Glossary OVERVIEW

The following are terms commonly used in research. The terms and definitions are gathered from various resources.

Numerical The WMed IRB office should receive reports within 14 calendar days of the event or investigator's receipt of notification of the event. (Because the reporting of Adverse Events can be a time- 14 Calendar days sensitive issue researchers are encouraged to establish a system for logging or date-stamping information related to Adverse Event notifications and reports from subjects, sponsors and other sources.) Title 21 - Food and Drugs: Title 21 of the Code of Federal Regulations houses all the regulations related to the Food, Drug and Cosmetics Act can be found. Some of the more popular are:

Part: 11: Electronic Records, Electronic Signatures 21 CFR… 50: Protection of Human Subjects 54: Financial Disclosure by Clinical Investigators 56: Institutional Review Boards 312: Investigational New Drug Application 812: Investigational Device Exemptions Title 45, Part 46 of the Code of Federal Regulations covers the Protection of Human Subjects. These regulations govern human subject research conducted by all federal agencies. Together, this body of regulations governs the conduct of human subject 45 CFR 46 research today. 45 CFR 46 Subpart A is often called the Common Rule as nearly all divisions, centers or institutes within the DHHS has agreed to follow the regulations in the protection of human subjects. A medical device that is considered substantially equivalent to a 510(K) Device device that was or is being legally marketed. A sponsor planning to market such a device must submit notification to the FDA 90

days in advance of placing the device on the market. If the FDA concurs with the sponsor, the device may then be marketed. 510(k) is the section of the Food, Drug and Cosmetic Act that describes premarket notification; hence the designation "510(k) device." The WMed IRB office should receive reports within 7 working days of the event or investigator's receipt of notification of the event. (Because the reporting of Adverse Events can be a time- 7 Calendar days sensitive issue researchers are encouraged to establish a system for logging or date-stamping information related to Adverse Event notifications and reports from subjects, sponsors and other sources.)

A All harmful and unintended responses to a research use of a medicinal product (drug) related to any dose should be Adverse Drug considered adverse drug reactions. The phrase "responses to a Reaction (ADR) medicinal product" means that a causal relationship between the drug and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Any experience or abnormal finding that has taken place during the course of a research project and was harmful to the subject participating in the research, or increased the risks of harm from the research, or had an unfavorable impact on the risk/benefit ratio. The FDA also includes in its definition abnormal preclinical or laboratory findings which may not yet have resulted in direct harm to subjects (e.g., a bacteria is identified in a culture from Adverse Event the same batch of cells used to produce a vaccine which has (AE) been administered, even if no cases of infection have been reported). The event may or may not be caused by an intervention (e.g., headache following spinal tap, death from the underlying disease, car collision). Adverse Events also include psychological, social, emotional, and financial harms. See also Serious Adverse Event, Adverse Drug Reaction, and abnormal preclinical finding. An undesirable and unintended effect, although not necessarily unexpected, result of therapy or other intervention (e.g., Adverse headache following spinal tap or intestinal bleeding associated Reaction with aspirin therapy). Onset may be sudden or develop over time. See Adverse Event, Side Effects

An individual appointed to the IRB to serve in the same capacity as the specific IRB member(s) for whom the alternate is named, Alternate who substitutes for the member at convened meetings when the Member member is not in attendance. IRB members and alternates have equal responsibilities in terms of required education, service, and participation. A change in the terms and conditions of a grant or contract mutually agreed upon by the agency and the recipient organization; may also be referred to as a modification. Amendment Amendments are completed in iMedRIS in order to modify an (AME) already approved project. Some examples of changes include updates to the protocol or informed consent, or changes to the study team. Anonymity exists when there are no identifiers on project materials which could link the data with individual subjects. Even Anonymity the research investigator cannot know the identity of participants. Anonymous means entirely without name or identifier, so the individual cannot be discerned in any way by anyone. No one can link an individual person to the responses of that person, including the investigator. For this reason, face-to-face Anonymous interviews are never anonymous. If phone numbers are not stored, then telephone interviews could be considered anonymous. Questionnaires that are returned via US Mail are considered anonymous only if no tracking codes are used. Request for reconsideration of an IRB determination in research involving human subjects, including (but not limited to) decisions regarding approval status, conditions for approval, and Appeal noncompliance. An appeal is reviewed by the convened IRB (Decision) responsible for the determination being appealed; for a decision made by expedited review, the corresponding convened IRB may review the appeal. PIs may submit a request for reconsideration if a decision is not positive. A scheduling deviation is a reportable occurrence if and when a procedure or intervention did not take place in accordance with the time frame established in the protocol for safety and/or Appointment / scientific purposes of testing and evaluation. Protocol Visit Deviation descriptions of treatment(s) to be administered, dosing schedule(s), treatment period(s), and follow-up period(s) should reflect reasonable flexibility in accordance with sound experimental design. Deviations are reported using the

Interim/Event Reporting Form. This is found on the WMed IRB website. The first date that research could be performed (following notification from the IRB).For research reviewed by the convened IRB, the approval date is the date that the research was approved at a convened meeting, or if modifications were required (to secure approval), the date that modifications were Approval Date met by the investigator. For research reviewed using expedited procedures, the approval date is the date that the research was approved by expedited review, or if modifications were required, the date that modifications were met by the investigator. See also Approval Period. An IRB action taken when the required determinations are made Approved that allow research involving human subjects to proceed (Decision) consistent with federal regulations, state and local laws, and University policy. The FDA must approve a substance as a drug before it can be marketed. The approval process involves several steps including pre-clinical laboratory and animal studies, clinical trials for safety Approved Drugs and efficacy, filing of a New Drug Application by the manufacturer of the drug, FDA review of the application, and FDA approval/rejection of application. Any of the treatment groups in a research project. Many projects Arms have two "arms," but some have three "arms," or even more. Agreement to participate in proposed research, given by an individual not competent to give legally valid informed consent (e.g., a child or mentally limited person). Mere failure to object may not be construed as assent.

• Assent means a child's affirmative agreement (verbal or written) to participate in a clinical investigation. Children Assent age 10 and up are generally able to provide their assent. • Assent is an adult's affirmative agreement (verbal or written) to participate in a clinical investigation. Adults may be assented (instead of consent) if they have a cognitive disability rendering them unable to consent for themselves. Steps should be in place to assure that all participants are given the opportunity to consent or assent. Association for The AAHRPP promotes high quality research through an the Accreditation accreditation process that helps organizations worldwide

of Human strengthen their human research protection programs. An Research independent, non-profit accrediting body, AAHRPP uses a Protection voluntary, peer-driven, educational model to ensure that HRPPs Programs meet rigorous standards for quality and protection. To earn (AAHRPP) accreditation, organizations must provide tangible evidence, through policies, procedures, and practices, of their commitment to scientifically and ethically sound research and to continuous improvement. A formal written, binding commitment that is submitted to a federal agency in which an institution promises to comply with Assurance applicable regulations governing research with human subjects and use of animals and stipulates the procedures through which compliance will be achieved. Personal capacity to consider alternatives makes choices, and Autonomy act without undue influence or interference of others.

B Collection of data and/or specimens obtained and stored for Bank future research uses and/or distribution, including a collection not originally or primarily obtained for research purposes. The initial time point in a clinical trial, just before a participant starts to receive the experimental treatment which is being Baseline tested. At this reference point, measurable values are recorded. Safety and efficacy of a drug are often determined by monitoring changes from the baseline values. The scope and diversity of research areas in the behavioral and social sciences is quite broad. Some research is readily applicable to human affairs; other studies may broaden understanding without any apparent or immediate application. Some research is designed to test hypotheses derived from Behavioral theory; other research is primarily descriptive. Still other Research research may be directed at evaluating an intervention or social program. Behavioral research involving human subjects generates data by means of questionnaires, observation, studies of existing records, and experimental designs involving exposure to some type of stimulus or intervention. A document that is part of the Federal Register that sets forth fundamental ethical principles that form the foundation for rules

Belmont Report for all government funded research involving human subjects. There are three basic ethical principles that are particularly

relevant to the protection of human participants. They are: Respect for persons, Beneficence, and Distributive Justice. (hyperlink each term) An ethical principle discussed in the Belmont Report that entails an obligation to protect persons from harm. The principle of Beneficence beneficence can be expressed in two general rules: (l) do not harm; and (2) protect from harm by maximizing possible benefits and minimizing possible risks of harm. Benefit A valued or desired outcome; an advantage. A type of donation or gift. Bequests and gifts are awards given with few or no conditions specified. Gifts may be provided to Bequests establish an endowment or to provide direct support for existing programs. Frequently, gifts are used to support developing programs for which other funding is not available. When a point of view prevents impartial judgment on issues relating to the subject of that point of view. In clinical studies, Bias bias is controlled by blinding and randomization. See Blind and Randomization

• A biological product subject to licensure under the Public Health Service Act is any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, applicable to the prevention, treatment or cure of diseases or injuries to humans. Examples include, but are not limited to, Biologic(s) bacterial and viral vaccines, human blood and plasma and their derivatives, and certain products produced by biotechnology. • Any therapeutic serum, toxin, antitoxin, or analogous microbial product applicable to the prevention, treatment, or cure of diseases or injuries.

Of or related to life or to living organisms Biological • • A drug derived from a biological source. A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of a Biological disease or condition of human beings. Biological products also product include immunoglobulin products, monoclonal antibodies, products containing cells or microorganisms, and most proteins intended for therapeutic use.

Biomedical research employs many methods and research designs. Studies designed to evaluate the safety, effectiveness, or usefulness of an intervention include research on therapies (e.g., drugs, diet, exercise, surgical interventions, or medical devices), diagnostic procedures (e.g., CAT scans or prenatal diagnosis through amniocentesis), and preventive measures (e.g., vaccines, diet, or fluoridated toothpaste). Research on Biomedical normal human functioning and development can include studies Research of the human body while exercising, fasting, feeding, sleeping, or learning, or responding to such things as stress or sensory stimulation. Subjects of some biomedical studies engage in ordinary tasks while measurement of physiological and bodily functions are made. Some biomedical studies, particularly those conducted to evaluate new therapies or treatments, use such rigorous experimental methods as random assignment to treatment and control groups. A randomized study is "Blind" if the participant is not told which arm of the study he is on. A clinical project is "Blind" if Blind participants are unaware on whether they are in the experimental or control arm of the study; also called masked. See Single Blind Study and Double Blind Study A study in which one party, either the investigator or participant, is unaware of what medication or study arm the participant is assigned to (Single-Blind study). A clinical study design in which neither the participating individuals nor the study staff knows Blinded Study which participants are receiving the experimental drug and Design which are receiving a placebo or another therapy (Double-Blind study). Double-blind studies are thought to produce more objective results, since the impact of expectations of the doctor and the participant about the experimental drug are minimized. Also referred to as a "masked" study.

C A paper or electronic questionnaire specifically used in clinical trial research. The CRF is the tool used by the sponsor of the Case Report clinical trial to collect data from each participating site. All data Form (CRF) on each patient participating in a clinical trial are held and/or documented in the CRF, including adverse events. Case-control A study comparing persons with a given condition or disease Study (the cases) and persons without the condition or disease (the

controls) with respect to antecedent factors. See also: Retrospective Studies An assessment made by the investigator and/or sponsor regarding the proper attribution of an adverse event. Examples: Cause Study intervention (e.g., drug, device, or therapy); Concurrent non-research therapy; Disease progression; Other or unknown source. The CIRB is designed to help reduce the administrative burden Central on local IRBs and investigators while continuing a high level of Institutional protection for human research participants. A local IRB's use of Review Board the CIRB facilitated review mechanism enables an investigator (CIRB) to enroll patients into studies significantly faster than when employing traditional method of IRB review. Certificates of Confidentiality are issued to protect identifiable research information from forced or compelled disclosure. They allow the investigator and others who have access to research records to refuse to disclose identifying information on research participants in civil, criminal, administrative, legislative, or other proceedings, whether federal, state, or local. Certificates of Certificate of Confidentiality protect subjects from compelled disclosure of Confidentiality identifying information but do not prevent the voluntary (CoC) disclosure of identifying characteristics of research subjects. Researchers, therefore, are not prevented from voluntarily disclosing certain information about research subjects, such as evidence of child abuse or a subject's threatened violence to self or others. However, if a researcher intends to make such voluntary disclosures, the consent form should clearly indicate this. A certified translation is one that has been formally verified by a licensed translator or translation company for use in official purposes. Certified translators attest that the target-language Certified text is an accurate and complete translation of the source- Translation language text. Certified translation of consent documents ensures that the tone, meaning and content of the translated documents remain consistent with the IRB-approved English version. Persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, Children under the applicable law of the jurisdiction in which the clinical investigation will be conducted. In Michigan, the legal age is 18 years old with some exceptions.

