1. Ethical Issues in Translational Research
Emma A. Meagher, MD

2. Clinical Care vs. Research
provide direct benefit to the patient
Research
Contribute to generalizable knowledge
Medicine depends on research to elucidate mechanism of disease and identify treatment strategies
Special attention to possible harm to the subject
Regulatory codes place the responsibility for the ethical conduct of research primarily on the shoulders of the researchers

3. Research Interfaces

4. The Evolution of HSR Standards
1947 – Nuremberg Code
1964 – Declaration of Helsinki
1979 – Belmont Report
DHHS and FDA to adopt regulatory requirements for IRB review (1981)
1991 – The Common Rule
Now codified by 18 federal agencies
1997 – Good Clinical Practices

5. The Belmont Report
Purpose of the report is to provide three principles (prescriptive judgments) to assist researchers, subjects, reviewers and interested citizens with an understanding of the ethical issues inherent in HSR
Statement consists of 3 parts
Distinction between research and medical practice
Establishment of 3 ethical principles
Remarks regarding application of the principles

6. The Belmont Report Practice Research
Interventions designed solely to enhance the wellbeing of the patient and that have a reasonable expectation of success
Research
An activity designed to test an hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge

7. The Belmont Report Three Ethical Principles
Principle of respect for persons autonomy
Principle of beneficence
Principle of justice

8. Respect for Persons Autonomy
Enters research voluntarily and with adequate information
Implies everyone is capable of self determination
Matures during life span
May be lost in whole or in part as a result of illness, mental disability or circumstances that restrict liberty
Cannot exclude those incapable of self determination
Respect for such situations requires protection
Explicit requirement that each class of incompetent patient be considered on its own terms
Third parties whose primary goal is to protect the subject from harm should be used and that these individuals be allowed to observe the research

9. The Belmont Report - Three Ethical Principles
Principle of respect for persons autonomy
Principle of beneficence
Principle of justice

10. Beneficence
Acts of kindness or charity that go beyond strict obligation
Strict sense of obligation
Do not harm
Maximize possible benefits
Minimize possible harms
Seek benefit despite certain risks
Benefits should be forgone because of the risk
Requires a risk benefit assessment be made

11. The Belmont Report - Three Ethical Principles
Principle of respect for persons autonomy
Principle of beneficence
Requires a risk benefit assessment be made
Principle of justice
Fairness in selection of subjects
Potential benefit is denied
Burden is imposed

12. How to Apply the 3 Principles
Autonomy - Informed consent
Information
Comprehension
Voluntariness
Beneficence – determination of the risk and benefits
Investigator – study design
Peer review – risks are justified
Subject – the determination to participate
Justice
Selection of subjects described by the researcher
Reviewed during the peer review process
Determined to be equitable

13. The Evolution of HSR Standards
1947 – Nuremberg Code
1964 – Declaration of Helsinki
1979 – Belmont Report
DHHS and FDA to adopt regulatory requirements for IRB review (1981)
1991 – The Common Rule
Now codified by 18 federal agencies
1997 – Good Clinical Practices

14. The Common Rule Requires institutional assurance of compliance
First time after more than 25 years in the making a comprehensive regulatory framework existed that formally governed all human subjects research conducted by the federal government or in facilitates receiving federal funds
Mandates role of the IRB
Defines requirements for informed consent
Codifies special requirements for vulnerable populations
Pregnant women, fetuses, IVF subpart A
Prisoners –subpart C
Children –sub part D
Requires institutional assurance of compliance

15. Responsibility of the IRB
Protect the rights and welfare of research subjects
Oversight of the conduct of ALL human research
Guidance and support to research staff through IRB review and administrative IRB support staff
Ensures compliance with all federal, state, local and institutional requirements in human subject research

16. Risk/Benefit Analysis
IRB Decision Matrix
BENEFICENCE
JUSTICE
RESPECT FOR PERSONS
Risk/Benefit Analysis
Experimental Design
Qualifications of PI
Subject selection
Inclusion/exclusion
Recruitment
The application of these general principles leads to the 3 requirements of informed consent, risk/benefit assessment and just selection of subjects for research.
Privacy & Confidentiality Protection of subjects (especially vulnerable populations)
Informed consent
Surrogate consent
Assent

17. Expanded IRB Decision Matrix Seven Principles
Social or scientific value
Scientific validity
Fair subject selection
Favorable risk benefit ratio
Independent review
Informed consent
Respect for autonomy

18. The Common Rule Requires institutional assurance of compliance
First time after more than 25 years in the making a comprehensive regulatory framework existed that formally governed all human subjects research conducted by the federal government or in facilitates receiving federal funds
Mandates role of the IRB
Defines requirements for informed consent
Codifies special requirements for vulnerable populations
Pregnant women, fetuses, IVF subpart A
Prisoners –subpart C
Children –sub part D
Requires institutional assurance of compliance

19. Elements of Informed Consent
Purpose
Methods and procedures
Painstakingly precise
Risks and discomforts
Known and unknown
Risks of disease versus research participation
Benefits
Promise of benefit
Alternatives to participation
Decision relative to their own clinical condition
Voluntary and uncoerced
Payment considerations
Cost consideration

