“Ethics from fundamentals to justice & fair-play”

1. “Ethics from fundamentals to justice & fair-play” Sisira Siribaddana Forum for Research & Development

2. Introduction to bio ethics(this section is adapted from slides by Doug Wassener)

3. What is the role of ethics in research with human participants? • The objective of clinical research is to develop generalizable knowledge to improve health and/ or increase the understanding of human biology • The aims of research are a recognized good, but research has the potential to inflict harms and to treat participants as just “means to an end” • The aim of ethics is to ensure that participants are treated with dignity and respect while they contribute to the social good • Ethics may help us find the ‘least harmful’ route

4. What is the role of ethics in research? cont’d • Ethics aims to protect participants from harm and to promote their welfare:  acts to restrain science • However, ethics also promotes good science as participants who feel respected may: • Actively engage with research requests • Answer truthfully • Provide critical & honest feedback • Return for follow up • Therefore increasing the quality of the data

5. What are the key principles in research ethics? • NON-MALEFICENCE: “Do no harm” • There should be no intentional injury or harm to participants as a result of participation; researchers are obligated not to deliberately harm participants • BENEFICENCE: Minimize potential harms & maximize expected benefits of the research; Researchers should take active and positive steps to reduce possible harms to a minimum and to maximize anticipated benefits of the research • In some research there may be no direct benefit for the participant, but benefits to society in terms of important knowledge

6. What are the key principles in research ethics cont’d? • RESPECT FOR AUTONOMY: “self-rule” • A person’s freedom of thought & action should be respected and researchers must respect rights of participants who can make decisions to do so • Researchers must take special measures to protect vulnerable participants whose freedom to make choices is limited, or those with no capacity to choose

7. What are the key principles in research ethics cont’d? • JUSTICE: Fair balance of risks and benefits • Those who stand to benefit from research must contribute to its risks and discomforts • No group of persons should be asked to bear more than their fair share of the burdens of research; no group (e.g. impoverished) should be asked to bear research risks in order that others (e.g. the wealthy) enjoy benefits (new knowledge or products) • International collaborative research growth • No group should be deprived of fair access to the benefits of research; No class of person should be unfairly excluded from research (e.g. women) as this denies them relevant knowledge/ health interventions

8. What makes research ethical? The requirements for ethical research: 1 Community Participation 2 Social value 3 Scientific validity 4 Fair selection of participants 5 Favorable risk / benefit ratio 6 Independent review 7 Adequate informed consent 8 Ongoing respect for dignity

9. Community participation • Rationale: Based on right and responsibility to participate in research development activities; and can offset potential vulnerabilities. • Mechanisms: Include the formation of a Community Advisory Board (CAB). • Possible role: Includes inputs to design (e.g. IC); advising on cultural conventions, expectations; evaluating impact of the research. • Community participation should be based on a genuine partnership geared towards mutual respect, education & consensus building.

10. Community participation cont’d • Benefits of community participation include: • Enhanced cultural appropriateness • Increased acceptability of the research to the participating community • Fairness and equity regarding important decisions (e.g., adequate incentives) • Sound bi-directional information exchange. • E.g.,in preparation for HIV vaccine trials in South Africa community structures are being formed at sites (e.g. Gauteng CAB and interim DBN CAB).

11. Community participation cont’d • Complexities: • Defining community: which stakeholders and interest groups must be represented? • Difficulties in ensuring mandated representation • Defining “participation” (from recipients of education  full and equal partners) • Determining what “participation point” on the research continuum? (from protocol development  dissemination of results)

12. What makes research ethical?1. Social or scientific value • To be ethical, research must be valuable • Society should gain important generalizable knowledge. • Why? Researchers can not expose human beings to inconvenience or risk of harm without possible benefit to society

13. What makes research ethical?2. Validity • Even a valuable question can be poorly researched, resulting in unreliable data. • Research must also be well designed and conducted (e.g. clear aims, rigorous design, adequate sample, adherence to GCP, sound data analysis). • Why? Poorly designed & conducted research is unethical as it exposes subjects to risks and inconvenience for no purpose.