Class I, II, III Classification by the FDA of medical devices according to Devices degree of potential risks or hazards. Working together as a national consortium, at least 60 CTSA Clinical and institutions have committed to improve human health by Translational streamlining science, transforming training environments and Science Award improving the conduct, quality and dissemination of clinical and (CTSA) translational research. The CTSA program is part of the NIH. A clinical investigator involved in a clinical research project is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the Clinical investigational plan, and applicable regulations; for protecting Investigator the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. The qualifications must be outlined in a current resume and readily available for auditors.

• A prospective study involving human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions; these may include drugs, treatments, surgical procedures, devices, behavioral or nutritional strategies. Clinical trials are typically conducted by investigators who have entered into an agreement with a sponsor to conduct the study. For clinical drug and device trials, investigators agree to conditions regarding the conduct of the study outlined by FDA. • A clinical trial is a research study to answer specific Clinical Trial questions about vaccines, new therapies or new ways of using known treatments. Clinical trials are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people. Trials are in four phases: Phase I tests a new drug or treatment in a small group; Phase II expands the study to a larger group of people; Phase III expands the study to an even larger group of people; and Phase IV takes place after the drug or treatment has been licensed and marketed. (hyperlink each Phase) Not all human subject research projects are ‘clinical trials’. The CFR is a codification of the general and permanent rules Code of Federal published in the Federal Register by the executive departments Regulations and agencies of the Federal Government. The CFR is divided (CFR) into 50 titles representing broad areas subject to Federal

Regulation. Each Title is divided into chapters that are assigned to agencies issuing regulations pertaining to that broad subject area. Each chapter is divided into parts and each part is then divided into sections -- the basic unit of the CFR. The purpose of the CFR is to present the official and complete text of agency regulations in one organized publication and to provide a comprehensive and convenient reference for all those who may need to know the text of general and permanent Federal regulations. Direct personal identifiers have been removed (e.g., from data or specimens) and replaced with words, letters, figures, symbols, or a combination of these (not derived from or related Coded to the personal information) for purposes of protecting the identity of the source(s), but the original identifiers are retained in such a way that they can still be traced back to the source(s). Persuasion (i.e., of an unwilling person) to do or agree to Coercion something by using obvious or implied force or threats. A person having a psychiatric disorder (e.g., psychosis, neurosis, personality or behavior disorders), an organic impairment (e.g., dementia) or a developmental disorder (e.g., mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is Cognitively significantly diminished. Others, including persons under the Impaired influence of or dependent on drugs or alcohol, those suffering from post-traumatic or degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps, may also be compromised in their ability to make decisions in their best interests. A group of subjects initially identified as having one or more characteristics in common who are followed over time. In social Cohort science research, this term may refer to any group of persons who are born at about the same time and share common historical or cultural experiences. Cohort Study A form of longitudinal study used in medicine and social science Any individual member of the clinical trial team designated and Co-investigator supervised by the principal investigator at a trial site to perform (Co-I) critical trial-related procedures and/or to make important trial- related decisions. See also Investigator, Sub-Investigator. Collaborating Entities engaged in human subject research by virtue of subject Entities accrual, transfer of identifiable information, and/or in exchange

of something of value, such as material support (e.g., money, drugs, or identifiable specimens, co-authorship, intellectual property, or credits). The ‘Common Rule’ is the Federal Policy for the Protection of Common Rule Human Subjects, as set forth in 45 CFR 46 subpart A, and parallel regulations promulgated by agencies such as the FDA. Is designed as an instrument to be used to document AEs identified through a combination of clinical and laboratory evaluation. CTCAE is NOT a tool to assist with data extraction from source documents without the direct participation and supervision of clinical investigators. AE grading and attribution require documentation by medical personnel who are directly involved in the clinical care of protocol subjects. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term.

Common Grade is an essential element of the Guidelines and, in general, Terminology relates to severity for the purposes of regulatory reporting to NCI Criteria for as follows: Grade Description: 0: No AE (or within normal limits). Adverse Events 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic (CTCAE) observations only; intervention not indicated. 2: Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) indicated; limiting age-appropriate instrumental activities of daily living. 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 4: Life-threatening consequences; urgent intervention indicated. 5: Death related to AE. A severe AE, as defined by the above grading scale, is NOT the same as serious AE which is defined in Section 2.1.22 (FDA, 21 CFR 312.32; ICH E2A and ICH E6).

• A method of providing experimental therapeutics prior to final FDA approval for use in humans. This procedure is used with very sick individuals who have no other treatment options. Often, case-by-case approval must be Compassionate obtained from the FDA for "compassionate use" of a drug Use or therapy. • Use of an investigational drug or biologic or unapproved medical device for a single subject (or small group of subjects) with a serious disease or condition, who does not meet the requirements for inclusion in a clinical

investigation, and for whom no standard acceptable treatment is available. Prior FDA and IRB approval are required for compassionate use. Note: The terms compassionate use and emergency use are not synonymous. Payment, merchandise, class credit, or other gift or service provided to research participants or their legally authorized representatives to reimburse them for their time, effort, and/or for any out-of-pocket expenses associated with research Compensation participation. Compensation is sometimes distinguished from an incentive or inducement, which is generally thought of as a payment or other offering that is “over and above” reimbursement and intended to encourage research participation. A legal term used to denote capacity to act on one’s own behalf. The ability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. Competence may fluctuate as a function of the natural course of a mental illness, response to treatment, effects of medication, general physical health and other factors. Therefore, mental status should be reevaluated periodically. As Competence a designation of legal status, competence or incompetence pertains to an adjudication in court proceedings that a person’s abilities are so diminished that his or her decisions or actions (e.g., writing a will) should have no legal effect. Such adjudications are often determined by inability to manage business or monetary affairs and do not necessarily reflect a person’s ability to function in other situations. Proposals that are submitted for the first time or unfunded Competing proposals that are resubmitted; either must compete for Proposals research funds. Ongoing projects must compete again if the term of the original award has expired. In relation to research: Adherence to all relevant trial-related requirements, good clinical practice (GCP) requirements, and Compliance the applicable institutional, state and federal regulatory requirements. Withholding of full information of the study. Misleading or omitted information might include the purpose of the research,

Concealment the role of the researcher, or what procedures in the study are actually experimental. The IRB recognizes that deception or concealment may be necessary for certain types of behavioral

research. Because people act differently depending on circumstances, full knowledge by the subject might bias the results in some cases. Treatment (e.g., surgery, drug) a subject is receiving while participating in a research study that is not the treatment under Concurrent investigation; treatment the subject would be offered even if not Standard enrolled in the research study. For example, in a comparison Therapy study of two anti-nausea drugs in cancer patients, the chemotherapy would be the "concurrent standard therapy" and the anti-nausea drugs would be the "investigational therapy." Reporting should occur in parallel or no later than 5 calendar Concurrent days to all oversight bodies or agencies. Exceptions to this rule Reporting may be requested by submitting a study-specific reporting plan for IRB approval. Confidential means that the investigator can (or could) identify individuals who participated in a study, perhaps through a code. Although the identities may be recorded, data can be kept confidential if they are carefully coded, if face sheets and consent documents are separated from survey instruments, if computer sheets and other papers are properly disposed, if access to identifiable data is limited, if research staff are educated about the importance of protecting confidentiality, and if records are stored in secured locations. More elaborate procedures may be appropriate for research involving sensitive Confidential data that may involve a greater risk should confidentiality be breached, and investigators may want to seek Certificates of Confidentiality to protect such data from subpoena.

Unless federal statutes mandate this confidentiality confidential surveys that are not anonymous are not eligible for exemption using these criteria. Confidential surveys may still be eligible for exemption if any disclosure of the human subjects' responses outside the research could not possibly place them at risk of criminal or civil liability or be damaging to their financial standing, employability, or reputation.

• Pertains to the treatment of information that an individual has disclosed in a relationship of trust and with the expectation that it will not be divulged to others without Confidentiality written permission in ways that are inconsistent with the understanding of the original disclosure. (OHRP) • Right of privacy and of non-release of disclosed personal information. The investigator should protect subjects

against invasion of privacy and loss of confidentiality. Lack of secure handling of completed personality tests, questionnaires, interview protocols or data and recorded materials augments risk and must be avoided. Refers to maintaining the confidentiality of trial participants including their personal identity and all personal medical Confidentiality information. The trial participants' consent to the use of records Regarding Trial for data verification purposes should be obtained prior to the trial Participants and assurance must be given that confidentiality will be maintained.

• A COI occurs when an individual or organization is involved in multiple interests, one of which could possibly corrupt the motivation for an act in another. A COI can only exist if a person or testimony is entrusted with some impartiality; a modicum of trust is necessary to create it. The presence of a COI is independent from the execution of impropriety. Therefore, a COI can be discovered and voluntarily defused before any corruption occurs. A conflict could be financial and it includes both actual and perceived conflicts. • A conflict of interest is a situation in which an employee Conflict of has the opportunity to influence a University decision that Interest (COI) could lead to financial or other personal advantage, or that involves other conflicting official obligations. A COI can also occur when the conduct of research or other sponsored activities is or has the potential to be influenced by the outside financial interests of an investigator. • A financial interest or other opportunity for tangible personal benefit of an individual or his/her immediate family that may exert a substantial and improper influence on the individual's professional judgment in exercising any University duty or responsibility, including the review of research. Consent See: Informed Consent. Consortium Group of collaborative investigators/institutions; arrangement Agreement can be formalized with specified terms and conditions. Individuals hired to give professional advice or services for a fee Consultant as long as they are not an employee of the University. Consultants do not perform a portion of the programmatic work.

Applicable to grants and cooperative agreements only. A project approved for multiple-year funding, although funds are typically committed only one year at a time. At the end of the initial Continuation budget period, progress on the project is assessed. If Project (Non- satisfactory, an award is made for the next budget period, Competing) subject to the availability of funds. Continuation projects do not compete with new project proposals and are not subjected to peer-review beyond the initial project approval. Non-compliance (serious or non-serious) that has been previously reported, or a pattern of ongoing activities that indicate a lack of understanding of human subjects protection requirements that may affect research participants or the validity of the research and suggest the potential for future Continuing Non- noncompliance without intervention. Examples of continuing Compliance non-compliance may include but are not limited to: repeated failures to provide or review progress reports resulting in lapses of IRB approval, inadequate oversight of ongoing research, or failure to respond to or resolve previous allegations or findings of noncompliance. DHHS Regulations, 45 CFR 46, require at Section 46.109(e) that "an IRB shall conduct continuing review …at intervals appropriate to the degree of risk, but not less than once per Continuing year…" Continuing review must be substantive and meaningful. Review (CR) Review by the convened IRB, with recorded vote, is required unless the research is otherwise appropriate for expedited review under Section 46.110. Also known as a Scheduled Continuing Review (SCR). Disadvantageous, perhaps dangerous; a treatment that should not be used in certain individuals or conditions due to risks (e.g., Contraindicated a drug may be contraindicated for pregnant women and persons with high blood pressure). A contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment. Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action. For example, children and teenagers with viral infections should Contraindication not be given aspirin because of the risk of Reye's syndrome; and a person with an anaphylactic food allergy should never eat the food to which they are allergic. Other contraindications are relative, meaning that the patient is at higher risk of complications, but that these risks may be outweighed by other considerations or mitigated by other measures. For example, a

