel.
Examples of Problems:
200
The purpose of this study is to determine if there are differences in pain control with nurse versus patient administered analgesia following surgery.
Research Question: Does the administration of analgesic by nurses vs. by patients themselves affect pain intensity during postoperative recovery in older adults?
Hypothesis: Patients who self-administered narcotics will be more satisfied than patients who receive narcotics administered by nurses.
Sample size: To achieve a power of 80% to detect a 20% difference in the total morphine dose in the first 24 hours surgery, 30 subjects in each group will be required.
STUDY VARIABLES
Variables: Characteristic or quality that takes on different values.
In Research Identify:
1. Dependent or outcome variables (the presumed effect). 2. Independent or predictor variables (the presumed cause). Note: Variables are not inherently independent or dependent. In descriptive and exploratory studies, this distinction is not made. 3. Confounding variables confounding variable is an extraneous variable that: 1. is a risk factor for the outcome variable. 2. Is associated with the predictor variable.
Example:
Dependent variable: undergoing colonoscopy.
Independent variable: residing in urban or rural area.
Confounding variable: degree of specialization of physicians.
Keys to Success
1. Clearly identify study variables and their role in the study 2. Select only variables that are measurable
STUDY DESIGNS
201
The overall plan for obtaining an answer to the research question or for testing the research hypothesis.
Will have been chosen based on:
1. Research question/hypothesis. 2. Strengths and weaknesses of alternative designs. 3. Feasibility, resources, time frame, ethical considerations.
Examples:
1. The purpose of this study is to determine the major physiologic, psychosocial and lifestyle concerns of women two weeks and eight weeks after an unplanned cesarean delivery.
Methods
202
We will use a descriptive survey design in which all patients at weeks two and eight following an unplanned cesarean delivery will be mailed a questionnaire designed to assess physiologic, psychosocial and lifestyle concerns.
2. Patients residing in rural areas of Alberta are less likely than urban patients to undergo a colonoscopy within 18 months of a curative resection for colorectal cancer.
Methods
This will be a cross-sectional survey. Patients with a diagnosis of colorectal cancer who underwent a curative resection will be mailed a questionnaire 18 months following surgery asking about diagnostic tests performed since surgery.
OR
This will be a historical cohort-study. Patients with a diagnosis of colorectal cancer will be identified using the Alberta Cancer Registry and divided into two groups based on place of residence. Subsequent colonoscopies will be detected by linkage to the Alberta Health Insurance Claims Database for the 18 months following surgery.
3. Does the administration of analgesic by nurses vs. by patients themselves affect pain intensity during postoperative recovery in older adults?
Methods
This will be a two-group randomized clinical trial. Preoperatively patients will be randomized to nurse-administered or patient administered post-operative analgesia.
KEYS TO SUCCESS
A. Clearly identify and label study design using standard terminology. 1. Quantitative/qualitative 2. Intervention/descriptive 3. Cross-sectional/longitudinal 4. Prospective/retrospective 5. True Experiment/Quasi-Experiment
B. Must specify the major elements of the design 1. Variables, instruments 2. Subjects: sampling frame, sample size, selection procedures 3. Timing of testing/intervention
C. Use a diagram if needed
203
D. Must be consistent with objectives/hypothesis
E. Must justify choice of design: 1. appropriate choice to answer question 2. lack of bias/validity 3. precision/power 4. feasible 5. ethical
EXAMPLES OF PROBLEMS IN RESEARCH DESIGNS
A randomized quasi-experimental design. (quasi-experimental studies are not randomized)
The primary objective is to determine if coffee drinking causes pancreatic cancer. A case-control study will be conducted. (case-control studies can determine associations but not causation)
SUBJECTS (STUDY PARTICIPANTS)
I. Who will be studied? II. How will they be recruited? III. How will they be allocated to study groups? (if appropriate) I. Who Will be Studied
A. Specify eligible subjects a. Target population: clinical & demographic characteristics b. Accessible population: temporal & geographic characteristics c. Inclusion/Exclusion Criteria
Examples
Women following an unplanned cesarean delivery at the Foothills hospital between January 1 and March 30, 1997. Inclusion Criteria: a. Age > 16 b. English-speaking c. Calgary resident Exclusion Criteria: a. Refuse to give informed consent
204
b. Concomitant severe medical problem preventing participation
All patients undergoing elective orthopedic surgery of the knee, ankle or shoulder at the Peter Lougheed Centre.
Inclusion Criteria:
Age > 18
Able to understand instructions
Exclusion Criteria:
Allergy to study medications Drug/alcohol dependence Surgery completed after 2000H Refuse to give informed consent
B. How Will they be Selected
Sampling: the process of selecting a portion of the population to represent the entire population of interest (target population). Types of Sampling
A. Probability: each element in the population has an equal, independent chance of being selected. The goal is to obtain a sample representative of the target population. Nonprobability samples may differ in important ways from the target population because of how they were selected (selection bias). This is of greatest concern when the study is defining the characteristics of a population (i.e. a survey).
Examples:
1. Simple random sampling 2. Stratified random sampling 3. Cluster sampling
B. Non-probability
1. Consecutive sampling: commonly used in intervention studies. 2. Convenience sampling 3. Purposive sampling: commonly used in qualitative research.
KEYS TO SUCCESS
205
1. Clear description of study population. 2. Appropriate inclusion/exclusion criteria. 3. Justification of study population and sampling method (bias). 4. Clear description of sampling methods.
Examples
1. Consecutive patients admitted to the Peter Lougheed Hospital for orthopedic surgery.
2. The survey will be mailed to a random sample of 100 women who underwent a Cesarean section from January 1 to December 31, 1996. Sampling will be stratified based on the hospital where they delivered.
3. All patients who underwent curative surgery for colorectal cancer between April 1, 1985 and March 30, 1994 in the Province of Alberta.
4. We will recruit a convenience sample of 25 patients attending a prenatal clinic.
II. How Will They Be Recruited?
Describe what methods will be used to recruit subjects. Important to document that the study will be feasible and that there will be no ethical problems.
Examples
1. Patients admitted for orthopedic surgery will be asked by their attending surgeon for permission to be contacted about the study. Those who agree will be seen by the study nurse who will explain the nature of the study to the patient and assess eligibility for the study. Willing patients will then be seen by the principal investigator and informed consent obtained.
2. A poster will be placed in the prenatal clinics requesting people who are interested in participating in a research study to complete and return a stamped, self-addressed card.
206
III. How Will They Be Allocated To Study Groups?
Random Allocation: The assignment of subjects to treatment conditions in a manner determined by chance alone.
Goal of Randomization: to maximize the probability that groups receiving differing interventions will be comparable.
Goals of the Randomization Technique a. True random allocation b. Tamperproof c. Allocation concealment
Methods of randomization a. Drawn from a hat b. Random number table c. Computer generated
Methods that are NOT Random Alternate days of the week Alternate patients
In the protocol:
Describe the randomization technique in detail Justify any special techniques used stratification blocking disproportionate randomization
Example
Subjects will be allocated to study groups using simple randomization performed using a computer-generated randomization list and sequentially-number, sealed, opaque envelopes. After a subject has signed informed consent, the next envelope will be opened to determine which treatment the subject will receive.
Subjects will be allocated to active treatment or placebo in a 2:1 ratio. It is believed that this ratio will increase the likelihood that patients will be willing to participate in the study and therefore increase recruitment rates.
Example of Problem in Describing Allocation to Study Groups
We will randomize 50 patients to either treatment or control group. During the 4 weeks of the study, it is anticipated that approximately 60 patients will be eligible. Therefore, a random sample of fifty will be chosen. (mixing up creating a random sample and random allocation. Must randomized control trials recruit consecutive patients who are then randomly allocated to the different study groups.)
207
INTERVENTION
In experimental research, the experimental treatment or manipulation. The literature review should have provided a justification for the use of this application, including information on dosing, expected benefits and the risk of side effects. In the methods section, how intervention should be described in terms of when and how it will be administered, dosing, etc.
KEYS TO SUCCESS Careful description of intervention including potential risks
Be aware of unintended interventions
DATA COLLECTION
Measurement: The assignment of numbers to objects according to specified rules to characterize quantities of some attribute. This can range from a very simple relationship between variables and number (i.e. age) to a very complex relationship (i.e. satisfaction, quality of life).
Scale: A composite measure of an attribute, consisting of several items that have a logical or empirical relationship to each other; involves the assignment of a score to place subjects on a continuum with respect to the attribute. i.e. Quality of Life, Patient Satisfaction, General Well Being, Social Support
Criteria for Instrument Selection a. Objective of the study b. Definitions of concept and measuring model c. Reliability: degree of consistency with which an instrument or rater measures a variable (i.e., internal consistency, test-retest reproducibility, inter-observer reliability). d. Validity: degree to which an instrument measures what it is intended to measure e. (i.e., content validity, concurrent validity and construct validity). f. Sensitivity: ability to detect change. g. Interpretability: the degree to which one can assign qualitative meaning to an instrument’s quantitative scores. h. Burden
Questionnaire: A method of gathering self-report information from respondents through self-administration of questions in a paper and pencil format. Often questionnaires include scales.
Keys to Success
a. Are the words simple, direct and familiar to all?
208
b. Is the question as clear and specific as possible? c. Is it double question? d. Does the question have a double negative? e. Is the question too demanding? f. Are the questions leading or biased? g. Is the question applicable to all respondents? h. Can the item be shortened with no loss of meaning? i. Will the answers be influenced by response styles? j. Have you assumed too much knowledge? k. Is an appropriate time referent provided? l. Does the question have several possible meanings? m. Are the response alternatives clear and mutually exclusive (and exhaustive)? n. Always pretest questionnaires. o. Be specific about the purpose of the pretest. p. Use colleagues, potential participants, experts and potential users of the data.
Methods of Collecting Data
1. Personal Interview
Advantages a. Flexible b. High response rates c. Control over who is the respondent and over sequence of questions d. No systematic exclusion of illiterate or physically handicapped people e. Clarification and probing possible by interviewers f. Spontaneous responses may be obtained Disadvantages a. Expensive b. Possibility of interviewer cheating c. Bias due to socially acceptable answers by respondents d. Age, race or sex of interviewer may introduce bias
2. Telephone Surveys
Advantages a. Less expensive than personal interviewer b. Control over interviewer bias better than in personal interviews c. Higher response rates than mail-out questionnaires d. Fast e. Interviewer can encourage respondent to participate, can probe for incomplete answers and can clarify answers.
Disadvantages Non-telephone owners (and possibly those with unlisted numbers) cannot be reached May be perceived as a sales pitch Certain techniques cannot be used (the use of cards) Limit to length of interview Interviewer voice may cause bias
209
3. Mailed Surveys
Advantages Inexpensive Respondents may be more frank and honest on sensitive issues No interviewer bias Certain segments of the population may be reached more readily by mail Respondents can take time to think about responses
Disadvantages Low response rates Sequence of question cannot be controlled Mail-out questionnaires should be short Question with no answer difficult to interpret (i.e., deliberately or accidentally) No probing and clarification possible Not clear who has completed the questionnaire
Example of Problems
The primary objective is to determine the degree of satisfaction patients have with outpatient surgery. A questionnaire will be mailed to patients that ask about their degree of satisfaction with their hospital stay.
DATA ANALYSIS
Procedures for 1. recording, storing and reducing data 2. assessing data quality 3. statistical analysis
Step 1: Descriptive statistics
Describe the shape, central tendency and variability Looking at variables one at a time: mean, median, range, proportion
Purposes Summarize important features of numerical data
Pick up data entry errors: i.e. 3 genders, age 150 Characterize subjects Determine distribution of variables Assess assumptions for statistical tests: i.e. normality
Step 2: Analytic/inferential statistics
Looking at associations among two or more variables
210
Purposes Estimate pattern and strength of associations among variables Test hypotheses
Example
The distribution of the ages of patients undergoing and not undergoing colonoscopy will be examined with descriptive statistics (median, mean, standard deviation) and boxplots. If the normality and equal variance assumptions are satisfied, the difference in mean age in the two groups will be tested using a t test. If the assumptions are not met, a non-parametric test will be used (Wilcoxon rank-sum test). All statistical tests will be two-sided. A P value of ≤ 0.05 will be considered statistically significant.
Keys to Success
The analysis section should correspond to the specific objectives: describe the planned analysis for the primary study objective first and then for any secondary objectives. Describe the exact statistical methods that will be used.
SAMPLE SIZE
Purpose: To make a rough estimate of how many subjects required to answer the research question. During the design of the study, the sample size calculation will indicate whether the study is feasible. During the review phase, it will reassure the reviewer(s) that not only is the study feasible, but that resources are not being wasted by recruiting more subjects than is necessary.
Two basic methods of sample size estimation 1. Hypothesis-based 2. Confidence interval-based
Example
- If primary objective is to test whether one group has less pain than the other: 50 subjects per group will provide 80% power to detect a 20% difference in mean pain score. - If primary objective is to estimate a proportion: To estimate the proportion of patients undergoing colonoscopy within 18 months of surgery with a 95% confidence interval of ±5%, 380 subjects will be required.
Keys to Success
- Always justify the sample size - Provide data necessary to calculate sample size
211
- State how the estimates were obtained
Example
The sample size estimates were based on the primary hypothesis: Patients who self- administer narcotics post-operatively will have a smaller mean total dose of drug used than patients who receive there analgesia by nurses. From a review of nurse-administered narcotic doses, we estimate that the mean dose of narcotics in this group will be 100 mg with a standard deviation of 40 mg. To achieve a 90% power to detect a 20% difference in the mean narcotic dose, with an alpha of 0.05 using a two-sided test, we estimate that 63 subjects in each group will be required.
Brief Overview of Sample Size Calculations
Hypothesis-based sample sizes indicate the number of subjects necessary to reasonably test the primary study hypothesis. Hypotheses can be shown to be wrong, but they can never be proven correct. This is because the investigator cannot test all people in the world with the condition of interest. The investigator attempts to test the research hypothesis through a sample of the larger target population. From the data collected, inferences are made about the larger population. For example, if 80% of patients self-administering analgesia report good pain control, whereas only 40% of patients receiving nurse-administered analgesia report good pain control, one would conclude that there is a difference between the two methods and that self-administered analgesia is superior. However, there is always a possibility that since we have only used a sample of all possible patients, there may, in fact, be no difference between the two but the results have just occurred due to chance. To test this formally, a statistical test would be done. In this case the P value is 0.03. This P value means that the probability of obtaining these results or results even more extreme, if in truth there is no difference between the two methods, is no more than 3%. Therefore, either self-administered analgesia is better than nurse-administered analgesia or a very unusual event has occurred. When there is truly no difference between two interventions, but the results of our study suggest there is a difference, a type 1 error has occurred (false negative). Generally, studies will accept a 5% risk (α level) of making a type 1 error. The calculated P value is the probability that we may have made a type 1 error. A type 2 error occurs when we conclude there is no evidence of a difference between two groups, when in truth there is (false positive). Most investigators accept a greater risk of making a type 2 error, usually 10% or 20% (β level).
212
The risk that an investigator is willing to take in making a type 1 or type 2 error is important in determining the sample size. The less willing one is to make an error the more subjects that will be required. The two other important factors in estimating the sample size is the magnitude of the difference in the outcome (= effect size) that the investigator wishes to be able to detect and the amount of variation that is seen between subjects. The smaller the effect size or the larger the variation, the more subjects that will be required. For example, if one wished to detect at least a 20 mg/dl difference in serum cholesterol between two treatment groups, more patients would be needed than if a 40 mg/dl difference was the smallest difference one wished to be able to detect.
Components of the Hypothesis-based Sample Size Calculation:
1. Type 1 error (α): falsely rejects null hypothesis - Usual risk 0.05
2. Type 2 error (β): falsely accepts null hypothesis - Usual risk 0.1 - 0.2 - Study’s power = 1-β
3. Effect size: magnitude of the association in the target population 4. Variability: variability of the outcome variable among the subjects 5. One/Two-tailed tests 6. Type of statistical test: test of means, proportions, etc.
Example
Study Hypothesis: There will be a difference in mean analgesic use of at least 20mg difference between nurse-administered and patient-administered analgesic groups. Null Hypothesis: There will be no difference. Effect size = 20mg Estimate mean for nurse-administered group will be 100mg Variability: Standard deviation = 40mg α=0.05 β=0.10 Two-sided test Computer output . sampsi 100 80, power(.9) sd1(40) alpha(.05) Estimated sample size for two-sample comparison of means Test Ho: m1 = m2, where m1 is the mean in population 1 and m2 is the mean in population 2 Assumptions: alpha = 0.0500 (two-sided) power = 0.8000 m1 = 100 m2 = 80 sd1 = 40 sd2 = 40 n2/n1 = 1.00 Estimated required sample sizes: n1 = 63 n2 = 63 Therefore, necessary sample size: 63 in each group
213
Confidence interval-based sample size calculations are more applicable to surveys. For example, the investigator may be interested in determining what proportion of a population has undergone has a specific characteristic. This characteristic could be a risk factor (i.e. cigarette smoking), a disease or a history of having undergone a certain health care intervention (i.e. colonoscopy). Since the investigator determines whether or not every person in the population has the characteristic, the investigator must rely on obtaining an estimate of the true population proportion by examining a random sample of the population. How accurate this estimate is will depend in part on the size of the sample. The larger the sample the more closer it is likely to be to the true proportion. In determining how large of a sample is required, the investigator must consider what magnitude of the difference he wishes to tolerate between the sample and the population proportions. For example, is being within ± 10% good enough or is this too large?
For example, an investigator may wish to estimate the proportion of patients with colorectal cancer that have undergone a colonoscopy within 18 months of surgery. The investigator specifies the maximum discrepancy between the sample and population proportion of ± 5%. To determine the sample size, the investigator would use the formula:
n = (z/p)2 π(1-π),
n = the required sample size p = the desired maximum discrepancy (i.e. ± 5%) π = the population proportion z = corresponds to the appropriate z value from the normal distribution for the desired confidence interval, for 95% confidence interval = 1.96 for 99% confidence interval = 2.58
Since the population proportion (π) is not know some estimate or range of estimates is required. So if believe population proportion is about 50% and wish 95% confidence intervals which will be no more than ± 5% of true population proportion, n = (1.96/0.05)2 0.5(1-0.5) = 384
The required sample size will increase if more precise estimates are required (i.e. ± 2% would require 2401 subjects) or if a 99% confidence interval is desired. The sample size will also change depending on the population proportion as shown in the table below:
214
Two things can be seen from the table. First is that the sample size will be largest when the estimated population proportion is closest to 50%. Second is that the formula does not work for very small (or very large) proportions. As a general rule of thumb, the sample size multiplied by the estimated population proportion should be at least 5. If it is smaller than advice from a statistician should be sought for calculating the necessary sample size. For example, 15 * 0.01 = 0.15. In the sample size section, the investigator should provide the numbers that were used in calculating the sample size.
Examples of Problems in the Analysis Section
The data will be analyzed with appropriate parametric and nonparametric tests using SPSS for Windows, Version 7. The data will be analyzed using means, standard deviations, t tests, chi-square tests, correlation coefficients and analysis of variance. (Neither of these statements indicates how the investigators will actually conduct their statistical analysis. It is often useful to describe how each objective will be addressed or hypothesis tested.)
ETHICAL CONSIDERATIONS
Ethical Principles
Respect for persons (autonomy) Non-maleficence (do not harm) Beneficence (do good) Justice (exclusion)
Ethical Considerations
1. Scientific validity 2. Recruitment 3. Informed consent Study purpose What does participation involve? What are the alternatives to participation? What are the potential harms and benefits?
Most Institutional Ethics Committees will provide you will be able to provide you with guidance, including a copy of a sample consent form and/or guidelines for questionnaires and telephone surveys
BUDGET
Getting funded is the primary reason for submitting a grant application.
Keys to Success
215
. Read instructions (i.e., overhead, issues not covered, if in doubt call the person in charge of the grants) . Itemization of costs o Personnel (salary and benefits) o Consultants (salary) o Equipment o Supplies (be complete, include cost per item) o Travel o Patient care costs o Other expenses o Indirect costs . Do not inflate the costs . Justify the budget . Inquire about the granting agency’s range
GRANTING AGENCIES
Major Variation in Application Forms Sections in application form Overall amount of detail required Components and structure of proposal content Personal information Budget
Helpful Hints
Review a successful application Start early, pay attention to instructions/criteria Carefully develop research team Justify decisions (in particular those that reviewers might question) Have others review your proposal
WORK PLAN
Personnel (include hiring and training) Tasks Timeline
216
COMMON PITFALLS
Pitfall #1
Example:
In this innovative study, we will elucidate, categorize, and illustrate the myriad of characteristics that typify the consumers of emergency health care services. Previous researchers have done a lousy job in view of the fact that their methods were bad. We also had a notion to study this problem. The findings from our pilot study were great. After a thorough search of the literature, we firmly and honestly believe that an in-depth study which generates a large body of useful information will, in the final analysis, allow better management of emergency room resources in view of the fact that health care resources are stretched thin.
Keys to Effective Writing
Simplicity Clarity Parsimony
Important Rules Avoid jargon. Avoid trendy words
217
Avoid abbreviations Avoid colloquialisms Do not try to sound “intellectual” Avoid redundant phrases Avoid overused phrases
For example: in view of the fact that because utilize use elucidate, categorize, and illustrate describe an in-depth study a study audible to the ear audible
Other Keys to Success Read and reread the grant’s guidelines and instructions carefully. Always follow formatting instructions: margin size, font size, number of pages. Have someone read the proposal.
Pitfall #2:
The purpose of this study is to determine the major concerns of women after a cesarean delivery.
Unclear: immediately after delivery, a year after delivery? Concepts not identified: what kind of concerns?
