planning ahead: ethical considerations in study design

1. Planning ahead: ethical considerations in study design Paul KomesaroffDirectorMonash Centre for the Study of Ethics in Medicine and SocietyMonash University, Melbourne, Australia

2. Ethics and science cannot be separated Scientific projects are driven by ethical goals Ethical issues are not merely supplemental to the science but arise from within it Bad science is bad ethics

3. A project�s objectives may be ethically questionable The study design may raise ethical questions The methods themselves may generate ethical issues

4. Researchers and IRBs have ethical responsibilities with respect to study purpose, design and methods To scrutinize the goals of the project To ensure that it is scientifically valid To ensure that the conduct of the study will not lead to major ethical problems (Sleight P. J Intern Med. 2004 Feb;255(2):151-8.)

5. Questions for researchers and IRBs from an ethical perspective What are the underlying objectives of the project? Are these objectives clearly formulated? Is the study design sufficient to achieve the goals of the research? Who will the participants be? What will be the risks to the participants? Are the researchers competent to carry out the study? Do the researchers have any dualities that need to be examined? Are other issues raised by the methods or proposed protocol? How will data be analysed? How will results be disseminated?

6. A project�s objectives may be ethically questionable For example, research into: Weapons of mass destruction Biological warfare Nuclear weapons Environmentally destructive technologies

7. Ethically controversial research: an example The ethical content of research may be dependent on the social context.

8. Ethically controversial research: an example Research into atebrin, a new anti-malarial agent, in Australia during World War II, involving junior servicemen infected with plasmodium falciparum and treated with the new drug or placebo This research was risky, involved vulnerable participants and consent was doubtful. However, it was judged socially acceptable as it served what was considered to be an important social purpose at the time.

9. Possible objectives of a project To increase understanding of a biological process To contribute to the treatment of disease To study the social causes or impact of a health problem To contribute to the development of a marketable product To test a hypothesis To collect pilot data to allow a preliminary assessment of a topic or develop a new method To provide training for students

10. Assessing whether the study design is adequate to achieve the research goals A scientific question but an ethical responsibility Are there sufficient subjects to ensure adequate testing of the hypotheses? Are the controls adequate? Is the population the right one in which to test the questions? Has the study been designed to secure a particular outcome?

11. The study participants Who with the participants be? How will they be recruited? Will they belong to a vulnerable group? Are there special cultural issues that need to be considered? How will consent be obtained?

12. Consent The ethical and legal requirements of consent have two aspects: Provision of information about the purpose, methods, demands, risks, inconveniences, discomforts, and possible outcomes of the research Exercise of a voluntary choice to participate. A third component - that of communication - is also essential

13. Participants with reduced capacity to consent Children and young people Persons with an intellectual or mental impairment Patients in emergency care Patients in intensive care Terminally ill people Unconscious persons Persons in dependent or unequal relationships Teachers and students Doctors and patients (J Med Philos. 2004 Jun;29(3):351-78 Kopelman LM.; Seedat S, Pienaar WP, Williams D, Stein DJ. Curr Psychiatry Rep. 2004 Aug;6(4):262-7.; Lind C, Anderson B, Oberle K. Nurs Ethics. 2003 Sep;10(5):504-11.)

14. Possible consequences of including vulnerable populations Consent may be compromised The risk of adverse events may be greater There may be lack of attention to special needs An unfair burden may be placed on particular groups

15. Research involving particular cultural groups May raise special sensitivities related to the beliefs or customs of the group or their particular vulnerabilities.

16. Research involving particular cultural groups Example: Research involving Australian Aboriginal people Consent may need to involve a collective component Recording of names and photographs of dead people may be culturally offensive There may be religious issues concerning use of tissue samples Ownership of intellectual property can be politically sensitive (Mooney G. Aust N Z J Public Health. 2002;26(3):201-2.; Holmes W, Stewart P, Garrow A, Anderson I, Thorpe L. Soc Sci Med. 2002 Apr;54(8):1267-79.)

17. Research involving particular cultural groups Example: International HIV/AIDS research Often involves poor, illiterate, populations with limited access to local health care There is limited local surveillance or monitoring of the research process Local communities are often unlikely to receive any benefit from participation (Ahn MJ, Grimwood A, Schwarzwald H, Herman A. J Int Assoc Physicians AIDS Care (Chic Ill). 2003 Apr-Jun;2(2):81-7.)