pregnant woman should normally avoid getting X-rays, but the risk may be outweighed by the benefit of diagnosing (and then treating) a serious condition such as tuberculosis. In Science: Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, and then allow one group to try the drug. Another example might be testing plant fertilizer by giving it to only half the plants in a garden (the plants that receive no fertilizer are the control group, because they are kept normal) Control In Research: Subject(s) used for comparison who are not given a treatment under study or who do not have a given condition, background, or risk factor that is the object of study. Control conditions may be concurrent (occurring more or less simultaneously with the condition under study) or historical (preceding the condition under study). When the present condition of subjects is compared with their own condition on a prior regimen or treatment, the study is considered historically controlled. The standard by which experimental observations are evaluated. In many clinical trials, one group of patients will be Control Group given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo. See Placebo and Standard Treatment Control is a standard against which experimental observations may be evaluated. In clinical trials, one group of participants is Controlled Trials given an experimental drug, while another group (i.e., the control group) is given either a standard treatment for the disease or a placebo. Review of proposed human subject research by an IRB that meets the membership requirements specified in federal Convened IRB regulations regarding the number, qualifications, diversity, and Review affiliation of its members, at which a majority of the members are present including at least one member whose primary concerns are in nonscientific areas. Cooperative An award similar to a grant, but in which the sponsor's staff may Agreement be actively involved in proposal preparation, and anticipates

having substantial involvement in research activities once the award has been made. Programs involving multi-protocol, multi-site research, in which Cooperative data from standardized protocols are pooled across institutions. Protocol These protocols, conducted or sponsored by DHHS, are Research approved and monitored by DHHS Protocol Review Committees Program (CPRP) that are recognized by OHRP as satisfactorily addressing the quality of human subject protections. Research projects covered by 45 CFR 46 that involve more than Cooperative one institution. In the conduct of cooperative research projects, Research each institution is responsible for safeguarding the rights and Projects welfare of human subjects and for complying with federal policy [45 CFR 46.114]. A type of clinical trial in which each subject experiences, at different times, both the experimental and control therapy. For Cross-Over example, half of the subjects might be randomly assigned first to Design the control group and then to the experimental intervention, while the other half would have the sequence reversed. A device that necessarily deviates from devices generally available or from an applicable performance standard or premarket approval requirement to comply with the order of an individual physician or dentist and that is

• Not generally available or generally used by other physicians or dentists; Not generally available in finished form for purchase or Custom Device • for dispensing upon prescription; • Not offered for commercial distribution through labeling or advertising; and • Intended for use by an individual patient named in the order of a physician or dentist and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice. D When data is anonymous, they are not linked to the identity of individual subjects in any way that would make it possible to connect the information to the individual from whom it came. Data Anonymous data does NOT have direct identifiers like names, addresses, clinic or hospital number, Social Security Number, or insurance agency numbers. Data that is linked to subjects via a

CODE are NOT anonymous. When data is confidential, there is a link between data and the individuals who provide it, but the link is obscured by coding or other procedures so that even someone who has access to the raw data cannot identify a subject without also having access to the link between the subject code and the subject's identity. An individual assigned to conduct interim monitoring of accumulating data from research activities to assure the Data and Safety continuing safety of research participants, relevance of the study Monitor question, appropriateness of the study, and integrity of the accumulating data. The individual should have expertise in the relevant medical, ethical, safety and scientific issues. An appointed independent group consisting of at least three (3) members assigned to conduct interim monitoring of accumulating data from research activities to assure the Data and Safety continuing safety of research participants, relevance of the study Monitoring question, appropriateness of the study, and integrity of the Board (DSMB) accumulating data. Membership should include expertise in the relevant field of study, statistics, and research study design. Also known as a Data and Safety Monitoring Committee (DSMC). A defined process to protect the safety of human subjects and maintain the scientific integrity of human subject research and the validity of the data. A DSMP may be a stand-alone document or the section of a protocol that describes the steps to identify physical, social, or psychological occurrences that may result from participation in the research study and explains in detail how such occurrences will be handled and reported. A DSMP describes the timing, tools and/or method(s) for monitoring and evaluation, procedures for treatment or Data and Safety resolution (including circumstances which would result in halting Monitoring Plan or terminating research). It includes procedures for and timing of (DSMP) reports to oversight bodies, and description of oversight bodies involved with the study (e.g., study team, FDA, IRB, or DSMB). It describes the frequency with which each oversight group reviews the collected information. A study does not need to have a DSMB to have a DSMP. The purpose of a DSMP is to minimize risks for subjects to the extent possible by explicating procedures for monitoring their safety. A DSMP would formalize action items such as

• methodology for notifying an attending physician of emergent events • obtaining psychiatric consults for findings of likely suicide • procedures and education for staff regarding protection of private information • procedures to follow when subjects experience significant social or emotional upset in response to the research interaction (e.g., a panic attack after an interview and questionnaire)

Note that data collected for safety monitoring (or for research purposes) does not necessarily have to be submitted to IRB as an adverse event report. Data Points Any text or numbers generated during a study. A DUC is the application a user submits for consideration for authorized use of controlled dbGaP data. The DUC should include a list of the controlled data set(s) required by the user and a brief description of the proposed research use of the requested data. The user must also offer the following assurances in the DUC that

• the data will only be used for approved research; • data confidentiality will be protected; • all applicable laws, local institutional policies, and terms and procedures specific to the study's data access policy for handling dbGaP data will be followed; Data Use • no attempts will be made to identify individual study Certification participants from whom data were obtained; (DUC) • controlled-access data from dbGaP will not be sold or shared with third parties; • the contributing investigator(s) who conducted the original study and the funding organizations involved in supporting the original study will be acknowledged in publications resulting from the analysis of those data; • all NIH supported genotype/phenotype data and conclusions derived directly from them will remain in the public domain, without licensing requirements; • an annual research progress report will be submitted.

The completed DUC must be co-signed by a designated official representing the institution for which the applicant works.

dbGaP was developed to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype. Such studies include genome-wide association Database of studies, medical sequencing, molecular diagnostic assays, as Genotypes and well as association between genotype and non-clinical traits. Phenotypes The advent of high-throughput, cost-effective methods for (dbGaP) genotyping and sequencing has provided powerful tools that allow for the generation of the massive amount of genotypic data required to make these analyses possible. An expelled or delivered fetus that exhibits no heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, or pulsation of the umbilical cord (if still Dead Fetus attached) [45 CFR 46.203(f)]. Generally, some organs, tissues, and cells (referred to collectively as fetal tissue) remain alive for varying periods of time after the total organism is dead. Reports generally refer to the death of a research subject but also death of another (a person not enrolled in the study) that is definitely, probably, or possibly related to the study must be Death reported (e.g., in a study of anti-psychotic medications, the study drug is found to increase irritability and the research subject commits murder). Giving subjects previously undisclosed information about the Debriefing (in research project following completion of their participation in Research) research. The intentional misleading of a subject about the nature of the study. Deception increases ethical concerns and should be used with discretion, because it interferes with the ability of the subject to give informed consent. Misleading or omitted information might include the purpose of the research, the role

Deception of the researcher, or what procedures in the study are actually experimental. The IRB recognizes that deception or concealment may be necessary for certain types of behavioral research. Because people act differently depending on circumstances, full knowledge by the subject might bias the results in some cases. A code of ethics for clinical research approved by the World Medical Association in 1964 and widely adopted by medical Declaration of associations in various countries. The fundamental principle is Helsinki respect for the individual, their right to self-determination and the right to make informed decisions regarding participation in research, both initially and during the course of the research.

The investigator's duty is solely to the patient or volunteer, and while there is always a need for research, the subject's welfare must always take precedence over the interests of science and society, and ethical considerations must always take precedence over laws and regulations. The recognition of the increased vulnerability of individuals and groups calls for special vigilance. It is recognized that when the research participant is incompetent, physically or mentally incapable of giving consent, or is a minor, then allowance should be considered for surrogate consent by an individual acting in the subject's best interest, in which case their assent should still be obtained if at all possible. An IRB action that specifies conditions under which research can be reconsidered for approval, pending substantive Deferred clarifications or modifications to the protocol and/or informed consent process/document, without which the IRB could not fully evaluate the research under review. An adverse event that

• is a known effect of the drug, device, or procedure (e.g., listed in the protocol documents including IB, consent, publications) • follows an obvious sequence of time, from the drug’s Definitely related administration, device’s implantation or activation, or adverse event procedure, for which the event is directly attributed to the administration, implantation, activation, or procedure • ceases with discontinuation of the drug, device, or procedure (and reoccurs on restarting) • includes data that was only collected for the study • included disturbing or upsetting questions that the subject was asked for the purpose of the research All direct personal identifiers are permanently removed (e.g., from data or specimens), no code or key exists to link the materials to their original source(s), and the remaining information cannot reasonably be used by anyone to identify the De-identified source(s). For purposes of the HRPP policy, health information is de-identified when it does not contain any of the 18 identifiers specified by the HIPAA Privacy Rule at 45 CFR 164 (or has been determined to be de-identified by a statistician in accordance with the standards established by the Privacy Rule). An incident involving noncompliance with the protocol, but one Deviation that does not have a significant effect on the subject's rights,

safety or welfare, and/or on the integrity of the data. Deviations may result from the action of the participant, researcher, or staff. In informed consent: lacking the ability to provide valid informed Diminished consent to participate in research, e.g., as a result of trauma, Decision-Making intellectual disability, certain mental illnesses, cognitive Capacity impairment, or dementia. Diminished decision-making capacity may be temporary, permanent, progressive, or fluctuating. An IRB action taken when the determinations required for Disapproved approval of research cannot be made, even with substantive (Decision) clarifications or modifications to the protocol and/or informed consent process/document. Dose Limiting Size-effects severe enough to prevent giving more of the Toxicity (DLT) treatment. A clinical trial in which two or more doses of an agent (such as a Dose-Ranging drug) are tested against each other to determine which dose Study works best and is least harmful. A clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental drug and which are receiving a placebo (or another Double-Blind therapy). Double-blind trials are thought to produce objective Study results, since the expectations of the doctor and the participant about the experimental drug do not affect the outcome; also called double-masked study. A study design in which neither the investigators nor the Double-Masked subjects know the treatment group assignments of individual Design subjects. Sometimes referred to as "double-blind." A modification of the effect of a drug when administered with Drug-Drug another drug. The effect may be an increase or a decrease in Interaction the action of either substance, or it may be an adverse effect that is not normally associated with either drug. E A measure used to estimate the risk resulting from an exposure of ionizing radiation, calculated as a weighted average of Effective Dose exposure to different body tissues. The effective dose is measured in rems or sieverts. Of a drug or treatment: The maximum ability of a drug or treatment to produce a result regardless of dosage. A drug Efficacy passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the procedure

mandated by the FDA, Phase II clinical trials gauge efficacy and Phase III trials confirms it. See Phase II and III Trials

In medicine: Is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances. Eligibility Summary criteria for participant Criteria selection. See Inclusion/Exclusion Criteria For purposes of Adverse Event reporting: An event that was not life-threatening but still warranted urgent professional treatment Emergency for physical or psychological trauma or injury such as treatment and/or Urgent in an emergency room, urgent care center, psychiatrist's office, Treatment psychologist office, or other facility providing immediate care (e.g., battered women's shelter). Use of an investigational drug or biologic or unapproved medical device for a human subject in a life-threatening situation for which no standard acceptable treatment is available and when there is not sufficient time to obtain full IRB approval. An urgent Emergency Use page to the IRB Chair on Call can replace the IRB approval prior to use. Please note: After the Emergency Use is accomplished; a WMed application still needs to be completed to notify the IRB of the use. Denotes information acquired by means of observation or experimentation. Empirical data are data produced by an observation or experiment. A central concept in modern science and the scientific method is that all evidence must be empirical, or empirically based, that is, dependent on evidence or consequences that are observable by the senses. It is usually Empirical differentiated from the philosophic usage of empiricism by the use of the adjective empirical or the adverb empirically. The term refers to the use of working hypotheses that are testable using observation or experiment. In this sense of the word, scientific statements are subject to, and derived from, our experiences or observations. The process of encoding a message so that it can be read only Encryption by the sender and the intended recipient. Software whose main task is encryption and decryption of data, Encryption usually in the form of files on hard drives and removable media, software or email messages sent over computer networks or the Internet. In clinical research: Overall outcome that the protocol is Endpoint designed to evaluate. Common endpoints are severe toxicity,

disease progression, or death. In a clinical research project, an endpoint generally refers to occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial, but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual or entity from the trial, and then often termed humane (clinical) endpoint. Involved in human subject research in such a way (or to the extent) that the ethical and regulatory requirements for human subject protection are applicable. An individual (or organization) becomes engaged in human subject research when for the purposes of non-exempt research the individual (or organization’s employee or agent) obtains any of the following:

Data about research participants through intervention or Engaged • interaction • Identifiable private information about research participants • Informed consent of research participants.