Which operative method of treating a fractured pelvis is better—the Miller procedure or the Morgan procedure?
Unclear: better what? functional results? fewer complications? shorter length of stay?
Does the administration of analgesic by nurses vs. by patients themselves affect how older patients feel during postoperative recovery?
Constructs not defined: feel Immeasurable: feel
Be as specific as possible:
Does the administration of narcotic analgesics by nurses versus patient self-administration affect pain intensity, as measured by the McGill pain scale, 24 hours following laparoscopic surgery.
218
PITFALL #3
The purpose of this study is to determine if there are differences in pain control with nurse versus patient administered analgesia following surgery.
Research Question: Does the administration of analgesic by nurses vs. by patients themselves affect pain intensity during postoperative recovery in older adults?
Hypothesis: Patients who self-administered narcotics will be more satisfied than patients who receive narcotics administered by nurses.
Sample size: To achieve a power of 80% to detect a 20% difference in the total morphine dose in the first 24 hours surgery, 30 subjects in each group will be required.
What is the primary objective? Do the researchers know?
PITFALL #4
A randomized quasi-experimental design.
A quasi experimental design cannot be randomized.
PITFALL #5
The primary objective is to determine if coffee drinking causes pancreatic cancer. A case-control study will be conducted. Better: The primary objective of this study is to determine if there is an association between coffee consumption and pancreatic cancer.
Pitfall #6:
We will randomize 50 patients to either treatment or control group. During the 4 weeks of the study, it is anticipated that approximately 60 patients will be eligible. Therefore, a random sample of fifty will be chosen.
- How will random allocation be performed? - Why and how will a random sample be obtained?
Pitfall #7:
The primary objective is to determine the degree of satisfaction patients have with outpatient surgery. A questionnaire will be mailed to patients about their degree of satisfaction with their hospital stay.
- Where did the questionnaire come from? - How was it developed? - What does it consist of? - Has it been pretested?
219
- Is it a reliable and valid measure of patient satisfaction?
Better: The primary objective is to determine the degree of satisfaction patients have with outpatient surgery. We will use the Patients Satisfaction Scale. This instrument was developed to determine patient satisfaction with outpatient surgery. It is a 15-item self- administered questionnaire. On repeat testing two weeks a part, it had a test-retest reliability of 0.76.
Pitfall #8:
The data will be analyzed with appropriate parametric and non-parametric tests using SPSS for Windows, Version 7. or in other words
I do not have the foggiest idea about what I will be doing.
The data will be analyzed using means, standard deviations, t tests, chi-square tests, correlation coefficients and analysis of variance. or in other words
The data will be beaten with a bunch of statistical tests in hopes that it will talk.
Devise an analysis plan not a statistical shopping list. Descriptive analysis first. Analytic tests second which address specific research questions.
Better The mean 24-hour total morphine dose and standard deviation for each study group will be computed. Difference in the mean morphine dose between the two groups will be tested using a t test.
Pitfall #9:
Example: Statistical analysis will be conducted with the aid of a statistician.
Name the statistician Consultant (?fee) or Co-Investigator Attach a letter of support Describe the statistician’s role
Dr. R. Fisher from the Department of Community Health Sciences will act as a statistical consultant. He has calculated the estimated sample size and will aid in the analysis of the data. or
220
Dr. R. Fisher from the Department of Community Health Sciences will be hired to conduct the statistical analysis. or Dr. R. Fisher from the Department of Community Health Sciences will be a co-investigator in this study. He has participated in the design of the study and has written the sample size and data analysis sections of the protocol. He will be responsible for creation of the study database, performing validity checks on the data, and for conducting the data analysis.
Pitfall #10: Missing Items
Signatures Budget items Sections: sample size
221
References:
1. Verhoef MJ and Hisden Robert J. Writing an Effective Research Proposal General Research Methods. Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada, 2004. 2. Portney LG and Watkins MP. Foundations of Clinical Research: Applications to Practice. 2nd Ed. New Jersey: Prentice Hall Health, 2000. (Directed at physical and occupational therapists.) 3. Polit DF and Hungler BP. Nursing Research: Principles and Methods. 5th Edition. J.B. Lippincott Company, Philadelphia, 1995 4. DePoy E and Gitlin L. Introduction to Research: Multiple Strategies for Health and Human Services. 2nd Ed. Mosby, St. Louis, 1998. 5. Booth WC, Colomb GG, and Williams JM. The Craft of Research. The University of Chicago Press, Chicago, 1995. 6. Babbie E. The practice of social research. Belmont, CA: Wadsworth Publishing Company, Inc., 1989. 7. ** Hulley BS, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Designing clinical research. An epidemiological approach. Philadelphia PA: Lippincott Williams & Wilkins, 2001. 8. Okolo EN (Ed.) Health research design and methodology. CRC Press; Boca Raton, Florida, 1990. 9. Fletcher RH, Fletcher SW, Wagner EH. Clinical Epidemiology: The essentials. 3rd Ed. Baltimore: Williams & Wilkins, 1996 Physiatric research: A hands-on approach. Am J Phys Med Rehabil 1991;70(suppl):S1- S171. 10. Lewith G, Jonas WB, Walach H. Clinical Research in Complementary Therapies. Edinburgh: Churchill Livingstone, 2002 11. Bryman A. Social research methods. Oxford: Oxford University Press, 2001 (Includes both sections on both quantitative and qualitative research) Clinical Trials 12. **Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3rd Edition. Mosby, St. Louis, 1996. 13. Spilker B. (ed). Guide to Clinical Trials. Philadelphia: Lippincott-Raven, 1996. Qualitative Research 14. Creswell JW. Research Design: Qualitative and Quantitative Approaches. Sage Publications, Thousand Oaks, 1994. 15. Denzin NK and Lincoln YS. Handbook of Qualitative Research. Sage Publications, Thousand Oaks, 1994. Proposal Writing Guides 16. Lock LF, Spirduso WW, Silverman SJ. Proposals that work. Newbury Park, CA: Sage Publications, 1993. 17. Gitlin LN, Lyons KJ. Successful grant writing. Strategies for health and human service professionals. New York: Springer Publishing Co., 1996. 18. Streiner DL. “While you’re up, get me a grant”: A guide to grant writing. Can J Psychiatry. 41:137-143, 1996.
222
19. Ries JB & Leukefeld CG. Applying for research funding. Getting started and getting funded. Thousand Oaks, CA: Sage Publications, 1995. 20. Woodward DK, Clifton GC. Development of a successful research grant application. Am J Hosp Pharm. 51:813-822, 1994. 21. Cuca JM, McLouglin WJ. Why clinical research grant applications fare poorly in review and how to recover. Cancer Investigation. 5:55-58, 1987. Statistics 22. Altman DG. Practical statistics for medical research, London:Chapman & Hall, 1991 (Well-written book written for non-statisticians) 23. Ramsey FL, Schafer DW. The statistical sleuth. A course in methods of data analysis. Pacific Grove, Ca: Duxbury, 2002 24. Internet Sample Size Calculator http://www.health.ucalgary.ca/~rollin/stats/ssize/ http://www.stat.uiowa.edu/~rlenth/Power/ http://hedwig.mgh.harvard.edu/sample_size/size.html Instruments & Measures 25. McDowell I, Newell C. Measuring Health, 2nd Edition. New York, Oxford University Press, 1996 (Review of health measurement methods and instruments) 26. Bowling A. Measuring health. A review if quality of life measurements scales. Milton Keynes, Philadelphia, PA: Open University Press 1991. 27. Stromborg MF. Instruments for clinical nursing research. Norwalk CT: Appleton & Lange, 1988. 28. Lorig K, Stewart A, Ritter P, Gonzalez V, Laurent D, Lynch J. Outcome measures for health education and other health care interventions. Thousand Oaks, Ca: Sage Publications, 1996. 29. Streiner DL and Norman GR. Health Measurement Scales (2nd ed). Oxford: Oxford Medical Publications,1995. 30. DeVellis RF. Scale Development: Theory and Applications. Thousand Oaks, Ca: Sage Publications, 1991. 31. Woodward CA, Chambers LW, Smith K. Guide to improved data collection in health and health care surveys. Parkdale, On: Canadian Public Health Association, 1982. 32. Fowler FJ. Improving survey questions: Design and Evaluation. Thousand Oaks, Ca: Sage Publications, 1995. 33. Woodward CA, Chambers LW. Guide to questionnaire construction and question writing. Parkdale, On: Canadian Public Health Association, 1982. 34. Converse JM, Presser S. Survey questions: Handcrafting the standardized questionnaire. Pretesting: Strategies, Purposes and Phases. Newbury Park, Ca: Sage Publications, 1986. Ethics 35. Weijer C, Dickens B, Meslin EM. Bioethics for clinicians: 10. Research ethics. Can Med Assoc J. 156:11531157, 1997. 36. Medical Research Council of Canada. Guidelines on research involving human subjects. Ottawa: Minister of Supply and Services (Cat No MR21-5/1987E), 1987. 37. University of Calgary. Research Policy: Ethics of Human Studies. University of Calgary, 1994 (http://www.ucalgary.ca/~rs/pethics.htm) Misc. 38. Zeiger M. Essentials of Writing Biomedical Research Papers. New York: McGraw-Hill Inc, 1991.
223
Appendix I: Useful Information Resources
Pakistan – Web Pages
http://www.dra.gov.pk/ The Drug Regulatory Authority of Pakistan (DRAP) http://www.pmrc.org.pk/ Pakistan Medical and Research Council Mandate is to promote, organize and coordinate medical research in Pakistan http://www.hsa.edu.pk/ Health Services Academy Institute of training and research in public health, health policy, epidemiology and biostatistics http://www.pakmedinet.com/ Pakistan’s medical information gateway http://jpma.org.pk/ Journal of Pakistan Medical Association http://www.jcpsp.pk/ Journal of the College of Physicians and Surgeons Pakistan http://www.nclbmoh.gov.pk/ Ministry of National Health Services, Regulations and Coordination, Drug Regulatory Authority of Pakistan, National Control Laboratory for Biologicals
Clinical Trials - Web Pages
www.cancer.org/docroot/ETO/ETO_6.asp American Cancer Society: Clinical Trials www.centerwatch.com Centerwatch Clinical Trials Listing Service www.clinicalstudyresults.org ClinicalStudyResults (PhRMA) www.fda.gov/oashi/clinicaltrials/default.htm FDA Clinical Trials -- Information for Consumers and Patients www.firstclinical.com/studies/search/ First Clinical Research Registry www.fda.gov/oc/gcp/ Good Clinical Practice in FDA-Regulated Clinical Trials. www.nimh.nih.gov/studies/index.cfm NIMH: Clinical Trials http://www.who.int/ictrp/network/trds/en/index.html International Clinical Trials Registry Platform (ICTRP) http://www.controlled-trials.com/isrctn/isrctn_faqs.asp Trial registration, unique identification scheme, International databases CFR-Code of Federal Regulations: http://ecfr.gpoaccess.gov/cgi/t/text/textidx? c=ecfr&tpl=%2Findex.tpl http://www.diahome.org/ DIA-Drug Information Association http://www.fda.gov/
224
FDA-Food and Drug Administration:
Clinical Research Societies (Global)
www.acrohealth.org/ Association of Clinical Research Organizations (ACRO) www.acrpnet.org Association of Clinical Research Professionals (ACRP)
Others:
Association of Clinical Research Professionals Association for Clinical Data Management DIA (Drug Information Association) The Society for Clinical Trials The American Statistical Association The International Biometric Society The Regulatory Affairs Professionals Society AICRC (Association of Independent Clinical Research Contractors) ARENA (Applied Research Ethics National Association) ASCPT (American Society for Clinical Pharmacology and Therapeutics) BARQA (British Association of Research Quality Assurance) BRAPP (British Association of Pharmaceutical Physicians) The Clinical Research Associate RegistryT DIA (Drug Information Association) EFGCP (European Forum for Good Clinical Practice) EFSPI (European Federation of Statisticians in the Pharmaceutical Industry) EUFEPS (European Federation for Pharmaceutical Sciences) FIP (International Pharmaceutical Federation) ISPOR (International Society for Pharmacoeconomics and Outcomes Research) PhRMA (Pharmaceutical Research and Manufacturers of America) PSI (Statisticians in the Pharmaceutical Industry) RAPS (Regulatory Affairs Professionals Society) ResearchQuest.net SCDM (Society for Clinical Data Management) SCT (Society for Clinical Trials) SoCRA (Society of Clinical Research Associates) SQA (Society of Quality Assurance)
Clinical Trial Registration Websites http://www.centerwatch.com/ CenterWatch
225
http://clinicaltrials.gov/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world
International & National Regulatory Authorities
www.ispor.org/htaroadmaps/healthauthorityeurope.asp
Global List
www.afigp.fgov.be/ Belgian Regulatory www.dkma.dk/ Danish Regulatory www.emea.eu.int EMEA www.fda.gov FDA www.fimea.fi/frontpage Finnish Regulatory www.legifrance.gouv.fr/ French laws www.agmed.sante.gouv.fr French Regulatory www.bfarm.de/ German Regulatory www.ich.org ICH www.imb.ie/ Irish Regulatory www.health.gov.il/ Israeli Regulatory www.oss-sper-clin.sanita.it/ Italian Regulatory/Ministry of Health www.ministerosalute.it Italian Regulatory/Ministry of Health www.farmacovigilanza.org/ Italian Regulatory/Ministry of Health (Pharmacovigilance) www.legemiddelverket.no/templates/InterPage____16645.aspx Norwegian Regulatory www.etikkom.no/ Norwegian Ethics committees www.infarmed.pt/ Portuguese Regulatory www.msc.es/ Spanish Regulatory www.mpa.se/eng/index.html Swedish Regulatory
226
www.corec.org.uk UK Ethics www.mhra.gov.uk UK Regulatory
Journals
www.actmagazine.com Applied Clinical Trials Journal digital.findpharma.com/nxtbooks/advanstar/biopharm0212_supp/ BioPharm International www.cticon.org/default.aspx Clinical Trial Magnifier www.iku-dergisi.com GCP Journal (IKU) (in Turkish) www.gcpj.com GCPj www.firstclinical.com/journal/ Journal of Clinical Research Best Practices www.acrpnet.org/MainMenuCategory/Resources/TheMonitor.aspx The Monitor http://www.freemedicaljournals.com/ Free Medical Journals
227
Appendix II: CDISC Clinical Research Glossary Version 7.0
Tuesday, January 06, 2009
Term. The word or phrase being defined is followed by a period. Only proper nouns are capitalized. Definition. Multiple meanings of the same term are numbered 1., 2., 3., etc. NOTE: Comments including usage or domain knowledge related to a term may follow the definition. Source(s). The sources for definitions are cited (see “Reference Citations”) in square brackets. Where the definition has been altered by CDISC, the citation states “modified from.” Where the definition has been drawn by CDISC from text that is not itself a definition, the citation states “after” or “from.” Where no source is listed, the definition is from CDISC. Related terms. Some definitions offer synonyms (See), comments, or related terms (See also or Compare to) to sharpen or expand upon the definition. *See Reference Citations, p. 50, for Glossary Project Team Members
510(k). Premarket Notification (PMN) required for certain medical devices. See http://www.fda.gov/cdrh/510khome.html abbreviation. a set of letters that are drawn from a word or from a sequence of words and that are used for brevity in place of the full word or phrase. .NOTE: An abbreviation is NOT pronounced as a word, but each letter is read in sequence, e.g. NIH. Compare to acronym. absorption. The process by which medications reach the blood stream when administered other than intravenously, for example, through nasal membranes. See also ADME (pharmacokinetics).
*acronym. 1. A word formed from the beginning letters (e.g. ANSI) or a combination of syllables and letters (e.g. MedDRA) of a name or phrase. 2. The short set of letters that identify a clinical study protocol. NOTE an acronym is usually pronounced as a word, not by speaking each letter individually. Compare to abbreviation. action letter. An official communication from FDA to an NDA sponsor announcing an agency decision. See also approval letter, approvable letter, not-approvable letter. activation. Enabling an eClinical trial system to capture data; usually used for EDC systems.
228 admission criteria. Basis for selecting target population for a clinical trial. Subjects must be screened to ensure that their characteristics match a list of admission criteria and that none of their characteristics match any single one of the exclusion criteria set up for the study. See also inclusion criteria, exclusion criteria. adverse drug experience. See adverse drug reaction. adverse drug reaction (ADR). Any noxious and unintended response associated with the use of a drug in humans. 1. Post-approval: an adverse event that occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function. 2. Pre-approval: an adverse event that occurs at any dose and where a causal relationship is at least a reasonable possibility. NOTE: FDA 21 CFR 310.305 defines an adverse drug experience to include any adverse event, “whether or not considered to be drug-related.” CDISC recognizes that current usage incorporates the concept of causality. [WHO Technical Report 498(1972); ICH E2A] adverse event (AE). Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. NOTE: For further information, see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. “[Modified from ICH E2A]” Synonyms: side effect, adverse experience. See also serious adverse event, serious adverse experience. adverse experience. See adverse event. adverse reaction. See adverse drug reaction. algorithm. Step-by-step procedure for solving a mathematical problem; also used to describe step-by-step procedures for making a series of choices among alternative decisions to reach a calculated result or decision. alpha error. The likelihood that a relationship observed between 2 variables is due to chance. The probability of a Type 1 error. [Modified from AMA Manual of Style] amendment. A written description of a change(s) to, or formal clarification of, a protocol.
American National Standards Institute (ANSI). Founded in 1918, ANSI itself does not develop standards. ANSI’s roles include serving as the coordinator for U.S. voluntary standards efforts, acting as the approval body to recognize documents developed by other national organizations as American National Standards, acting as the U.S. representative in international and regional standards efforts, and serving as a clearinghouse for national and international standards development information. [HL7]
229 analysis dataset. An organized collection of data or information with a common theme arranged in rows and columns and represented as a single file; comparable to a database table. NOTE: Standardizing analysis datasets is intended to make review and assessment of analysis more consistent [ADaM]. analysis set. A set of subjects whose data are to be included in the main analyses. This should be defined in the statistical section of the protocol. NOTE: There are a number of potential analysis sets, including, for example the set based upon the intent-to-treat principle. [ICH E9] analysis variables. Variables used to test the statistical hypotheses identified in the protocol and analysis plan; variables to be analyzed. [PR Project] See also variable. anchor. Designation for a planned activity, often marking the transition between epochs or elements of a clinical study plan (e.g., “FPFV—first patient first visit”). applet. A small application, typically downloaded from a server. application software. See application. application. 1. Computer application: software designed to fill specific needs of a user; for example, software for navigation, project management, or process control. 2. Regulatory application: application made to a health authority to investigate, market, or license a new product or indication. Synonyms: 1. computer application, application software. approvable letter. An official communication from FDA to an NDA/BLA sponsor that lists issues to be resolved before an approval can be issued. [Modified from 21 CFR 314.3; Guidance to Industry and FDA Staff (10/08/2003)] approval (in relation to institutional review boards). The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, good clinical practice (GCP), and the applicable regulatory requirements. [ICH E6] approval letter. An official communication from FDA to inform an applicant of a decision to allow commercial marketing consistent with conditions of approval. [Modified from 21 CFR 314.3; Guidance to Industry and FDA Staff (10/08/2003)] arm. A planned sequence of elements, typically equivalent to a treatment group. [SDTM] See element. assessment. A measurement, evaluation or judgment for a study variable pertaining to the status of a subject. NOTE: Assessments are usually measured at a certain time, and usually are not compounded significantly by combining several simultaneous measurements to form a derived assessment (e.g., BMI) or a result of statistical analysis. See variable; outcome, endpoint. The term assessment is intended to invoke some degree of evaluation or judgment concerning subject status.
230
audit. A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s). [ICH E6 Glossary] audit certificate. Document that certifies that an audit has taken place (at an investigative site, CRO, or clinical research department of a pharmaceutical company). [ICH E6 Glossary] audit report. A written evaluation by the auditor of the results of the audit. [Modified from ICH E6 Glossary] audit trail. A process that captures details such as additions, deletions, or alterations of information in an electronic record without obliterating the original record. An audit trail facilitates the reconstruction of the history of such actions relating to the electronic record. [after ICH E6, CSUICI] back translation (natural language). The process of translating a document that was translated from one language to another back to the original language. Used to ensure that consent forms, surveys, and other clinical trial documents will be clear and accurate in the translated form. background material. Information pertinent to the understanding of a protocol. NOTE: Examples include investigator brochure, literature review, history, rationale, or other documentation that places a study in context or presents critical features. [PR Project] balanced study. Trial in which a particular type of subject is equally represented in each study group. bandwidth. An indicator of the throughput (speed) of data flow on a transmission path; the width of the range of frequencies on which a transmission medium carries electronic signals. All digital and analog signal channels have a bandwidth. baseline assessment. Assessment of subjects as they enter a trial and before they receive any treatment. baseline characteristics. Demographic, clinical, and other data collected for each participant at the beginning of the trial before the intervention is administered. NOTE: Randomized, controlled trials aim to compare groups of participants that differ only with respect to the intervention (treatment). Although proper random assignment prevents selection bias, it does not guarantee that the groups are equivalent at baseline. Any differences in baseline characteristics are, however, the result of chance rather than bias. The study groups should be compared at baseline for important demographic and clinical characteristics. Baseline data may be especially valuable when the outcome measure can also be measured at the start of the trial. [CONSORT Statement]
231 baseline imbalance. Systematic error in creating intervention groups, such that they differ with respect to prognosis. That is, the groups differ in measured or unmeasured baseline characteristics because of the way participants were selected or assigned. NOTE: Also used to mean that the participants are not representative of the population of all possible participants. [ICH E9]
Bayesian approaches. Approaches to data analysis that provide a posterior probability distribution for some parameter (e.g., treatment effect), derived from the observed data and a prior probability distribution for the parameter. The posterior distribution is then used as the basis for statistical inference. [ICH E9 Glossary]
Bayesian statistics. Statistical approach named for Thomas Bayes (1701–1761) that has among its features giving a subjective interpretation to probability, accepting the idea that it is possible to talk about the probability of hypotheses being true and of parameters having particular values. beta error. Probability of showing no significant difference when a true difference exists; a false acceptance of the null hypothesis. See also Type 2 error. [AMA Manual of Style] bias. Situation or condition that causes a result to depart from the true value in a consistent direction. Bias refers to defects in study design or measurement. [AMA Manual of Style. See also ICH E9, CONSORT Statement] bioanalytical assays. Methods for quantitative measurement of a drug, drug metabolites, or chemicals in biological fluids. bioavailability. Rate and extent to which a drug is absorbed or is otherwise available to the treatment site in the body. bioequivalence. Scientific basis on which drugs with the same active ingredient(s) are compared. NOTE: To be considered bioequivalent, the bioavailability of two products must not differ significantly when the two products are given in studies at the same dosage under similar conditions. biological marker. See biomarker.
