ETHICS IN RESEARCH INVOLVING HUMAN PARTICIPANTS Foundations

1. ETHICS IN RESEARCH INVOLVING HUMAN PARTICIPANTSFoundations Sana Loue, J.D., Ph.D., M.P.H., MSSA Sponsored by Case Western Reserve University and PRIZMA March 30, 2010 Funded by the Fogarty International Center

2. HISTORY OF HUMAN EXPERIMENTATION IN U.S. 1. Standards • Early 20th century • Cannot use humans in experiments until after the safety of a new drug or procedure was established in animals (Osler, 1907) • Full consent of patient prerequisite to application of a new therapy • Patients entrusted to care of physician not to be recruited for experimentation unless new therapy had potential to result in direct benefit to patient • Participation of healthy volunteers permissible, subject to requirement of full knowledge of circumstances and agreement to participate

3. HISTORY OF HUMAN EXPERIMENTATION IN U.S. 2. Questionable Experiments • Experimentation with female slaves to cause and repair vesico-vaginal fistulas (Sims, 1894) • Injection of sterilized gelatin into two young boys and feeble-minded girls (Abt, 1903) • Injection of tuberculin solution into >164 children less than 8 years old, most in orphanage (Belais, 1910; Hammill, Carpenter, and Cope, 1908) • Tuskegee Syphilis Study, 1932-1972 • Vanderbilt Nutrition Study (Hagstrom et al., 1969) • Fernald State School Experiments, 1946-1953 (Welsome, 1999) • University of Cincinnati Radiation Experiments (Welsome, 1999) • Holmesburg Prison Experiments, 1956-1969 (Hornblum, 1998) • Atlanta Malaria Experiments, 1946 (George, 1946) • Diethylstilbesterol experiments, 1940s(NIH, 1992) • Willowbrook Hepatitis Experiments, 1950-60s(Beecher, 1970) • Tearoom Trade(Humphreys, 1970)

4. GOVERNING DOCUMENTS--INTERNATIONAL • Nuremberg Code (1947) • Helsinki Declarations (1964, 1975, 1983, 1989, 1996) • CIOMS International Guidelines for Ethical Review of Epidemiological Studies (1991) • CIOMS International Ethical Guidelines for Biomedical research Involving Human Subjects (1993, 2002) • International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Guidelines for Good Clinical Practice (1996) • International Guidelines for Ethical Review of Epidemiological Studies (1991) • International Guidelines for Biomedical Research Involving Human Subjects (1993) • World Medical Association, Statement on Fetal Tissue Transplantation (1989) • World Medical Association, Declaration on the Human Genome Project (1992) • Recommendation Concerning Medical Research on Human Beings (1990) • Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (1996) • Scientific Research and/or Experimentation on Human Gametes, Embryos and Foetuses and Donation of Such Human Material (1989) • Council of Europe, Recommendation on Genetic Testing and Screening for Health Care Purposes (1992) • European Medical Councils Gene Therapy in Man (1988) • International Covenant on Civil and Political Rights, entered into force 1976; U.S. ratified 1992; Article 7; General Comment 20, adopted by Human Rights Committee, 1992

5. NUREMBERG CODE • Voluntary consent is essential. • The experiment must yield fruitful results for the good of society. • The experiment should be based on the results of animal experimentation and a knowledge of the natural history of the disease under study to justify performance of the study. • The experiment should be conducted to avoid all unnecessary physical and mental suffering and injury. • In general, no experiment should be conducted where there is a priori reason to believe that death or disabling injury will occur • Proper precautions must be taken to provide adequate facilities to protect the participant against the risk of injury, disability, or death. • The experiment may be conducted by only scientifically qualified persons. • The participant may end the experiment. • The researcher must be prepared to end the experiment at any time.

6. FOUR BASIC PRINCIPLES • Respect for Autonomy • Informed Consent • Capacity • Information • Understanding • Voluntariness • Special Protections • Nonmaleficence • Beneficence • Justice • Purpose: • Protecting people from harm • Respect for an individual’s autonomy

7. HELSINKI DECLARATIONS • Added provisions for surrogate consent • Special protections

8. GOVERNING DOCUMENTS U.S. RESEARCH ETHICS POLICIES • Federal Policy for Protection of Human Subjects: “Common Rule,” adopted by 17 agencies, Subpart A, Part 46, Title 45 of Code of Federal Regulations • Food and Drug Administration, 21 CFR 314.126 (1985) • FDA, Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (1993) • FDA, Accelerated Approval of New Drugs, 21 CFR 314.500 et seq. • FDA, Exception from Informed Consent Requirements for Emergency Research, 21 CFR 50.24 • NIH, Research Involving Impaired Human Subjects: Clinical Center Policy for the Consent Process (1986) • NIH, Report of the Human Embryo Research Panel (1994)

9. THRESHOLD QUESTIONS: Research • Are mentally ill/retarded/cognitively impaired individuals “vulnerable?” • Should the research be conducted at all? • Can a vulnerable population participate in the research? • Is the state of knowledge, if a clinical/intervention trial, in a state of clinical equipoise?

