Ethical Considerations in Substance Abuse and Addiction Research

1. Ethical Considerations in Substance Abuse and Addiction Research Sandra L. Alfano, Pharm.D. Chair, HIC II and IV Research Scientist, General Internal Medicine

2. Objectives • Understand the ethical foundations of human subjects research • Explore the conflicts and tension between and among the principles and roles of researchers • Review special considerations in doing research with human subjects with substance abuse or addiction disorders • Delineate additional safeguards that may be necessary when involving vulnerable populations in research

3. Ethical Foundations of Human Subjects Research • Nuremberg Code (1949) • Nazi war crimes • Code stresses voluntary informed consent • Idea of ‘do no harm’

4. Ethical Foundations of Human Subjects Research • Declaration of Helsinki (1964, last updated 2008) • http://www.wma.net/e/policy/b3.htm • World Medical Association’s best known policy statement • Distinction between therapeutic and non-therapeutic research • Best care standard raises problems with placebo controls; 2002 clarification allows some placebo use

5. Helsinki, placebos • 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

6. Ethical Foundations of Human Subjects Research • Outrage over Tuskegee Syphilis Trial • National Research Act enacted in 1974 • Established National Commission for Protection of Human Subjects of Biomedical and Behavioral Research • Issued Belmont Report (1979) • Established the IRB system for regulating research

7. INSTITUTIONAL REVIEW BOARD • Responsible for protecting the rights and welfare of human subjects participating in research studies • Ensure research is conducted in accordance with accepted ethical standards

8. Role of the IRBs • Each biomedical IRB meets weekly • Reviews and approves every research protocol involving human subjects, along with consent forms and all materials shared with subjects • Approval must be in place before the research can begin, and each protocol must be re-approved at least once a year • Changes to protocols must be approved prior to implementation

9. Belmont Report Ethical Principles • Respect for Persons • Beneficence • Justice • Contains the ethical principles upon which the U.S. Federal regulations for protection of human subjects are based

10. Belmont Report Ethical Principles • Provide an analytical framework that will guide resolution of ethical problems • Acknowledges tensions between principles, need for trade offs

11. First Ethical Principle: Respect for Persons • Individuals should be treated as an autonomous agents; avoid paternalism; let subject make decision about what will or will not happen • However, not every human being is capable of self-determination. Therefore, those with diminished autonomy should be protected • Voluntary participation

12. Respect for Persons • Demonstrated through informed consent • Capacity • Information, comprehension, voluntariness

13. Four Elements of Consent • Informing • Convey information • Not a legal document, avoid legalese • Assessing comprehension • Assessing autonomy • Consenting • Agreeing to be a subject

14. Consent issues • Informed consent is not only a document. • It is a process: a dialogue between the researcher and the subject. Information exchange needs to take place before, during, and sometimes after the study. • Information, comprehension, and voluntariness. • Intended to facilitate understanding.

15. Consent Issues: Information • Purpose of the research • Research procedures/expectations explained • Known (and unknown) risks explained with possible consequences • Economic considerations (impact on individual) • Benefits stated reasonably in relation to phase of protocol • Alternatives noted to inform decision • Procedures to protect privacy and ensure confidentiality

16. Consent Issues: Comprehension • The manner and context in which information is conveyed are as important as the information itself • Organized presentation of the material • Providing private, appropriate space, and sufficient time to ask questions and to consider participation • Investigator getting consent must assure comprehension

17. Consent Issues: Voluntariness • Begin with an invitation to participate • Free of coercion (overt threat of harm) • Free of undue influence (offer or promise of excessive or improper reward) • Participant is free to decline or to withdraw at any time without repercussions

18. Consent issues • Be sure that the informed consent process is not misleading • Benefit is not overstated • Risk/Benefit ratio is carefully considered

19. Process of consent • Ensure autonomy: begin with an invitation to participate, ensure there is no coercion or undue influence (remove impediments) • Allow ample time for considered response, take home and sharing • Consider breaking up the material into multiple sessions • Pay attention to verbal and non-verbal cues • Verify understanding, comprehension • Use of witnesses or consent monitors • Consider use of quiz

20. Process of consent • Process of consent should be described in the protocol, including time, place, and who will do it • Involves discussion as an educational interchange (not handing person the form to read) • Avoid jargon, medical acronyms • Use the reasonable person standard for amount of information to be shared • Solicit consent in advance, not day of surgery

21. Background “Confluence of several considerations, including perceived gaps in the federal system for the protection of human subjects; historical and contemporary cases in which the protection of human subjects appears to be inadequate; and the need to ensure that research designed to develop better treatments for mental disorders can proceed with full public confidence in its ethical framework. The continuing vitality of the research enterprise ultimately depends on the public’s trust that appropriate ethical constraints are in place and will be followed.” http://govinfo.library.unt.edu/nbac/capacity/TOC.htm

22. Background • Regulatory citation: ‘When some or all of the subjects are likely to be vulnerable to coercion or undue influence, including those with cognitive limitations, the IRB must be sure that additional safeguards have been included in the study to protect the rights and welfare of these subjects {45 CFR 46.111 (b)}

23. Definitions • Adults with decisional impairment: ‘Limited decision making capacity covers a broad spectrum. A healthy person in shock may be temporarily decisionally impaired. Another may have been severely mentally retarded since birth, while yet a third who has schizophrenia may have fluctuating capacity. Researchers should be sensitive to the differing levels of capacity and use assessment methods tailored to the specific situation. Further, researchers should carefully consider the timing of assessment to avoid periods of heightened vulnerability when individuals may not be able to provide valid informed consent.’ http://grants.nih.gov/grants/policy/questionablecapacity.htm

24. Assessment of Capacity • Society has not decided what degree of impairment counts as a lack of capacity • Case by case basis • Protocol-specified method • Quizzes, consent monitor, formal assessment via Mc-CAT, etc

25. Transitional capacity • Fluctuating: consider delaying consent process, or re-consenting • Progressive: consider using advance directives while capacity is retained

26. Second Ethical Principle: Beneficence • Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being (an obligation) • Two general rules • Do not knowingly cause harm • Maximize possible benefits/minimize possible harms • Are the risks presented justified?