Note: An organization is also engaged in human subject research whenever it receives a direct federal award to support the research. The act of signing up participants into a study. Generally this process involves evaluating a participant with respect to the Enrolling eligibility criteria of the study and going through the informed consent process. For conflict of interest matters, this term refers to the company or organization in which an investigator is disclosing their Entity financial interests. An "entity" may be, but is not necessarily, a "sponsor" of a project.

Fair or just; used in the context of selection of subjects to Equitable indicate that the benefits and burdens of research are fairly distributed.

FDA regulation 21 CFR 50.24 provides a narrow exception to the requirement for informed consent from each human subject, Exception from or his or her legally authorized representative, prior to initiation Informed of an experimental intervention. The exception would apply to a Consent (EFIC) limited class of research activities involving human subjects who are in need of emergency medical intervention but who cannot

give informed consent because of their life-threatening medical condition, and who do not have a legally authorized person to represent them. The intent of the new regulation is to allow research on life-threatening conditions for which available treatments are unproven or unsatisfactory and where it is not possible to obtain informed consent, while establishing additional protections to provide for safe and ethical studies. The federal government has identified certain categories of research involving human subjects that qualify for exemption from federal regulations. WMed is authorized by the federal government to determine whether studies thought by the PI to be exempt from federal regulations -- actually qualify for exemption. Only the IRB has authority to make a determination that a study is exempt from federal regulations and from IRB review and approval. When the IRB notifies a PI that a research project is EXEMPT, it also notifies the PI that the research is approved for initiation or continuation. In order to qualify for exemption, a research study must fall entirely within one or more of the six categories for exemption and it cannot place subjects at greater than minimal risk. If the research involves Exempt Review prisoners, then it does not qualify for exemption from federal regulations and IRB review.

What Exemption Means: "Exemption" as used in this document means exemption from the requirements set forth in Regulations for the Protection of Human Subjects (45 CFR 46), such as the requirement for a written informed consent document. What Exemption Does Not Mean: "Exemption" does not mean that the research activity is exempt from the law, and it does not mean that the research need not conform to the canons of sound research ethics. For additional information regarding Exempt Review categories, see OHRP Decision Charts #2-7for Exempt Categories. Available data (or specimens) at the time the research is Existing submitted for a determination of exempt. Refers to any of the FDA procedures, such as compassionate use, parallel track, and treatment IND that distribute Expanded experimental drugs to participants who are failing on currently Access available treatments for their condition and also are unable to participate in ongoing clinical trials. Expanded Policy and procedure that permits individuals who have serious Availability or life-threatening diseases for which there are no alternative

therapies to have access to investigational drugs and devices that may be beneficial to them. Examples of expanded availability mechanisms include Treatment INDs, Parallel Track, and open study protocols. An event that is expected in that it has been addressed or described in one or more of the following: Informed consent document(s) for this study, IRB application for this study, grant application or study agreement, protocol or procedures for this study, investigators' brochure or equivalent (for FDA regulated Expected Event drugs or devices), DSMB Reports, published literature, other documentation, or characteristics of the study population. If an 'expected' event is of unexpected duration, magnitude, or frequency then the occurrence(s) should be reported within the timeframe of an unexpected Adverse Event. The IRB Chair and those experienced IRB members designated Expedited IRB by the Chair who may perform some or all types of expedited Reviewer reviews. A procedure through which certain kinds of research may be reviewed and approved without convening a meeting of the IRB. An IRB may use the expedited review procedure to review either or both of the following:

• Some or all of the research appearing on the list of categories of research and found by the reviewer(s) to involve no more than minimal risk, • Minor changes in previously-approved research during the period for which approval is authorized. The following criteria must be met in order for research to be considered for expedited review: Expedited • The research activities must present no more than Review minimal risk to human subjects. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. • All of the research activities involve only procedures listed in one or more of the research categories established in the Federal Register. The categories in this list apply regardless of the age of subjects, except as noted. Categories one (1) through (7) pertain to both initial and continuing IRB review.

For additional information regarding expedited review categories, see OHRP Guidance and OHRP Decision Chart #8. An IRB member determined by the IRB Chair to be qualified to perform reviews using expedited procedures. The following Experienced IRB criteria are considered when determining whether an IRB Member member is experienced: length of IRB service, training regarding expedited review procedures, research experience/expertise, and/or work with the research participants being studied. Any use of a drug except for the use of a marketed drug in the Experiment course of medical practice or any evaluation of the safety and efficacy of a medical device. A term often used to denote a therapy (drug, device or procedure) that is unproven or scientifically un-validated with Experimental respect to safety and efficacy. A procedure may be considered “experimental” without necessarily being part of a formal study to evaluate its usefulness. Synonymous with Research. An experimental study is one in which subjects are randomly assigned to groups that experience carefully controlled Experimental interventions manipulated by the experimenter according to a Study strict logic allowing causal inference about the effects of the interventions under investigation. See also: Quasi-Experimental Study The date that the IRB’s approval of research has lapsed and research can no longer be performed; an expiration date may Expiration Date not be longer than one year from the date the approval period begins. From the perspective of an Investigator engaged in a multicenter clinical trial, external adverse events are those External adverse events experienced by subjects enrolled by Adverse Event investigators at other institutions engaged in the clinical trial (not under WMed authority). An event occurring in research at a site(s) other than WMed, External event over which another IRB has jurisdiction.

F The FDA has oversight over clinical trials involving FDA Oversight investigational drugs, devices, and biologics, and some trials involving approved drugs, devices and biologics. Contact

the IRB Office if there is any question regarding whether FDA oversight of a clinical trial is required. The FDP is a cooperative initiative among federal agencies and Federal institutional recipients of federal funds. It was established to Demonstration increase research productivity by streamlining the administrative Partnership(FDP process and minimizing the administrative burden on principal ) investigators while maintaining effective stewardship of federal funds. The federal policy that provides regulations for the involvement of human subjects in research. The Policy applies to all research involving human subjects conducted, supported, or Federal Policy otherwise subject to regulation by any federal department or agency that takes appropriate administrative action to make the Policy applicable to such research. Sixteen federal agencies have adopted the Policy known as the "Common Rule." The Policy for the Protection of Human Subjects requires that each institution "engaged" in Federally-supported human subject research file in "Assurance" of protection for human Federal Wide subjects. The Assurance formalizes the institution's commitment Assurance to protect human subjects. The requirement to file an Assurance includes both "awardee" and collaborating "performance site" institutions. The WMed’s FWA number is 00009755. The expiration date changes regularly as IRBs update their Rosters. The placenta, amniotic fluid, fetal membranes, and umbilical Fetal Material cord. The product of conception from the time of implantation until delivery. If the delivered or expelled fetus is viable, it is designated an infant [45 CFR 46.203(c)]. The term "fetus" Fetus generally refers to later phases of development; the term "embryo" is usually used for earlier phases of development. See also: embryo. An interest of an individual (or his/her immediate family) of monetary value that would reasonably appear to be affected by the research or an individual’s interest in any entity whose Financial financial interests would reasonably appear to be affected by Conflict of the research. Financial interests include, but are not limited to: Interest salary or other payments for services (e.g., consulting fees or honoraria), equity interests (e.g., stocks, stock options, or other ownership interests), and intellectual property rights (e.g., patents, copyrights, and royalties from such rights).

Written declaration of external, financial interests of an individual that are related or potentially related to research or Financial other sponsored activities taking place within the university. Disclosure Disclosures are required under requirements promulgated by federal and state agencies and the IRB.

An occurrence or determination of noncompliance that does not Finding of Non- require further confirmation or investigation (e.g., failure to Compliance respond to the IRB within established deadlines, allegation of noncompliance determined by the IRB to be true). A supplemental report from a sponsor or investigator providing Follow up report additional information, clarification, or corrections to a previously reported (to WMed) Adverse Event. Food and Drug The FDA oversees safety of foods, drugs, devices, biologics Administration ( and cosmetics for human use. The FDA also works with the

FDA) blood banking industry to safeguard the nation's blood supply. An audit of research and/or investigators initiated at the request of the IRB or Institutional Official to obtain or verify information For-Cause necessary to ensure compliance with regulations and Audit/Review institutional requirements and to inform decisions about the conduct of human subject research and/or human subject protection. The FDA-483 is the written notice of objectionable practices or deviations from the regulations that is prepared by the FDA investigator at the end of an inspection. The items listed on the form serve as the basis for the exit discussion with the researcher at which time the PI can either agree or disagree Form 483 with the items and can offer possible corrective actions to be taken. The PI may also respond to the district office in writing after it has had sufficient time to properly study the FDA-483 (hyperlink). The receipt of and a PI’s response to the Form 483 is submitted to IRB as an ORIO (hyperlink). The FOIA is a federal freedom of information law that allows for the full or partial disclosure of previously unreleased information Freedom of and documents controlled by the US government. The Act Information Act defines agency records subject to disclosure, outlines (FOIA) mandatory disclosure procedures and grants nine exemptions to the statute. Review of proposed research at a convened meeting at which a Full Board / majority of the membership of the IRB is present, including at Committee least one member whose primary concerns are in nonscientific Review areas. For the research to be approved, it must receive the approval of a majority of those members present at the meeting. If the study does not meet the criteria for exempt or expedited Full Review review, then it must be submitted for full review.

G Information from which one may infer a general conclusion; knowledge brought into general use or that can be applied to a wider or different range of circumstances. For example, publication and presentation are typical methods used to Generalizable disseminate research findings, thereby contributing to Knowledge “generalizable knowledge.” However, not all information that is published or presented represents generalizable knowledge. Generalizable knowledge is also interpreted to include data intended for general use, regardless of its eventual distribution or acceptance. Genetic GINA is a federal law that protects Americans from being Information treated unfairly because of differences in their DNA that may Nondiscriminatio affect their health. The new law prevents discrimination from n Act (GINA) health insurers and employers. Tests to identify persons who have an inherited predisposition to Genetic a certain phenotype or who are at risk of producing offspring Screening with inherited diseases or disorders. All the genetic material in the chromosomes of a particular Genome organism; its size is generally given as its total number of base pairs. A GWAS is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. Genome-Wide Once new genetic associations are identified, researchers can Association use the information to develop better strategies to detect, treat Studies (GWAS) and prevent the disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease and mental illnesses. Genotype The genetic constitution of an individual. A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that Good Clinical provides assurance that the data and reported results are Practice (GCP) credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. GLP Standard compliance monitoring program ensures the Good Laboratory quality and integrity of test data submitted in support of product Practice (GLP) registration.

"Group C" Treatment IND was established by agreement between the FDA and the National Cancer Institute (NCI). The Group C program is a means by which oncologists can use investigational drugs for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are generally Phase III study drugs that have shown evidence of relative and Group C reproducible efficacy in a specific tumor type. They can Treatment IND generally be administered by properly trained physicians without the need for specialized supportive care facilities. Group C drugs are distributed only by the NIH under NCI protocols. Although treatment is the primary objective and patients treated under Group C guidelines are not part of a clinical trial, safety and effectiveness data are collected.