10. CHARACTERISTICS OF VULNERABLE POPULATIONS • Lack of power; potentially coercive situation • “insufficient power, prowess, intelligence, resources, strength, or other needed attributes to protect their own interests through negotiations for informed consent” (Levine, 1988) • Institutionalized persons, prisoners, military personnel, students • Marginalized populations • Minorities, stigmatized groups • Lack of/diminished understanding • Children, mentally ill, mentally retarded

11. ETHICAL AND LEGAL ISSUES: CONSENT ELEMENTS OF INFORMED CONSENT • Knowledge • Understanding • Capacity (distinguish between capacity and competence) • Ability to evidence a choice • Ability to understand relevant information • Ability to appreciate situation and its consequences • Ability to manipulate information rationally • Voluntariness

12. LEGAL INTERFACE: RESEARCH (2): COMMON RULE • Content of informed consent, e.g. research, right to withdraw, duration, procedures, contact information to ask questions, foreseeable risks, disclosure of available alternative treatments or procedures, availability of compensation, extent of confidentiality • Institutional Review Board: composition, responsibilities, procedures • Special protection: children, pregnant women, prisoners

13. FEDERAL REGULATIONS: 1. Required Information • Information • Statement that it involves research • Explanation of purposes of study • Expected duration of participation • Description of procedures • Identification of any procedures that are experimental • Description of reasonably foreseeable risks or discomforts • Description of reasonably expected benefits • Disclosure of appropriate alternative treatments • Extent of confidentiality of records • For research involving more than minimal risk, explanation of compensation, medical treatments • Explanation of whom to contact re: questions • Statement that participation is voluntary, participant may discontinue at any time without penalty or loss of benefits to which otherwise entitled

14. FEDERAL REGULATIONS: 1. Discretionary Information • Additional elements of information • Treatment may involve unforeseeable risks • Circumstances under which participation may be involuntarily terminated • Additional costs to participant • Consequences of participant’s decision to withdraw • Statement that significant new findings will be provided to participant • Number of participants in study

15. FACTORS AFFECTING UNDERSTANDING • Language used • Layout of information • Amount of information • Modality of information (written, other visual, auditory, etc.) • Provider of information • Therapeutic misconception

16. STANDARDS OF INCOMPETENCE/INCAPACITY • Inability to express or communicate a decision or choice • Inability to understand one’ situation and its consequences • Inability to understand relevant information • Inability to give a reason • Inability to give a rational reason • Inability to give reasons related to risks and benefits • Inability to reach a reasonable decision as judged by a mythical reasonable person

17. DECISIONAL LIMITATIONS • Fluctuating incapacity • Prospective incapacity • Limited incapacity • Complete incapacity

18. DISORDERS AFFECTING DECISIONAL CAPACITY • Dementias • Delirium • Schizophrenia • Depression • These circumstances raise significant issues: • Consent and refusals over time • Continuity of personal identity and effect on original consent • Changes in risk-benefit ratio

19. VOLUNTARINESS:Forms of Influence • Coercion • Intentional use of a credible or severe threat of harm or force • Exorbitant incentive so that individual cannot refuse • Judged subjectively • Persuasion • Use of meritorious reasons to convince • Manipulation • Swaying person to consent by means other than coercion or persuasion; often informational

20. ISSUES IN CONSENT PROCESS • Failure to provide information regarding assessment of capacity • Under what conditions will capacity be assessed • Who will assess capacity? • What substantive criteria will be utilized to assess capacity? • Incomplete disclosure of risks and research design; relation to therapeutic misconception • Inappropriate characterization of risks as minimal • Overemphasis on benefits • Failure to discuss monitoring procedures • Ongoing validity of informed consent and continuing assessment

21. ISSUES IN CONSENT PROCESS (2) • Consent form written at too high readability level • Translation not accurate and/or not understandable • Lack of adequate data safety monitoring plan

22. RISKS AND BENEFITS • Medical • Social • Psychological • Legal • Economic

23. MINIMIZING AND PROTECTING AGAINST MEDICAL RISKS • Appropriate acknowledgement of risks in informed consent process • Adequate monitoring procedures • DSMB and reliance on stopping rules • Provision of care during study • Referral where appropriate • Involuntary or voluntary termination of participation

24. HELSINKI DECLARATION 2008:Clinical Trials • 32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances: • • The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or • • Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.

25. HELSINKI DECLARATION 2008:Clinical Trials • 33. At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits.

26. MINIMIZING AND PROTECTING AGAINST SOCIAL RISKS • Protection of privacy • Protection of confidentiality • Measures • Locked doors • Locked cabinets • Password protection on computers • Limited access • Letterhead/envelopes • Telephone messages • Cell phone/e-mail/fax

27. MINIMIZING AND PROTECTING AGAINST PSYCHOLOGICAL RISKS • Development of appropriate referral procedures • Procedures to address emergencies • Stopping the interview • Involuntary or voluntary termination of participation

28. MINIMIZING AND PROTECTING AGAINST ECONOMIC RISKS • Provision of incentive/stipend to reimburse • Lost wages • Transportation costs • Child care costs • Value of time