Conducting Human Subjects Research
Introduction to Research: Lecture 6 Conducting Human Subjects Research
Shari Zeldin Clinical Research Compliance and Regulatory Officer Department Of Medicine Learning Objectives To gain an understanding of and appreciation for: • The ethical responsibility of conducting human subjects research • Good Clinical Practice • The Protocol • The difference between Clinical Care and Clinical Research 2 Ethics in Human Subjects Research
3 Ethics in Human Subjects Research: A Quick Lesson History Lesson
The Nuremberg Code (1947) The Declaration of Helsinski (1975)
• First set of research ethical • Set of ethical principles developed by the World Medical Association for principles for human human research experimentation put forth after the Nuremberg Trials as a result of • Established that medical research is subject to ethical standards that and response to the atrocities promote and ensure respect for all committed by the Nazis during human subjects and protect their health WWII and rights • Introduced the concept of • Established that voluntary consent independent committees (IRBs) to is essential oversee research ethics
5 History Lesson The Belmont Report (1978) FDA‐ Code of Federal Regulations
• Prompted in part by the Tuskegee (CFR) for the protection of Human Syphilis Study, expounded on the 3 Subjects (1980)‐ 21 CFR 50, 56, fundamental Ethical Principles for the Protection of Human Subjects 312, 812‐ of Research: Rule of ethics governing FDA‐regulated • Respect for Persons‐ Informed investigational drugs, biologics, devices in Consent, researchers must be human subjects research truthful/no deception • Beneficence‐ Do no harm‐ maximize benefits, minimize risks DHHS‐ “The Common Rule”(1981) • Justice‐ Selection of subjects should 45 CFR 46 be fair Rule of ethics regarding biomedical and behavioral human subjects research “Be Nice, Be Good, Be Fair” Recently revised 6 ICH Good Clinical Practice (GCP), 1997
ICH E6: GCP: International guidelines for the ethical and scientific quality standards for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected. • Covers all aspects of human subjects research.
7 By following ICH GCP
We are applying the ethical principles to our conduction of human subjects research
8 Applying GCP: Informed Consent Process
• The ICF must have all the required elements ( plus applicable additional elements) and be IRB approved (stamped) .
• In order to conduct the informed consent process with a potential subject, it is imperative that you first:
Make certain to know the protocol. Review the study parameters and the study schedule so questions can be answered easily
Make certain to read and thoroughly review the informed consent form BEFORE presenting it to a subject so that it is presented to the subject in a way that conveys a clear understanding of the study
If you are asking someone to participate in a study, it is your obligation to know what the study is and what it entails! You must be informed! 9 Informed Consent Process: Challenges
• Legal requirements of the consent documents- “scary” language
• Complexity of the research/low scientific literacy- difficult to put it in lay terms
• Difficulty with comprehension due to age, severity of illness, cognitive impairment, literacy level, preconceptions about clinical research
• Concepts such as placebo, control group, randomization can affect understanding
• Length of the ICF can be daunting to try to get through it
• Therapeutic Misconception- subjects may feel their physician wouldn’t suggest participation unless good for them or they may underestimate risk because their doctor wouldn’t suggest if too risky
10 Obtaining Consent: Ethically & Effectively
• Building rapport is essential to the process
• Ask questions to ensure listening and comprehension (no zoning out!)
• After you discuss each part, CHECK IN: “Does that make sense?”, Does that sound like something that you could commit to/ be interested in?”, “Do you have any specific questions before we continue?”
• This is intended to be a discussion, not a lecture! 11 Some Tips for ethical & effective ICP • Make sure to approach potential subjects in a private location (i.e. exam room, hospital room)
• Always bring 2 copies of the ICF, one for you and one for the potential subject. You never want to be reading over their shoulder or having them read over yours!
• Make certain you have enough time allocated to be able to review the consent in it’s entirety
• Don’t push‐ Always give the potential subject/family appropriate time to process the study‐ you may have to come back later or reschedule another meeting
• Try not to read directly from the consent form ( except when appropriate, like the compensation for injury language). If you need to stop and check something, just pause and read for a minute, “just want to make sure before we continue”…
• If you don’t know the answer to a question, don’t make it up! Tell them you will ask the PI and get back to them…and then make sure you get back to them!!!! 12 How to discuss: Voluntariness
• Emphasize at numerous points that participation is completely voluntary. “You do not have to participate. If you decide not to participate, that’s completely fine and it will not affect your care here in any way.”