H The HITECH Act was signed into law on February 17, 2009, to Health promote the adoption and meaningful use of health information Information technology. Subtitle D of the HITECH Act addresses the privacy Technology for and security concerns associated with the electronic Economic & transmission of health information, in part, through several Clinical Health provisions that strengthen the civil and criminal enforcement of (HITECH) the HIPAA rules. The HIPAA Privacy Rule regulates the use and disclosure of Protected Health Information (PHI) held by "covered entities" (generally, employer sponsored health plans, health insurers, and medical service providers that engage in certain transactions). By regulation, the DHHS extended the HIPAA Health Insurance privacy rule to independent contractors of covered entities who Portability and fit within the definition of "business associates". PHI is any Accountability information held by a covered entity which concerns health Act of 1996 status, provision of health care, or payment for health care that (HIPAA) can be linked to an individual. This is interpreted rather broadly and includes any part of an individual's medical record or payment history. They also must disclose PHI when required to do so by law, such as reporting suspected child abuse to state child welfare agencies. OHRP: “A living individual about whom an investigation conducting research obtains (1) Data through intervention or Human Subject interaction with the individual or (2) identifiable private information.” 45 CFR 46.102 (f)

FDA: “An 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 (g), 21 CFR 56.102 (e) Humanitarian An application that permits the marketing of a humanitarian use Device device. Exemption (HDE) An FDA regulated medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affect Humanitarian fewer than 4000 individuals in the US per year, but not yet Use Device approved for unrestricted use. The use of a HUD is subject to IRB oversight. Contact WMed IRB Office for guidance.

I The medical or other standards determining whether a person may or may not be allowed to enter a research study. These Inclusion / criteria are based on such factors as age, gender, the type and Exclusion stage of a disease, previous treatment history, and other Criteria medical conditions. It is important to note that inclusion and exclusion criteria are not used to reject people personally, but rather to identify appropriate participants and keep them safe. This agreement is used when a collaborating investigator engages in research with a collaborating investigator who is not affiliated with the covered entity; a collaborating investigator Individual who is affiliated with an institution/hospital/clinic that may not Investigator have its own IRB to review the study; a collaborating Agreement (IIA) investigator who is not acting as an employee of any institution with respect to his or her involvement in the research being conducted by the institution. The term 'individually identifiable health information' means any information, including demographic information collected from an individual, that

Individually • is created or received by a health care provider, health Identifiable plan, employer, or health care clearinghouse; and Health • relates to the past, present, or future physical or mental Information health or condition of an individual, the provision of health care to an individual, or the past, present, or future payment for the provision of health care to an individual, and-- • identifies the individual; or

• with respect to which there is a reasonable basis to believe that the information can be used to identify the individual. Informed consent is the exercise of a free power of choice without undue inducement, force, fraud, deceit, duress or other form of constraint or coercion. If the subjects are minors or are not capable of giving consent, parental, guardian or other legal representative consent is required.

• Use of a written consent form that includes all of the basic elements. • The process of learning the key facts about a research study. A process by which a subject voluntarily confirms his or Informed • her willingness to participate in a particular research Consent project. • Informed consent is documented by means of a written, signed, and dated informed consent form unless such documentation is waived by the IRB. (45 CFR 46.116) • In giving informed consent, subjects may not waive or appear to waive any of their legal rights, or release or appear to release the investigator, the sponsor, the institution or agents thereof from liability for negligence (21 CFR 50.20 and 50.25). • It is a continuing process throughout the study to provide information for participants. A document that describes the rights of the study participants, Informed and includes details about the study, such as its purpose, Consent duration, required procedures, and key contacts. Risks and Document (ICD) potential benefits are explained in the informed consent or Informed document. The participant then decides whether or not to sign Consent Form the document. Informed consent is not a contract, and the (ICF) participant may withdraw from the trial at any time.

• Any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical Institutional research involving human subjects. The primary purpose Review Board of such review is to assure the protection of the rights (IRB) and welfare of the human subjects. The term has the same meaning as the phrase institutional review committee as used in section 520 (g) of the act. (FDA)

• A specially constituted review body established or designated by an institution to protect the welfare of human subjects recruited to participate in biomedical or behavioral research (OHRP) Institutional Review Board of WMed has 1 individual review Board. WMed Analysis of clinical trial results that includes all data from Intent to Treat participants in the groups to which they were randomized even if they never received the treatment. See Randomization. A research related communication or interface between an investigator and a research subject other than those that involve an investigational agent or procedure as it relates to a disease Interaction or disorder (an intervention). Interactions may occur in person, by phone, computer, fax, or mail. Examples include surveys, focus groups, fMRI, and tests on healthy normal subjects. From the perspective of an Investigator engaged in a multicenter clinical trial, internal adverse events are those adverse Internal Adverse events experienced by subjects enrolled by the Investigator(s) Event or at their site. In the context of a single-site study, all adverse events would be considered internal adverse events. A qualified interpreter is an individual who is fluent (can speak, read and write) in English and the language of the subject, and (preferably) understands human research informed consent Interpreter requirements. The interpreter should not be a member of the potential subject's family. Family members may have their own biases regarding research participation. Intervention includes both physical procedures by which data are gathered (e.g., venipuncture) and manipulations of the subject or the subject’s environment that are performed for Intervention research purposes. Interventions may occur in person, by phone, computer, fax, or mail. Examples include clinical trials, behavioral or nutritional counseling, and surgeries. Clinical investigation means any experiment in which a test article, even an approved drug, is administered or dispensed to, or used involving, one or more human subjects. (FDA) The use Investigational of a marketed drug in the course of medical practice that is outside the label indications ("off-label" use or innovative care) does not in and of itself constitute investigational use of a drug,

unless that use is part of an experiment or systematic investigation meeting the criteria for human subject research. A device permitted by FDA to be tested in humans but not yet determined to be safe and effective for a particular use in the general population and not yet licensed for marketing. Devices Investigational are classified as significant and non-significant risk. A significant Device risk device means an investigational device thatpresents a potential for serious risk to the health, safety, or welfare of a subject. (FDA) Approval by FDA for investigational device exemption (IDE) permits a device that otherwise would be required to comply Investigational with a performance standard or to have premarket approval to Device be shipped lawfully across state and international boundaries for Exemption (IDE) the purpose of conducting investigations of that device. (FDA) Most devices under investigation should have an IDE. A new drug or biologic (i.e., not approved for marketing by FDA) Investigational used in a clinical investigation, including a biological product Drug used in vitro for diagnostic purposes. A drug permitted by FDA to be tested in humans but not yet determined to be safe and effective for a particular use in the Investigational general population and not yet licensed for marketing. Use of New Drug (IND) investigational drugs requires application to the FDA and is usually limited to subjects enrolled in clinical studies covered by an Investigational New Drug agreement with the FDA. Investigational An application that permits an investigational drug that would New Drug otherwise be required to have pre-market approval by FDA to Application (IND) be legally shipped for a clinical investigation. A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a Investigational product with a marketing authorization when used or assembled Product (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.

• 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 Investigator the team and may be called the principal investigator. (ICH Guidelines) • 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. (FDA) See also Co-Investigator and/or Sub-Investigator. An assessment made by the investigator and/or sponsor regarding whether or not an adverse event, or DSMB or other Investigator Report, necessitates a change to the study protocol, informed Response consent document or process, or investigator's brochure in order to promote subject safety and/or autonomy. The IB is a comprehensive document summarizing the body of information about an investigational product ("IP" or "study drug") obtained during a drug trial. The IB is critically important throughout the drug development process and is updated with new information as it becomes available.

• The purpose of the IB is to compile data relevant to studies of the investigational product in human subjects gathered during preclinical and other trials. • An IB is intended to provide the investigator with insights necessary for management of study conduct and study Investigator’s subjects throughout a clinical trial. Brochure (IB) • An IB may introduce key aspects and safety measures of a protocol, such as: • Dose (of the study drug), • Frequency of dosing interval, • Methods of administration, and • Safety monitoring procedures. • The sponsor is responsible for keeping the information in the IB up-to-date. The IB should be reviewed annually and must be updated when any new and important information becomes available, such as when a drug has received marketing approval and can be prescribed for use commercially. Investigator- A proposal submitted to a sponsor that is not in response to an Initiated RFP, RFA, or a specific program announcement. Proposal Any radiation capable of displacing electrons from atoms or Ionizing molecules, thereby producing ions. Examples include alpha, Radiation beta, gamma, and X-rays. High doses of ionizing radiation may produce severe skin or tissue damage.

This agreement is used when one institution engages in IRB research with: A performance site with whom institution ‘a’ (Institutional) currently does not have a Cooperative Review Authorization Agreement and Only one institution's IRB will review the study Agreement (IAA) to avoid the need for dual review - Either institution ‘a’ or the performance site. J An ethical principle discussed in the Belmont Report requiring fairness in distribution of burdens and benefits; often expressed Justice in terms of treating persons of similar circumstances or characteristics similarly.

L 1. Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the Legally research. (FDA) Authorized 2. A person authorized either by statute or by court Representative appointment to make legal decisions on behalf of (LAR) another person. In human subject research, an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. Health information that excludes certain direct identifiers, but may include city, state, and ZIP code; elements of date; and other numbers, characteristics, or codes that cannot be used to identify an individual or the individual's relatives, employers, or household members. Limited data sets may be used or Limited Data Set disclosed for purposes of research with a data use agreement as described by the HIPAA Privacy Rule at 45 CFR 164. For more information, including the list of identifiers that must be removed from health information in a limited data set, see HIPAA and Human Subjects Research. An event which occurs in a study under the supervision of the Local Event WMed IRB and whose principal investigator is a WMed faculty / WMed Event or staff member. The event is a WMed Event when it occurs at

WMed-Bronson-Borgess site or any other site where the WMed PI has oversight, even when the PI is physically in another location. It does not matter where the subject experiences or is treated for the adverse event. If interventions take place at several different WMed locations, please specify at which location the event occurred. M Masked The knowledge of intervention assignment. See Blind. Study designs comparing two or more interventions in which either the investigators, the subjects, or some combination Masked Study thereof do not know the treatment group assignments of Designs individual subjects. Sometimes called "blind" study designs. See also: Double-Masked Design and Single-Masked Design A MTA is a contract that governs the transfer of tangible research materials between two organizations, when the recipient intends to use it for his or her own research purposes. The MTA defines the rights of the provider and the recipient with respect to the materials and any derivatives. Biological materials, such as reagents, cell lines, plasmids, and vectors, Material Transfer are the most frequently transferred materials, but MTAs may Agreement (MTA) also be used for other types of materials, such as chemical compounds and even some types of software. Three types of MTAs are most common at academic institutions: transfer between academic or research institutions, transfer from academia to industry, and transfer from industry to academia. Each call for different terms and conditions. The highest dose of a biologically active agent given during a Maximally chronic study that will not reduce longevity from effects other Tolerated Dose than carcinogenicity.

• A diagnostic or therapeutic article that does not achieve any of its principal intended purpose through chemical action within or on the body (that is, not a drug or biologic). Such devices include diagnostic test kits, crutches, electrodes, pacemakers, arterial grafts, Medical Device intraocular lenses, and orthopedic pins or other orthopedic equipment. (OHRP) • A medical device is any instrument, apparatus, or other similar or related article, including component, part, or accessory, which is… intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation,

treatment, or prevention of disease, in humans or other animals… The range of devices is broad and diverse, including bandages, thermometers, ECG electrodes, IUDs, cardiac pacemakers, and hemodialysis machines. For further information, see the information sheets entitled "Medical Devices," "FAQ about IRB Review of Medical Devices" and "Significant Risk and Non- significant Risk Medical Device Studies." (FDA) An event which does not pose any significant or permanent risk Mild Adverse of harm to the subject. A mild adverse event is considered Event Grade I using CTC Common Toxicity Criteria. See also Severity. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in the daily life or during the performance of routine physical or psychological Minimal Risk examinations or tests. 45 CFR 46.102(i)

Prisoners: Research projects with Prisoners automatically incur a higher risk level than those of non-Prisoners. Changes to research that in the judgment of the IRB do not affect assessment of the risks and benefits of the study by substantially altering any of the following: research aims or methodology, nature of subject participation, level of risk, Minor Changes proposed benefits, participant population, qualifications of the research team, or the facilities available to support the safe conduct of the research. A minor change does not increase risk more than minimally or add procedures in research categories other than those that qualify for expedited initial review. An event which causes discomfort and perhaps requires Moderate treatment, but does not pose any significant or permanent risk Adverse Event or harm to the subject or require in-patient hospitalization. An event that is Grade II by CTC Common Toxicity Criteria. An IRB action that specifies conditions under which research can be approved, pending the completion of minor, non- substantive (i.e., not directly relevant to the determinations Modifications required for approval by the IRB) clarifications or modifications Required to the protocol and/or informed consent process/document. Review of the investigator’s response(s) may be performed by expedited review.

