1. Science at the heart of medicine Ruth Macklin, PhD Ethical Issues in HIV Microbicide Research Who should be enrolled and with what protections?

2. | 1 4/11/2015 Science at the heart of medicine Two broad areas of inquiry Intertwining biomedical research and public health What protections do women need?

3. | 2 4/11/2015 Science at the heart of medicine Intertwining research and public health Public health challenge: reduce incidence of HIV > Best single hope is effective biomedical prevention > Women (especially younger women) are increasingly at risk for acquiring HIV Safety in microbicide trials Ethics of placebo controls in future trials Proper prevention package for women in microbicide trials Obligations to community or country when microbicide research yields successful product

4. | 3 4/11/2015 Science at the heart of medicine Safety in microbicide trials In two past trials, more women in the experimental group became HIV-infected than women in the placebo control group > Unanticipated result > Clinical trials may pose unexpected risks to subjects

5. | 4 4/11/2015 Science at the heart of medicine Ethics of placebo controls Use of placebo in clinical trials is very controversial when an effective prevention or treatment already exists Huge controversy arose in placebo controlled trials to prevent mother-to-child HIV infection in developing countries > Controversy led to revision of Declaration of Helsinki and other international ethics guidance > Questions remain for future prevention trials

6. | 5 4/11/2015 Science at the heart of medicine

7. | 6 4/11/2015 Science at the heart of medicine UNAIDS/WHO Guidance 2007 The use of a placebo control arm is ethically acceptable in a biomedical HIV prevention trial only when there is no HIV prevention modality of the type being studied that has been shown to be effective in comparable populations (Guidance Point 15)

8. | 7 4/11/2015 Science at the heart of medicine Control groups  How to interpret ‘the type being studied’?  Is the “type” any preventive HIV microbicide?  Or is it a specific type of microbicide?  What are criteria for comparability among populations?  Different racial or ethnic groups?  Different geographic locations?  Different nutritional or health status?  Differences in risk behavior?

9. | 8 4/11/2015 Science at the heart of medicine Proper prevention package What should be provided in a biomedical prevention trial to reduce the risk of participants becoming HIV-infected as a result of their behavior, not the experimental product itself? > Researchers, research staff, and trial sponsors should ensure, as an integral component of the research protocol, that appropriate counseling and access to all state of the art HIV risk reduction methods are provided to participants throughout the duration of the biomedical HIV prevention trial –UNAIDS/WHO ethical guidance

10. | 9 4/11/2015 Science at the heart of medicine Methods of prevention COUNSELING

11. | 10 4/11/2015 Science at the heart of medicine Researchers’ challenge and reply Do you really mean all state of the art prevention methods? > Would that include a partially effective vaccine or microbicide when such methods become available? > This requirement will make it difficult, if not impossible, to analyze the results of HIV prevention trials > Researchers may not be able to provide all state of the art HIV risk reduction methods Implementation of this recommendation must be consistent with scientific design and feasibility

12. | 11 4/11/2015 Science at the heart of medicine Global Campaign for Microbicides in India

13. | 12 4/11/2015 Global Campaign for Microbicides Study Objective > To explore the microbicide field’s progress toward achieving the ethical aspirations laid out in key ethics guidance documents Major finding > Microbicide trials are meeting or exceeding the ethical obligation to provide access to proven HIV preventive methods, including risk-reduction counseling, provision of male condoms, and access to female condoms (when requested) Science at the heart of medicine

14. | 13 4/11/2015 Intertwining research with public health practice GCM recommendations > Where abortion is legal, site staff should be trained to counsel women on all options, including termination. Even where abortion is illegal, staff should additionally be trained to counsel on the dangers of unsafe abortion, as well as when and where to seek care in the event of post- abortion complications > The need for counseling and provision of safe, appropriate contraception > Counseling and provision of emergency contraception Science at the heart of medicine

15. | 14 4/11/2015 Care and treatment: GCM findings Provision of antiretroviral treatment to women who become HIV positive during a microbicide trial and those found to be positive at the initial screening Continuity of care for women who need care and treatment after a trial ends > Not limited to antiretroviral medications for women who seroconverted during the trial, but could include treatments for sexually transmitted infections and other conditions that were made available to them while the trial was ongoing Science at the heart of medicine

16. | 15 4/11/2015 Science at the heart of medicine What protections do women need? Level of effectiveness of microbicide Informed consent Enrolling pregnant women Involvement of men Enrolling adolescents

17. | 16 4/11/2015 Science at the heart of medicine Level of effectiveness What should be the level of effectiveness of a microbicide before the product is developed further and approval sought from a regulatory agency? > Views of experts ranged from 20 to 80 per cent effective Most people fell between 30 and 50 per cent > But what do people most at risk of infection think about this question? Women at risk should be involved in the discussion Community engagement should be a part of preparation for, conduct, and follow-up of HIV prevention trials.