Biologics Licensing Application (BLA). An application to FDA for a license to market a new biologic product in the United States. biomarker. A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. [Biomarker definitions working group] biostatistics. Branch of statistics applied to the analysis of biological phenomena. blind review. Checking and assessing data prior to breaking the blind, for the purpose of finalizing the planned analysis. [Modified ICH E9]
232
blinded (masked) medications. Products that appear identical in size, shape, color, flavor, and other attributes to make it very difficult for subjects and investigators (or anyone assessing the outcome) to determine which medication is being administered. blinded study. A study in which the subject, the investigator, or anyone assessing the outcome is unaware of the treatment assignment(s). NOTE: Blinding is used to reduce the potential for bias. [Modified ICH E6 Glossary] See also blinding/masking, double-blind study, single-blind study, triple-blind study; contrast with open-label or unblinded study. blinding. A procedure to limit bias by preventing subjects and/or study personnel from identifying which treatments or procedures are administered, or from learning the results of tests and measures undertaken as part of a clinical investigation. NOTE: Masking, while often used synonymously with blinding, usually denotes concealing the specific study intervention used. [from ICH E9] The term masking is often preferred to blinding in the field of ophthalmology. [from AMA Manual of Style]. See also blinding, double-blind study, masking, single-blind study, triple-blind study. Contrast with open-label and/or unblinded study. branch. Point within a study design where there is an allocation of subject subsets to particular procedures or treatment groups. brand name. See proprietary name. Synonyms: trade name; proprietary name. [SPL] browser. Computer program that runs on the user’s desktop computer and is used to navigate the World Wide Web. See also Web browser. cache. Storage area on a computer’s hard drive where the browser stores (for a limited time) Web pages and/or graphic elements. carry-over effect. Effects of treatment that persist after treatment has been stopped, sometimes beyond the time of a medication’s known biological activity. case history. An adequate and accurate record prepared and maintained by an investigator that records all observations and other data pertinent to the investigation on each individual administered the investigational drug (device or other therapy) or employed as a control in the investigation. NOTE: Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual’s hospital chart(s), and the nurses’ notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. [21 CFR 312.62b] case record form. See case report form. case report form (CRF). 1. A printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor for each trial subject. 2. A record of clinical study observations and other information that a study protocol
233 designates must be completed for each subject. NOTE: In common usage, CRF can refer to either a CRF page, which denotes a group of one or more data items linked together for collection and display, or a casebook, which includes the entire group of CRF pages on which a set of clinical study observations and other information can be or have been collected, or the information actually collected by completion of such CRF pages for a subject in a clinical study [ICH E6 Glossary]. See also CRF (paper). case report tabulations (CRT). In a paper submission, listings of data that may be organized by domain (type of data) or by subject. See also eCRT. categorical data. Data evaluated by sorting values (for example, severe, moderate, and mild) into various categories. causality assessment. An evaluation performed by a medical professional concerning the likelihood that a therapy or product under study caused or contributed to an adverse event.
CDISC Standard (The). CDISC term for a proposed uniform CDISC standard intended to address the full life-cycle of a clinical trial including protocol representation, capture of source data, submission and archiving using a set of fully integrated and consistent models, terms, and controlled vocabularies derived from the current set of CDISC standards. certified copy. A copy of original information that has been verified as indicated by a dated signature, as an exact copy having all of the same attributes and information as the original. NOTE: The copy may be verified by dated signature or by a validated electronic process. : A certified copy of a source document may serve as source for a clinical investigation. See also source data, source. [After CSUICI]
Certified IRB Professional (CIP). Certification awarded to persons who satisfy the educational and employment requirements and pass an examination conducted by the Applied Research Ethics National Association (ARENA), the membership division of Public Responsibility in Medicine and Research (PRIM&R). clean database. A set of reviewed data in which errors have been resolved to meet QA requirements for error rate and in which measurements and other values are provided in acceptable units; database that is ready to be locked. See also database lock, clean file. clean file. When all data cleaning is completed and database is ready for quality review and unblinding. client. A program that makes a service request of another program, usually running on a server, that fulfills the request. Web browsers (such as Netscape Navigator and Microsoft Explorer) are clients that request HTML files from Web servers. clinical benefit. A therapeutic intervention may be said to confer clinical benefit if it prolongs life, improves function, and/or improves the way a subject feels.
234 clinical clarification. A query resolution received from the sponsor staff (medical monitors, DSMB monitoring board, etc.). See also self-evident change. clinical data. Data pertaining to the medical well-being or status of a patient or subject. clinical development plan. A document that describes the collection of clinical studies that are to be performed in sequence, or in parallel, with a particular active substance, device, procedure, or treatment strategy, typically with the intention of submitting them as part of an application for a marketing authorization. NOTE: The plan should have appropriate decision points and allow modification as knowledge accumulates. [from ICH E9] See also development plan. clinical document architecture. Specification for the structure and semantics of “clinical documents” for the purpose of exchange. [HL7; SPL] clinical document. A documentation of clinical observations and services. NOTE: An electronic document should incorporate the following characteristics: persistence, stewardship, potential for authentication, wholeness, and human readability. [SPL] clinical efficacy. Power or capacity to produce a desired effect (i.e., appropriate pharmacological activity in a specified indication) in humans. [SQA] clinical investigation. See clinical trial, clinical study. NOTE: Increased usage of investigation or study in the U. S. rather than “trial”, may reflect the appearance of the term in FDA regulations concerning clinical research activities. clinical pharmacology. Science that deals with the characteristics, effects, properties, reactions, and uses of drugs, particularly their therapeutic value in humans, including their toxicology, safety, pharmacodynamics, and pharmacokinetics (ADME). clinical protocol. See protocol. clinical research and development. The testing of a drug compound in humans primarily done to determine its safety and pharmacological effectiveness. Clinical development is done in phases, which progress from very tightly controlled dosing of a small number of subjects to less tightly controlled studies involving large numbers of patients. [SQA] clinical research associate (CRA). Person employed by a sponsor, or by a contract research organization acting on a sponsor’s behalf, who monitors the progress of investigator sites participating in a clinical study. At some sites (primarily in academic settings), clinical research coordinators are called CRAs. clinical research coordinator (CRC). Person who handles most of the administrative responsibilities of a clinical trial on behalf of a site investigator, acts as liaison between investigative site and sponsor, and reviews all data and records before a monitor’s visit. Synonyms: trial coordinator, study coordinator, research coordinator, clinical coordinator, research nurse, protocol nurse.
235
clinical significance. Change in a subject’s clinical condition regarded as important whether or not due to the test intervention. NOTE: Some statistically significant changes (in blood tests, for example) have no clinical significance. The criterion or criteria for clinical significance should be stated in the protocol. The term “clinical significance” is not advisable unless operationally defined. clinical study (trial) report. A written description of a study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analysis are fully integrated into a single report. NOTE: For further information, see the ICH Guideline for Structure and Content of Clinical Study Reports. [ICH E6 Glossary] clinical study. See clinical trial. clinical trial. A research investigation involving human subjects that is designed to answer specific questions about the safety and efficacy of a biomedical intervention (drug, treatment, device) or new ways of using a known drug, treatment, or device). [modified from ICH E6 Glossary, Directive 2001/20/EC] Synonym: clinical investigation or study. clinical trial data. Data collected in the course of a clinical trial. See also clinical trial information. clinical trial exemption (CTX). A scheme that allows sponsors to apply for approval for each clinical study in turn, submitting supporting data to the Medicines Control Agency (MCA), which approves or rejects the application (generally within 35 working days). NOTE: Approval means that the company is exempt from the requirement to hold a clinical trial certificate (CTC). [UK] clinical trial information. Data collected in the course of a clinical trial or documentation related to the integrity or administration of that data. A superset of clinical trial data. clinical trial materials. Complete set of supplies provided to an investigator by the trial sponsor. clinician reported outcome. Clinician assessment of patient outcomes, based on objective or subjective data evaluated by the clinician. codelist. Finite list of codes and their meanings that represent the only allowed values for a data item. See also controlled vocabulary. A codelist is one type of controlled vocabulary. coding. In clinical trials, the process of assigning data to categories for analysis NOTE: Adverse events, for example, may be coded using MedDRA. cognitive debriefing. A qualitative research tool used to determine whether concepts and items are understood by patients in the same way that PRO instrument developers intend. NOTE: Cognitive debriefing interviews involve incorporating follow-up questions in a field
236 test interview to gain better understanding of how patients interpret questions asked of them and to collect and consider all concepts elicited by an item. [from PRO Draft Guidance Glossary] cohort. 1. A group of individuals who share a common exposure, experience or characteristic. 2. A group of individuals followed-up or traced over time in a cohort study. [AMA Manual of Style] cohort study. Study of a group of individuals, some of whom are exposed to a variable of interest, in which subjects are followed over time. Cohort studies can be prospective or retrospective. [AMA Manual of Style] See also prospective study. combination product. 1. A product comprising two or more individual products. 2. Two or more separate products packaged together in a single package or as a unit. 3. A product that is packaged separately but is used only with another product. [Modified from SPL Glossary] common data element. A structured item characterized by a stem and response options together with a history of usage that can be standardized for research purposes across studies conducted by and for NIH. NOTE: The mark up or tagging facilitates document indexing, search and retrieval, and provides standard conventions for insertion of codes. [NCI, CaBIG]. See also item.
Common Technical Document. A format agreed upon by ICH to organize applications to regulatory authorities for registration of pharmaceuticals for human use. [ICH] See also eCTD. comparative study. One in which the investigative drug is compared against another product, either active drug or placebo. comparator (product). An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial. [ICH E6 Glossary] See also control.
Competent Authority (CA). The regulatory body charged with monitoring compliance with the national statutes and regulations of European Member States. complete file. File for which all data cleaning is complete and database is ready for quality review and unblinding. completion. 1. Subject completion: the case where a subject ceases active participation in a trial because the subject has, or is presumed to have, followed all appropriate conditions of a protocol. 2. Study completion: according to the study protocol, the point at which all protocol-required activities have been executed. [Modified EU CTD] compliance (in relation to trials). Adherence to trial-related requirements, good clinical practice (GCP) requirements, and the applicable regulatory requirements. [Modified ICH E6 Glossary]
237 computer application. See application. concept. Discrete notion having a single meaning. In a controlled vocabulary a concept is mapped to one or more of the words that convey its meaning. confidence interval. A measure of the precision of an estimated value. The interval represents the range of values, consistent with the data, that is believed to encompass the “true” value with high probability (usually 95%). The confidence interval is expressed in the same units as the estimate. Wider intervals indicate lower precision; narrow intervals, greater precision. [CONSORT Statement] confidentiality. Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identity. [ICH E6 Glossary] confirmatory trial. Phase 3 trial during which the previously revealed actions of a therapeutic intervention are confirmed. NOTE: Procedures in confirmatory trials should be set firmly in advance. Compare to exploratory trial. conformity assessment. The process by which compliance with the EMEA’s Essential Requirements is assessed. See also Notified Body. consent form. Document used during the informed consent process that is the basis for explaining to potential subjects the risks and potential benefits of a study and the rights and responsibilities of the parties involved. NOTE: The informed consent document provides a summary of a clinical trial (including its purpose, the treatment procedures and schedule, potential risks and benefits, alternatives to participation, etc.) and explains an individual’s rights as a subject. It is designed to begin the informed consent process, which consists of conversations between the subject and the research team. If the individual then decides to enter the trial, s/he gives her/his official consent by signing the document. Synonym: informed consent form; see also informed consent. consumer safety officer (CSO). FDA official who coordinates the review process of various applications. content validity. The extent to which a variable (for example, a rating scale) measures what it is supposed to measure. [ICH E9 Glossary] contingent subject trial contact. Planned response to an anticipated but conditional event in a clinical trial. [CDISC Trial Design Project] contract research organization (CRO). A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions. [ICH E6 Glossary] contract. A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and,
238 if appropriate, on financial matters. The protocol may serve as the basis of a contract. [ICH E6 Glossary] control (of electronic records). To prepare and maintain case histories and other records for regulated clinical investigations. NOTE: Control is often used as a casual synonym for the terms in 21 CFR 312.62 requiring investigative sites to prepare, maintain and retain adequate and accurate case histories. control group. The group of subjects in a controlled study that receives no treatment, a standard treatment, or a placebo. [21 CFR 314.126] See also controls. control(s). 1. Comparator against which the study treatment is evaluated [e.g., concurrent (placebo, no treatment, dose-response, active), and external (historical, published literature)] 2. Computer: processes or operations intended to ensure authenticity, integrity, and confidentiality of electronic records. NOTE: The protocol incorporates scientific rationale for selection of comparator and describes how the comparator serves as a reference point for the evaluation. [1. After ICH E10. 2. After 21 CFR Part 11; CSUCT] controlled study. A study in which a test article is compared with a treatment that has known effects. The control group may receive no treatment, active treatment, placebo, or dose comparison concurrent control. NOTE: For further information on “adequate and well- controlled study” see 21 CFR 314.126. controlled terminology. Synonym for controlled vocabulary. controlled vocabulary. A finite set of values that represent the only allowed values for a data item. These values may be codes, text, or numeric. See also codelist. coordinating committee. A committee that a sponsor may organize to coordinate the conduct of a multicenter trial. [ICH E6] coordinating investigator. An investigator assigned the responsibility for the coordination of investigators at different centers participating in a multicenter trial. [ICH E6] correlation. The degree to which two or more variables are related. Typically the linear relationship is measured with either Pearson’s correlation or Spearman’s rho. NOTE: Correlation does not necessarily mean causation. [After HyperStat Online Glossary; ADaM] covariate (prognostic). Factor or condition that influences outcome of a trial. [ADaM]
CRF data. Subset of clinical trial data that are entered into fields on a CRF.
CRF (paper). Case report form in which the data items are linked by the physical properties of paper to particular pages. NOTE: Data are captured manually and any comments, notes, and signatures are also linked to those data items by writing or typescript on the paper pages. See also eCRF, case report form.
239 crossover trial. A trial design for which subjects function as their own control and are assigned to receive investigational product and controls in an order determined by randomizations, typically with a washout period between the two products. [Center for the Advancement of Clinical Research; ADaM] curriculum vitae (cv). Document that outlines a person’s educational and professional history. data. Representations of facts, concepts, or instructions in a manner suitable for communication, interpretation, or processing by humans or by automated means. [FDA] data acquisition. Capture of data into a structured, computerized format without a human- to-computer interface (i.e., from another measuring instrument or computerized source). Contrast with data entry, electronic data capture. data and safety monitoring board (DSMB). See data monitoring committee. data capture. See data entry. data clarification. Answer supplied by the investigator in response to a query. NOTE: The investigator may supply a new data point value to replace the initial value or a confirmation of the queried data point. data clarification form. A form used to query an investigator and collect feedback to resolve questions regarding data. data collection instrument. A substrate or tool (either electronic or paper) used to record, transcribe, or collect clinical data. [PR Project] data element. 1. For XML, an item of data provided in a mark up mode to allow machine processing. 2. Smallest unit of information in a transaction. 3. A structured item characterized by a stem and response options together with a history of usage that can be standardized for research purposes across studies conducted by and for NIH. NOTE: The mark up or tagging facilitates document indexing, search and retrieval, and provides standard conventions for insertion of codes. [1. FDA - GL/IEEE. 2. Center for Advancement of Clinical Research. 3. NCI, caBIG] data encryption standard (DES). A FIPS approved cryptographic algorithm for encrypting (enciphering) and decrypting (deciphering) binary coded information. Encrypting data converts it to an unintelligible form called cipher. Decrypting cipher converts the data back to its original form called plaintext. The standard specifies both enciphering and deciphering operations, which are based on a 64 bit binary number called a key. Unauthorized recipients of the cipher who know the algorithm but do not have the correct key cannot derive the original data algorithmically. NOTE: Data that is considered sensitive by the responsible authority or data that represents a high value should be cryptographically protected if it is vulnerable to unauthorized disclosure or undetected modification during transmission or while in storage. [from Federal Information Processing Standards (FIPS) Publication 46-2]
240
data entry. Human input of data into a structured, computerized format using an interface such as a keyboard, pen-based tablet, or voice recognition. NOTE: Although data capture is often used synonymously, capture implies direct entry of original source data into an electronic record rather than transcription (entry) from paper source. Contrast with data acquisition, electronic data capture; direct entry. data integrity. A dimension of data contributing to trustworthiness and pertaining to the systems and processes for data capture, correction, maintenance, transmission, and retention. Key elements of data integrity include security, privacy, access controls, a continuous pedigree from capture to archive, stability (of values, of attribution), protection against loss or destruction, ease of review by users responsible for data quality, proper operation and validation of systems, training of users. NOTE: In clinical research the FDA requires that data relied on to determine safety and efficacy of therapeutic interventions be trustworthy and establishes guidance and regulations concerning practices and system requirements needed to promote an acceptable level of data integrity. [FDA, CSUICI, IEEE]. Compare with data quality. data integrity verification. Process of manually supervised verification of data for internal consistency. data interchange. Transfer of information between two or more parties, which maintains the integrity of the contents of the data for the purpose intended. See also interoperability. data item. A named component of a data element. Usually the smallest component [ANSI]. See also data model, data element. data management. Tasks associated with the entry, transfer, and/or preparation of source data and derived items for entry into a clinical trial database. NOTE: Data management could include database creation, data entry, review, coding, data editing, data QC, locking, or archiving; it typically does not include source data capture. data management conventions. Procedures and policies for data management, e.g., documented procedure(s) for resolving self-evident changes. [ICH E6] See self-evident change. data model. Unambiguous, formally stated, expression of items, the relationship among items, and the structure of the data in a certain problem area or context of use. A data model uses symbolic conventions agreed to represent content so that content does not lose its intended meaning when communicated. data monitoring. Process by which clinical data are examined for completeness, consistency, and accuracy. data monitoring committee (DMC). Group of individuals with pertinent expertise that reviews on a regular basis accumulating data from an ongoing clinical trial. The DMC advises the sponsor regarding the continuing safety of current participants and those yet to be
241 recruited, as well as the continuing validity and scientific merit of the trial. NOTE: A DMC can stop a trial if it finds toxicities or if treatment is proved beneficial. [After FDA guidance on establishment and operation of clinical trial data monitoring committees] data quality. A dimension of data contributing its trustworthiness and pertaining to accuracy, sensitivity, validity, and suitability to purpose. Key elements of data quality include attributability, legibility (decipherable, unambiguous), contemporaneousness, originality (i.e., not duplicated), accuracy, precision, completeness, consistency (logical, not out of range). NOTE: Scientists may reasonably trust data that are accurate (high quality) that have also been reviewed by investigators and protected from unauthorized alteration (high integrity). See also ALCOA, data integrity. data security. Degree to which data are protected from the risk of accidental or malicious alteration or destruction and from unauthorized access or disclosure. [FDA] data selection criteria. The rules by which particular data are selected and/or transferred between the point of care and the patient record; subsequently, from the patient record to the database; and from database to inclusion in sub-population analyses. data transformations. Algorithmic operations on data or data sets to achieve a meaningful set of derived data for analysis. [ADaM] See also derived variable. data type. Data types define the structural format of the data carried in the attribute and influence the set of allowable values an attribute may assume. [HL7] data validation. 1. Checking data for correctness and/or compliance with applicable standards, rules, and conventions. 2. Process used to determine if data are inaccurate, incomplete, or unreasonable. The process may include format checks, completeness checks, check key tests, reasonableness checks, and limit checks. [1. FDA 2. ISO] data listing. Set of observations organized by domain. database. A collection of data or information, typically organized for ease and speed of search and retrieval. database lock. Action taken to prevent further changes to a clinical trial database. NOTE: Locking of a database is done after review, query resolution, and a determination has been made that the database is ready for analysis. dataset. A collection of structured data in a single file. [CDISC, ODM and SDS] Compare with analysis dataset, tabulation dataset. decision rule. Succinct statement of how a decision will be reached based upon the expected foreseen clinical benefits in terms of outcomes of the primary endpoint. [FDA documentation]
242
Declaration of Helsinki. A set of recommendations or basic principles that guide medical doctors in the conduct of biomedical research involving human subjects. It was originally adopted by the 18th World Medical Assembly (Helsinki, Finland, 1964) and recently revised (52nd WMA General Assembly, Edinburgh, Scotland, October 2000). define.XML. Table used by XML review tools to configure a review engine to deal with CDISC standard data for a trial. demographic data. Characteristics of subjects or study populations, which include such information as age, sex, family history of the disease or condition for which they are being treated, and other characteristics relevant to the study in which they are participating. dependent variable. Outcomes that are measured in an experiment and that are expected to change as a result of an experimental manipulation of the independent variable(s). [Center for Advancement of Clinical Research] deployment. Readying an electronic clinical trial system for field use by providing or disseminating capture devices, tokens, or passwords for users of an activated system. See activation. derived variable. New variable created as a function of existing variables and/or application of mathematical functions. See also variable, raw data. design. 1. In the context of clinical trials, see design configuration. 2. In the context of eClinical trials systems, a design for an application to support actions on electronic records. design configuration. Clinical trial design developed to compare treatment groups in a clinical trial. NOTE: The configuration usually requires randomization to one or more treatment arms, each arm being allocated a different (or no) treatment. Examples include: Parallel Group Design, Crossover Design, Factorial Designs. [from ICH E9] development plan. An ordered program of clinical trials, each with specific objectives. [Adapted from ICH E9, see ICH E8]. See also clinical development plan. development process. See drug development process. direct access. Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. NOTE: The party (e.g., domestic and foreign regulatory authorities, sponsor’s monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subject’s identities and sponsor’s proprietary information. [ICH E6 Glossary] direct entry. Recording of data by human or automated action where an electronic record is the original means of capturing the data into an electronic records system without a paper source document. Examples are an individual keying original observations into a system or the automatic recording into the system of the output from measuring devices such as a