18. Evaluation of risks to the participants A key question for researchers and IRBs May be difficult to decide May need specialised knowledge May be difficult to balance against possible �benefits�

19. Evaluation of risks  Risks may be physical, psychological or social Dangers from drugs, devices or invasive procedures Costs, inconvenience, discomfort Exposure to legal or social consequences Revival of anxieties or traumatic memories Interference with staff duties Effects on other patients Sometimes can be quantified on the basis of previous evidence Phase I and II studies of a drug Personal experience of investigator Often data are limited or unreliable

20. Evaluation of risks Balancing of risks and benefits can be difficult: Projects must carry some potential community benefit There are no guaranteed benefits to individual participants There is no �ratio� of risks and benefits The conclusion depends on a conversation about both scientific facts and ethical values (Weijer C. J Law Med Ethics. 2000 Winter;28(4):344-61; Beyrer C, Kass NE. Lancet. 2002 Jul 20;360(9328):246-51.)

21. Issues concerning researchers Researchers must be competent and dualities must be identified and managed Personal experience and understanding of investigators may be important Dualities may include: Relationships with industry Roles as clinicians and researchers Direct or indirect payments Potential non-pecuniary benefits from research (Komesaroff PA et al. Endocrinology. 2004 Jun;145(6):3032-41)

22. Ethical issues arising out of the study methodology Impact on medical treatment of patients Nature of treatment in comparison with existing best practice Actions that will be taken in relation to new information Use of placebo controls Issues arising in relation to genetic research Issues arising in qualitative research

23. Use of placebo controls Controversial question in public debates, especially in relation to revision of the Declaration of Helsinki. Issues concern alleged denial of proven effective treatment and exploitation of vulnerable groups Nonetheless, placebos may still be justified in certain circumstances Costs and scientific requirements of non-placebo studies may be prohibitive. (Saunders J, Wainwright P. Clin Med. 2003 Sep-Oct;3(5):435-9.)

24. Issues in genetic research A subject of extensive and intense public debate. Many issues, including: Access to data bases and other genetic information Complexities of consent processes involving blood relations Implications of results for individuals and families, including with respect to prediction of medical conditions, possibilities of treatment and misuse of information (Knoppers BM, Chadwick R. Nat Rev Genet. 2005 Jan;6(1):75-9.)

25. Ethical issues in qualitative research Includes a variety of methodological approaches distinct from quantitative methodologies and both overlapping and distinctive ethical issues Ethical questions include: Consent � may need to be verbal Nature and representativeness of study populations Relationships between researchers and participants Risks of psychological and social harm Maintenance of confidentiality Publication issues (Fossey E, Harvey C, McDermott F, Davidson L. Aust N Z J Psychiatry. 2002 Dec;36(6):717-32; Fam Pract. 1995 Mar;12(1):104-14; Britten N, Jones R, Murphy E, Stacy R. Fam Pract. 1996 Apr;13(2):208.)

26. Analysis and publication of data Is there a Data and Safety Monitoring Board? Who are the members of this Board? Who will be responsible for analysis? Will all the investigators have access to consolidated data? Are there dualities of interests that need to be managed in relation to data analysis and publication? How will data be analysed? Will trial participants be provided with study results? Is there a commitment to publication of data, regardless of results? (Jones AH and McLellan F. (Baltimore, Johns Hopkins, 2000))

27. Questions for researchers and IRBs from an ethical perspective What are the underlying objectives of the project? Are these objectives clearly formulated? Is the study design sufficient to achieve the goals of the research? Who will the participants be? What will be the risks to the participants? Are the researchers competent to carry out the study? Do the researchers have any dualities that need to be examined? Are other issues raised by the methods or proposed protocol? How will data be analysed? How will results be disseminated?

28. Summary  Ethics and science cannot be separated: bad science is bad ethics The design and methods themselves may generate ethical issues Researchers and IRBs have ethical responsibilities with respect to study design Ethical considerations must be built into research projects from the beginning

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30. Study design may not meet the project�s purpose Hypotheses may not be adequately formulated Methods may be inadequate to test hypotheses The methods themselves may generate problems Risks to participants Issues in recruitment Conflicts of interest Privacy issues

31. Ways in which pharmaceutical studies can be distorted Drug tested on population in which positive outcome is most likely New drug tested versus placebo or the worst alternative Highest tolerable doses tested to prove efficacy Lowest dose tested to prove safety Many outcome measures so that statistical significance is easy to demonstrate Misleading analysis or data presentation (Bero, Int J Technol Assess Health Care 1996; 12: 209-237)