18. | 17 4/11/2015 Science at the heart of medicine Informed consent Ethics of withholding information > Women are asked to return the applicator used to apply the microbicide at each study visit > Applicator includes a dye that changes color when it comes in contact with vaginal mucous > Women are not told the purpose of having to return the applicators Purpose is to determine whether women adhered to the procedures in the protocol > Is it ethical to withhold this information from women in the microbicide trial?

19. | 18 4/11/2015 Science at the heart of medicine Enrolling pregnant women Long-standing prohibition of enrolling pregnant women in biomedical research > Concerns for safety of both woman and fetus Many women in microbicide trials in developing countries become pregnant during the trials > They are removed then from the trial > But many return soon Abortion or “chemical pregnancy” Time to reverse long-standing prohibition > Products should be tested during research as a smaller number of women will be at risk than once the product is available on the market

20. | 19 4/11/2015 Science at the heart of medicine Involvement of men Some argue that male partners of women participants be notified that their sex partners are in a microbicide trial > Microbicide might be harmful to the male partner > Women could not easily use it covertly > If discovered she could risk violence for covert use Others contend that it is paradoxical to consider men’s involvement in the very type of activity designed to empower women to protect themselves against the risk of HIV infection

21. | 20 4/11/2015 Science at the heart of medicine WHO Ethical Guidance “Partner Notification: If there is any physical risk to the partner of the research subject, such as infertility or infection, and/or pregnancy in the case of the female partner, notification of the partner is justified. Depending on the circumstances of the research, notification may even be required.” Applying this to microbicide research suggests that partner notification (but not consent) should take place

22. | 21 4/11/2015 Science at the heart of medicine Enrolling adolescents in microbicide trials Parental permission almost always required Efficacy trials require sexually active participants at high risk of HIV infection > Parental permission would involve knowledge of adolescent’s risk > Most adolescents would not want parents to know > Required pregnancy tests would exclude such adolescents Parents would ask about reason for exclusion

23. | 22 4/11/2015 Science at the heart of medicine Why enroll adolescents? Adolescents may respond differently from more mature women > Safety and efficacy Waiting until trials are done first in more mature women would delay access to adolescents in need of HIV prevention One article says: “it may amount to public health negligence not to include women under the age of 18 years in Phase III trials.”

24. | 23 4/11/2015 Science at the heart of medicine Post-trial obligations What is owed to research participants and others in the Community or country when the trial is over?

25. | 24 4/11/2015 Science at the heart of medicine UNAIDS/WHO Guidance 2007 Researchers should inform trial participants and their communities of the trial results. During the initial stages of development of a biomedical HIV prevention trial, trial sponsors and countries should agree on responsibilities and plans to make available as soon as possible any biomedical HIV preventive intervention demonstrated to be safe and effective…to all participants in the trials in which it was tested, as well as to other populations at higher risk of HIV exposure in the country. Guidance Point 19

26. | 25 4/11/2015 Science at the heart of medicine Critiques This recommendation is aspirational, aiming at an ideal impossible to achieve in practice > Researchers, sponsors, host countries could not and would not provide results of successful microbicide trials to the community or country > If this were to be an absolute requirement, future research on microbicides would grind to a stop > Other benefits to the population in a developing country could be more fair than requiring successful products of research

27. | 26 4/11/2015 Science at the heart of medicine Reply to critiques Purpose of conducting biomedical research is to prevent, cure, or ameliorate diseases in human beings If research does yield successful products, and these are not made available to the population in a resource- poor country but are accessible to people in wealthier countries, there is no ethical justification for conducting the research in the developing country

28. | 27 4/11/2015 Science at the heart of medicine Toward a more hopeful future Mintaka Foundation, a small, not-for-profit research organisation in Geneva, Switzerland, has developed an anti-HIV microbicide 5P12-RANTES is among the most powerful anti-HIV substances known, and therefore likely to have much greater efficacy than the previous tested microbicides “Microbicides-- Giving women and girls at risk a means of protection against infection by HIV/AIDS which they can control themselves.”

29. | 28 4/11/2015 Science at the heart of medicine Mintakafoundation.org