FACULTY RESEARCH TRAINING PROGRAM MODULE 3

FACULTY RESEARCH
TRAINING PROGRAM
MODULE 3
A Brief Introduction to Clinical Research Ethics
Richard L. Elliott, MD, PhD
Professor and Director, Medical Ethics
Mercer University School of Medicine
DISCLOSURE STATEMENT
I have no relevant financial relationships to disclose.
OBJECTIVES
• Purpose of clinical research
• History of clinical research ethics
• Seven principles of ethical clinical
research
• Key documents and resources
Why clinical research ethics?
• Research is a systematic investigation in
order to establish facts and reach new
conclusions
• Clinical research uses human subjects
• Although subjects may benefit from
participating in research, this is not the
primary purpose
• The goal of clinical research ethics is to
protect human subjects
• A brief history of clinical research ethics
OR
• How did we end up with all these
regulations and guidelines?
James Lind
First clinical trial - scurvy
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1747 12 sailors divided into six
groups of two each. Each group
received usual diet plus a
supplement: vinegar, citrus fruit (two
oranges and a lemon), sulfuric acid,
cider, sea water, paste plus barley
water.
Only the two sailors receiving citrus
fruit recovered within days
Edward Jenner
1796 Jenner inoculated James Phipps, the 8
year-old son of his gardener, with cowpox
pus from Blossom, the cow. He then
injected Phipps with smallpox material and
produced only mild symptoms.
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Jenner is said to have saved more lives than
any other single person.
The statue of Jenner is in Gloucester
cathedral.
Blossom’s hide is preserved in St. George’s
medical school library.
Jesse Lazear
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1900 Worked with Walter
Reed in Cuba to determine
cause of yellow fever.
Allowed himself to become
infected via mosquito
bites, documented
development of Yellow
fever, died.
Tuskegee Study of Untreated Syphilis
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1929-1972
Syphilis major public health problem
Treatment: arsenicals, malaria, mercury
Benefits of treatment in secondary
syphilis uncertain
PHS study started with treatment arm
Study: 399 men with disease, 201 without
Men told they were receiving treatment
Penicillin withheld after it appeared
during WWII
“Study” continued after Nazi Doctors’ trial
raised questions
Finding published regularly
Stopped in 1972: Washington Star story
National Research Act of 1974
Ethics and TSUS
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Lack of informed consent
Lying to subjects (LP as “treatment”)
Withholding effective treatment
Continuing study after questions raised,
and after Nuremberg Code
• Failure to protect families
Other research scandals
• Injection with hepatitis Willowbrook), syphilis
(Guatemala), cancer cells (Jewish Chronic
Disease Hospital)
• Irradiation Experiments (X-rays, plutonium, bombs)
• Psychological (Milgram, Zimbardo)
• Drugs (LSD, amphetamine)
• Study of Babies Did Not Disclose Risks, U.S. Finds
• NY Times, April 10, 2013
National Research Act, 1974
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National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
The Commission’s four goals for analysis:
1. boundaries between medical and behavioral research and what accepted, routine practices of medicine were
2. assessing risks and benefits of the appropriateness of research involving human subjects
3. determining appropriate guidelines for how human subjects can be chosen
4. defining what informed consent is in each research setting.
The Commission made recommendations for the protection of Human subjects. Reports included:
Research on the fetus (1975)
Research Involving prisoners (1976)
Research Involving children (1977)
Psychosurgery Report and Recommendations (March 1977)
Disclosure of Research Information Under the Freedom of Information Act(April 1977)
Research Involving Those Institutionalized as Mentally Infirm (1978)
Ethical Guidelines for the Delivery of Health Services by DHEW (1978)
Appendix to Ethical Guidelines for the Delivery of Health Services by DHEW (1978)
Institutional review Boards(1978)
Special Study Implications of Advances in Biomedical and Behavioral Research (1978)
The Belmont Report: Ethical Principles and Guidelines for Protection of Human Subjects of Biomedical and
Behavioral Research (1979)
Belmont Report
• 1979
• Ethical Principles and Guidelines for the Protection of Subjects of
Research
• (1) respect for persons: protecting the autonomy of all people and
treating them with courtesy and respect and allowing for informed
consent
• (2) beneficence: maximizing benefits for the research project while
minimizing risks to the research subjects; and
• (3) justice: ensuring reasonable, non-exploitative, and well-considered
procedures are administered fairly (the fair distribution of costs and
benefits.)