27. Beneficence • Not exactly the Hippocratic Oath • Even avoiding harm requires learning what is harmful • Researchers and their IRBs must decide with imperfect knowledge when it is justifiable to seek certain benefits despite the risks involved, versus when the potential benefits are so small that the risks outweigh the benefits

28. Beneficence • Initial analysis as part of approval of the proposed protocol: sound scientific design, and favorable risk:benefit assessment • Ongoing monitoring of risks and benefits throughout the study (via data and safety monitoring plan)

29. Research Risks • Research by its very nature involves risk • Subjects may be exposed to risk and may be harmed • Obligation to minimize probability of harm, maximize potential benefits and never knowingly cause (permanent) injury • IRBs must ensure risks are reasonable in relation to benefits expected; an acceptable risk:benefit relationship must exist for a protocol to be approved

30. Research Risks • Investigators must identify risks and objectively estimate magnitude and likelihood • Both the risks and the benefits should be presented to prospective subjects in the consent form • Vulnerable subjects deserve special protections; may be reasonable to place limits on the level of risk to which these subjects may be exposed

31. Research Design • Need reasonable precautions when designing a study • Good design, data and safety monitoring, and selection of least susceptible subjects • Identify opportunities for risk exposure

32. Risks in Consent form • What to disclose? • At least what a “reasonable volunteer” would find important to decision making • Reasonable Man Theory: the reasonable person is a hypothetical, rational, reasonably intelligent individual who is intended to represent a sort of ‘average’ citizen • How would a reasonable person act under the circumstances?

33. Minimizing Risks • Highly competent research team • Well designed study • Procedures that have the least likelihood of harm • Adequate monitoring • Adverse events quickly identified, managed and reported • Privacy and confidentiality protected

34. Risk:Benefit Assessment • Probability and magnitude of possible harms Versus • Anticipated benefits • Imperfect knowledge

35. Therapeutic Misconception • prone to misunderstand the risks and potential benefits associated with participation and to have unreasonable expectations about potential individual benefits • May lead to discounting of risks and overestimating personal benefits • Especially problematic when treating physician is researcher as well

36. Risk:Benefit Assessment Approach • In the absence of a regulatory framework, many people will adopt a model that incorporates aspects of an existing regulatory framework, such as Subpart D, Children

37. Third Ethical Principle: Justice • The Belmont Report tells us, “An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly…” • Ethical Obligation: fair sharing of burdens and benefits • Requirement: Equitable selection of research subjects; fairness in inclusion and exclusion criteria

38. Justice • Fair distribution of the burdens and the benefits of research • Must be borne by some but not all members of a society • ‘Representative’: should not select for convenience/ease • Good research design

39. Justice • Does the research involve individuals who are unlikely to benefit from the results of the research? • Who is likely to benefit? What connection do they have to the research subjects?

40. Inclusion/Exclusion Criteria • Attributes necessary to accomplish purpose of the research • Well defined criteria increase the likelihood of producing reliable and reproducible results, decrease likelihood of harm, and guard against exploitation of vulnerable populations

41. Conflicts between Principles • One does not ‘trump’ the others • Weighing and prioritizing conflicting ethical norms is a difficult task • Discussion, debate, struggle

42. IRB Approval considerations • Risk:Benefit ratio reasonable? • Selection of subjects equitable? • Appropriate informed consent? • Data collected adequately monitored? • Adequate provisions to protect privacy and maintain confidentiality of data/information? • Risks are minimized? • Additional safeguards for those who need it (children, prisoners, etc.)?

43. How are the principles applied? • Careful review of the protocol • Inclusion/Exclusion Criteria • DSMP and Stopping Rules • Risks/Benefits • Consent Process • In Case of Injury Section

44. How are the principles applied? • Careful review of the consent form • Purpose • Research Procedures • Risks • Anticipated Benefits • Alternative Treatments • Voluntariness • Confidentiality

45. Recruitment • Advertisements • Internet • Registries • Targeted letters • Phone calls • All considered beginning of consent process • IRB must review and approve methodology and content

46. Economic Considerations and ICOI • Inform participants about costs of participation, and payments to made (if any) • Costs of research should be clearly differentiated from costs of standard care • Tell them what will happen in case of injury (who will pay)

47. Additional protections • For those who need them • Vulnerability of a given population or person sometimes changes

48. Vulnerability • A condition, either permanent or temporary • Substantial inability to protect one’s own interests • Interferes with autonomy or decision-making capacity • Personal circumstances may make them subject to intimidation or exploitation

49. Special considerations in human subjects research: Vulnerable subjects • “…vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons…” • “…additional safeguards have been included in the study to protect the rights and welfare of these subjects.” Subparts B, C, D

50. Examples of Potentially Vulnerable Populations • Clinic population • Prisoners • Critically ill • Students who need money • Homeless who need money • Third world countries who need care