A research project conducted according to a single protocol but Multicenter at more than one site, and, therefore, carried out by more than Research Project one set of investigators.

N Neonate A newborn up to four weeks old. Failure (intentional or unintentional) to comply with applicable federal regulations, state or local law, the requirements or determinations of the IRB, or University policy regarding Non-Compliance research involving human subjects. Non-compliance can result from action or omission. Non-compliance may be non-serious (minor) or serious, and may also be continuing. Non- An Adverse Event involving social or psychological trauma, physiological insult or injury rather than physiological or biomedical harm. Adverse Event An individual appointed to the IRB who (due to training, background, and/or occupation) is inclined to view research Non-Scientist activities from the standpoint of someone outside the scientific or scholarly discipline of the IRB on which he/she serves. Noncompliance that does not increase risk to research participants, compromise participants’ rights or welfare, or affect the integrity of the research/data or the human subject Non-Serious or protection program. Examples of minor noncompliance may Minor Non- include, but are not limited to: lapses in continuing IRB Compliance approval, failure to obtain exempt determination before exempt research involving human subjects is conducted, minor changes in or deviations from an approved protocol, or administrative errors. An investigational medical device that does not present Non-Significant significant risk. The determination that a device presents a non- Risk Device significant risk is first made by the sponsor. If the IRB agrees (NSR) with the sponsor’s finding that a device presents non-significant risk, the device is considered a non-significant risk device. Research that has no likelihood or intent of producing a Non-Therapeutic diagnostic, preventive, or therapeutic benefit to the current Research subjects, although it may benefit subjects with a similar condition in the future. An expelled or delivered fetus which, although it is living, Non-Viable Fetus cannot possibly survive to the point of sustaining life

independently, even with the support of available medical therapy [45 CFR 46.203 (d) and (e)]. Although it may be presumed that an expelled or delivered fetus is nonviable at a gestational age less than 20 weeks and weight less than 500 grams [Federal Register 40 (August 8, 1975): 33552], a specific determination as to viability must be made by a physician in each instance. See also: Viable Infant. Subjects used in study of normal physiology and behavior, or subjects who do not have the condition under study in a particular protocol used as comparisons with subjects who do have the condition. “Normal” does not necessarily Normal Subject connote normal in all respects. For example, patients with broken legs may serve as normal volunteers in studies of metabolism, cognitive development and the like. Similarly, patients with heart disease but without diabetes may be “normal” in a study of diabetes complicated by heart disease. Written acknowledgement from the IRBMED, regarding the outcome of the review of that application. Outcomes may be "approved", "acknowledged", or "disapproved". Adverse Event Notice of and Unanticipated Events NOT Adverse Events reports are Outcome generally acknowledged, but if accompanying changes to the protocol or consent form are requested these require approval in order to take effect. The proposition, to be tested statistically, that the experimental intervention has "no effect," meaning that the treatment and control groups will not differ as a result of the intervention. Null Hypothesis Investigators usually hope that the data will demonstrate some effect from the intervention, thereby allowing the investigator to reject the null hypothesis. A code of research ethics developed during the trials of Nazi war criminals following World War II and widely adopted as a Nuremberg Code standard during the 1950s and 1960s for protecting human subjects.

O Federal civil rights laws and the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule, together protect Office for Civil your fundamental rights of nondiscrimination and privacy. Civil

Rights (OCR) Rights help to protect you from unfair treatment or discrimination, because of your race, color, national origin, disability, age, gender, or religion. Federal laws also provide

conscience protections for health care providers. The Privacy Rule protects the privacy of your health information; it says who can look at and/or receive your health information, and also gives you specific rights over that information. An office within the DHHS responsible for implementing DHHS Office for Human regulations (45 CFR 46) governing research involving human Research subjects. The office within the NIH, an agency of the Public Protection (OH Health Service, DHHS, responsible for implementing DHHS RP) regulations governing research involving human subjects. A drug prescribed for conditions other than those approved by the FDA. The off-label use of a marketed drug in the course of medical practice does not in and of itself constitute Off-Label Use investigational use of a drug, unless that use is part of an experiment or systematic investigation meeting the criteria for human subject research. An experimental design in which both the investigator(s) and Open Design the subjects know the treatment group to which subjects are assigned. A clinical trial in which doctors and participants know which Open-Label Trial drug or vaccine is being administered. An FDA category that refers to medications used to treat diseases and conditions that occur rarely. There is little financial incentive for the pharmaceutical industry to develop Orphan Drugs medications for these diseases or conditions. Orphan drug status, however, gives a Manufacturer specific financial incentives to develop and provide such medications. Reports to or from internal oversight bodies or outside agencies Oversight Body (such as the FDA, NCI, NIH, or sponsor) should be submitted or Agency to the WMed IRB for review. The terms Oversight Body or Agency or Entity are interchangeable. P The FDA's Parallel Track policy permits wider access to new drugs for life-threatening diseases under a separate treatment protocol (Parallel Track IND) that "parallels" the controlled Phase II and III clinical trials performed to establish the safety Parallel Track IND and effectiveness of investigational new drugs. For example, under this prospective mechanism, persons with AIDS and HIV-related diseases who are not able to take standard therapy or for whom standard therapy is no longer effective, and who are not able to participate in ongoing controlled clinical trials,

can have access to promising investigational new drugs. Applications to permit expanded availability of an investigational new drug under the Parallel Track mechanism must be submitted (typically by the manufacturer of the drug) to the FDA as an amendment to the existing IND. When participation is anonymous, it is impossible to know whether or not an individual participated in a study. When participation is confidential, the study participation of a specific Participation individual is recorded, but cannot be known by anyone except the researcher and authorized research staff that has legitimate access to participation records. Phase 0 is a designation for exploratory, first-in-human trials conducted in accordance with the FDA’s Guidance on Exploratory IND Studies. Phase 0 trials are also known as human micro-dosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single sub-therapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the Phase 0 Trial agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs). A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data. Phase I trials are the first stage of testing in human subjects. Normally, a small group of 20-100 healthy volunteers will be recruited. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often Phase I Trial conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organizations who conduct these studies on behalf of pharmaceutical companies or other research investigators. The subject who receives the drug is usually observed until several half-lives of the drug have

passed. Phase I trials also normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing. Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and lack other treatment options. Volunteers are paid a fee for their time spent in the volunteer center. Pay depends on length of participation. There are different kinds of Phase I trial: Single Ascending Dose; Multiple Ascending Dose; and Food effect. Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (100-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. 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. When the development process for a new drug fails, this usually occurs during Phase II trials when Phase II Trial the drug is discovered not to work as planned, or to have toxic effects. Phase II studies are sometimes divided into Phase IIA and Phase IIB.

• Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). • Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).

Some trials combine Phase I and Phase II, and test both efficacy and toxicity. Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of Phase III Trial their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the

appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug.

Studies in this phase are by some companies categorized as "Phase IIIB studies." While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as the FDA. Once a drug has proved satisfactory after 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 the appropriate regulatory authorities. They will review the submission, and, it is hoped, give the sponsor approval to market the drug. Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. Phase IV trial is also known as Post-marketing surveillance Trial. Phase IV trials involve the safety surveillance and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested Phase IV Trial for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term AE over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted

to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx). Phase V is a growing term used in the literature of translational research to refer to comparative effectiveness research and Phase V Trial community-based research; it is used to signify the integration of a new clinical treatment into widespread public health practice. A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's Placebo effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or treatment.

• A method of investigation of drugs in which an inactive substance (the placebo) is given to one group of participants, while the drug being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment Placebo- is more effective in treating the condition. Controlled Study • A chemically inert substance given in the guise of medicine for its psychologically suggestive effect; used in controlled clinical trials to determine whether improvement and side effects may reflect imagination or anticipation rather than actual power of a drug. A physical or emotional change, occurring after a substance is taken or administered, that is not the result of any special Placebo Effect property of the substance. The change may be beneficial, reflecting the expectations of the participant and, often, the expectations of the person giving the substance. Research involving human subjects who are in need of emergency medical intervention (e.g., comparison of methods Planned for providing cardiopulmonary resuscitation), but who cannot Emergency give informed consent because of their life-threatening medical Research conditions and who do not have an available legally authorized representative to provide consent. An adverse event that Possibly related adverse event • is a lesser known or possible effect of the drug, device, or procedure

• occurred within a sequence of time from the drug’s administration, device implantation and/or activation, or procedure, for which the event may be attributed to the administration, implantation, activation, or procedure • could be explained by the characteristics of the population under study The process performed by a WMed IRB staff to determine that a submission for IRB review is complete, including the required Pre-Review materials, and that institutional requirements, such as completion of human subjects protection education and conflict of interest disclosure, have been met. A specific adverse event that has not yet been reported to the WMed IRB. For example, the hospitalization of a subject due to infection after the second dose of a study medication would be Previously a "previously unreported adverse event" even if there had been Unreported an earlier report submitted to WMed IRB when that same Adverse Event subject had been previously hospitalized due to similar infection after the first dose. All previously unreported adverse events are reported to WMED IRB using the Interim/Event Reporting Form. The scientist or scholar responsible for the conduct of research or other activity, described in a proposal for an award. The PI is responsible for all programmatic and administrative aspects of Principal a project or program. The scientist or scholar with primary Investigator (PI) responsibility for the scientific, technical and administrative conduct of a funded research project. See also: Investigator and Lead Researcher Federal Regulations define "prisoner" as "any individual involuntarily confined or detained in a penal institution”. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals Prisoner detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. Control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others. Privacy The state of being free from the observation, intrusion, or attention of others. Private Private information includes information about behavior that information occurs in a context in which an individual can reasonably

expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects. An adverse event that

• is lesser known or suspected effect of the drug, device, or procedure (listed in the protocol documents including IB, consent, publications, etc.) Probably related • follows a reasonable sequence of time from the drug’s adverse event administration, device implantation, activation, or procedure, for which the event may be attributed to the administration, implantation, activation, or procedure • ceases or diminishes with discontinuation of the drug, removal/discontinued activation of the device, or procedure An application for funding that contains all information necessary to describe project plans, staff capabilities, and Proposal funds requested. Formal proposals are officially approved and submitted by an organization in the name of a principal investigator. Studies designed to observe outcomes or events that occur subsequent to the identification of the group of subjects to be Prospective studied. These studies need not involve manipulation or Studies intervention, but may be purely observational or involve only the collection of data. (Including demographic information) about a patient that (i) is created or received by a health care provider or health plan; (ii) Protected Health relates to the past, present, or future physical or mental health Information (PHI) of the patient; and (iii) identifies the patient or with respect to which there is a reasonable basis to believe it could be used to identify the patient The formal design or plan of an experiment or research activity; specifically, the plan submitted to a Scientific or Peer Review Protocol committee for review and to an agency for research support. The protocol usually also gives the background and rationale for the trial. The protocol includes a description of the research

design, methodology to be employed, the eligibility requirements for prospective participants and controls, the treatment regimen(s), and the proposed methods of analysis that will be performed on the collected data. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a project, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment. A written description of any change(s) to or formal clarification of a protocol. Submit protocol amendments to the WMed IRB using the Modification Request Form. Except to avoid the Protocol possibility of immediate harm to subjects, protocols should not Amendment be changed without prior IRB authorization. When changes for safety are made, an amendment should be submitted to the WMed IRB within 7 days of the action. Accidental or unintentional changes to, or non-compliance with the research protocol that does not increase risk or decrease benefit or; does not have a significant effect on the subject's Protocol rights, safety or welfare; and/or on the integrity of the data. Deviation Deviations may result from the action of the subject, researcher, or research staff. Departure from the IRB approved research protocol without prior IRB approval for the variation. Term used by FDA and some sponsors to refer to a departure from the protocol that receives approval from the IRB before implementation (a one-time exception as distinguished from an amendment to the protocol). Approval requests for a protocol exception should be submitted using the using the Protocol Interim/Event Reporting Form. This is found on the WMed IRB Exception website. Investigator should specify the extent of the exception (e.g., one-time only for patient X and note if data will be included in the study analysis). If the exception is to become a permanent change, a Modification Request Form needs to be submitted. Accidental or unintentional changes to or non-compliance with the IRB approved protocol without prior sponsor and IRB Protocol Violation approval. Violations generally increase risk or decrease benefit, affects the subject's rights, safety, or welfare, and/or the integrity of the data.