243 balance that measures subject’s body weight or an ECG machine. Compare with data entry, data acquisition. discontinuation. The act of concluding participation, prior to completion of all protocol- required elements, in a clinical study by an enrolled subject. NOTE: Four categories of discontinuation are distinguished: 1) dropout: active discontinuation by a subject [also a noun referring to such a discontinued subject]; 2) investigator-initiated discontinuation [e.g., subject experiences an unexpected adverse event]; 3) loss to follow-up: cessation of participation without notice by the subject and without ability to subsequently contact the subject to obtain further data; 4) sponsor-initiated discontinuation [e.g.,, change in protocol]. Note that subject discontinuation does not necessarily imply exclusion of subject data from analysis. “Termination” has a history of synonymous use, but is now considered non-standard. See also withdrawal and ICH E3, Section 10.1 and FDA Guidance for Industry: Submission of Abbreviated Reports & Synopses in Support of Marketing Applications, IV A. discrepancy. The failure of a data point to pass a validation check. NOTE: Discrepancies may be detected by computerized edit checks or observed/identified by the data reviewer as a result of manual data review. See also query. disease. Any deviation from or interruption of the normal structure or function of a part, organ, or system of the body as manifested by characteristic symptoms and signs. [Dorland’s Medical Dictionary] distribution. 1. In statistics, a group of ordered values; the frequencies or relative frequencies of all possible values of a characteristic. 2. In pharmacokinetics, the processes that control transfer of a drug from the site of measurement to its target and other tissues. [1. AMA Manual of Style]. See also ADME. document (HL7). An ordered presentation of XML elements, possibly including text and tabular analyses, description, and figures. Descriptors for HL7 documents include type, class, and element. NOTE: In HL7, a document can be either physical (referring to the paper) or logical (referring to the content) with the following characteristics: 1) Stewardship; 2) Potential for authentication; 3) Wholeness; 4) Human readability; 5) Persistence; 6) Global vs. local context. document root. The element in an XML document that contains all other elements; the first element in the document. [SPL Glossary] document type definition (DTD). XML specification for content and presentation of data and text in a document including definitions for the elements considered to be legal in the document. NOTE: Agreeing on a common DTD facilitates interoperability among systems incorporating the agreed standards. [from XML files.com] documentation. All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. [ICH E6 Glossary]
244
domain. A collection of observations with a topic-specific commonality about each subject in a clinical investigation. NOTE: CDISC classifies domains. For example, the Interventions class is a domain that captures investigational treatments, therapeutic treatments, and surgical procedures that are intentionally administered to the subject (usually for therapeutic purposes) either as specified by the study protocol (e.g., exposure), coincident with the study assessment period (e.g., concomitant medications), or other substances self- administered by the subject (such as alcohol, tobacco, or caffeine). The Events class captures occurrences or incidents independent of planned study evaluations occurring during the trial (e.g., “adverse events” or “disposition”) or prior to the trial (e.g., “medical history”). The Findings class captures the observations resulting from planned evaluations such as observations made during a physical examination, laboratory tests, ECG testing, and sets of individual questions listed on questionnaires. domain name. The way a particular Web server is identified on the Internet. For example, www.fda.gov names the World Wide Web (www) server for the Food and Drug Administration, which is a government (.gov) entity. [Center for Advancement of Clinical Research] dosage. The amount of drug administered to a patient or test subject over the course of the clinical study; a regulated administration of individual doses. [AMA Manual of Style] dosage form. Physical characteristics of a drug product, (e.g., tablet, capsule, or solution) that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients. [21 CFR §314.3]. See also drug product. dosage regimen. The number of doses per given time period; the elapsed time between doses (for example, every six hours) or the time that the doses are to be given (for example, at 8 a.m. and 4 p.m. daily); and/or the amount of a medicine (the number of capsules, for example) to be given at each specific dosing time. [from Center for Advancement of Clinical Research] dosage strength. 1. Proportion of active substance to excipient, measured in units of volume or concentration. 2. The strength of a drug product tells how much of the active ingredient is present in each dosage. [2. FDA Glossary of Terms] dose. The amount of drug administered to a patient or test subject at one time or the total quantity administered. [AMA Manual of Style] double-blind study. A study in which neither the subject nor the investigator nor the research team interacting with the subject or data during the trial knows what treatment a subject is receiving. double-dummy. A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made identical. Supplies are prepared for Treatment A (active and indistinguishable placebo) and for Treatment B (active and
245 indistinguishable placebo). Subjects then take two sets of treatment; either A (active) and B (placebo), or A (placebo) and B (active). [ICH E9] dropout. A subject in a clinical trial who for any reason fails to continue in the trial until the last visit or observation required of him/her by the study protocol. [from ICH E9] drug. 1. Article other than food intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; or intended to affect the structure or any function of the body. Not a device or a component, part, or accessory of a device. 2. Substance recognized by an official pharmacopia or formulary. [from FDA Glossary of Terms, CDER] drug development process. The program for advancing an investigational product from preclinical studies through approval for marketing following review by regulatory agencies. drug product. 1. A dosage form that contains an active drug ingredient or placebo. 2. A finished dosage form as described in regulations. [SPL Glossary] dynamic HTML. Collective term for a combination of tags and options, style sheets, and programming that allows users to create Web pages in Hypertext Mark-up Language (HTML) that are more responsive to user interaction than previous versions of HTML. eClinical trial. Clinical trial in which primarily electronic processes are used to plan, collect (acquire), access, exchange, and archive data required for conduct, management, analysis, and reporting of the trial. Synonyms: eClinical study, eClinical investigation. eCRF. 1. Auditable electronic record designed to capture information required by the clinical trial protocol to be reported to the sponsor on each trial subject. 2. A CRF in which related data items and their associated comments, notes, and signatures are linked electronically. NOTE: eCRFs may include special display elements, electronic edit checks, and other special properties or functions and are used for both capture and display of the linked data. [FDA CSUCT] eCRT. CRTs provided in electronic format for eSubmissions (electronic regulatory submissions). NOTE: According to FDA guidance, eCRTs are datasets provided as SAS Transport files with accompanying documentation in electronic submissions. They enable reviewers to analyze each dataset for each study. Each CRF domain should be provided as a single dataset; however, additional datasets suitable for reproducing and confirming analyses may also be needed. Becoming obsolete, being replaced by SDTM. edit check. An auditable process, usually automated, of assessing the content of a data field against its expected logical, format, range, or other properties that is intended to reduce error. NOTE: Time-of-entry edit checks are a type of edit check that is run (executed) at the time data are first captured or transcribed to an electronic device at the time entry is completed of each field or group of fields on a form. Back-end edit checks are a type that is run against data that has been entered or captured electronically and has also been received by a centralized data store.
246 effect. An effect attributed to a treatment in a clinical trial. In most clinical trials, the treatment effect of interest is a comparison (or contrast) of two or more treatments. [ICH E9] See also treatment effect. effectiveness. The desired measure of a drug’s influence on a disease or condition as demonstrated by substantial evidence from adequate and well-controlled investigations. efficacy. The capacity of a drug or treatment to produce beneficial effects on the course or duration of a disease at the dose tested and against the illness (and patient population) for which it is designed. electronic data capture (EDC). The process of collecting clinical trial data into a permanent electronic form. NOTE: Permanent in the context of these definitions implies that any changes made to the electronic data are recorded with an audit trail. EDC usually denotes manual entry of CRF data by transcription from source documents. The transcription is typically done by personnel at investigative sites. See also data entry, direct data entry, data acquisition. electronic health record (EHR). An electronic record for health care providers to create, import, store, and use clinical information for patient care, according to nationally recognized interoperability standards. NOTE: The EHR has the following distinguishing features: able to be obtained from multiple sources; shareable; interoperable; accessible to authorized parties. [After National Office of Health Information Technology – HIT, USHHS] electronic medical record (EMR). An electronic record for health care providers within one healthcare organization to create, store, and use clinical information for patient care. An electronic record derived from a computerized system used primarily for delivering patient care in a clinical setting. NOTE: EMRs may serve as source documents, and such data could serve also as source data for clinical trials provided that the controls on the EMR system and the transfer of such data to the eClinical trial system were to fulfill regulatory requirements, e.g. 21 CFR Part 11. electronic personal health record (ePHR): An electroni record for individuals to create, import, store, and use clinical information to support their own health. electronic record. Any combination of text, graphics, data, audio, pictorial, or any other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system. [FDA CSUCT; 21 CFR Part 11.3 (7)] electronic signature. A computer data compilation of any symbol or series of symbols, executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature. [CSUCT Glossary; 21 CFR Part 11.3(7)] element. 1. In trial design, a basic building block for time within a clinical trial comprising the following characteristics: a description of what happens to the subject during the element; a definition of the start of the element; a rule for ending the element. 2. A section of text in an XML document delimited by start and end tags; or, in the case of empty
247 elements (elements with no content, only attributes) indicated by an empty tag. [1. PR Project,.2. HL7] endpoint. Variable that pertains to the efficacy or safety evaluations of a trial. NOTE: Not all endpoints are themselves assessments since certain endpoints might apply to populations or emerge from analysis of results. That is, endpoints might be facts about assessments (e.g., prolongation of survival). See also variable. enroll. To register or enter a subject into a clinical trial. NOTE: Once a subject has been enrolled, the clinical trial protocol applies to that subject. enrollment. 1. The act of enrolling one or more subjects. 2. The class of enrolled subjects in a clinical trial. enrollment (cumulative). Current enrollment as well as any ever-enrolled subjects who have ended participation. enrollment (current). Subjects actively continuing to participate in a clinical trial as of the current date. enrollment (target). The number of subjects in a class or group (including the total for the entire trial) intended to be enrolled in a trial. NOTE: Target enrollments are set so that statistical and scientific objectives of a trial will have a likelihood of being met as determined by agreement, algorithm, or other specified process.
Enterprise Vocabulary Services (EVS). A U.S. national resource to house and maintain a number of health-related glossaries and controlled vocabularies under strict versioning. NOTE: Includes the CDISC Glossary. [NCI] epoch. Interval of time in the planned conduct of a study. An epoch is associated with a purpose (e.g., screening, randomization, treatment, follow-up), which applies across all arms of a study. NOTE: Epoch is intended as a standardized term to replace: period, cycle, phase, stage. See also arm, visit. ePRO. PRO data initially captured electronically. NOTE: Usually ePRO data is captured as eSource. [DIA ePRO Working Group]. See also patient reported outcome, PRO, eSource. equipoise. A state in which an investigator is uncertain about which arm of a clinical trial would be therapeutically superior for a patient. NOTE: An investigator who has a treatment preference or finds out that one arm of a comparative trial offers a clinically therapeutic advantage should disclose this information to subjects participating in the trial. equivalence trial. A trial with the primary objective of showing that the response to two or more treatments differs by an amount that is clinically unimportant. NOTE: This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of clinically acceptable differences.
248 eSource. Source record that is electronic. See also source, electronic record. eSource data (electronic source data). Source data captured initially into a permanent electronic record used for the reconstruction and evaluation of a clinical study. NOTE: “Permanent” in the context of these definitions implies that any changes made to the electronic data are recorded via an audit trail. [ICH, CDISC]. See also source data, permanent data. eSource document. The electronic record used to aggregate a particular instance of eSource data items for capture, transmission, storage, and/or display and serving as a source document for a clinical investigation. NOTE: Electronic source documents are recorded in electronic systems according to conventions (such as those for PDF documents) that ensure that all the fields of eSource data and associated contextual information (e.g., time of capture, time zone, authorship, signatures, revisions) are linked to each other in a particular structure for presentation. The encoded specifications in the electronic record thus serve the same role as have the physical properties of paper (binding items together). eSource documents are subject to regulations and guidance that apply to source documents. See also source documents. [after eSDI, CDISC] essential documents. Documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced. [ICH E6 Glossary] established name. The official name of a drug substance. [Food, Drug and Cosmetic Act] ethics committee. See institutional review board, independent ethics committee. ethnicity. Denotes social groups with a shared history, sense of identity, geography and cultural roots.
European Medicines Agency (EMEA). The regulatory agency for the EU. evaluable (for efficacy and safety). Pertains to data or subjects that meet Statistical Analysis Plan criteria for inclusion in Efficacy/Safety datasets. exclusion criteria. List of characteristics in a protocol, any one of which may exclude a potential subject from participation in a study. excretion. The act or process of eliminating waste products from the body. See also ADME. exploratory IND study. A clinical study that is conducted early in Phase 1; involves very limited human exposure and has no therapeutic or diagnostic intent (eg, screening studies, microdose studies) [FDA Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies, January 2006] See also Phase 0. exploratory study. Phase 1 or 2 study during which the actions of a therapeutic intervention are assessed and measured. NOTE: Procedures in exploratory studies may appropriately be altered to expand the scope or method of investigation. Compare to confirmatory study.
249
extraction transformation load (ETL). A class of software applications for data extraction, transformation, and loading that are used to implement data interfaces between disparate database systems, often to populate data warehouses. field. Locus on a data collection instrument (usually a CRF) for recording or displaying a data element. See data item.
File Transfer Protocol (FTP). A standard protocol for exchanging files between computers on the Internet. See also TCP/IP. final report. A written description of a study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report. [ICH E3] finding. A meaningful interpretation of data or observations resulting from planned evaluations. Compare to conclusion, hypothesis. first subject in (FSI, FPI). The date and time the first subject is enrolled and randomized into a study. The subject will have met the inclusion/exclusion criteria to participate in the trial and will have signed an informed consent form. Synonym: first patient in. first subject screened. First subject who signs the informed consent form and is screened for potential enrollment and randomization into a study, but has not yet been determined to meet the inclusion/exclusion criteria for the trial. first subject treated. First subject who receives the test article or placebo in a clinical investigation. first-in-humans study. The first Phase 1 study in which the test product is administered to human beings. first-in-man study. See first-in-humans study.
Food and Drug Administration (FDA). The United States regulatory authority charged with, among other responsibilities, granting IND and NDA approvals.
Form. A collection of items and item groups for capturing and displaying clinical trial data. frequentist methods. Statistical methods, such as significance tests and confidence intervals, which can be interpreted in terms of the frequency of certain outcomes occurring in hypothetical repeated realizations of the same experimental situation. [ICH E9] frozen. Status of a database, file, or element that has been presumed to be in its final state pending “lock” and where further editing is prevented without “unfreezing.” NOTE: Freezing and unfreezing are usually formalized in audit trails and differ from “locking” and “unlocking” only in the degree of approval required. See database lock.
250
functional roles (in a study). See role. gender. Subject self-identification re: masculine/feminine. [IOM] See also sex. generalizability. The extent to which the findings of a clinical trial can be reliably extrapolated from the subjects who participated in the trial to a broader patient population and a broader range of clinical settings. [ICH E9] generic name. The drug identifying name to which all branded (proprietary) names for that indication are associated. global assessment variable. A single variable, usually a scale of ordered categorical ratings, which integrates objective variables and the investigator’s overall impression about the state or change in state of a subject. [ICH E9] glossary. A collection of specialized words or terms with their meanings. good clinical practice (GCP). A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. NOTE: For Guidance on Good Clinical Practice see COMP/ICH/135/95; Declaration of Helsinki; 21 CFR 50, 21 CFR 54, 21 CFR 56, and 21 CFR 312. [ICH] good clinical research practice (GCRP). Term sometimes used to describe GCP. See good clinical practice. granularity. Refers to the size of an information unit in relation to a whole. NOTE: Structuring “privileges” in electronic systems is said to be highly granular when each of many roles can differ in their capacity to act on electronic records. group sequential design. A trial design that allows a look at the data at particular time points or after a defined number of patients have been entered and followed up based on formulating a stopping rule derived from repeated significance tests. [Center for Advancement of Clinical Research] handwritten signature. The scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form. NOTE: The act of signing with a writing or marking instrument such as a pen or stylus is preserved. [21CFR 11] harmonized standard. A European Norm (EN) that has been accepted by all Member States and has been published in the Official Journal of the European Communities (OJEC). health authority. Synonym for regulatory authority. NOTE: Used in the European Union.
251
Health Level 7 (HL7). An ANSIaccredited Standards Developing Organization (SDO) operating in the healthcare arena. NOTE: Level 7 refers to the highest level of the International Standards Organization’s (ISO) communications model for Open Systems Interconnection (OSI), the application level. The application level addresses definition of the data to be exchanged, the timing of the interchange, and the communication of certain errors to the application. Level 7 supports such functions as security checks, participant identification, availability checks, exchange mechanism negotiations, and, most importantly, data exchange structuring. healthcare provider. 1. One who directly or indirectly administers interventions that are designed to improve the physical or emotional status of patients. 2. A person licensed, certified, or otherwise authorized or permitted by law to administer health care in the ordinary course of business or practice of a profession, including a healthcare facility. [1. PR Project; 2. HL7] healthy volunteer. Subject (not a patient) in a clinical trial. NOTE: Usually healthy volunteers serve as subjects in Phase 1 trials. human subject. Individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. [21 CFR 50.3]. Synonym: subject/trial subject.
Huriet Law. France’s regulations covering the initiation and conduct of clinical trials.
HyperText Markup Language (HTML). A specification of the W3C that provides markup of documents for display in a Web browser. [HL7] Contrast to XML. hypertext. Links in a document that permit browsers to jump immediately to another document. NOTE: In most browsers links are displayed as colored, underlined text. hypothesis to test. In a trial, a statement relating to the possible different effect of the interventions on an outcome. The null hypothesis of no such effect is amenable to explicit statistical evaluation by a hypothesis test, which generates a P value. [CONSORT Statement] impartial witness. A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. [ICH] inclusion criteria. The criteria in a protocol that prospective subjects must meet to be eligible for participation in a study. NOTE: Exclusion and inclusion criteria define the study population. See also exclusion criteria. independent data monitoring committee (IDMC). A committee established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify, or terminate the trial. [ICH E9] See also data monitoring committee.
252
independent ethics committee (IEC). An independent body (a review board or a committee, institutional, regional, national, or supranational) constituted of medical/scientific professionals and non-scientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. NOTE: The legal status, composition, function, operations, and regulatory requirements pertaining to independent ethics committees may differ among countries, but should allow the independent ethics committee to act in agreement with GCP as described in the ICH guideline. [ICH] See also institutional review board. indication. A health problem or disease that is identified as likely to be benefited by a therapy being studied in clinical trials. NOTE: Where such a benefit has been established and approved by regulatory authorities, the therapy is said to be approved for such an indication. informed consent. An ongoing process that provides the subject with explanations that will help in making educated decisions about whether to begin or continue participating in a trial. Informed consent is an ongoing, interactive process, rather than a onetime information session. NOTE: Under 21 CFR 50.20, no informed consent form may include any “language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.” [ICH] See also consent form. inspection. The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). [ICH] See also audit. institution (medical). Any public or private entity or agency or medical or dental facility where clinical trials are conducted. [ICH] institutional review board (IRB). An independent body constituted of medical, scientific, and non-scientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects. [ICH E6 1.31] Synonyms: independent review board, independent ethics committee, committee for the protection of human subjects. instrument. A means to capture data (e.g., questionnaire, diary) plus all the information and documentation that supports its use. NOTE: Generally, instruments include clearly defined methods and instructions for administration or responding, a standard format for data
253 collection, and well-documented methods for scoring, analysis, and interpretation of results. [from PRO Draft Guidance] Compare to questionnaire, survey (see Comments on Draft PRO Guidance, April 4, 2006 by ISOQoL, p. 8) intention-to-treat. The principle that asserts that the effect of a treatment policy can be best assessed by evaluating the basis of the intention to treat a subject (i.e., the planned treatment regimen) rather than the actual treatment given. NOTE: This has the consequence that subjects allocated to a treatment group should be followed up, assessed, and analyzed as members of that group irrespective of their compliance with the planned course of treatment. The principle is intended to prevent bias caused by loss of participants that may reflect nonadherence to the protocol and disrupt baseline equivalence established by random assignment. [ICH E9; after CONSORT Statement] interaction (qualitative and quantitative). The situation in which a treatment contrast (e.g., difference between investigational product and control) is dependent on another factor (for example, the center). A quantitative interaction refers to the case where the magnitude of the contrast differs at the different levels of the factor; for a qualitative interaction, the direction of the contrast differs for at least one level of the factor. interim analysis(es). Analysis comparing intervention groups at any time before the formal completion of the trial, usually before recruitment is complete. [CONSORT Statement] interim analysis schedule. The time/information points at which interim analyses are planned. interim clinical trial/study report. A report of intermediate results and their evaluation based on planned analyses performed during the course of a trial. [ICH] internal consistency. Pertaining to data that do not include contradictions.