14. What makes research ethical?3. Fair choice of participants • Selection of participants should be fair and just. • Firstly: Participants should be chosen according to the scientific goals of the study and not for non-scientific reasons (E.g. not acceptable to select participants because they are convenient, or vulnerable, or less able to protect their rights). • Also, participants should not be excluded from research without sound justification (E.g. while pregnant women will be excluded from HIV vaccine research, justifications will rest on potential risks to the foetus).

15. What makes research ethical?3. Fair choice of participants • A challenge for researchers is to address potential misperceptions that vulnerable individuals and communities will be unjustly targeted, and to demonstrate safeguards that will be taken to offset specified vulnerabilities. • This is important in international collaborative research between developed and developing countries.

16. What makes research ethical?3. Fair choice of participants • Secondly: Volunteers should be chosen to minimize risks. • It is possible that potential participants will be eligible for scientific reasons, but they may be at substantially higher risk of harm (e.g. impoverished and vulnerable to undue inducements). • “Rule of thumb”: Researchers should avoid involving the vulnerable when less vulnerable persons could be involved, must justify why vulnerable persons are included, and articulate safeguards to minimize risks for vulnerable persons and communities. • See MRC (2002) book 1

17. What makes research ethical?3. Fair choice of participants • Thirdly, individuals and communities should be selected so that the benefits and burdens are fairly distributed. • Individuals and groups who bear the burdens of the research should share its benefits (new knowledge or products). E.g., after phase I trials, knowledge or other benefits should be made available to participating individuals and communities; e.g., after phase III trials, any successful vaccine should be made reasonably available to participants and community.

18. What makes research ethical?4. Favorable risk- benefit ratio • The potential risks to individual participants must be identified and minimized. • The potential benefits of the research must be identified and maximized. • The potential risks to individual participants should be outweighed by the benefits to the individual - or society (favorable risk-benefit ratio).

19. What makes research ethical?4. Favorable risk-benefit ratio • Risk minimization measures must be undertaken: E.g. in HIV vaccine trials: • Ongoing monitoring for effects • Risk reduction counseling (optimal) • Counseling around possible negative consequences (e.g. stigma) of disclosure • Provision of support counseling • Testing to differentiate between antibody response and natural infection; ID card; and support.

20. What makes research ethical?4. Favorable risk-benefit ratio • The potential risks to individual subjects should be outweighed by the benefits to the individual or society: • Who decides this? • Research ethics committees at every participating institution • Participating communities via establishment of representative participatory structures • Each and every individual via informed consent.

21. Maximizing benefits: Access to successful products • E.g., Ensuring access to an HIV vaccine that is demonstrated to be safe and effective: South African AIDS Vaccine Initiative: • Planning is being undertaken now to ensure that once a successful vaccine is developed will be accessible and affordable to SA • E.g. AlphaVax – IAVI agreement that spells out commitment to pricing close to cost if licensed. • Access to ART for seroconverters: Required – mechanism being finalised (cf. Lancet…)

22. What makes research ethical?4. Favorable risk-benefit ratio • Use of placebo controls: • Unease of public: • From 1) “deceptiveness” or • 2) appears to consign placebo group to an “unfair disadvantage” • Placebo controls may be regarded as acceptable if “clinical equipoise” exists, if there is no comparator, (?assay sensitivity even if there is a comparator (Temple)

23. What makes research ethical?5. Independent review • Researchers operate at the interface of multiple obligations and interests • undertake research; publish; acquire funding; further careers; protect human subjects • These conflicting interests can potentially bias how researchers perceive their research designs and conduct research • Research should be reviewed by persons independent of the research (“at arm’s length”). • But REC’s should be competent and confident to review complex designs.