R Any substance defined as a drug the Federal Food, Drug and Cosmetic Act that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons. Included are any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of a Radioactive Drug radioactive drug and "radioactive biological products," as defined in 21 CFR 600.3(ee). Drugs such as carbon-containing compounds or potassium-containing salts containing trace quantities of naturally occurring radionuclides are not considered radioactive drugs. A type of scientific experiment - a form of clinical research - most commonly used in testing the safety (or more specifically, information about adverse drug reactions and adverse effects of other treatments) and efficacy or effectiveness of healthcare services (such as medicine or nursing) or health technologies (such as pharmaceuticals, medical devices or surgery). Study subjects, after assessment of eligibility and recruitment, but before the intervention to be studied begins, are randomly Randomized allocated to receive one or other of the alternative treatments Control (RC) under study. Random allocation is complex, but conceptually, Study the process is like tossing a coin. After randomization, the two (or more) groups of subjects are followed up in exactly the same way, and the only differences between the care they receive, for example, in terms of procedures, tests, outpatient visits, follow-up calls, etc. should be those intrinsic to the treatments being compared. The most important advantage of proper randomization is that it minimizes allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments." The period during which a trial is attempting to identify and enroll participants. Recruitment activities can include Recruiting advertising and other ways of soliciting interest from possible participants. See recruitment status and enrolling. Materials, compensation, and other practices or procedures used to inform potential participants about research. Recruiting

Methods Methods for recruiting research participants are generally distinguished from those of marketing, advertising, or public

relations’ efforts, which have promoting a product, service, or idea as goals. Payment, merchandise, or other gift or service offered by a sponsor as an incentive or reward to an organization, Recruitment investigator, or key personnel conducting research designed to Bonus accelerate recruitment that is tied to enrollment rate, timing, or numbers. Announcements; advertisements; flyers; posters; scripts for telephone or other oral communication; letters or email Recruitment messages; bulletin board tear-offs; Internet postings; Materials newspaper, radio, television, or video broadcasts, or other media used to attract potential participants for research. Indicates the current stage of a trial, whether it is planned, ongoing, or completed. Possible values include:

• Not yet recruiting: participants are not yet being recruited or enrolled • Recruiting: participants are currently being recruited and enrolled • Enrolling by invitation: participants are being (or will be) selected from a predetermined population • Active, not recruiting: study is ongoing (i.e., patients are Recruitment being treated or examined), but enrollment has Status completed • Completed: the study has concluded normally; participants are no longer being examined or treated (i.e., last patient's last visit has occurred) • Suspended: recruiting or enrolling participants has halted prematurely but potentially will resume • Terminated: recruiting or enrolling participants has halted prematurely and will not resume; participants are no longer being examined or treated • Withdrawn: study halted prematurely, prior to enrollment of first participant Following the rules set by a governing body. There is a category called ‘continuing non-compliance’ where an Regulatory investigator or study team repeatedly fails to follow the Compliance regulations. For example, year after year they are late in submitting their scheduled continuing reviews, therefore their study lapses each year.

As it relates to the need to report to the IRB, this would be an issue or incident of non-compliance with laws and regulation or to an incident or information that regulations require an IRB consider. Unanticipated Problems/Events that are NOT AEs submission the term is used as a criterion for determining what kinds of submission should be sent to the IRB within 7 days. Examples include but are not limited to:

• Unanticipated problems. Regulatory • Deviations from the research in order to eliminate Concern hazards to subjects or others. • New information about safety concerns. • Failure to obtain consent. • Documenting informed consent of a non-English speaking/reading subject or the legally authorized representative of the subject on an English-only informed consent document. • Improper training of study team (e.g., the PI did not require new staff, fellows, or students to complete the appropriate CITI human subject modules). Failure to adhere to regulations, policies, procedures or special conditions related to the conduct of research. Examples of Regulatory Non- such noncompliance include, but are not limited to, failure to Compliance obtain/maintain approval for research; coercion of human subjects; performing unapproved procedures; and conducting research at unapproved sites. An assessment regarding the causal relationship between a drug or intervention and an adverse event.

EVENTS RELATED

Definitely Related • The event is a known effect of the drug, device, or Relatedness procedure (e.g., listed in the protocol documents (adverse events) including IB, consent, publications) • The event follows an obvious sequence of time, from the drug’s administration, device’s implantation or activation, or procedure, for which the event is directly attributed to the administration, implantation, activation, or procedure. • The event ceases with discontinuation of the drug, device, or procedure (and reoccurs on restarting).

• The event includes data that was only collected for the study. • The event included disturbing or upsetting questions that the subject was asked for the purpose of the research.

Probably Related • The event is lesser known or suspected effect of the drug, device, or procedure (listed in the protocol documents including IB, consent, publications, etc.) • The event follows a reasonable sequence of time from the drug’s administration, device implantation, activation, or procedure, for which the event may be attributed to the administration, implantation, activation, or procedure. • The event ceases or diminishes with discontinuation of the drug, removal/discontinued activation of the device, or procedure.

Possibly Related • The event is a lesser known or possible effect of the drug, device, or procedure. • The event occurred within a sequence of time from the drug’s administration, device implantation and/or activation, or procedure, for which the event may be attributed to the administration, implantation, activation, or procedure. • The event could be explained by the characteristics of the population under study.

EVENTS NOT RELATED

Unlikely Related • The event is NOT a previously known or suspected effect of the test drug, device, or procedure. • The event does NOT follow a sequence of time from drug administration, device implantation and/or activation, or procedure, for which the event could be attributed to the administration, implantation, activation, or procedure. • The event can be readily explained by the characteristics of the population under study. • Unrelated

• The event is NOT known to be an effect of the test drug, device, or procedure. • The event does NOT follow a sequence of time from drug administration, device implantation and/or activation, or procedure, for which the event could be attributed to the administration, implantation, activation, or procedure. • The event can be readily and easily explained by the characteristics of the population under study. • Subject never received study drug, study device, or underwent research study procedure. Payment for participation in research. It is wise to confine use Remuneration of the term "compensation" to payment or provision of care for research-related injuries. Also known as Compensation. Applicable to grants and cooperative agreements only. A Renewal competitively reviewed proposal requesting additional funds extending the scope of work beyond the current project period. Collection of data and/or specimens obtained and stored for Repository future research uses and/or distribution, including a collection not originally or primarily obtained for research purposes. Under HHS Regulations (46.102)research is defined as a “systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” The general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects. For example, some “demonstration” and “service” programs may include research activities.

Under FDA Regulations (21 CFR 56.102) the term “clinical investigation” is synonymous with “research” and is defined as Research “any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the FDA under section 505(i) or 520(g) of the Food, Drug and Cosmetic Act, or need not meet the requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit. Clinical investigations regulated by the FDA under Sections 505(i) and 520(g) of the Act, include investigations of food, dietary supplements that bear a nutrient content claim or a health

claim, infant formulas, food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products. The term “clinical investigation” does not include experiments that must meet the provisions of part 58, regarding nonclinical laboratory studies. The terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous for purposes of this part. Research is subject to 21 CFR 50 and 56 when it involves the use of any drug other than the use of an approved drug in the course of medical practice. Research is subject to 21 CFR 50 and 56 when it involves the use of any medical device other than the use of an approved medical device in the course of medical practice. Location/site at which human subjects research may be Research performed because of an understanding of the local research Performance Site context and appropriate oversight mechanisms that ensure protection of research participants. An ethical principle discussed in the Belmont Report requiring Respect for that individual autonomy be respected and persons with Persons diminished autonomy are protected. Research conducted by reviewing records (i.e., birth and death certificates, medical records, school or employment records) or Retrospective information about past events elicited through interviews with Studies persons who have, and controls who do not have, a disease under investigation. The concurrent oversight of research on a periodic basis by an Review (of IRB. In addition to the at least annual reviews mandated by the research) federal regulations, reviews may, if deemed appropriate, also be conducted on a continuous or periodic basis. A modified and resubmitted request for funding for a project Revision that was previously not funded either because it was denied by the sponsor or withdrawn by the principal investigator. The probability of harm or injury (physical, psychological, social or economic) occurring as a result of participation in a research Risk study. Both the probability and magnitude of possible harm may vary from minimal to significant. Federal regulations define only “minimal risk.” See also “Minimal Risk.” The risk to individual participants versus the potential benefits Risk Benefit Ratio to the individual and/or society. The risk/benefit ratio may differ depending on the condition being treated. The IRB must

determine that the risk benefit ratio of a research project is sufficiently favorable in order to approve the research, and reexamines that determination in light of adverse event, other reportable incidents, and unanticipated problems. An assessment or examination of something (e.g., a practice or Routine (Not-for- procedure) with the possibility or intention of instituting change Cause) Review if necessary. S Scheduled SCRs are completed using Continuing Review Request and Continuing are required to be submitted and approved prior to Review (SCR) expiration. See also Continuing Review.

• Refers to the outcome of an adverse event. Serious • An event is "serious" if it adversely alters the risk-benefit relationship of the research. Any adverse experience occurring at any dose or level of participation that results in any of the following outcomes: Serious Adverse death, a life-threatening experience, hospitalization or Event prolongation of existing hospitalization, a persistent or significant disability or capacity, or a congenital anomaly or birth defect.

• Any untoward occurrence that: • Results in death, • Is life-threatening Requires inpatient hospitalization or prolongation of Serious Adverse • existing hospitalization, Event (SAE) or Results in persistent or significant disability/incapacity, Serious Adverse • or Drug Reaction Is a congenital anomaly/birth defect. (Serious ADR) • • An unexpected result of therapy or other intervention that is severe, life threatening, or fatal, corresponding to grades III, IV, or V using NCI/CTC Common Toxicity Criteria. Non-compliance that has the potential to increase risk to research participants, compromise participants’ rights or welfare, or affect the integrity of the research/data or the Serious Non- human subjects protection program. Examples of serious Compliance noncompliance may include, but are not limited to: conducting or continuing non-exempt human subjects research without IRB approval; lack of legally effective informed consent from research participants; failure to report or review serious

adverse events, unanticipated problems, or substantive changes in research; or inappropriate oversight of the research to insure the safety of human subjects and the integrity of the research/data. Severe Social or Loss of job, insurance, benefits; criminal prosecution, Psychological stigmatization of community/group, destruction of familial/social Trauma relations. Refers to diseases or conditions that cause major irreversible Severely morbidity (e.g., blindness, loss of limb, loss of hearing, Debilitating paralysis, or stroke). Serious adverse events result in death, disability, hospitalization (or prolongation of a hospital stay), or birth defects. Therefore, an adverse event that in and of itself would be graded as mild or moderately-severe becomes a serious adverse event if it leads to one of those outcomes. For example, a case of myelosuppression could require Severe-Serious prolongation of an existing hospitalization, making it a "serious Distinction AE" for reporting purposes even if the myelosuppression was itself only moderately severe (Grade II). Compare to a subject experiencing a migraine after a hormone injection-the patient might consider the migraine to be severe, but if it did not result in hospitalization or other serious problems, it is not reported as a serious adverse event. See Serious Adverse Event Severe, and Severity. An assessment regarding the intensity of an Adverse Event Severity (rating the event mild, moderately severe, severe, life threatening or fatal; or Grade I, II, III, IV or V). A written document stating that the elements of informed consent required by regulation have been presented orally to the participant or the participant's legally authorized Short Form representative. The short form consent document must be written in a language understandable to the participant or the participant's legally authorized representative. Any undesired actions or effects of a drug or treatment. Negative or AE may include headache, nausea, hair loss, skin Side Effects irritation, or other physical problems. Experimental drugs must be evaluated for both immediate and long-term side effects. See also Adverse Event. Significant Risk An investigational device that is: (SR) Device

• Intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; • For use in supporting or sustaining human life and represents a potential for serious risk to the health, safety, or welfare of a subject; • For a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or • Otherwise presents a potential for serious risk to a subject. A study in which one party, either the investigator or Single-Blind participant, is unaware of what medication the participant is Study taking; also called single-masked study. See Blind and Double- Blind Study. Typically, a study design in which the investigator, but not the Single-Masked subject, knows the identity of the treatment assignment. Design Occasionally the subject, but not the investigator, knows the assignment. Sometimes called "single-blind design." This term refers to the location of the responsible oversight Site investigator and IRB. If the event occurred on a study directed/supervised by WMed faculty or staff, it is local. Harm, insult, or injury affecting social status or standing, or relationships, or psychological health/well-being. Such harms include but are not limited to: invasion of privacy; breach of Social or confidentiality; significant embarrassment; stigmatization; Psychological anxiety; fear; effects of stereotyping; loss of insurance or other Trauma benefits; criminal prosecution; effects on employment including job loss or demotion; interruption, disruption, or destruction of familial/social relations.