Internet. A global system of computer networks that provides the common TCP IP infrastructure for email, the World Wide Web, and other online activities.
Internet service provider (ISP). A company that provides access to the Internet for individuals and organizations. interoperability. Ability of two or more systems or components to exchange information and to use the information that has been exchanged. [IEEE Standard Computer Dictionary]. See also syntactic, semantic. inter-rater reliability. The property of scales yielding equivalent results when used by different raters on different occasions. [ICH E9] intervention. The drug, device, therapy, or process under investigation in a clinical study that is believed to have an effect on outcomes of interest in a study: e.g., health-related quality of life, efficacy, safety, pharmacoeconomics. Synonyms: therapeutic intervention,
254 medical product. See also: test articles; devices; drug product; medicinal product; combination product. investigational product. A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. NOTE: CDISC includes test articles in its definition of investigational products. [ICH] investigational treatment. An intervention under investigation in a clinical study. investigator. An individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. [21 CFR 50.3] See also sponsor-investigator, site investigator. investigator/institution. An expression meaning “the investigator and/or institution, where required by the applicable regulatory requirements.” [ICH E6 1.35] investigator’s brochure. A compilation of the clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s) in human subjects. item. 1. A representation of a clinical variable, fact, concept, or instruction in a manner suitable for communication, interpretation, or processing by humans or by automated means. NOTE: Items are collected together to form item groups. 2. An individual question, statement, or task that is evaluated by the patient to address a particular concept to be measured by a PRO instrument. [1. CDISC. 2. from PRO Draft Guidance] See also response option. item definition. 1. In a questionnaire or form to be completed in a clinical trial, the specification of a question and the specification of the format and semantics of the response. 2. Formal specification of the properties of an item or field of data in an eClinical trial. [2. ODM] item generation. Establishing the content to be covered by the items in a PRO instrument, including generating item wording, evaluating the completeness of item coverage of the concepts of interest, and performing initial assessment of clarity and readability. NOTE. PRO instrument item generation is potentially incomplete without patient involvement. [from ISOQOL comments on PRO Draft Guidance] item group definition. The specification in an eClinical trial of a collection of items often clinically related to each other and useful to consider as an ensemble. NOTE: Item groups are likely to have greater granularity in analysis datasets using SDTM which can, for
255 example, distinguish between different therapy types: study therapy, prior therapy, concomitant therapy, protocol forbidden therapies, rescue therapies. [ODM]
Janus. 1. A logical design conceived by the FDA for a data warehouse intended to integrate submission data, protocol descriptions, and analysis plans from clinical and animal studies into as an FDA review environment that uses a set of validated, standards-based tools to allow reproducible cross-study, data mining, and retrospective comparative analysis. 2. The name assigned to a component of the NCI’s caBIG Clinical Research Information Exchange (CRIX) initiative, representing a joint NCI/FDA project to develop a physical implementation of the Janus model. NOTE: Sometimes written as JANUS, the term is not an acronym, but harkens to the Roman god of gates and doors, beginnings and endings. label. Description of a drug product/device that includes: the indication, who should use it, adverse events, instructions for use, and safety information. NOTE: Labels must be approved by regulatory authorities. [FDA; SPL] Synonyms: package insert, patient package leaflet. labeling (content of). All text, tables, and figures in labeling as described in regulations for a specific product (e.g., 21 CFR 201.56 and 201.57 for human prescription drugs; 201.66 for human over-the-counter drugs; 21 CFR 801 for medical devices; and 21 CFR 606.122 for blood products). See also structured product label. laboratory (clinical). A laboratory providing analyses of samples collected in clinical care or research. last subject out/complete (LSC/LPC or LSO/LPO). 1. The date and time when the last subject has reached a planned or achieved milestone representing the completion of the trial. 2. The last subject to complete a trial. See also subject, patient, completion. last subject/patient in (LSI/LPI). Date and time when the last subject to participate in a clinical trial is enrolled. See also enroll, study initiation. legal authentication. A completion status in which a document has been signed manually or electronically by the individual who is legally responsible for that document. [HL7] legally acceptable representative. An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical trial. [ICH, E6 Glossary]
Leiter der klinischen Prüfung. Under the German Drug Law, the physician who is head of the clinical investigation. life-threatening adverse event/experience. Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death. [FDA 21 CFR §312.32; ICH-E2A]
256 longitudinal study. Investigation in which data are collected from a number of subjects over a long period of time (a well-known example is the Framingham Study). mapping. In the context of representing or exchanging data, connecting an item or symbol to a code or concept. Compare with translation. marketing support trials. Clinical studies that are designed to clarify therapeutic benefits of a marketed product or to show potential decisionmakers the rationale for preferring one therapy over another. markup. Computer-processable annotations within a multimedia document. NOTE: In the context of the HL7 specification, markup syntax is according to the XML Specification. [HL7] masking. See blinding. matched-pair design. A type of parallel trial design in which investigators identify pairs of subjects who are “identical” with respect to relevant factors, then randomize them so that one receives Treatment A and the other Treatment B. See also pairing. matching. See pairing. mean. The sum of the values of all observations or data points divided by the number of observations; an arithmetical average. median. The middle value in a data set; that is, just as many values are greater than the median and lower than the median value. (With an even number of values, the conventional median is halfway between the two middle values.) medical monitor. A sponsor representative who has medical authority for the evaluation of the safety aspects of a clinical trial. medical product. See intervention. medicinal product. Synonym for therapeutic intervention, but usually a drug.
Medicines and Healthcare products Regulatory Agency (MHRA). The UK government agency responsible for ensuring that medicines and medical devices work, and are acceptably safe. [MHRA] mega-trials. Massive clinical trials that test the advantages of therapeutic interventions by enrolling 10,000 or more subjects. Synonym: large sample trials.
Memorandum of Understanding (MOU). A formal agreement between the Food and Drug Administration (FDA) and federal, state, or local government agencies; academic institutions; and other entities. NOTE: The MOU constitutes an understanding between the parties but is a non-binding agreement. It is FDA’s policy to enter into MOUs with other
257 entities whenever there is a need to define lines of authority or responsibility, or to clarify cooperative procedures.. message (HL7). The atomic unit of data transferred between systems. It comprises a group of segments in a defined sequence. Each message has a message type that defines its purpose. NOTE: For example, the Admission, Discharge and Transfer (ADT) Message type is used to transmit portions of a patient’s ADT data from one system to another. In HL7, a three-character code contained within each message identifies its type. [HL7] meta-analysis. The formal evaluation of the quantitative evidence from two or more trials bearing on the same question. NOTE: This most commonly involves the statistical combination of summary statistics from the various trials, but the term is sometimes also used to refer to the combination of the raw data. [from ICH E9 Glossary] metabolism. The biochemical alteration of substances introduced into the body. metadata. Data that describe other data, particularly XML tags characterizing attributes of values in clinical data fields. migration. The act of moving a system or software product (including data) from an old to new operational environment in accordance with a software quality system. [ISO/IEC/IEEE 12207:1995 §5.5.5] missing data. 1. Data not completed, or corrupted in reports and case report forms. 2. Particularly the data not captured when a subject withdraws from a trial. NOTE: Reviewers are concerned about missing data (meaning 2) since patients who are not improved or who believe they have experienced side effects may be particularly prone to leave a trial, thus skewing the analysis of results if such analysis were to be done only on the subjects who had continued with the trial. Trial designs therefore specify plans for how such missing data will be treated in analysis. See also intention to treat. mode. The most frequently occurring value in a data set. model. A formal structure for representing and analyzing a process such as a clinical trial or the information pertaining to a restricted context, e.g., clinical trial data. [CDISC] modem. From modulator/ demodulator; a device that converts digital data into analog data that can be transmitted via telephone or cable lines used for communications. monitor. Person employed by the sponsor or CRO who is responsible for determining that a trial is being conducted in accordance with the protocol and GCP guidance. NOTE: A monitor’s duties may include, but are not limited to, helping to plan and initiate a trial, assessing the conduct of trials, and assisting in data analysis, interpretation, and extrapolation. Monitors work with the clinical research coordinator to check all data and documentation from the trial. [from ICH E6, 5.18] See also clinical research associate.
258 monitoring. The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s). [ICH E6 Glossary] monitoring committee. See independent data-monitoring committee. monitoring report. A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs. [ICH] monitoring visit. A visit to a study site to review the progress of a clinical study and to ensure protocol adherence, accuracy of data, safety of subjects, and compliance with regulatory requirements and good clinical practice guidelines. [from ICH E6, 5.18] multicenter study. See multicenter trial. multicenter trial. Clinical trial conducted according to a single protocol but at more than one site, and, therefore, carried out by more than one investigator. [ICH E9 Glossary] Synonym: multicenter study. See investigator/institution. natural language. Language as used in ordinary communications among humans and distinguished from controlled terminologies and structured languages used exclusively for communication and interoperability among machines.
New Drug Application (NDA). An application to FDA for a license to market a new drug in the United States. n-of-1 study. A trial in which an individual subject is administered a treatment repeatedly over a number of episodes to establish the treatment’s effect in that person, often with the order of experimental and control treatments randomized. nomenclature. Application of naming conventions. Compare with vocabulary, terminology. nonclinical study. Biomedical studies not performed on human subjects. [ICH E6 Glossary] not approvable letter. An official communication from FDA to inform a sponsor of a marketing application that the important deficiencies described in the letter preclude approval unless corrected.
Notified Body (NB). A private institution charged by the Competent Authority with verifying compliance of medical devices (not drugs) with the applicable Essential Requirements stated in the Medical Device Directive. This process, called Conformity Assessment, has EU-wide validity once completed by the NB. null hypothesis. The assertion that no true association or difference in the study outcome or comparison of interest between comparison groups exists in the larger population from which the study samples are obtained. NOTE: A null hypothesis (for example,“subjects will
259 experience no change in blood pressure as a result of administration of the test product”) is used to rule out every possibility except the one the researcher is trying to prove, and is used because most statistical methods are less able to prove something true than to provide strong evidence that it is false. The assertion that no true association or difference in the study outcome or comparison of interest between comparison groups exists in the larger population from which the study samples are obtained. See also research hypothesis. [from AMA Manual of Style]
Nuremberg Code. Code of ethics, set forth in 1947, for conducting human medical research. objective. The reason for performing a trial in terms of the scientific questions to be answered by the analysis of data collected during the trial. NOTE: The primary objective is the main question to be answered and drives any statistical planning for the trial (e.g., calculation of the sample size to provide the appropriate power for statistical testing). Secondary objectives are goals of a trial that will provide further information on the use of the treatment. objective measurement. A measurement of a physiological or medical variable such as blood glucose level that is obtained by a measuring device rather than a human judgment or assessment. See also outcome, patient-reported outcome; objective measures are observations (SDTM) and could be endpoints. Patient-reported outcomes are subjective measurements. observation. 1. An assessment of patient condition or analysis of data collected on an individual patient or group of patients. 2. (SDTM) A discrete piece of information collected during a study. NOTE: Observations (meaning 1) are required by protocol (e.g., require evaluation of patient or data by investigator/staff). Such planned observations are typically distinguished from anecdotal comments noted during a clinical trial (which qualify as observations under meaning 2). See also variable. Referring to an ad hoc comment as an observation is colloquial. [1. CONSORT Statement. 2. SDTM] observer assessment. An assessment of patient condition made by an observer (investigator, nurse, clinician, family member, etc.). NOTE: Distinguished from self- assessment. The observer relies on his or her judgment to assess the subject. An interviewer simply capturing subject self assessments is not making an observer assessment. Compare to PRO, proxy assessment. ontology. An explicit formal specification of how to represent relationships among objects, concepts, and other entities that belong to a particular domain of experience or knowledge. See also terminology. open-label study. A trial in which subjects and investigators know which product each subject is receiving; opposite of a blinded or double-blind study. See blinding. open to enrollment. The status of a study such that a subject can be enrolled into that study. NOTE: Registry terminology in common use is “open to recruitment”; however, recruitment can begin upon IRB approval of the site; whereas enrollment requires
260 availability of study supplies, subject informed consent, etc., to allow participation of eligible subjects. operational model. The set of CDISC data standards (including ODM and LAB) used to capture and archive data from clinical trials. opinion (in relation to independent ethics committee). The judgment and/or the advice provided by an independent ethics committee. [ICH E6 Glossary] origin. 1. Source of information collected in the course of a clinical trial. Specifically used to differentiate between data collected at point of patient contact and data that are derived or calculated. 2. (SDTM) A metadata attribute defined for each dataset variable in the “Define” document of an SDTM submission that refers to the source of a variable (e.g., CRF, derived, sponsor defined, PRO, etc.). [1. CONSORT Statement. 2. from SDTM for descriptions of the Define document] original data. The first recorded study data values. NOTE: FDA is allowing original documents and the original data recorded on those documents to be replaced by copies provided that the copies have been verified as identical in content and meaning. (See FDA Compliance Policy Guide 7150.13). [Modified from CSUICI] See also certified copy, source. outcome (of adverse event). Refers to the resolution of an adverse event. NOTE: Often denoted using a pick list from a controlled terminology such as: Recovered/resolved, recovering/ resolving, not recovered/not resolved, recovered /resolved with sequelae, fatal, or unknown. [SDTM Events class of observation] outcome. 1. Events or experiences that clinicians or investigators examining the impact of an intervention or exposure measure because they believe such events or experiences may be influenced by the intervention or exposure. 2. (SDTM) The result of carrying out a mathematical or statistical procedure. NOTE: 1. Such events and experiences are called clinical outcomes independently of whether they are part of the original question/protocol of the investigation. [1. Guyatt, G., Schunemann H., Dept. Epidemiology & Statistics, McMaster University—personal communication] See also variable; outcome can be a result of analysis; outcome is more general than endpoint in that it does not necessarily relate to a planned objective of the study. outcomes research. Research concerned with benefits, financial costs, healthcare system usage, risks, and quality of life as well as their relation to therapeutic interventions. NOTE: Usually distinguished from research conducted solely to determine efficacy and safety. [Guyatt et al., 1993] See also pharmacoeconomics, quality of life. outliers. Values outside of an expected range. packaging. The material, both physical and informational, that contains or accompanies a marketed or investigational therapeutic agent once it is fully prepared for release to patients and/or subjects in clinical trials.
261 pairing. A method by which subjects are selected so that two subjects with similar characteristics (for example, weight, smoking habits) are assigned to a set, but one receives Treatment A and the other receives Treatment B. See also matched-pair design. parallel trial. Subjects are randomized to one of two or more differing treatment groups (usually investigational product and placebo) and usually receive the assigned treatment during the entire trial. Synonyms: parallel group trial, parallel design trial. parameter. A variable in a model, or a variable that wholly or partially characterizes a probability distribution (mathematics and statistics). NOTE: In clinical trials the term is often used synonymously with “variable” for factual information (age, date of recovery), measurements, and clinical assessments. It is most appropriately linked to statistical conventions and as a numeric characteristic of a population. Parameters are rarely known and are usually estimated by statistical computation from samples. Thus the term is narrower than variable. [Parexel Barnett; ADaM; HyperStat Online] See also variable, outcome. participant. A person or entity with a role in healthcare or a clinical study. NOTE: Participants in a clinical trial may include subjects and study personnel. A subject participates as part of the group of people who are administered the therapeutic intervention or control. See also subject, patient. password aging. A practice applying to multi-user computer systems where the validity of a password expires after a certain pre-set period. NOTE: FDA requires that passwords that are part of electronic signatures be “periodically checked, recalled or revised”, but does not mandate password aging. [After NIST, 21 CFR Part 11] patient. Person under a physician’s care for a particular disease or condition. NOTE: A subject in a clinical trial is not necessarily a patient, but a patient in a clinical trial is a subject. See also subject, trial subject, healthy volunteer. Although often used interchangeably as a synonym for subject, a healthy volunteer is not a patient. patient file. One that contains demographic, medical, and treatment information about a patient or subject. It may be paper- or computer-based or a mixture of computer and paper records. patient-reported outcome (PRO). Information coming directly from patients or subjects through interviews or self-completed questionnaires or other data capture tools such as diaries about their life, health condition(s), and treatment. NOTE: PROs are used to assess outcomes involving the patients’/subjects’ perceptions, symptoms, satisfaction with treatment, adherence to prescribed regimens. PROs include outcomes recorded by interviewers transcribing the views expressed by the patient, but the term does not apply to outcomes recorded by observers who rely on their own judgment. A PRO is usually a subjective assessment of feeling or function distinguished from a self-reported objective measurement such as body weight. [from PRO Draft Guidance, Gordon Guyatt and Holger Schuneman-personal communication; Patrick, D.L., 2003. After Acquardo C., Berzon C., et
262 al., 2001] Synonym: subject-reported outcome (SRO). See also outcome, subject, patient, instrument. performed activity. Clinical trial events as they actually occurred (as compared with events planned in the protocol). permissible values. Limited universe of options for data items. (e.g., drop-down menus, codelists, pick lists). per-protocol analysis set. The set of data generated by the subset of subjects who complied with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment according to the underlying scientific model. [ICH E9] period effect. An effect occurring during a period of a trial in which subjects are observed and no treatment is administered. permanent data. Data that become or are intended to become part of an electronic record in relation to a regulatory submission. NOTE: Any changes made to such permanent data are recorded via an audit trail so that prior values are not obscured. pharmacodynamics. Branch of pharmacology that studies reactions between drugs and living structures, including the physiological responses to pharmacological, biochemical, physiological, and therapeutic agents. pharmacoeconomics. Branch of economics that applies cost-benefit, cost-utility, cost- minimization, and cost-effectiveness analyses to assess the utility of different pharmaceutical products or to compare drug therapy to other treatments. pharmacogenetic test. An assay intended to study interindividual variations in DNA sequence related to drug absorption and disposition or drug action. Compare to pharmacogenomic test. pharmacogenetics. Study of the way drugs interact with genetic makeup or the study of genetic response to a drug. pharmacogenomic test. An assay intended to study interindividual variations in wholegenome or candidate gene maps, biomarkers, and alterations in gene expression or inactivation that may be correlated with pharmacological function and therapeutic response. Compare to pharmacogenetic test. pharmacogenomics. Science that examines inherited variations in genes that dictate drug response and explores the ways such variations can be used to predict whether a person will respond favorably, adversely, or not at all to an investigational product. pharmacokinetics. Study of the processes of bodily absorption, distribution, metabolism, and excretion (ADME) of medicinal products.
263 pharmacology. Science that deals with the characteristics, effects, and uses of drugs and their interactions with living organisms. pharmacovigilance. Term used for adverse event monitoring and reporting. phase. One in a set of successive stages in a progression or sequence such as 1. a step in the progression of a therapy from initial experimental use in humans to postmarket evaluation. 2. a stage in the conduct of a clinical trial. NOTE: Clinical trials are generally categorized into four (sometimes five) phases. A therapeutic intervention may be evaluated in two or more phases simultaneously in different trials, and some trials may overlap two different phases. For meaning 1, see Phase 0–5. For meaning 2, see epoch.
Phase 0. First-in-human trials, in a small number of subjects, that are conducted before Phase 1 trials and are intended to assess new candidate therapeutic and imaging agents. The study agent is administered at a low dose for a limited time, and there is no therapeutic or diagnostic intent. NOTE: FDA Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies, January 2006 classifies such studies as Phase 1. [Improving the Quality of Cancer Clinical Trials: Workshop Summary – Proceedings of the National Cancer Policy Forum Workshop, Improving the Quality of Cancer Clinical Trials (Washington, DC – Oct 2007)]
Phase 1. The initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. NOTE: These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug’s pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80. Phase 1 studies also include studies of drug metabolism, structure–activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. [After FDA CDER Handbook, ICH E8]
Phase 2. Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. NOTE: Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects. [After FDA CDER Handbook, ICH E8]
Phase 2A. Controlled clinical studies that occur after the completion of Phase 1 studies and the first set of exposure-response studies in patients, and before beginning Phase 2B (i.e., patient dose-ranging trial) and Phase 3 clinical efficacy-safety studies. [FDA draft Guidance for Industry End of Phase 2A meetings, 9/08].
264
Phase 3. Studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to confirm efficacy and evaluate the overall benefit–risk relationship of the drug and to provide an adequate basis for physician labeling. NOTE: Phase 3 studies usually include from several hundred to several thousand subjects. [After FDA CDER Handbook, ICH E8]
Phase 3B. A subcategory of Phase 3 trials done near the time of approval to elicit additional findings. NOTE: Dossier review may continue while associated Phase 3B trials are conducted. These trials may be required as a condition of regulatory authority approval.
Phase 4. Postmarketing (Phase 4) studies to delineate additional information about the drug’s risks, benefits, and optimal use that may be requested by regulatory authorities in conjunction with marketing approval. NOTE: These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in Phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time. [After FDA CDER Handbook, ICH E8]
Phase 5. Postmarketing surveillance is sometimes referred to as Phase 5. See also outcomes research. placebo. A pharmaceutical preparation that does not contain the investigational agent. In blinded studies, it is generally prepared to be physically indistinguishable from the preparation containing the investigational product. population. Any finite or infinite collection of subjects from which a sample is drawn for a study to obtain estimates for values that would be obtained if the entire population were sampled. [AMA Style Manual] postmarketing surveillance. Ongoing safety monitoring of marketed drugs. See also Phase 4 studies, Phase 5 studies. pragmatic trial. Term used to describe a clinical study designed to examine the benefits of a product under real world conditions. preamble. A section preceding the text of a final FDA regulation published in the Federal Register. NOTE: “The preamble is to contain a thorough and comprehensible explanation of the reasons for the Commissioner's decision on each issue” raised in comments submitted in response to the proposed regulation. [from 21CFR10.40] preclinical studies. Animal studies that support Phase 1 safety and tolerance studies and must comply with good laboratory practice (GLP). NOTE: Data about a drug’s activities and effects in animals help establish boundaries for safe use of the drug in subsequent human testing (clinical studies or trials).
