Richard L. Elliott, MD, PhD Professor and Director, Medical Ethics Mercer University School of Medicine

Richard L. Elliott, MD, PhDProfessor and Director, Medical EthicsMercer University School of Medicine

FACULTY RESEARCH TRAINING PROGRAM

MODULE 3

A Brief Introduction to Clinical Research Ethics

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

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

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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.

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.

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Jesse Lazear

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.

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Tuskegee Study of Untreated Syphilis

1929-1972 Syphilis major public health problemTreatment: arsenicals, malaria, mercuryBenefits of treatment in secondary syphilis uncertainPHS study started with treatment armStudy: 399 men with disease, 201 withoutMen told they were receiving treatmentPenicillin withheld after it appeared during WWII“Study” continued after Nazi Doctors’ trial raised questionsFinding published regularlyStopped in 1972: Washington Star storyNational Research Act of 1974

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Ethics and TSUS

• 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

• 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• 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

• 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

• 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.