• Help alleviate feelings of “obligation” in situations where the potential subject’s treating physician is also the PI for the study
• Emphasize that they can change their mind at any time “Even if you decide now to participate, you can change your mind at any time.”
13 How to discuss: Study Procedures
• Provide an overview of what will be done and when during the study • We’ll ask you to come in 5 times over the next 9 months • At each visit, you will have your blood drawn, vitals, and a chest x‐ray
• Be truthful about time estimates and expectations for visits (i.e. will need to come in fasting, each visit will take approx. 1.5 hours)
• Talk about expectations of them with the study ( i.e. We will ask you to keep a diary of when you take your study meds or record every bowel movement and rank the consistency)
• Nothing should come as a surprise to them during the study (i.e. Visit 4 is for biopsy only)
14 How to discuss: Study Risks
• Don’t sugar coat or underestimate the risks
• The IRB approved the ICF with the risk language in it, that means the potential subject must be aware of the stated possible risks of participating
• You can discuss the risks by stating the % of people known to experience these risks or discuss categories given in the ICF (i.e. common, rare)
• You can discuss that, “because these risks are known, there are contingencies in the protocol for how to handle them if a subject experiences them”, which can be reassuring.
• When you discuss unanticipated risks, emphasize that subjects will be followed very closely and informed about any unforeseen risks that may occur during the study, and they will be able to decide whether they want to continue in the study. 15 How to discuss: Study Benefits
• There is no direct benefit to you for participating. We hope that the information we gather from this study will help us better treat patients like yourself in the future.
• We cannot state the benefits because we don’t know if there are benefits, that’s why we’re doing the research
• Possible benefit that you can discuss, if IRB approved and if applicable: Medication provided at no cost
• Never discuss compensation or payments as a benefit! Compensation for study participation, if applicable, is discussed in the compensation section
16 How to discuss: Confidentiality
• Important to explain how their confidentiality will be protected:
“We assign you a number, and that’s what is used to identify you. We won’t provide your name, address, medical record number or anything that identifies you. Your identifiable information is maintained on a secure password‐protected computer network server.”
• Must always disclose that there is always a slight chance of a breach of confidentiality, but that precautions are taken to avoid that.
• Must disclose who and what agencies/organizations can potentially see their PHI • Study staff, medical billing, sponsor, FDA, IRB, etc.
17 The Goal of Clinical Research
To develop and test out new therapies, treatments, interventions all while:
Ensuring the rights, safety and welfare of research participants
Ensuring the quality and integrity of the data collected and avoiding deviations and non‐compliance along the way (because these things directly affect the integrity of the data and can potentially put the subjects at risk)
The means by which to achieve that goal: Follow the protocol
18 GCP & The Protocol
The protocol is the study plan on which all research is based It is the…. • Instruction Manual • Rule Book • Guide …..on how the study must be conducted to ensure ethical conduction, patient safety and data integrity
It is also the way you told the IRB that you would be conducting the study, and what they approved!
19 The Protocol
• It is designed to safeguard the health of the subjects while aiming to answer specific research questions
• It includes specific information to how to carry out the protocol, including: who may participate in the trial, schedule of tests, procedures, treatment, length of study, potential risks, etc.
• It allows researchers at multiple locations ( multi‐site) to perform the study in exactly the same way, so that their data can be combined
20 Elements of a Protocol Contact Information
21 Inclusion/Exclusion Criteria: Rationale • It is critical to consider and follow the inclusion and exclusion criteria for a given study to ensure patient safety
• Each criteria should have a specific rationale for it’s inclusion or exclusion (i.e. Why did the investigator choose this specific range? Is it purposeful or is it arbitrary?)
• When designing a study, all contraindicated medical conditions, concomitant medications, age, etc. must be considered knowing the potential risks of the drug, biologic or device that is being studied
• If we understand the rationale, we are more likely to comply with the parameters of the protocol (i.e. Chemo Nurse training)
• If there is a change, amend the protocol! DO NOT act on the change until it is IRB approved ( also consider if ICF needs to be amended)
22 Before a protocol can be conducted:
• It must be reviewed and approved by a scientific review committee (or peer‐ reviewed) to ensure it is scientifically sound and designed in such way to ensure patient safety and data integrity
• It must then be reviewed and approved by an Institutional Review Board to ensure that it is ethically sound and that the risk/benefit ratio is considered
23 Eligibility Determinations: Considerations
Can you perform a study test to see if a potential subject is eligible before they sign consent?