Pre-Market Approval Application (PMA). An application to FDA for a license to market a new device in the United States.
265
primary objective. The primary objective(s) is the main question to be answered and drives any statistical planning for the trial (e.g., calculation of the sample size to provide the appropriate power for statistical testing). [ICH E6 6.3] See also objective. primary variable. An outcome variable specified in the protocol to be of greatest importance to the primary objective of the trial, usually the one used in the sample size calculation. NOTE: Differences between groups in the primary and secondary variable(s) are believed to be the result of the group-specific interventions. [PR Project; CONSORT Statement] Synonyms: primary endpoint, outcome. See also primary objective. product. 1. Drug product: A finished dosage form that contains a drug substance. 2. A physical entity that is intended to diagnose, treat, or prevent a disease or other abnormal condition, and subject to regulatory authority. [Modified from FDA Glossary of Terms]
PROMIS. NIH-sponsored project for the development and evaluation of PRO item banks and computer adaptive testing for pain, fatigue, physical function, social function, and emotional well-being. [NIH] proprietary name. A commercial name granted by a naming authority for use in marketing a drug/device product. [SPL] Synonyms: trade name, brand name. prospective study. Investigation in which a group of subjects is recruited and monitored in accordance with criteria described in a protocol. protocol. A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments. NOTE: Present usage can refer to any of three distinct entities: 1) the plan (i.e., content) of a protocol, 2) the protocol document, and 3) a series of tests or treatments (as in oncology). [ICH E6 Glossary] protocol amendment(s). A written description of a change(s) to or formal clarification of a protocol. [ICH E3] protocol approval (Sponsor). Sponsor action at the completion of protocol development that is marked when the signature of the last reviewer on the protocol approval form has been obtained, signifying that all reviewer changes to the protocol have been incorporated. NOTE: Approval by the sponsor usually initiates secondary approvals by IRBs, regulatory authorities, and sites. Protocol amendments usually also require a cycle of approval by sponsor and study staff prior to taking effect. protocol deviation. A variation from processes or procedures defined in a protocol. Deviations usually do not preclude the overall evaluability of subject data for either efficacy or safety, and are often acknowledged and accepted in advance by the sponsor. NOTE: Good clinical practice recommends that deviations be summarized by site and by category
266 as part of the report of study results so that the possible importance of the deviations to the findings of the study can be assessed. Compare to protocol violation. [See ICH E3]
Protocol Identifying Number. Any of one or more unique codes that refers to a specific protocol. NOTE: There may be multiple numbers (Nat’l number, coop group number). [PR Project; eudraCT] protocol referenced documents. Protocol referenced documents that optionally supplement the ICH GCP recommended sections of a protocol giving background information and rationale for the trial. [from ICH E6 1.44] See also protocol. protocol title. Three categories of protocol title have evolved to address distinct standardized use cases. 1) Scientific Title: A comprehensive summary of study design and objectives, aimed at scientific audience. 2) Public Title: A brief description intended for the lay public in easily understood language. 3) Trial Acronym: Brief popular identifier. NOTE: The scientific title should include the trial acronym, if applicable [WHO http://www.who.int/ ictrp/data_set/en/index1.html]. Scientific title may also be referred to as ”official title.” Public title may also be referred to as “brief title.” protocol violation. A significant departure from processes or procedures that were required by the protocol. Violations often result in data that are not deemed evaluable for a perprotocol analyis, and may require that the subject(s) who violate the protocol be discontinued from the study. Compare to protocol deviation. proxy (as an origin of outcome measures). A proposed standardized qualifier variable to describe the origin of observations of the Findings class resulting from outcomes measures. Proxy describes outcome data furnished by someone other than the patient and distinguishes the origin of the outcome from a self-report (PRO) directly from the patient. NOTE: The term proxy helps qualify outcomes measures that record feelings and symptoms reported by the patient but not recorded directly. [CDISC (extension of SDTM based on Table 2 Patrick, D.L., 2003)] See also observer assessment. proxy respondent. Someone other than the patient who is responding about the patient on behalf of the patient, not as an observer. [Patrick, D.L., 2003; DIA ePRO Workgroup] Compare to observer assessment. psychometric reliability. See reliability, psychometric. psychometric validation. The specialized process of validating questionnaires used in outcomes research to show that they measure what they purport to measure. NOTE: Several types of validity are distinguished. For example, face validity means that an assessment instrument appears by inspection and consideration of the semantic content of items in it to be measuring what it is supposed to measure. Construct validity means that a scale based on one or more items measures an unobservable psychological construct (e.g., “distress”) that it is proposed to measure. Construct validity is usually tested by measuring the correlation in assessments obtained from several scales purported to measure the same
267 construct. [Guyatt et al., 1993; DIA ePRO Workgroup] See also validation; compare to psychometric reliability. psychometrics. The science of assessing the measurement characteristics of scales that assess human psychological characteristics. p-value. Study findings can also be assessed in terms of their statistical significance. The p- value represents the probability that the observed data (or a more extreme result) could have arisen by chance when the interventions did not differ. [CONSORT Statement] qualitative variable. One that cannot be measured on a continuum and represented in quantitative relation to a scale (race or sex, for example). Data that fit into discrete categories according to their attributes. quality assurance (QA). All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with good clinical practice (GCP) and the applicable regulatory requirement(s). [ICH] quality control (QC). The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial related activities have been fulfilled. [ICH] quality of life. A broad ranging concept that incorporates an individual’s physical health, psychological state, level of independence, social relationships, personal beliefs, and their relationships to salient features of the environment. NOTE: Quality of Life is one way to measure the benefits or negative impacts of an “improvement” measured in terms of a physiological or psychological symptom. QOL research seeks to quantify what an intervention means to a patient’s sense that their life has changed. [WHO Group, 1994] quantitative variable. One that can be measured and reported numerically to reflect a quantity or amount, ideally on a continuum. query. A request for clarification on a data item collected for a clinical trial; specifically a request from a sponsor or sponsor’s representative to an investigator to resolve an error or inconsistency discovered during data review. query management. Ongoing process of data review, discrepancy generation, and resolving errors and inconsistencies that arise in the entry and transcription of clinical trial data. query resolution. The closure of a query usually based on information contained in a data clarification. questionnaire. A set of questions or items shown to a respondent in order to get answers for research purposes. [PRO Draft Guidance] See also instrument, survey.
268 random allocation. Assignment of subjects to treatment (or control) groups in an unpredictable way. NOTE: In a blinded study, assignment sequences are concealed, but available for disclosure in the event a subject has an adverse experience. random number table. Table of numbers with no apparent pattern used in the selection of random samples for clinical trials. random sample. Members of a population selected by a method designed to ensure that each person in the target group has an equal chance of selection. randomization. The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. NOTE: Unequal randomization is used to allocate subjects into groups at a differential rate; for example, three subjects may be assigned to a treatment group for every one assigned to the control group. [ICH E6 1.48] See also balanced study. raw data. Data as originally collected. Distinct from derived. Raw data includes records of original observations, measurements, and activities (such as laboratory notes, evaluations, data recorded by automated instruments) without conclusions or interpretations. Researcher’s records of subjects/patients, such as patient medical charts, hospital records, X-rays, and attending physician’s notes. NOTE: These records may or may not accompany an application to a Regulatory Authority, but must be kept in the researcher’s file. See also eSource, source data, source documents.
RCRIM. Regulated Clinical Research and Information Management, which is a Technical Committee within HL7 (an acronym pronounced “arcrim”). reconstruction (of a study). For eClinical trials FDA expects archival trial records to support review of the data as well as the processes used for obtaining and managing the data so that the trustworthiness of results obtained can be evaluated. NOTE: Reconstruction from records should support evaluation of the operation and validity of computerized systems and the conformance of the systems to applicable regulations during design and execution of the trial as well as during the period of record retention. [from CSUCT VI D, 21 CFR Parts 11, 312] recruitment (investigators). Process used by sponsors to identify, select, and arrange for investigators to serve in a clinical study. recruitment (subjects). Process used by investigators to find and enroll appropriate subjects (those selected on the basis of the protocol’s inclusion and exclusion criteria) into a clinical study. recruitment period. Time period during which subjects are or are planned to be enrolled in a clinical trial.
269 recruitment target. Number of subjects that must be recruited as candidates for enrollment into a study to meet the requirements of the protocol. In multicenter studies, each investigator has a recruitment target.
Reference Information Model (RIM). An information model used as the ultimate defining reference for all HL7 standards. [HL7] registry. A data bank of information on clinical trials for drugs for serious or life-threatening diseases and conditions. NOTE: The registry should contain basic information about each trial sufficient to inform interested subjects (and their healthcare practitioners) how to enroll in the trial. [FDAMA 113] regulatory authorities. Bodies having the power to regulate. NOTE: In the ICH GCP guideline the term includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities. [ICH] Synonym: regulatory agencies. reliability, psychometric. The degree to which a psychometric “instrument” is free from random error either by testing the homogeneity of content on multi-item tests with internal consistency evaluation or testing the degree to which the instrument yields stable scores over time. NOTE: Reliability pertains to questions concerning whether an instrument is accurate, repeatable, sensitive. Reliability is distinguished from validation, which answers whether the instrument (e.g., questionnaire) actually measure the selected “construct” (latent variable). For example a balance (scale) is easily understood as a possibly valid instrument to measure body weight. Its reliability would be assessed by measuring the sensitivity, repeatability and accuracy of the balance. The validity of using the balance for a particular purpose could then be established by comparing the measured reliability to the reliability required for that purpose. [After Patrick, D.L., 2003] Compare to psychometric validation; see also validation; instrument. repeat rule. Guide for repeating activities specified in protocol, including such features as the number of cycles and the criteria for stopping. replacement. The act of enrolling a clinical trial subject to compensate for the withdrawal of another. representative. See legally acceptable representative. research hypothesis. The proposition that a study sets out to support (or disprove); for example, “blood pressure will be lowered by [specific endpoint] in subjects who receive the test product.” See also null hypothesis. response option. One of several choices to be available for selection in response to a prompt, question or instruction (i.e., a stem) in a PRO item. See also common data element, stem.
270 retrospective. Capture of clinical trial data is retrospective when it is recalled from memory rather than captured contemporaneously in realtime. NOTE: Retrospective capture is important in PROs because of “recall bias” and other errors documented in psychological research comparing contemporaneous self-reported assessments and those that rely on recall from memory. risk. In clinical trials, the probability of harm or discomfort for subjects. NOTE: Acceptable risk differs depending on the condition for which a product is being tested. A product for sore throat, for example, will be expected to have a low incidence of troubling side effects. However, the possibility of unpleasant side effects may be an acceptable risk when testing a promising treatment for a life-threatening illness. role. 1. The function or responsibility assumed by a person in the context of a clinical study. Examples include data manager, investigator. 2. Classifier for variables that describe “observations” in the SDTM. Role is a metadata attribute that determines the type of information conveyed by an observation-describing variable and standardizes rules for using the describing variable. [1. HL7. 2. SDTM] See also functional role. safety. Relative freedom from harm. In clinical trials, this refers to an absence of harmful side effects resulting from use of the product and may be assessed by laboratory testing of biological samples, special tests and procedures, psychiatric evaluation, and/or physical examination of subjects. safety and tolerability. The safety of a medical product concerns the medical risk to the subject, usually assessed in a clinical trial by laboratory tests (including clinical chemistry and hematology), vital signs, clinical adverse events (diseases, signs, and symptoms), and other special safety tests (e.g., ECGs, ophthalmology). The tolerability of the medical product represents the degree to which overt adverse effects can be tolerated by the subject. [ICH E9] sample size. 1. A subset of a larger population, selected for investigation to draw conclusions or make estimates about the larger population. 2. The number of subjects in a clinical trial. 3. Number of subjects required for primary analysis. sample size adjustment. An interim check conducted on blinded data to validate the sample size calculations or re-evaluate the sample size. schedule of activities. A standardized representation of planned clinical trial activities including interventions (e.g., administering drug, surgery) and study administrative activities (e.g,. obtaining informed consent, distributing clinical trial material and diaries, randomization) as well as assessments. See also schedule of assessments. schedule of assessments. A tabular representation of planned protocol events and activities, in sequence. [after E3 Annexes IIIa and IIIb] Synonym: flow chart. Compare to study design schematic.
271 screen failure. Potential subject who did not meet one or more criteria required for participation in a trial. See also screening of subjects. screen/screening (of substances). Screening is the process by which substances are evaluated in a battery of tests or assays (screens) designed to detect a specific biological property or activity. It can be conducted on a random basis in which substances are tested without any preselection criteria or on a targeted basis in which information on a substance with known activity and structure is used as a basis for selecting other similar substances on which to run the battery of tests. [SQA] screening (of sites). Determining the suitability of an investigative site and personnel to participate in a clinical trial. screening (of subjects). A process of active consideration of potential subjects for enrollment in a trial. See also screen failure. screening trials. Trials conducted to detect persons with early, mild, and asymptomatic disease. script. A program or a sequence of instructions that are interpreted or carried out by another program or by a person. secondary objective. See objective. secondary sponsor. Additional individuals, organizations or other legal persons, if any, that have agreed with the primary sponsor to take on responsibilities of sponsorship. [WHO, CTR Item 6] secondary variable. The primary outcome is the outcome of greatest importance. Data on secondary outcomes are used to evaluate additional effects of the intervention. [CONSORT Statement] See also outcome, endpoint. self-evident change. A data discrepancy that can be easily and obviously resolved on the basis of existing information on the CRF, e.g., obvious spelling errors or the patient is known to be a male and a date of last pregnancy is provided. See also discrepancy. semantic. In the context of a technical specification, semantic refers to the meaning of an element as distinct from its syntax. Syntax can change without affecting semantics. [HL7] serious adverse event (SAE) or serious adverse drug reaction (serious ADR). Any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. [ICH] See also adverse experience.
272 serious adverse experience. Any experience that suggests a significant hazard, contra- indication, side effect or precaution. See also serious adverse event. server. A computer that controls a central repository of data, files, and/or applications that can be accessed and/or manipulated in some manner by client computers. A file server hosts files for use by client machines. An application server runs programs that may process and display data exchanged with client machines. After the arrival of the Web, server often refers to software and computers that perform database queries and collect and present timely data to users running browsers or other client applications. sex. Phenotypic expression of chromosomal makeup that defines a study subject as male, female, or other. Compare to gender. side effects. Any actions or effects of a drug or treatment other than the intended effect. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems. Experimental drugs must be evaluated for both immediate and long- term side effects. See also adverse reaction. single-blind study. A study in which one party, either the investigator or the subject, does not know which medication or placebo is administered to the subject; also called singlemasked study. See also blind study, double-blind study, triple-blind study. single-masked study. See singleblind study. site. See trial site. site investigator. A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. [ICH E6 1.35. 2.] See also investigator. software. Computer programs, procedures, rules, and any associated documentation pertaining to the operation of a system. software validation. Confirmation by examination and provision of objective evidence that software specifications conform to user needs and intended uses, and that the particular requirements implemented through software can be consistently fulfilled. NOTE: Validating software thus should include evaluation of the suitability of the specifications to “ensure user needs and intended uses can be fulfilled on a consistent basis” (21 CFR 820.20). General Principles of Software Validation; Final Guidance for Industry and FDA Staff, Jan 11, 2002. ISO/IEC/IEEE 12207:1995 §3.35; 21 CFR 820.20; 21 CFR 11.10(a); ISO 9000-3; Huber, L. (1999) See also validation, verification. Verification usually concerns confirmation that specified requirements have been met, but typically refers to the tracing of requirements and evidence of conformance in the individual phases or modules rather than suitability of the complete product. Validation is, “the evaluation of software at the end of the software development process to ensure compliance with the user requirements” (ANSI/ASQC A3- 1978) and should not be thought of as an “end-to-end” verification.
273
source. 1. The specific permanent record(s) upon which a user will rely for the reconstruction and evaluation of a clinical investigation. 2. Sometimes used as shorthand for source documents and/or source data. NOTE: Accuracy, suitability, and trustworthiness are not defining attributes of “source”. The term identifies records planned (designated by the protocol) or referenced as the ones that provide the information underlying the analyses and findings of a clinical investigation. [After ICH E6, CSUICI] See also original data, certified copy source data. All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). [ICH E6; CSUCT] source data verification. The process of ensuring that data that have been derived from source data accurately represent the source data. source document verification. The process by which the information reported by an investigator is compared with the source records or original records to ensure that it is complete, accurate and valid. [Schuyl and Engel, 1999; Khosla et al., Indian J. Pharm 32:180– 186, 2000] Synonym: SDV. See also validation of data. source documents. Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medicotechnical departments involved in the clinical trial). See also eSource document, source, original data, certified copy. [ICH; CSUICI] special populations. Subsets of study populations of particular interest included in clinical trials to ensure that their specific characteristics are considered in interpretation of data (e.g., geriatric). [FDA] sponsor. 1. An individual, company, institution, or organization that takes responsibility for the initiation and management of a clinical trial, although may or may not be the main funding organization. If there is also a secondary sponsor, this entity would be considered the primary sponsor. 2. A corporation or agency whose employees conduct the investigation is considered a sponsor and the employees are considered investigators. [1. After ICH E6, and WHO. 2. 21 CFR 50.3 (e)] See also secondary sponsor. sponsor-investigator. An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. NOTE: The term does not include any person other than an individual (i.e., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator. [21 CFR 50.3f] [ICH]
274
standard. Criterion or specification established by authority or consensus for 1. measuring performance or quality; 2. specifying conventions that support interchange of common materials and information. NOTE: CDISC standards exist to support the exchange of clinical data, for example, at both the syntactic and semantic levels. See interoperability. standard deviation. Indicator of the relative variability of a variable around its mean; the square root of the variance. standard of care. A guideline for medical management and treatment. standard operating procedures (SOPs). Detailed, written instructions to achieve uniformity of the performance of a specific function. [ICH] standard treatment. A treatment currently in wide use and approved by the FDA or other health authority, considered to be effective in the treatment of a specific disease or condition. statistical analysis plan. A document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. [ICH E9] statistical method. The particular mathematical tests and techniques that are to be used to evaluate the clinical data in a trial. [ICH E9; from the Center for Advancement of Clinical Research] statistical significance. State that applies when a hypothesis is rejected. Whether or not a given result is significant depends on the significance level adopted. For example, one may say “significant at the 5% level.” This implies that when the null hypothesis is true there is only a 1 in 20 chance of rejecting it. stem. The prompt, question or instruction in a PRO item. See also response option, item. stochastic. Involving a random variable; involving chance or probability. stopping rules. A statistical criterion that, when met by the accumulating data, indicates that the trial can or should be stopped early to avoid putting participants at risk unnecessarily or because the intervention effect is so great that further data collection is unnecessary. stratification. Grouping defined by important prognostic factors measured at baseline. [ICH E9] structured product label (SPL). The Structured Product Labeling (SPL) specification is an HL7 ANSI-approved document markup standard that specifies the structure and semantics for the exchange of product information. [HL7]
275
study. See clinical trial. NOTE: Occasionally refers to a project of several related clinical trials. study coordinator. See clinical research coordinator. study description. Representation of key elements of study (e.g., control, blinding, gender, dose, indication, configuration). study design. Plan for the precise procedure to be followed in a clinical trial, including planned and actual timing of events, choice of control group, method of allocating treatments, blinding methods; assigns a subject to pass through one or more epochs in the course of a trial. Specific design elements, e.g., crossover, parallel; dose-escalation [Modified from Pocock, Clinical Trials: A Practical Approach] See Trial Design Model. See also, arm, epoch, and visit. study design rationale. Reason for choosing the particular study design. study design schematic. Schematic diagram (not tabular) of study design, procedures and stages. [example: ICH E3 Annexes IIIa and IIIb] Compare to schedule of assessments. study initiation date. Date and time of first subject enrollment into a study, as verifiable by a convention that is consistent with authoritative regulatory criteria. [modified from ICH E3] Compare with study start. Synonym: date of first enrollment. study population. Defined by protocol inclusion/exclusion criteria. study protocol. See protocol. study start. The formal recognition of the beginning of a clinical trial that is referred to in the clinical study report. study treatment. See investigational intervention. study variable. A term used in trial design to denote a variable to be captured on the CRF. See also variable. sub-investigator. Any member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). [ICH] See also investigator. subject data event. A subject visit or other encounter where subject data are collected, generated, or reviewed. [SDTM]
276 subject identification code. A unique identifier assigned by the investigator to each trial subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports adverse events and/or other trial-related data. [ICH] subject trial contact. Any activity, anticipated in the study protocol, involving a subject and pertaining to collection of data. See visit. subject/trial subject. An individual who participates in a clinical trial, either as recipient of the investigational product(s) or as a control. [ICH] See also healthy volunteer, human subject. subject-reported outcome (SRO). An outcome reported directly by a subject in a clinical trial. [Patrick, D.L., 2003] See also patient-reported outcome (PRO). submission model. A set of data standards (including SDTM, ADaM, and define.xml) for representing data that are submitted to regulatory authorities to support product marketing applications. NOTE: CDISC submission data consist of: tabulations that represent the essential data collected about patients; analysis data structured to support analysis and interpretation; and metadata descriptions. superiority trial. A trial with the primary objective of showing that the response to the investigational product is superior to a comparative agent (active or placebo control). [ICH E9] supplier. An organization that enters into a contract with the acquirer for the supply of a system, software product, or software service under the terms of a contract. [ISO/IEC/IEEE 12207:1995 §3.30] supporting variables. See variable. [FDA Drug Review Glossary] surrogate marker. A measurement of a drug’s biological activity that substitutes for a clinical endpoint such as death or pain relief. surrogate variable. A variable that provides an indirect measurement of effect in situations where direct measurement of clinical effect is not feasible or practical. [ICH E9] survey. Any means (e.g., questionnaire, diary, interview script, group of items) that is used to collect PRO data. NOTE: Survey refers to the content of the group of items and does not necessarily include the training and scoring documents generally not seen by respondents. [from ISOQOL comments on PRO Guidance] Compare to instrument. synopsis. Brief overview, prepared at the conclusion of a study as a routine part of a regulatory submission, summarizing the study plan and results; includes numerical summary of efficacy and safety results, study objective, criteria for inclusion, methodology, etc. [after ICH E3]
277 syntactic. The order, format, content of clinical trial data and/or documents as distinct from their meaning. NOTE: Syntactic interoperability is achieved when information is correctly exchanged between two systems according to structured rules whether or not sensible meaning is preserved. See also semantic, semantic interoperability. system. People, machines, software, applications, and/or methods organized to accomplish a set of specific functions or objectives. [ANSI] table of roles and responsibilities. A cumulative record documenting operational access and authorizations of study personnel to electronic systems used in eClinical trials. tabulation dataset. A dataset structured in a tabular format. NOTE: The CDISC Study Data Tabulation Model (SDTM) defines standards for tabulation datasets that fulfill FDA requirements for submitting clinical trial data. target enrollment. The number of subjects in a class or group (including the total for the entire trial) intended to be enrolled in a trial to reach the planned sample size. Target enrollments are set so that statistical and scientific objectives of a trial will have a likelihood of being met as determined by agreement, algorithm, or other specified process. target study population. Demographic and health condition of the population to be included in a clinical study. technology provider. A person, company, or other entity who develops, produces, and sells software applications and/or hardware for use in conducting clinical trials and/or in analyzing clinical trial data and or submitting clinical trial information for regulatory approval. Synonym: vendor. term. One or more words designating something. NOTE: In a controlled vocabulary, terms are considered to refer to an underlying concept having a single meaning. Concepts may be linked to several synonymous terms. termination (of subject). Now considered nonstandard. See discontinuation. termination (of trial). Premature discontinutation of a trial prior to plan. [EU Clinical Trial Directive] terminology. 1. Set of concepts, designations, and relationships for a specialized subject area. See Glossary. 2. In the context of clinical research in human subjects, a standardized, finite set of terms (e.g., picklists, medDRA codes) that denote patient findings, circumstances, events, and interventions. Compare with glossary, which is a list of words and their definitions pertaining to usage in a particular field or context. Often used synonymously with vocabulary. Contrast with nomenclature. therapeutic intervention. See intervention. token. Physical key that provides access to a secure electronic system or location.