24. What makes research ethical?5. Independent review • Review process examines the scientific and ethical quality of the research, minimizes conflicts of interest, and aims to ensure that participants are protected and treated with dignity (1, 2, 3, 4, 6, 7). • In upcoming phase I HIV vaccine trials, the protocols must be reviewed and approved by the FDA in the USA, the MCC in SA, and ethics committees at every participating institution (E.g. Nelson Mandela REC, Wits REC, MRC REC and Institutional Review Boards in the USA).

25. What makes research ethical?6. Informed consent • Research participants have a right to choose freely whether or not to participate based on an understanding of all relevant information. • This ensures that participants will only take part if the research is consistent with their interests, values and preferences (autonomy). • Easier to assert than to assure in developing country contexts • See Emanuel, E., Wendler, D. & Grady, C. (2000) “What makes clinical research ethical?” JAMA, 283, 2701 – 2711

26. What makes research ethical?6. Informed consent cont’d Generally, informed consent has a number of components 1. Disclosure of information 2. Comprehension or understanding 3. Voluntariness or freedom 4. Explicit formal consent In HIV vaccine trials, consent is also staged (screening, enrolment and HIV testing).

27. What makes research ethical?6. Informed consent cont’d • 1. Information • Participants must be informed of the following: • Aims, purpose, duration • Methods (e.g. randomization, placebo, blinding) • Practical aspects (VCT, tests, visits, use and storage of tissue samples, etc.) • Potential risks (e.g. trial related discrimination) • Expected benefits (e.g. counselling) • The right to withdraw • Compensation for research related injury • Confidentiality (and limits if any) • Personal implications.

28. What makes research ethical?6. Informed consent cont’d • Complexities:Transmission of complex information, compounded by language differences, translation. • Information transmission typically viewed as a one way process, whereas it is best conceptualized as bi-directional, where researchers & counsellors make every effort to hear the expectations & motivations of potential participants. • Determinations of “what” must be transmitted is governed by disclosure requirements, but should also be supplemented by recommendations from community representatives & constantly assessed.

29. What makes research ethical?6. Informed consent cont’d • 2. Comprehension • Disclosure is not sufficient and participants’ comprehension must be ensured and assessed. • Complexities: • Social desirability: Tendency to act to avoid disapproval that impacts on reported understanding. • Overemphasis on understanding of technical aspects (e.g. placebo) & less on understanding of implications for a participant’s personal and social life. • “Tests of understanding” may emphasize technical aspects and assess short-term memory and not actual understanding of the personal consequences.

30. What makes research ethical?6. Informed consent cont’d • Researchers and counsellors can enhance comprehension by: • Creating an optimal environment for decision making (vs. “consent counselling”) • Ensuring use of counsellors with “values match” to potential participants • Encouraging dialogue; discussion with family • Allowing time to reflect • Sensitivity to process aspects of counselling (e.g. social desirability, non-verbal cues) • Multiple methods of assessing comprehension.

31. What makes research ethical?6. Informed consent cont’d • 3. Voluntariness • Participants must be free to choose whether or not to participate, free of coercion (threat of negative sanction) or undue influence to participate (excessive incentives  pressure to volunteer against better judgement). • Special care must be taken with participants who are considered vulnerable and therefore constrained in their ability to make free choices.

32. "...John Rawls, perhaps the leading moral philosopher of our time, has argued that all human beings are endowed with moral capacities.  He is right to insist on this, but the deployment of those capacities are severely constrained by the epistemic difficulty in grasping what exactly is happening and how things could be actually different.  The lessons of the tsunami and the global response it has generated not only include the affirmation of the ethical capacity of people in general, sometimes even at great distance, but also the critical importance of communication and understanding.  The connection between epistemology and ethics can be very powerful, and this is part of the interdependence of the world in which we live.  Ignorance and incomprehension are enemies not only of science, but also of the practice of ethics..."