Can you use an existing test result to see if potential subject is eligible before they sign consent?
Prior test results can be used for inclusion (once consent has been obtained) if the protocol states that AND if they meet the specified timeline (i.e. per the protocol, bone scan must be obtained within 4 weeks of registration)
Timelines may be given for certain eligibility criteria (i.e. per the protocol, labs must be obtained within 48 hours of registration)
You cannot “make” the pt. eligible for the study. If their lab results are not within the range for eligibility, they are ineligible. If possible, you can have them come back at a later date to retest, but you cannot try to manipulate their lab values for eligibility into a study (i.e. treat with steroids to effect lab values) unless it is part of their clinical care.
The PI needs to sign and date an eligibility checklist prior to the subject being registered to the study. Why? To ensure that the PI has confirmed that the subject is eligible (ICH GCP)……because the PI is ultimately responsible for the conduct of the study! 24 Protocol Adherence: Treatment/Intervention
Treatment/Intervention must be administered strictly following the parameters laid out in the protocol
It should be clear in the research chart what treatment/Intervention group the individual subjects were assigned to ( i.e. Arm A or B) or there is potential for error
The Study Parameter/Study Schedule section of the protocol must be strictly adhered to, such that subjects receive all specified lab testing and procedures to ensure safety
Lab/test results must be resulted out and reviewed PRIOR to treatment, if mandated by the protocol (i.e. safety labs, ECG) • If the pt. presents for treatment but their labs/tests are not in range to treat (per protocol)‐ DO NOT TREAT‐ it is a protocol violation to do so 25 The Protocol
• There should be no room for subjective interpretation‐ if something is not clear, ask the PI for clarification
• If something in the protocol is not the intention of the PI, then that protocol needs to be amended and IRB approved before implementing the change
Eligibility Waivers • No Protocol Exception or Eligibility Waivers should be requested nor allowed
• It’s what the IRB approved as being conducted ethically and safely‐ so make sure you follow it! 26 Once a “patient” becomes a “subject” and is put “on study”
• The study parameters must be followed as outlined in the protocol
• The treatment of that subject must follow the guidelines set out in the protocol
• The PI no longer has the flexibility of what he/she would do in the clinical practice setting
27 Understanding the Difference Between Clinical Care and Clinical Research
28 Understanding the difference: Clinical Practice vs Clinical Research
• Clinical Practitioner: Clinicians treat individual patients using standard treatment strategies that in her/his opinion are best for the patient
• Clinical Researcher: As an investigator, that same clinician is now obligated to follow the study protocol that describes exactly how assessments and interventions must be carried out to ensure subject safety and data integrity
29 Challenge: Take the Hat Test Case Scenario: Patient presents in clinic with a platelet count of 75,000
Clinical Practice Hat: In clinical practice, the clinician uses her/his own discretion in the standard of care as to whether to treat the patient with this platelet count.
Clinical Research Hat: The investigator must first consult the protocol. Protocol states that patient cannot be treated unless platelet count is ≥100,000.
The trick is to remember which hat you are wearing!
30 An example of how the lines can get blurry
Treats Pt.1 Dr. X Clinician Treats Pt.2
• Pt.1 and Pt. 2 are Dr. X’s • Pt. 1 has been enrolled in Dr. X’s clinical patients. clinical trial • Dr. X can treat them • Dr. X no longer has flexibility in Pt.1’s according to Standard of treatment Care • Dr. X must follow the protocol in
treating Pt.1 31 Investigator Responsibilities
The regulations governing the conduction of clinical research outline potential consequences of not upholding their commitments as a investigator of overseeing the study and ensuring the safety and welfare of subjects and data integrity.
What can happen if noncompliant? • Penalties for significant noncompliance • FDA 483‐ deficiencies found at FDA audit • Warning Letters (posted on FDA website)‐ significant regulatory violations that can lead to enforcement action • Disqualifications/Restrictions/Debarments in conduction of FDA regulated research (posted on FDA website) • Criminal prosecutions/prison/fines
32 Investigator Responsibilities: Top 5 Common mistakes/Risk factors for non‐compliance
#5: Insufficient investigator involvement in study conduct #4: Inadequate supervision and training of study staff #3: Inappropriate delegation of study tasks to unqualified persons #2: Overcommitted investigator and overworked study staff (e.g. too many subjects, complex study with large data collection, too many concurrent studies) #1: Failure to follow the protocol ( even when it’s their own!)
33 Thank you for your attention!
Questions? 34