278
transcription. Process of transforming dictated or otherwise documented information from one storage medium to another. NOTE: often refers explicitly to data that is manually transcribed from source docs or measuring devices to CRFs or to eCRFs. transition rule. A guide that governs the allocation of subjects to operational options at a discrete decision point or branch (e.g., assignment to a particular arm, discontinuation) within a clinical trial plan. See branch. translation. Converting information from one natural language to another while preserving meaning. Compare with mapping. transmit. To transfer data, usually electronically. NOTE: In eClinical investigations data are commonly transmitted from subjects to clinical study sites, within or among clinical study sites, contract research organizations, data management centers, and sponsors, or to regulatory authorities. [modified from CSUICI] treatment effect. An effect attributed to a treatment in a clinical trial. In most clinical trials the treatment effect of interest is a comparison (or contrast) of two or more treatments. [ICH E9] treatment-emergent adverse event. An event that emerges during treatment, having been absent pretreatment, or worsens relative to the pretreatment state. [ICH E9] trial coordinator. See clinical research coordinator.
Trial Design Model. Defines a standard structure for representing the planned sequence of events and the treatment plan of a trial. NOTE: a component of the SDTM that builds upon elements, arms epochs, visits; suitable also for syntactic interpretation by machines. [CDISC] See study design. trial monitoring. Oversight of quality of study conduct and statistical interim analysis. [ICH E9] trial site. Synonym for investigative site, investigator site, site, site of the trial, study site. [ICH E6] trial statistician. A statistician who has a combination of education/ training and experience sufficient to implement the principles in the ICH E9 guidance and who is responsible for the statistical aspects of the trial. [ICH E9] trial subject. Subject in a clinical trial. See also participant, patient, subject. triple-blind study. A study in which knowledge of the treatment assignment(s) is concealed from the people who organize and analyze the data of a study as well as from subjects and investigators.
279 t-test. A statistical test used to compare the means of two groups of test data. trustworthy (electronic records). An attribute of records (data and documents) and signatures submitted to regulatory agencies referring to their suitability for making scientific findings of safety and efficacy that underlie public policy decisions pertaining to market authorization. Two key dimensions that determine the trustworthiness of eClinical trial data are data quality and data integrity. [after 21CFR Part 11] type 1 (or type I) error. Error made when a null hypothesis is rejected but is actually true. Synonym: false positive. type 2 (or type II) error. Error made when an alternative hypothesis is rejected when it is actually true. Synonym: false negative. type 3 (or type III) error. Some statisticians use this designation for an error made when calling the less effective treatment the more effective one. type of comparison. How treatment arms will be compared (e.g., Safety, Efficacy, PK/PD). May also include comparison to data from other studies or sources (e.g., historical control). [ICH E9, EUDRACT (p.18)] unblinding. Identification of the treatment code of a subject or grouped results in studies where the treatment assignment is unknown to the subject and investigators. unequal randomization. See randomization. unexpected adverse drug reaction. An adverse reaction, whose nature, severity, specificity, or outcome is not consistent with the term or description used in the applicable product information. [ICH E2] See also adverse drug reaction. uniform resource locator (URL). Address of a Web page, actmagazine.com, for example. use case. An explicit scenario designed to help in determining whether a system/process is capable of performing the functions required for a particular use. A use case might describe, for example, how a study coordinator would use a tablet computer to capture medical history data. user site testing (UST). Any testing that takes place outside of the developer’s controlled environment. NOTE: Terms such as beta test, site validation, user acceptance test, installation verification, and installation testing have all been used to describe user site testing. User site testing encompasses all of these and any other testing that takes place outside of the developer’s controlled environment. [from General Principles of Software Validation; Final Guidance, section 5.2.6] valid. 1. Sound. 2. Well grounded on principles of evidence. 3. Able to withstand criticism or objection. [FDA Glossary of Computerized System and Software Development Terminology]
280 validation. 1. Process of establishing suitability to purpose. 2. For software and systems, establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. NOTE: Validation is accomplished by planning how to measure and/or evaluate suitability to purpose; then executing the plan and documenting the results. [FDA Glossary of Computerized System and Software Development Terminology] validation of data. 1. A process used to determine if data are inaccurate, incomplete, or unreasonable. The process may include format checks, completeness checks, check key tests, reasonableness checks and limit checks. 2. The checking of data for correctness or compliance with applicable standards, rules, and conventions. NOTE: Meaning 1. is not “data verification” but meaning 2. could be [1. ISO; 2. FDA Glossary of Computerized System and Software Development Terminology] See source document verification. validity. See validation. validity, psychometric. See psychometric validation. variable. 1. Any entity that varies; any attribute, phenomenon, or event that can have different qualitative or quantitative values. 2. In SDTM “variables” are used to describe observations. Such describing variables have roles that determine the type of information conveyed by the variable about each observation and how it can be used. NOTE: 1. There is usually a form of metadata that goes with the variable, there is a variable definition that describes what is varying, and there is a value for the variable. In the context of a protocol, variables pertain to the study. 2. In SDTM a “study variable” would be an observation. Variable is an enveloping term that includes specific subtypes used in clinical research. “Study variable” is a term used in trial design to denote a variable to be captured on the CRF. An “assessment” is a study variable pertaining to the status of a subject. Assessments are usually measured at a certain time, and usually are not compounded significantly by combining several simultaneous measurements to form a derived assessment (e.g., BMI) or a result of statistical analysis. An “endpoint” is a variable that pertains to the trial objectives. Not all endpoints are themselves assessments since certain endpoints might apply to populations or emerge from analysis of results. That is, endpoints might be facts about assessments (e.g., prolongation of survival). When a “variable” is captured or measured, there is no necessary sense that any evaluation or judgment is involved. However, when a variable is to be measured that obviously or actively pertains to subject status, which is always the concern of the physician, that variable becomes or will always be an assessment. The term assessment is intended to invoke some degree of evaluation or judgment concerning subject status. A parameter is most properly a variable pertaining to statistical distributions though the word is often used synonymously with variable by engineers. variance. A measure of the variability in a sample or population. It is calculated as the mean squared deviation (MSD) of the individual values from their common mean. In calculating the MSD, the divisor n is commonly used for a population variance and the divisor n-1 for a sample variance.
281 verification. 1. The act of reviewing, inspecting, testing, checking, auditing, or otherwise establishing and documenting whether items, processes, services, or documents conform to specified requirements. 2. (of software). Provides objective evidence that the design outputs of a particular phase of the software development life cycle meet all of the specified requirements for that phase. NOTE: 2. Software verification looks for consistency, completeness, and correctness of the software and its supporting documentation, as it is being developed, and provides support for a subsequent conclusion that software is validated [FDA General Principles of Software Validation; ANSI/ASQC A3- 1978; ISO/IEC Guide 25]. Verification is used in the sense of matching elements of a report or results of system testing to individual requirements. Compare to validation where suitability to purpose is also established. verification of data. See source document verification (SDV). visit. A clinical encounter that encompasses planned and unplanned trial interventions, procedures, and assessments that may be performed on a subject. A visit has a start and an end, each described with a rule. [CDISC Trial Design Project] vocabulary. Terms that function in general reference to concepts that apply over a variety of languages are words, and their totality is a vocabulary. Synonym: terminology. See controlled vocabulary. volunteer. A person volunteering to participate as a subject in a clinical trial, often a healthy person agreeing to participate in a Phase 1 trial. See also Phase 1. vulnerable subjects. Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. [ICH]
Warning Letter. A written communication from FDA notifying an individual or firm that the agency considers one or more products, practices, processes, or other activities to be in violation of the Federal FD&C Act, or other acts, and that failure of the responsible party to take appropriate and prompt action to correct and prevent any future repeat of the violation may result in administrative and/or regulatory enforcement action without further notice. [FDA] washout period. A period in a clinical study during which subjects receive no treatment for the indication under study and the effects of a previous treatment are eliminated (or assumed to be eliminated).
282
Web browser. A computer program that interprets HTML and other Internet languages and protocols and displays Web pages on a computer monitor.
Web page. A single page on a Web site, such as a home page.
Web server. A computer server that delivers HTML pages or files over the World Wide Web. See also server.
Web site. A collection of Web pages and other files. A site can consist of a single Web page, thousands of pages, or custom created pages that draw on a database associated with the site. weighting. An adjustment in a value based on scientific observations within the data. well-being (of the trial subjects). The physical and mental integrity of the subjects participating in a clinical trial. [ICH] withdrawal. The subject-initiated act of discontinuing participation in a clinical study. NOTE: Withdrawal can range from the subject’s complete withdrawal from study procedures and follow-up activities, to the subject’s withdrawal from study-related interventions while the subject permits continued access to his/her medical records or identifiable information. Note that according to FDA regulations, when a subject withdraws from a study, the data collected on the subject to the point of withdrawal remain part of the study database and may not be removed. See also discontinuation. within-subject differences. In a crossover trial, variability in each subject is used to assess treatment differences.
World Wide Web. All the resources and users on the Internet that are using HTTP protocols. Also called the Web and www.
Changes or additions to References:
NIST: Minimum Security Requirements for Multi-user Operating Systems NISTIR 5153, March 1993, available at http://csrc.nist.gov/publications/nistir/ir5153.txt section 3.2.1.1
283
Appendix III: Acronyms, Abbreviations, and Initials, CDISC Version 9.0
AAAS American Association for the Advancement of Science
AABB American Association of Blood Banks
AADA Abbreviated Antibi otic Drug Application (FDA) (used primarily for generics)
AAMC Association of American Medical Colleges
AAPS American Association of Pharmaceutical Scientists
ABPI Association of the British Pharmaceutical Industry
ACCP American College of Clinical Pharmacology
ACDM Association for Clini- cal Data Management (UK)
ACE angiotensin-converting enzyme
ACIL A national trade association representing independent, commercial scientific, and engineering firms
ACPU Association of Clinical Pharmacology Units
ACRA Associate Commis sioner for Regulatory Affairs (FDA)
ACRP Association of Clinical Research Professionals (formerly Associates in Clinical Pharmacology, ACP)
ACRPI Changed its name to ICR—Institute of Clinical Research (UK)
ACT Applied Clinical Trials magazine
ACTG AIDS Clinical Trials Group (NIAID)
ACTU AIDS Clinical Trials Unit (NIH)
ADAM Analysis Data Model (a CDISC standard)
ADE Adverse Drug Event; Adverse Drug Effect
ADME absorption, distri- bution, metabolism, and excretion (used to describe pharmacokinetic processes)
284
ADR adverse drug reaction
AE adverse event
AEGIS ADROIT Electronically Generated Informa- tion Service, a subscrip- tion service that provides subscribing organizations with access to adverse drug reaction data from the Medicines Control Agency’s ADROIT (Adverse Drug Reaction On-line Information Tracking) database
AERS Adverse Event Report- ing System (FDA)
AFMR American Federa- tion for Medical Research, formerly the American Federation for Clinical Research (AFCR)
AHA American Heart Association
AHCPR Agency for Health- care Policy Research (NIH)
AHIC American Health Information Community.
A US government-charted commission providing input and recommendations to HHS on how to make health records digital and interop- erable, and assure the privacy and security of those records (HITSP)
AICRC Association of Independent Clinical Research Contractors (UK)
AIDS acquired immune deficiency syndrome, acquired immunodeficiency syndrome
ALCOA attributable, legible, contemporaneous, original, accurate (dimensions of data integrity)
AM ante meridian, morning (12:00 midnight thru 11:59:59)
AMA American Medical Association
AMC antibody-mediated cytotoxicity
AMFAR American Founda- tion for AIDS Research
AMG Arzneimittelgesetz (German Drug Law)
AMWA American Medical Writers Association
ANDA Abbreviated New Drug Application (for a generic drug)
ANOVA analysis of variance (statistics)
285
ANSI American National Standards Institute
AOAC Association of Official Analytical Chemists
APB Association Pharma- ceutique Belge (Belgium)
APHA American Pharma- cists Association
API active pharmaceutical ingredient
APPI Academy of Pharmaceutical Physicians and Investigators
ARCS Association of Regulatory & Clinical Scien- tists (Australia)
ARO academic research organization
ASAP administrative systems automation project (FDA)
ASCII American Standard Code for Information Inter- change (computer files)
ASCPT American Society for Clinical Pharmacology and Therapeutics
ASP application service provider delivering a computer application via the www
ASQ American Society for Quality, formerly American Society for Quality Control
ATC Anatomic-Therapeutic- Chemical Coding dictionary
AUC area under the curve (statistics)
BARQA British Association of Research Quality Assurance
BCE beneficial clinical event
BDPA Bureau of Drug Policy and Administration (China)
BEUC European Bureau of Consumer Unions
BFARM Bundesinstitut für Arzneimittel und Medizin- produkte (Federal Institute for Drugs and Medical Devices, Germany)
BGA Bundesgesundheit- samt (Federal health office; former German public health agency)
286
BGVV Bundesinstitut für gesundheitlichen verbrauch- erschutz und veterinär medizin (Federal Institute for Health Protection of Consumers and veterinary Medicine, Germany)
BIO Biotechnology Industry Organization
BIRA British Institute of Regulatory Affairs
BLA Biologics License Application (FDA)
BPI Bundesverband der Pharmazeutischen Industrie Ev (Germany)
BRAPP British Association of Pharmaceutical Physicians
BRIDG Biomedical Research Integrated Domain Group
BSA body surface area
C3C China CDISC Coordinat- ing Committee
CA Competent Authority (regulatory body charged with monitoring compli- ance with European Union member state national statutes and regulations)
CABIG Cancer Biomedical Informatics Grid
CACORE Cancer Common Ontologic Resource Environment
CADSR Cancer Data Standards Repository and toolset maintained by NCI
CAPRA Canadian Association of Professional Pharmaceutical Regulatory Affairs (also ACPR Association canadienne des profession- nels en réglementation)
CAS Chemical Abstracts Service
CBER Center for Biolog- ics Evaluation and Research (FDA)
CBIIT Center for Biomedical Informatics and Information Technology
CCI Committee on Clini- cal Investigations. See also Ethics Committee box in the Glossary.
CCPPRB Comité Consulta- tive pour la Protection des Personnes dans les Recherches Biomédicales (France). See also Ethics Committee box in the Glossary.
CCRA Certified Clinical Research Associate. Certifica- tion issued to monitors by ACRP.
CCRC Certified Clinical Research Coordinator. Certification issued to clinical coordinators by ACRP.
287
CCRP Certified Clinical Research Professional. SoCRA certification of coordinators, monitors, and other research professionals
CCSI Company Core Safety Information
CDA Clinical Document Architecture (HL7)
CDASH Clinical Data Acquisition Standards Harmonization (a 2006 CDISC initiative)
CDC Centers for Disease Control and Prevention
CDE common data element
CDER Center for Drug Evaluation and Research (FDA)
CDISC Clinical Data Interchange Standards Consortium
CDM clinical data management
CDMS clinical data management system
CDRH Center for Devices and Radiological Health (FDA)
CEN Comité Européen de Normalisation (European Committee for Standardization)
CEU Continuing Education Unit
CF consent form
CFR Code of Federal Regulations (usually cited by title and part; for example, Title 21, Part 211 is shown as 21 CFR 211)
CGMP current good manufacturing practices
CHI Consolidated Health Informatics. CHI began as an eGov initiative to establish a portfolio of existing health information interoperability standards (health vocabulary and messaging) enabling all agencies in the federal health enterprise to “speak the same language” based on common enterprise-wide business and information technology architectures. CHI is currently managed under the Office of the National Coordinator for Health Infor- mational Technology’s (ONC) Federal Health Architecture (FHA) Program Management Office. Ref: The United States Health Information Knowl- edgebase [USHIK]. (HITSP)
CHR Committee on Human Research. See also Ethics Committee box in the Glossary.
288
CIC clinical imaging center
CIOMS Council for Inter- national Organizations of Medical Sciences (postap- proval international ADR reporting, UK)
CIP Certified IRB Professional
CIS Commonwealth of Independent States
CLIA Clinical Laboratory Improvement Amendments
Cmax concentration maximum; used in pharma- cokinetics and bioequivalence to indicate maximum plasma concentration for a drug
CMc chemistry, manufac- turing, and control
CME Continuing Medical Education
CMS Centers for Medicare & Medicaid Services
CNS central nervous system
CONSORT Consolidated Standards of Reporting Trials
COP CDISC Operating Process/Procedure
CORE CDISC Operational Roadmap Environment (CDISC)
COSTART Coding Symbols for a Thesaurus of Adverse Reaction Terms. See also MedDRA.
CPHS Committee for the Protection of Human Subjects
CPMP Committee for Proprietary Medicinal Products (EU)
CPSC Consumer Product Safety Commission (US)
CRA clinical research associate. See also CCRA.
CRADA Cooperative Research And Development Agreement (with US Government entities such as FDA or NIH)
CRB case record book
CRB Central Review Board
CRC clinical research coordi- nator. See also CCRC, SC, SSC.
289
CRF case report form (sometimes case record form)
CRIX Clinical Research Infor- mation Exchange
CRO contract research organization. See also IPRO.
CRT Case Report Tabulation
CSDD Center for the Study of Drug Development (Tufts)
CSF Collaborative Standards Forum (CDISC)
CSF cerebrospinal fluid
CSF colony stimulating factor
CSM Committee on Safety of Medicines (UK)
CSO Consumer Safety Officer (FDA)
CSR clinical study report cSu clinical supply unit cSuici (replaces CSUCT) Computerized Systems Used In Clinical Investigations. NOTE: usually pronounced “seesweecy.”
CT clinical trial
CTA Clinical Trial Agreement
CTC Clinical Trial Certificate (UK)
CTCAE Common Terminology Criterion for Adverse Events. Standard terminology developed to report adverse events occurring in cancer clinical trials. CTCAE are used in study adverse event summaries and Investigational New Drug (IND) reports to the Food and Drug Administration. The CTCAE contain a grading scale for each adverse event term representing the severity of the event. (NCI)
CTD Common Technical Document
CTEP Cancer Therapy Evalu- ation Program
CTM clinical trials materials
CTX Clinical Trial Exemption (MCA)
290
CUI common unique identifier. A code used in the Enterprise vocabulary System (EvS) to link a partic- ular concept across one or more terms.
