Chapter 4

1. Chapter 4 Research Ethics

2. Learning Objectives • Trace the history of human subjects protection • Utilize the components of current protection regulations • Adapt study procedures to the special needs of vulnerable populations

3. Protection? “Two of the worst patients, with the tendons in the ham rigid (a symptom none the rest had) were put under a course of sea water. Of this they drank half a pint every day… ” (James Lind, A Treatise of the Scurvy, 1757).

4. Summary of Requirements for Protection • Beneficence • Do no harm • Autonomy • Respect for individuals • Justice • Groups should not unfairly bear the risks in research • Groups should not unfairly enjoy the benefits of research

5. Historical Development of Protections • Nazi “experiments”—Nuremburg Code (1947) • 1964 World Medical Association Declaration of Helsinki • Tuskegee Study of Untreated Syphilis in the Negro Male—National Research Act and 45 CFR 46 (1974) • The Belmont Report (1979)

6. Nazi “Experiments” • Nothing scientific about the horrific events that occurred in European concentration camps during World War II (1939-1945) • Josef Mengele – geneticist who “experimented” on concentration camp prisoners • injected dye into children’s eyes, sewed children together, froze people and deprived them of oxygen, performed unnecessary amputations and “living” autopsies

7. Nuremburg Code (1947) • The voluntary consent of the human subject is absolutely necessary. • The experiment should yield fruitful results for the good of society, with no alternative method for obtaining these results. • The experiment should be based on the results of animal experiments and knowledge of the natural history of the problem under study. • The experiment should avoid all unnecessary physical and mental harm.

8. Nuremburg Code (cont.) • No experiment should be conducted that is known or suspected to cause disabling injury or death. • Risks of the experiment should never outweigh the benefits. • Proper precautions should be made to prevent injury, disability, and death. • The experiment should be conducted only by scientifically qualified persons. • Subjects should be free to withdraw from the study at any time. • The investigator must terminate the experiment if injury, disability or death appears possible.

9. Declaration of Helsinki (1964) • 1964 World Medical Association Declaration of Helsinki set forth ethical principles, many of which addressed the requirement of informed consent • First to suggest an independent committee to evaluate and monitor the ethical conduct of human subject research • Expanded the notion of subject autonomy by formalizing what is and is not informed consent for persons who are and are not able to give such consent • Introduced issues of potential conflicts of interest involving investigators

10. Tuskegee Study of Untreated Syphilis in the Negro Male (1932-1972) • Conducted by the US Public Health Service • Natural history of syphilis among 600 mostly poor and uneducated black men in Tuskegee, AL • Denied treatment with penicillin for almost 30 years after the acceptance of penicillin as an effective treatment • Were not told the true purpose of the study • Not permitted to withdraw from the study

11. National Research Act and 45 CFR 46 (1974) • U.S. protections • Required voluntary informed consent from subjects • Established Institutional Review Boards (IRB) at universities and other research facilities • Mandated to review study protocols and approve them only if ethical requirements of voluntary informed consent and benefits greater than risks to subjects • Empowered with authority to prevent or stop studies that don’t meet the requirements

12. Other Landmark Studies • Willowbrook Hepatitis Study (1956) • Mentally disabled children in New York’s Willowbrook State School • Children injected with Hepatitis A virus • Violated beneficence • Made the children sick with no effective cure • Violated autonomy • Admission to school was conditional on parents consenting to the study • Mentally disabled children can’t assent to research • Violated justice • School teachers were also at risk for hepatitis but were not asked to participate in the study

13. Other Landmark Studies • NY Jewish Chronic Disease Hospital Study (1963) • Injected 19 terminally ill (with diseases other than cancer) patients with cancer cells • Consent was not informed • Patients and doctors were not told that the injected cells were cancerous • Compromised justice • Patients would not benefit from information gleaned from the study

14. The Belmont Report (1979) • Belmont Conference Center in Elkridge, MD • Meeting of 11-member National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research • Broaden and clarify existing regulations and guidelines • Report has 3 parts

15. Part A: Boundary between Practice and Research • Purpose of medical practice is to provide diagnosis, preventive treatment or therapy • Purpose of research is to test an hypothesis, draw conclusions and make generalizations • Research and practice can be combined when research is designed to evaluate a therapy • Treatment should not require research participation

16. Part B: Basic Ethical Principles • Respect for persons (autonomy) - subjects should enter research voluntarily and with adequate information • Beneficence - do no harm; maximize benefits and minimize possible risks • Justice - classes of subjects should not, without scientific justification, be included or excluded from research; benefits from treatment should be made available to all who need it, including those who participated in the study

17. Part C: Applications • Informed Consent (Autonomy) - complete disclosure of all aspects of the research; verified subject comprehension of research procedures; voluntary consent without coercion or undue influence • Assessment of Risks and Benefits (Beneficence) - probabilities and magnitudes of possible harm and anticipated benefits; systematic, nonarbitrary analysis of risks and benefits should be conducted whenever possible • Selection of Subjects (Justice) - individual justice means that beneficial research should not include only advantaged persons and risky research should not include only disadvantaged persons; social justice means the order of classes of subjects selected should start with the most competent (mature and able) and move to the least capable (children, disabled, prisoners) only when scientifically justifiable