20. Elements of Informed Consent
Other considerations
Study discontinuation by sponsor / FDA / investigator
Participation discontinuation by participant
Participation discontinuation by investigator
Injury during a study
Standard language concerning liability
Use of personal Information
Privacy
HIPPA
Human Subjects rights

21. The Common Rule Requires institutional assurance of compliance
First time after more than 25 years in the making a comprehensive regulatory framework existed that formally governed all human subjects research conducted by the federal government or in facilitates receiving federal funds
Mandates role of the IRB
Defines requirements for informed consent
Codifies special requirements for vulnerable populations
Pregnant women, fetuses, IVF subpart A
Prisoners –subpart C
Children –sub part D
Requires institutional assurance of compliance

22. The Evolution of HSR Standards
1947 – Nuremberg Code
1964 – Declaration of Helsinki
1979 – Belmont Report
DHHS and FDA to adopt regulatory requirements for IRB review (1981)
1991 – The Common Rule
Now codified by 18 federal agencies
1997 – Good Clinical Practices

23. Good Clinical Practice (GCP)
Provides: “ A unified standard for the design, conduct, recording, 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”.
Have been adopted by industry and academia worldwide
Clinical research must be conducted in a scientifically sound and ethical manner whether it is intended for regulatory submission (FDA) or not

24. Which Regulations Apply and When?
FDA: research involves products regulated by FDA (Title 21)
Common Rule: Federally supported or conducted or conducted in an institution that agrees to review all research under the Common Rule (CFR 46)
Both: if Federally funded research involves FDA regulated product or FDA regulated research conducted in an institution that agrees to review all research under the Common Rule
Common
Rule
FDA

25. Your Responsibility as an Investigator
21 CFR
50 Informed Consent
56 IRB Regulations
54 Financial Disclosure
312 Investigational New Drug
314 New Drug Application
600 Biological Products
812 Investigational Device Exemptions
45 CFR Part 46
DHHS Human Subjects Regulations Social or scientific value
Scientific validity
Fair subject selection
Favorable risk benefit ratio
Independent review
Informed consent
Respect for autonomy

26. GCP Defines Responsibilities of the investigator and/or sponsor
What is a clinical research protocol?
Requirement for informed consent and how to obtain it
Requirements for adverse event reporting
Interactions with IRB
Regulations governing the use of investigational drugs

27. 13 Principles of Good Clinical Practices
Trials are conducted in accordance with the ethical principles of the Declaration of Helsinki and consistent with GCP and other applicable regulations.
The risks and inconveniences of the trials should be weighed against the benefit.
Subject’s rights, safety and well-being prevail over science and society’s interest.
Available information on the investigational product should be adequate to support the study.

28. 13 Principles of Good Clinical Practices
Clinical trials should be scientifically sound and described in a clear concise protocol
The trial should be conducted in accordance with an IRB approved protocol
Medical decisions and care of the subject is always the responsibility of a qualified physician
Study team members should be qualified through education, training and experience to perform their study related tasks.

29. 13 Principles of Good Clinical Practices
Informed consent should be obtained from every subject before participation
All trial information should be recorded, handled and stored to ensure accurate reporting, interpretation and verification.
The confidentiality of records should be protected thus respecting the privacy and confidentiality of subjects.
Investigational products should be manufactured, stored and handled in accordance with GMPs.
Systems with procedures that assure the quality of every aspect of the trial should be implemented.

30. GCP and the Clinical Protocol
A clinical protocol for GCP addresses the
Science
Background, rationale, study design, statistics
Human subjects protection
Autonomy, beneficence, justice,
One step further it defines the procedures
Study procedures (time and event charts, dose escalation schedules)
Data collection/recording/storage/reporting/analysis
Monitoring / AE reporting
Requirement for case report forms

31. 7 Rules of a Good Protocol
Clearly identify your primary objective
- there should be only one primary objective
- it will drive the sample size.
- secondary objectives can be multiple
Tell the story of the study in the rationale
Why are you doing the study?
What is the logic?
What do you hope to demonstrate?
Design your study to achieve the primary objective
study procedures, study design, statistical analysis, use of control

32. 7 Rules of a Good Protocol
Ensure consistency from section to section
“The devil is the details”
Give clear directions for each step of the protocol
Consider the relationship of one procedure on another
Develop a flow sheet for study day or week
State how the data will be handled and analyzed
Carefully consider the conditions of the evaluations performed in the study
Avoid unnecessary measures, how often does a blood sample need to to taken?

33. GCP - 7 Rules of Good Protocol
Safety
For novel compounds, does the toxicology in animals cover the dose and duration in humans?
Has the route of dosing been studied in animals?
How will subject’s safety be evaluated, by whom, how often?
How will severe/serious events be evaluated?
Define AE and SAE and their reporting requirements.
How will the study be monitored?

34. Summary
Research conduct directed by existence of two sets of federal guidelines
GCP and the Common Rule
Both are centered on the 3 fundamental pillars of research ethics
Both mandate
Informed consent
Peer Review
Standards for clinical trial conduct

35. Research Interfaces

36. Upholding ethical responsibility
Autonomy - Informed consent
Information
Comprehension
Voluntariness
Beneficence – determination of the risk and benefits
Peer review – risks are justified
Investigator – study design
Subject – the determination to participate
Justice
Selection of subjects described by the researcher
Reviewed during the peer review process
Determined to be equitable