CV curriculum vitae
CVM Center for veterinary Medicine (FDA)
DAWN Drug Abuse Warning Network
DCGI Drugs Controller General of India (Indian regulatory authority)
DD Department of Drugs(Swedish regulatory agency)
DDF Data Definition File
DDI drug–drug interaction
DEA Drug Enforcement Administration (US)
DEN Drug Experience Network
DES Data Encryption Standard
DESI Drug Efficacy Study Implementation notice (FDA, to evaluate drugs in use before 1962)
DGPHARMED Deutsche Gesellschaft für Pharmazeutische Medizin (German Society of Pharmaceutical Medicine), formerly FÄPI
DHHS Department of Health and Human Services (US)
DHTMl Dynamic HTML (IT)
DIA Drug Information Association
DIBD Development Interna- tional Birth Date. Analogous to the International Birth Date (IBD) for a PSUR, defined as the date of first marketing approval, worldwide. [Ref: ICH E2F – Development Safety Update Report]
DICOM Digital Imaging and Communications in Medicine
DITA Darwin Information Typing Architecture
DlT dose-limiting toxicity
DD Department of Drugs(Swedish regulatory agency)
291
DDF Data Definition File
DDI drug–drug interaction
DEA Drug Enforcement Administration (US)
DEN Drug Experience Network
DES Data Encryption Standard
DESi Drug Efficacy Study Implementation notice (FDA, to evaluate drugs in use before 1962)
DGPHARMED Deutsche Gesellschaft für Pharmazeutische Medizin (German Society of Pharmaceutical Medicine), formerly FÄPI
DHHS Department of Health and Human Services (US)
DHTMl Dynamic HTML (IT)
DIA Drug Information Association
DIBD Development Interna- tional Birth Date. Analogous to the International Birth Date (IBD) for a PSUR, defined as the date of first marketing approval, worldwide. [Ref: ICH E2F – Development Safety Update Report]
DICOM Digital Imaging and Communications in Medicine
DITA Darwin Information Typing Architecture
DlT dose-limiting toxicity
DMB Data Management Biomedical (France)
DPC-PTR act Drug Price Competition and Patent Term Restoration Act of 1984 (also Waxman-Hatch or Hatch- Waxman bill)
DSI Division of Scientific Investigations (FDA)
DSM Diagnostic and Statis- tical Manual (of the American Psychiatric Association)
DSMB data safety monitor- ing board
DSNP Development of Standardized Nomenclature Project (FDA)
DST daylight saving time
292
DSTU Draft Standard for Trial Use. See HL7 definition.
DSUR Development Safety Update Report (ICH)
DTC direct-to-consumer (drug advertising)
DTD Document Type Defini- tion (XML)
E3C European CDISC Coordinating Committee
EAB Editorial Advisory Board (Applied Clinical Trials)
EAB Ethical Advisory Board. See also Ethics Committee in the Glossary.
EC ethics committee. See also Ethics Committee in the Glossary.
EC European Commission (in documents older than the mid-1980s, EC may mean European Community)
ECG electrocardiogram
ECG European CDISC Group ecJ European Court of Justice ecoG Eastern Cooperative Oncology Group (US)
ECPHIN European Commu- nity Pharmaceutical Information Network
ECRF electronic case report form
ECRIN European Clinical Research Infrastructures Network
ECTD electronic common technical document
EDC electronic data capture/collection
EDI electronic data interchange
EDT Electronic Data Transfer
EDMS electronic data management system
EDR electronic document room. NOTE: The EDR is an extension of the e-Submis- sions central document room. A check is performed on each submission sent to the EDR for file formats used and the integrity of bookmarks and hypertext links.
EEC European Economic Community, now EU; some regulatory documents still have EEC document numbers.
293
EFGCP European Forum for Good Clinical Practice
EFPIA European Federation of Pharmaceutical Industries and Associations
EFTA European Free Trade Association
EHR electronic health record
EIR Establishment Inspection Report (FDA)
ELA Establishment License Application (FDA)
EMA European Medicines Agency
EMWA European Medical Writers Association
EORTC European Organization for Research and Treatment of Cancer
EP European Parliament
EPAR European Public Assessment Report
EPO European Patent Office; erythropoietin
EPRG European Pharmaco- vigilance Research Group
ER Essential Requirements (EMA)
ERSR electronic regulatory submissions and review (FDA’s e-Submissions processing group)
ERX electronic prescribing
ESDI electronic Source Data Interchange
ESR Electronic Source Record. (see eSource)
ESRA European Society of Regulatory Affairs
ESTRI Electronic Standards for the Transfer of Regulatory Information (ICH)
EU European Union
EUDRA European Union Drug Regulatory Authorities
EUDRACT European Union clinical trials database
294
EVS Enterprise vocabulary Services (National Cancer Institute)
EWG expert working group
FAQ frequently asked questions
Farmindustria The Association of Italian Pharmaceutical Manufacturers
FD&C act Food, Drug, and Cosmetic Act (US)
FDA Food and Drug Administration (US)
FDAAA Food and Drug Administration Amendment Act (pronounced fedaahh or fedah-ah)
FDAMA FDA Moderniza- tion Act
FDLI Food and Drug Law Institute
FFPM Fellow of the Faculty of Pharmaceutical Medicine (UK)
FIPS Federal Information Processing Standards
FISMA Federal Information Security Management Act
FRCP Fellow of the Royal College of Physicians, sometimes followed by a place name—for example, FRCP (Edin.)—that indicates a university medical school
FTC Federal Trade Commis- sion (US)
FTP File Transfer Protocol
FWA Federalwide Assurance
GAO Government Accountability Office (US government)
GBP good business practice
GBPS gigabits, or billions of bits per second (data transmission)
GCP good clinical practice
GCRP good clinical research practice
GLP good laboratory practice
295
GMp good manufacturing practices
GMT Greenwich mean time.See UTC.
GP general practitioner; general practice (UK)
GPMS good postmarketing surveillance practice (Japan)
GRAS generally regarded as safe (foods)
GRP good review practice (CDER)
GXP good (pharmaceutical) practice
HA health authority (UK)
HCFA Healthcare Financing Administration; now renamed The Centers for Medicare & Medicaid Services (CMS)
HEX Human Experimenta- tion Committee. See also Ethics Committee box in the Glossary.
HHS Department of Health and Human Services (US, also called DHHS)
HIE Health Information Exchange. The mobilization of healthcare information electronically across organi- zations within a region or community. HIE provides the capability to electronically move clinical information between disparate healthcare information systems, while maintaining the meaning of the information being exchanged. The goal of HIE is to facilitate access to, and retrieval of, clinical data to provide safer, more timely, efficient, effective, equitable, and patient-centered care. (HITSP) HIMA Health Industry Manufacturers Association
HIMSS Healthcare Information and Management Systems Society (pronounced hymns)
HIPAA Health Insurance Portability and Accountability Act
HIT health information technology
HITSP Health Information Technology Standards Panel (pronounced hitspee)
HL7 Health Level 7 (a not-for-profit ANSI-accredited standards developing/devel- opment organization [SDO])
HPB Health Protection Branch, Laboratory Centre for Disease Control (Canada); has been superseded by Health Canada
HPLC high performance liquid chromatography
296
HSRC Human Subjects Review Committee. See also Ethics Committee box in the Glossary.
HTMl Hypertext Markup Language
HTTP Hypertext Transfer Protocol
I3C India CDISC Coordinating Committee
IAB Industry Advisory Board (for CDISC)
IB investigator’s brochure
IC informed consent
ICD9 International Classi- fication of Diseases, 9th revision. See also MedDRA.
ICF informed consent form
ICG India CDISC Group
ICH International Confer- ence on Harmonization of Technical Requirements for Registration of Pharmaceuti- cals for Human Use
ICR Institute of Clinical Research (formerly ACRPI, Association for Clinical Research in the Pharmaceuti- cal Industry, UK)
ICSR individual case safety report
ICTH International Commit- tee on Thrombosis and Haemostasis
ICTRP International Clini- cal Trials Registry Platform (WHO)
IDE Investigational Device Exemption Application to CDRH to get permission for investigational device testing in clinical trials
IEC independent ethics committee. See also Ethics Committee box in the Glossary.
IEEE Institute of Electrical and Electronic Engineers, Inc.
IFAPP International Federation of Associations of Pharmaceutical Physicians
IFPMA International Federation of Pharmaceutical Manufacturers and Associations
IG Inspector General (HHS)
297
IHE Integrating the Healthcare Enterprise (an international standards organization)
IHI Institute for Healthcare Improvement
IKS Interkantonale Kontrollstelle für Heilmittel (Switzerland)
IMI Innovative Medicines Initiative (European Commission)
IMP investigational medici- nal product; investigational materials plan
IMPD Investigational Medic- inal Product Dossier (EUDRA)
IND Investigational New Drug application (FDA). See also TIND.
INN International Nonproprietary Name
IOM Institute of Medicine (National Academy of Science, US)
IPRO independent pharmaceutical research organization. See also CRO.
IRB institutional review board; independent review board. See also Ethics Committee box in the Glossary.
IRD international registration document
IS International System of Units (may also be referred to as SI—Systéme Internationale)
ISCB International Society for Clinical Biostatistics
ISDN Integrated Services Digital Network
ISO International Organiza- tion for Standardization
ISOQOl International Society for Quality of Life Research
ISP Internet service provider
IT information technology
ITU-T International Telecommunication Union Telecommunication Standardization Sector
IUPAC International Union of Pure and Applied Chemistry
IVD in vitro diagnostics
IVRS interactive voice response system
298
J3C Japan CDISC Coordinating Committee
JCAHO Joint Commission on Accreditation of Healthcare Organizations
JCG Japan CDISC Group
JMA Japan Medical Association
JPMA Japan Pharmaceutical Manufacturers Association
KBPS kilobits, or thousands of bits per second (data transmission)
KFDA Korean Food and Drug Administration
LAB Laboratory Data Model (CDISC)
LAN local area network
LIF Swedish Pharmaceutical Industry Association
LKP Leiter der Klinischen Prüfung
LOA letter of agreement
LOINC logical observations, identifiers, names, and codes
LREC local research ethics committee (UK). See also Ethics Committee box in the Glossary.
MA marketing authorization
MAA Marketing Authorisa- tion Application (EMA, EU)
MAH Marketing Authorisation Holder (EU)
MAPP Manual of Policies and Procedures (CDER)
MBPS megabits, millions of bits per second (data transmission)
MDR medical device reporting
MedDRa Medical Dictionary for Regulatory Activities (new global standard medical terminology designed to supersede other termi- nologies used in the medical product development process, including COSTART, ICD9, and others)
MEDID Medicinal Product Identifier
299
MEDLARS Medical Litera- ture Analysis and Retrieval System
MEFA Association of the Danish Pharmaceutical Industry
MEP Member of the European Parliament
MHlW Ministry of Health, Labor and Welfare (Japan)
MHRA Medicines and Healthcare products Regula- tory Agency (UK)
MIAME minimum information about a microarray experiment (standard for microarray data)
MoH Ministry of Health (UK, Canada, others)
MopH Ministry of Public Health (Thailand, yemen, others)
MoU memorandum of understanding (an MOU between FDA and a regulatory agency in another country allows mutual recognition of inspections)
MPR Medical Products Agency (Swedish Regulatory Agency)
MR Medical Representative (Japan)
MRA medical research associate
MREC Multicentre Research Ethics Committee (UK). See also Ethics Committee in the Glossary.
MRI magnetic resonance imaging
MTD maximum tolerated dose
MVP master validation plan
NABR National Association for Biomedical Research
NAF Notice of Adverse Findings (FDA postaudit letter)
NAI No Action Indicated (most favorable FDA post- inspection classification)
NAS new active substance (UK)
NAS–NRC National Academy of Sciences–National Research Council (US)
300
NBAC National Bioethics Advisory Commission (US)
NCA national competent authority
NCI National Cancer Insti- tute (National Institutes of Health, USA)
NCICB National Cancer Institute Center for Bioinformatics
NEFARMA Dutch Association of the Innovative Pharmaceutical Industry
NEI National Eye Institute (NIH)
NGO nongovernmental organization
NHI National Health Insurance (Japan)
NHIN National Health Information Network
NHLBI National Heart, Lung, and Blood Institute (NIH)
NHS National Health Service(UK)
NIA National Institute on Aging (NIH)
NIAAA National Institute on Alcohol Abuse and Alcoholism (NIH)
NIAID National Institute of Allergies and Infectious Diseases (NIH)
NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH)
NIBIB National Institute of Biomedical Imaging and Bioengineering
NICHD National Institute of Child Health and Human Development (NIH)
NIDA National Institute on Drug Abuse (NIH)
NIDCD National Institute on Deafness and Other Commu- nication Disorders (NIH)
NIDCR National Institute of Dental and Craniofacial Research (NIH)
NIDDK National Institute of Diabetes and Digestive and Kidney Diseases (NIH)
NIEHS National Institute of Environmental Health Sciences (NIH)
NIGMS National Institute of General Medical Sciences (NIH)
301
NIH National Institutes of Health (DHHS)
NIMH National Institute of Mental Health (NIH)
NINDS National Institute of Neurological Disorders & Stroke (NIH)
NINR National Institute of Nursing Research (NIH)
NIRB See NRB. See also Ethics Committee, Independent IRB in the Glossary.
NlM National Library of Medicine (NIH)
NME new molecular entity
NOAEL no observed adverse effect level (IUPAC)
NOEL no observable effect level (dose of an experimental drug given preclinically that does not produce an observable toxicity)
NRB noninstitutional review board, also known as an independent review board. See also Ethics Committee in the Glossary, NIRB.
NSCLC non-small cell lung carcinoma
NTP National Toxicology Program
OAI Official Action Indicated (serious FDA postinspection classification)
OAM See NCCAM.
OASIS Open Accessible Space Information System
ODAC Oncologic Drugs Advisory Committee (US)
ODE Office of Drug Evaluation
ODM Operational Data Model (CDISC)
OGD Office of Generic Drugs (CDER, formerly DGB)
OGE Office of Government Ethics
OHITA Office of Health Information Technology Adoption (ONCHIT)
OHRP Office for Human Research Protections (pronounced O-harp)
302
OIG Office of the Inspector General
OIS Office of Interoperability and Standards
OJC Official Journal of the European Union–C Series (Information)
OJEC Official Journal of the European Communities
OJL Official Journal of the European Union–L Series (Legislation)
OMB Office of Manage- ment and Budget (US)
ONCHIT Office of the National Coordinator for Health Information Technol- ogy (HIMSS)
OPR Office of Policy and Research
OPRR Office for Protection from Research Risks (prede- cessor to OHRP)
OSHA Occupational Safety & Health Administration (US)
OTA Office of Technology Assessment (US, abolished 1995)
OTC over-the-counter (refers to nonprescription drugs)
PAB Pharmaceutical Affairs Bureau (Japan)
PAHO Pan American Health Organization
PCC Poison Control Center
PCP pneumocystis carinii pneumonia. (The older name pneumocystis carinii—which now only applies to the pneumocystis variant that occurs in animals—is still in common usage. As a result, pneumocystis pneumonia (PCP) is also known as pneumocystis jiroveci[i] pneumonia
PD pharmacodynamics
PDA personal digital assis- tant (Palm Pilot, for example)
PDF portable document format
PDQ Physicians’ Data Query (NCI-sponsored cancer trial registry)
PDR Physicians’ Desk Reference
PDUFA Prescription Drug User Fee Act (1992, US)
303
PDUFA IV Prescription Drug User Fee Act (FDA)
PEM prescription event monitoring
PERI Pharmaceutical Education & Research Institute (not-for-profit division of PhRMA)
PFT pulmonary function test
PGT pharmacogenetics pGX pharmacogenomics phpiD pharmaceutical product identifier
PHRMA Pharmaceutical Research and Manufacturers of America
PHS Public Health Service (US)
PIM product information management (a system introduced by the EMA)
PI principal investigator
PK pharmacokinetics
PKI public key infrastructure
PLA Product License Appli- cation (FDA)
PM post meridian, evening (12 noon thru 23:59:59)
PMA Premarket Approval application (FDA)
PMDA Pharmaceutical and Medical Devices Agency (Japanese regulatory authority)
PMS postmarketing surveillance
PPI Patient Package Insert
PPO preferred provider organization; policy and procedure order
PR partial response; pulse rate
PRG Protocol Representation Group (CDISC)
PRIM&R Public Responsibil- ity in Medicine and Research (Boston, MA)
PRM Protocol Reference Model
PRO patient-reported outcome
304
PROG Peer-Review Oversight Group (NIH)
PROMIS Patient Reported Outcomes Measurement Information Systems (pronounced promise)
PSUR periodic safety update report
PTC points to consider
PV pharmacovigilance
QA quality assurance
QAU quality assurance unit
QC quality control
QL quality of life
QOl quality of life (also QoL)
R&D research and development
RADAR risk assessment of drugs–analysis and response
RAPS Regulatory Affairs Professionals Society
RCRIM Regulated Clinical Research Information Management, a technical committee of HL7 with responsibility for developing technical standards for the exchange and management of health research information to be submitted to regulatory authority(ies)
RCT randomized clinical trial
RDE remote data entry
RDRC Radioactive Drug Research Committee (FDA)
REB research ethics board (Canada)
REMS Risk Evaluation and Mitigation Strategy
RFD retrieve form for data capture
RFP request for proposal
305
RHIO Regional Health Information Organization. A group of organizations with a business stake in improving the quality, safety and efficiency of healthcare delivery. RHIOs are the build- ing blocks of the proposed National Health Information Network (NHIN) initiative
RIM Reference Information Model (HL7)
RKI Robert-Koch-Institut, Bundesinstitut für Infektionskrankheiten und nich- übertragbare Krankheiten (Federal Institute for Infectious and Noncommunicable Diseases, Germany)
Rl Regulatory Letter (FDA—postaudit letter)
RPS Regulated Product Submission (HL7 RCRIM)
SACHRP Secretary’s Advisory Committee on Human Protection. See also OHRP.
SADR suspected adverse drug reaction (FDA)
SAE serious adverse event
SAFE Secure Access for Everyone
SAS Statistical Analysis System (commonly used statistical analysis package)
SATCM State Administration of Traditional Chinese Medicine (China)
SBA Summary Basis of Approval
SC study coordinator. See also CRC, CCRC, SSC.
SCDM Society for Clinical Data Management
SCT SOCIETY FOR CLINICAL TRIALS
SD standard deviation (statistics)
SDA State Drug Administration (China)
SDM Submission Data Model (CDISC)
SDO standards development organization
SDS Submission Data Standards (CDISC)
SDTM Study Data Tabula- tion Model (CDISC)
SDV source document (data) verification
306
SE standard error (statistics)
SEA Single European Act of 1987
SEER Surveillance, Epidemiology, and End Results program (National Cancer Institute)
SEND Standard for the Exchange of Nonclinical Data. NOTE: The focus of the SEND Team is on data collected from animal toxicology studies. (CDISC)
SFDA State Food and Drug Administration (Chinese regulatory authority)
SGMl Standard Generalized Markup Language
SHARE Shared Health and Research Electronic Library
SIAC Special Interest Area Community (DIA)
SIG Special Interest Group (HL7)
SLA service level agreement
SMART Submission Management and Review Tracking (FDA)
SME significant medical event
SMO site management organization
SMPC summary of product characteristics. See also SPC.
SNDA Supplemental New Drug Application
SNIP Syndicat National de l’Industrie Pharmaceutique (France)
SNOMED Systematized Nomenclature of Medicine. A structured nomenclature and classification of the terminology used in human and veterinary medicine developed by the College of Pathologists and American veterinary Medical Association. Terms are applied to one of eleven independent systematized modules.
SOAP simple object access protocol (a W3C XML initiative)
SOC System Organ Class (MedDRA)
SOCRA Society of Clinical Research Associates
SOP standard operating procedure
307
SPAC State Pharmaceutical Administration of China
SPC summary of product characteristics. See also SmPC.
SPIRIT Standard Protocol Items for Randomized Trials (CONSORT for protocols)
SPL Structured Product Administration of China
SPM Society of Pharmaceutical Medicine (UK)
SQA Society of Quality Assurance
SQAP systems quality assurance plan
SSC study site coordinator. See also CRC, CCRC, SC.
SSCT Swedish Society for Clinical Trials
SSFA Società di Scienze Farmacologiche Applicate (Italy)
STF study tagging file
STT short term test
SUAE serious unexpected adverse event
SUD sudden unexpected death
SUSAR Suspected Unexpected Serious Adverse Reaction
SWOG Southwest Oncology Group (US)
TAC Technical Advisory Committee (CDISC)
TC Technical Committee (HL7)
TCC Technical Coordinating Committee (CDISC)
TCP/IP Transmission Control Protocol/Internet Protocol
TERMID Controlled vocabulary Term Identifier
TESS treatment-emergent signs and symptoms
TGA Therapeutic Goods Administration (Australian regulatory authority)
308
TIND treatment IND. See also IND.
TK toxicokinetics
Tmax the time after dosing when Cmax occurs
TMO trial management organization
UMT universal mean time (also known as Greenwich mean time). See UTC.
URL uniform resource locator (address of a website)
USAN United States Adopted Name
USC United States Code (book of laws)
USDA US Department of Agriculture
USP United States Pharmacopeia
UST user site testing. Synonym for UAT (user acceptance testing)
UT universal time (also known as Greenwich mean time). See UTC.
UTC coordinated universal time (inter- national standard since 1972)
UUID Universally Unique Identifier
VA veterans Administration (officially, US Department of veterans Affairs)
VAERS vaccine Adverse Event Report- ing System
VAI voluntary Action Indicated (FDA post audit inspection classification)
VCDE vocabularies and common data elements (caBIG)
VGDS voluntary genomic data submission
VPN virtual private network
W3C World Wide Web Consortium
WAN wide area network
WHO World Health Organization
309
WHOART World Health Organization Adverse Reaction Terminology
Wl Warning Letter (most serious FDA post audit letter, demands immediate action within 15 days)
WR written request
WRAIR Walter Reed Army Institute of Research (DoD)
WTO World Trade Organization
WWW World Wide Web
XMl extensible Markup Language
310
311
“Our Dream , a healthier society”
PharmEvo’s CSR Programs
312