18. Practical Applications of Regulations • Scientific qualifications of the investigator • Outcome of the Nuremberg Code • Evaluated by the IRB and study funder (if there is one) • Students must be supervised by qualified faculty who are ultimately responsible for the treatment of human subjects

19. Practical Applications of Regulations • Risk-Benefit Assessment • Four relevant criteria: 1) risks to subjects are reasonable in relation to anticipated benefits 2) risks to subjects are minimized 3) when appropriate, there are adequate provisions to protect the privacy of subjects 4) when appropriate, the research plan makes adequate provisions for ongoing monitoring for subject safety

20. Minimal Risk • Term of art • “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” (DHHS, 2009).

21. Examples of Minimal Risk • chest palpitations • blood draws • urine collections • education exams • psychological tests such as the MMPI (Minnesota Multiphasic Personality Inventory)

22. Greater than Minimal Risk • Risks that are not ordinarily encountered in daily life or routine exams • Risks greater than minimal require special protections and should be balanced by greater benefits • Harm and discomfort can be physical, psychological, or social in nature • Common challenge of the assessment is determining the likelihood and severity of these

23. Examples of Risks Greater than Minimal • spinal taps • experimental medications and procedures • surveys about illegal behaviors • biopsies

24. Benefits • To the subjects • Direct – therapies that improve subjects’ health • Indirect – procedures, such as medical tests, that provide subjects with important information about their health • To society at large • Data used to develop preventions, therapies, and treatments sometime in the future

25. Incentives • Monetary and material incentives offered to subjects to participate in research are NOT considered benefits of their participation • More appropriately considered compensation for their time and effort • Incentives should not be so great as to be coercive • Magnitude of incentive should be evaluated within the context of the life experience of the subject population

26. Ideal Balance • Risks are no greater than benefits • Usually a difficult assessment with a great deal of gray area and guesses about study experiences

27. Voluntary Informed Consent • Very important component of the National Research Act (1974) • Primary aspect of autonomy • Subjects’ consent must be: • Informed – subjects told about all research activities and potential risks and benefits • Understood – great effort should be taken to make sure subjects clearly understand the information they are given • Voluntary – subjects should be clear that their decision to participate in any or all of the study is completely voluntary and that they will suffer no negative consequences if they do not consent to participate

28. Voluntary Informed Consent • Minors (usually defined as younger than age 18) cannot consent for themselves • Their youth makes them unable to effectively deliberate their decision to participate or not • Parents or guardians must consent on their behalf • Minors can assent—give agreement—to participate, but they cannot formally consent

29. Special Needs for Protection • Pregnant women • Fetuses and neonates • Prisoners • Children • Require additional protection measures and convincing justification for their involvement to the IRB

30. Pregnant Women, Fetuses, and Neonates • Mother consents for herself and her fetus or neonate • Preclinical studies of pregnant animals should be conducted first • Procedures should not intervene in any way in the outcome of the pregnancy or viability of the neonate • The research must directly benefit the mother and/or her fetus or neonate

31. Prisoners • Issue of voluntary consent is a particular concern with this population • Prison personnel cannot be part of the research process (i.e., selecting participants) • Participants should be chosen randomly • Must be clear to the prisoners that their participation will have no influence on any parole decisions

32. Prisoners (cont.) • Relative value of incentives must be evaluated in the context of prisoners’ living conditions • For example, a pack of cigarettes may be worth the equivalent of $500 for a smoker with limited access to cigarettes in prison • Value cannot be so great as to be coercive • Risks from the research should not be greater than what’s acceptable for non-prisoner populations

33. Prisoners (cont.) • Prisoners should only be used as subjects when the focus of the study is on conditions that affect prisoners as a class (i.e., related to the conditions of being incarcerated) • IRB committees that review studies using prisoners should include a prisoner or prisoner representative as a member

34. Children • Persons who have not attained the legal age for consent to treatment or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted • Children should be used as subjects only when their participation is directly relevant to the topic of the research • Medications and procedures should be tested on adults before testing on children

35. Children (cont.) • Children can assent or agree to participate in research • Consent for their participation must come from their parent or guardian or appropriate representative (who has no personal interest in the research) • Greater than minimal risk may require consent from both parents if possible

36. Research Practices to Avoid (Kimmel, 1979) • Involving people without their knowledge or consent • Coercing people to participate • Withholding information about the true nature of the research • Deceiving the participant • Inducing participants to commit acts diminishing their self-esteem • Violating rights of self-determination • Exposing individuals to physical or emotional stress • Invading privacy • Withholding benefits • Not treating participants with respect

37. Humane Treatment • Characterized by tenderness, compassion, and sympathy for peopleandanimals, especially for the suffering or distressed (dictionary.reference.com)