• The company/person who initiates the study. The sponsor is typically the manufacturer or research institute that developed the drug or device. In this case, the sponsor does not actually conduct the clinical trial but rather distributes the investigational drug or device Sponsor to clinical investigators who direct local conduct of the trial. A clinical investigator may, however, serve as both the sponsor and investigator (investigator-sponsor) of a clinical trial. The sponsor assumes general responsibility for the studies involving the investigational drug or

device, including responsibility for compliance with applicable laws and regulations. The sponsor is responsible for obtaining FDA approval to conduct a trial and for reporting the results of the trial to the FDA. • A person or other entity that initiates a clinical investigation, but that does not actually conduct the investigation, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate direction of another individual. A person other than that individual (e.g., a corporation or an agency) that uses one or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators. (FDA) An individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or Sponsor- dispensed to, or used involving, a subject. The term does not Investigator include any person other than an individual, e.g., it does not include a corporation or agency. The obligations of a sponsor- investigator under this part include both those of a sponsor and those of an investigator. (FDA) Is a medical or psychological treatment guideline, and can be general or specific. It specifies appropriate treatment based on scientific evidence and collaboration between medical and/or psychological professionals involved in the treatment of a given Standard of Care condition. Some common examples include: treatment standards applied within public hospitals to ensure that all patients receive appropriate care regardless of financial means; or treatment standards for gender identity disorders Express IRB provisions that must be satisfactorily addressed before a human subject research project can be approved and any involvement of human subjects in the Stipulation(s) research may begin. Under no circumstances do stipulations constitute contingent approval of the research project— approval is neither given nor implied until the PI has received written notice of IRB approval. The drug under investigation in a research study (includes Study Drug approved and unapproved drugs).

A primary or secondary outcome used to judge the Study Endpoint effectiveness of a treatment. An individual who participates in research, either as a recipient of the investigational product (s) or as a control. Individuals can Subject be the subject of research without being aware of their participation when informed consent is waived. Right and understanding of a subject that private data or protected health information will be divulged only as noted in the informed consent document, and/or as necessary for subject's health and safety, and/or as necessary by law. Investigators should take steps to protect subjects' Subject confidentiality including where appropriate removal of patient Confidentiality specific identifiers (patient name, registration number, social security number, etc.) in reports to the WMed IRB. Subject initials, unique coding specific to a study, and/or age are acceptable alternatives to names and registration numbers in WMed IRB reports, and useful in correlating subject/patient specific information. Studies designed to obtain information from a large number of Survey Studies respondents through written questionnaires, telephone interviews, door-to-door canvassing, or similar procedures. A study may be suspended for many reasons. Different parts of the study can be suspended, i.e., recruitment or all study Suspended activities. The suspension can be required by the Sponsor or the IRB, or the PI can voluntarily suspend the study. An action taken by the IRB Chair, Vice Chair, or convened IRBs to withdraw approval for some research activities, temporarily or permanently, or all research activities Suspension temporarily, short of permanently withdrawing approval for all research activities. The Institutional Official may also suspend research on an urgent basis. T An IRB “action” that indicates that review was not initiated or was not completed, resulting in postponement of convened Tabled IRB review, usually due to loss of quorum or other administrative issue. Research tabled at a convened meeting will be reviewed at a future convened meeting. Technology Tech Transfer is a process involving assessing an invention Transfer (Tech disclosure (technology), patenting the technology, marketing Transfer)

and finally licensing the technology or forming start-up companies based on technology. A study may be Terminated for many reasons. Different parts of the study can be terminated, i.e., recruitment or all study Terminated activities. The termination can be required by the Sponsor or the IRB, or the PI can voluntarily suspend the study. An action taken by the convened IRBs to permanently withdraw approval for all research activities (except for those follow-up procedures that may be necessary to protect the Termination health and/or welfare of participants). This may occur on a particular study or on all studies where an investigator is named PI. Any drug, biological product, medical device, human food additive, color additive, electronic product, or any other article Test Article under investigation in a research study (included approved and unapproved drugs, biologics and devices). Any investigational method (other than test articles) being developed, tested and evaluated, designed to develop or Test Procedure contribute to generalizable knowledge. Examples include surgical techniques and psychological therapy. The research physician’s intent to provide some benefit to improving a subject’s condition (e.g., prolongation of life, shrinking of tumor, or improved quality of life, even though cure or dramatic improvement cannot necessarily be effected). This Therapeutic Intent term is sometimes associated with Phase I drug studies in which potentially toxic drugs are given to an individual with the hope of inducing some improvement in the patient’s condition, as well as assessing the safety and pharmacology of a drug. Research participant's belief that enrolling in a research study will provide therapeutic benefit. Participants confuse the goal of clinical therapy which is to provide benefit to the individual Therapeutic patient and where any new knowledge gained is incidental and Misconception the goal of research which is to gain knowledge to help future patients (generalizable) and where therapeutic benefit to individual maybe secondary. Research involving an intervention that has the likelihood of Therapeutic providing a therapeutic, diagnostic or preventive benefit to the Research subjects. An adverse effect produced by a drug that is detrimental to the Toxicity participant's health. The level of toxicity associated with a drug

will vary depending on the condition which the drug is used to treat. Investigational new drugs may be made available outside of a Treatment and clinical trial, through a treatment protocol, to multiple patients Parallel Track with life-threatening or other serious diseases for which no INDs satisfactory alternative drug or other therapy exists. IND stands for Investigational New Drug application, which is part of the process to get approval from the FDA for marketing a new prescription drug in the US. It makes promising new drugs available to desperately ill participants as early in the Treatment IND drug development process as possible. Treatment INDs are made available to participants before general marketing begins, typically during Phase III studies. To be considered for a treatment IND a participant cannot be eligible to be in the definitive clinical trial. Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. Other Phase II trials are designed as randomized Trial design clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials. U An event is when "unanticipated" when it was unforeseeable at the time of its occurrence. Unanticipated and Unexpected are Unanticipated not synonymous. A research protocol can monitor for an unexpected event, but cannot monitor for an unforeseen event. All unanticipated events are unexpected but not vice versa. Often referred as an Unanticipated Problem. An unanticipated problem may be either an actual harmful or unfavorable occurrence or any development that potentially increased the likelihood of harm occurring in the future. Assessment Criteria: Unanticipated Problem Involving 1. Unanticipated Severity: The nature, severity, or Risks to Subjects frequency of the event(s) or information was NOT or Others expected, given descriptions in the study documents or (UPIRSO / UaP) the characteristics of the subject population being studied. 2. Related: There is a reasonable possibility that the procedures involved in the research caused the problem.

3. Increased Risk: The event(s) or information suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized (including physical, psychological, economic, or social harm). A device used for a purpose or condition for which the device Unapproved would require but does not have pre-market approval or an Medical Device approved investigational device exemption (IDE) from FDA. A disease or other circumstance affecting the research subject Underlying that is not a result of the intervention or experimental design of condition a research study. Excessive or inappropriate reward or other incentive in which a Undue Influence person is induced to act otherwise than by their own free will or without adequate consideration of the consequences. Not identified by nature, severity or frequency in the current Unexpected University IRB-approved research protocol or informed consent document A term used by some sponsors to refer to an adverse reaction, the nature or severity of which is not consistent with the Unexpected applicable product information (e.g., Investigator's Brochures Adverse Drug for an unapproved investigational product or package Reaction insert/summary of product characteristics for an approved product). Any adverse event occurring in one or more subjects in a research protocol, the nature, severity, or frequency of which is not consistent with either

1. the known or foreseeable risk of AEs associated with the procedures involved in the research that are described in (a) the IRB-approved documents (e.g., Unexpected applicable investigator brochure, current protocol Adverse Event narrative, current informed consent document), and (b) other relevant sources of information, such as product labeling and package inserts; or 2. the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the AE and the subject’s predisposing risk factor profile for the AE. Unexpected An event or occurrence(s) should be reported to the WMed Magnitude, IRB when the intensity (severity), how long the event takes or

Duration or persists, or the rate of occurrence is different than described in Frequency the informed consent document (ICD), even if the event is otherwise described in the ICD. For example, the ICD notes that some subjects experience mild, brief ringing in the ears following an fMRI. If a subject experiences ringing of significant intensity (such that she cannot work or attend classes) or the ringing persists for several weeks, the event would be reportable as an unexpected event. Likewise, if elevated liver enzymes were described in the ICD as expected at statistical rate of 2% but monitoring revealed 10% of subjects experienced such elevations, this should be reported as an unexpected adverse event. An adverse event that

• is NOT a previously known or suspected effect of the test drug, device, or procedure Unlikely related • does NOT follow a sequence of time from drug adverse event administration, device implantation and/or activation, or procedure, for which the event could be attributed to the administration, implantation, activation, or procedure • can be readily explained by the characteristics of the population under study Unassociated or without a timely relationship; evidence exists Unrelated that an outcome is definitely related to a cause other than the event in question. An adverse event that

• is NOT known to be an effect of the test drug, device, or procedure • does NOT follow a sequence of time from drug administration, device implantation and/or activation, or Unrelated procedure, for which the event could be attributed to the adverse event administration, implantation, activation, or procedure • can be readily and easily explained by the characteristics of the population under study • involves a subject who never received study drug, study device, or underwent research study procedure See also Cause, Relatedness.

As it pertains to a neonate, able to survive after delivery to the point of independently maintaining heartbeat and respiration. The Secretary may, from time to time, take in account medical advances and publish in the Federal Register guidelines to Viable assist in determining whether a neonate is viable for purposes of 45 CFR 46. If a neonate is viable, then it may be included in research only to the extent permitted and in accordance with the requirements of 45 CFR 46. Accidental or unintentional changes to or noncompliance with Violation the IRB approved protocol that affects the subject's rights, safety, welfare, and/or the integrity of the data. Free of coercion, duress, or undue inducement. Used in the Voluntary research context to refer to a subject's decision to participate (or to continue to participate) in a research activity. Vulnerable populations can be defined as children, prisoners, pregnant women, handicapped or mentally disabled persons, or economically or educationally disadvantaged persons. If vulnerable individuals are involved in clinical trials, IRBs must ensure that additional safeguards have been included to protect the vulnerable group. Safeguards may include the presence of interpreters or social workers to explain the Vulnerable research and ensure informed consent. IRBs have a specific Subjects obligation to protect those individuals who are particularly susceptible to coercion or undue influence (21 CFR 56.11). Studies involving vulnerable groups often pose difficult ethical questions. For example, vulnerable subjects may not be allowed to participate in research that involves more than minimal risk but conveys no benefits directly to the subjects. (21 CFR 56.11 and 45 CFR 46 Subparts B, C, D).

W Period of time without active treatment, usually scheduled before the beginning of the placebo and active treatment Washout Period arms. This can refer to a required period of withdrawal from treatment before active treatment starts. An event which occurs in a study under the supervision of the WMed IRB and whose PI is a WMed-Bronson-Borgess faculty or staff member. The event is a WMed Event when WMed Event it occurs at WMed-Bronson-Borgess or any other site where the WMed PI has oversight, even when the PI is physically in another location. It does not matter where the

subject experiences or is treated for the Adverse Event. If interventions take place at different WMed associated locations, please specify at which location the event occurred.

Based on University of Michigan IRBMED Revised 3/20/2015