Nuremberg Code
• 1947
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Voluntary consent of competent individual
Benefits society, not obtainable by other means
Sufficient scientific basis to justify experiment
Avoids unnecessary suffering and injury
Avoid disabling injury or death unless MDs are subjects
Degree of risk proportional to societal benefit
Facilities and preparations to protect subjects
Conducted by qualified investigators
Subject can terminate participation
Investigator should terminate if unsafe to participant
Declaration of Helsinki
•1964, World Medical Association, most recently clarified 2004
•Some research populations are vulnerable and need special
protection. The particular needs of the economically and
medically disadvantaged must be recognized. Special attention
is also required for those who cannot give or refuse consent
for themselves, for those who may be subject to giving
consent under duress, for those who will not benefit
personally from the research and for those for whom the
research is combined with care.
•Questioned use of placebos
Institutional Review Boards
• National Research Act of 1974 (Title 45 CFR Part 46) seeks to
ensure that:
• Risks to research subjects are minimized and are reasonable in
relation to anticipated benefits
• Welfare and human rights of subjects are protected and
informed consent is sought from each prospective subject or
the subject’s legally authorized representative
• Informed consent is appropriately documented
• Adequate provisions for monitoring data collection are in
place to assure the safety, and physical, emotional, and mental
wellbeing of research subjects
• Confidentiality of data and the privacy of subjects are assured
• Researchers are qualified to conduct the described research
Principles of ethical clinical research
Emanuel EJ, Wendler D, Grady C. What makes clinical
research ethical? JAMA 2000;283:2701-2711
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Scientific value
Scientific validity
Fair subject selection
Favorable risk-benefit ratio
Independent review
Informed consent
Respect for potential and enrolled subjects
Scientific value
• Are the right questions being asked?
• Would studying the questions provide valuable
information to clinicians, scientists, or society?
• Do the questions merit expenditure of
resources?
• Was there scientific value to the TSUS at the
start? Did this change?
Scientific validity
• Is the study designed properly, e.g.,
methodology, adequate controls,
statistical power, etc., so as to lead to
valid data and conclusions?
• Was TSUS scientifically valid?
• Many men in both groups received
penicillin
Fair subject selection
• Ethical principle of social justice
requires that risks and benefits of
research should be distributed fairly
• Subjects should be selected to meet
scientific needs, not on basis of
convenience
• Vulnerable subjects should not be
used unless necessary from a
scientific perspective
Risk-benefit ratio
• Minimize risks, maximize benefits
• Benefits proportional to or exceed risks
• Interests other than those of the subject
may on some occasions be sufficient by
themselves to justify the risks involved in
the research, so long as the subjects’ rights
have been protected. (Belmont)
Independent review
• Review by party with no stake in outcome
• Reduce potential conflicts of interest
• Institutional Review Boards
Informed consent
• Informed consent is
• Voluntary – potential for coercion in
vulnerable populations, by financial
inducement
• Informed – risks, benefits, rights, gain for
researchers
• Competent – assent vs consent
Respect for subjects
• Protect privacy and confidentiality
• Nonidentification of subjects
• Right to withdraw
• Right to emerging information
• Monitoring patient welfare
For the future
• Ethics and publication
• Publication bias
• Ghost authors
• Significant contribution by authors
• Conflicts of interest
• Data falsification and fabrication
Resources
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This presentation can be found at:
http://medicine.mercer.edu/ethics/research
Belmont report
Code of Nuremberg
Emanuel et al: What makes clinical research
ethical?
• Elliott RL. Evidence-debased medicine.