Vaccines: Key Issues in Ethics of Study Design and Implementation

Transcription

1 Vaccines: Key Issues in Ethics of Study Design and Implementation Holly Taylor, PhD, MPH Department of Health Policy and Management Bloomberg School of Public Health Berman Institute of Bioethics Johns Hopkins University

2 Overview Quick Review of Ethical Principles and Requirements Study Design Implementation HIV Ebola Source: Google Images

3 Overview Researchers have a fundamental obligation to plan, design, and conduct studies with honesty, truthfulness and integrity values demonstrated by how researchers observe, record and interpret their work. (Research Design, p.6) Source: Presidential Commission for the Study of Bioethical Issues (2015)

4 Principle of Beneficence Beneficence Moral requirements Do no harm Maximize benefits/minimize harms Practical applications Study design Risk/Benefit ratio Source: Belmont Report (1979)

5 Ethical Requirements Collaborative Partnerships Social or scientific value Scientific validity Fair subject selection Favorable risk-benefit ratio Independent review Informed consent Respect for participants Source: Emanuel, Wendler and Grady (2008)

6 Ethical Requirements Social Value Does the Project have social value? If no, study cannot go forward Source: Emanuel, Wendler and Grady (2008)

7 Ethical Requirements Scientific Validity Is the study design valid? Sample size Too small? Too large? Source: Presidential Commission for the Study of Bioethical Issues (2015)

8 Ethical Requirements Scientific Validity Is the study design valid? Is there uncertainty about potential benefit of the proposed intervention? If no, study cannot go forward as designed If yes, is randomized controlled trial (RCT) appropriate design» Is randomization to a placebo acceptable? Source: Emanuel, Wendler and Grady (2008)

9 Ethical Requirements Favorable Risk-Benefit Ratio Are the risks and benefits to study subjects balanced? If no, study cannot go forward as designed If yes, study can go forward as designed Source: Emanuel, Wendler and Grady (2008)

10 Ethical Requirements Risk Prediction of some future occurrence of harm Benefit Something hoped for, of value to individuals or society Balancing Risk and Benefit Minimizing risk, maximizing benefit Source: Levine (1986)

11 Vaccine Development Human trials Phase I Assessment of safety and immune response Challenge Study Phase II Assessment of safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery. Usually placebo controlled May be conducted among those at higher risk of infection

12 Vaccine Development Human trials Phase I Assessment of safety and immune response Challenge Study Phase II Assessment of safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery. Usually placebo controlled May be conducted among those at higher risk of infection

13 Vaccine Development Human trials Phase III/Field Study Safety assessment of rare side effects Vaccine efficacy People were actually exposed to the virus How many people might naturally avoid infection Compare to how many vaccinated people avoid infection

14 Vaccine Development Field Study Natural exposure/infection (in the field ) Infection itself is not a study risk (background risk) Can be slow to test prophylaxis (need a lot of people to be exposed) What if epidemic temporarily wanes? Prospect of direct benefit (if experimental intervention)

15 Vaccines: Study Design Field Study HIV Ebola

16 HIV April 23, DHHS held a press conference where HHS Secretary Margaret Heckler announced that Dr. Robert Gallo of NCI had found the cause of AIDS, the retrovirus HTLV- III. She also announced the development of a diagnostic blood test to identify HTLV-III and expressed hope that a vaccine against AIDS could be produced within two years.

17 HIV First Phase I Trial First Phase II Trial First Phase III Trial First Phase III Trial in Africa Phase III Trial in Thailand Completed» Modest preventive effect, n=16, Products Tested to date Phase III in South Africa Initiated» 1000 South Africans infected everyday, n=5,400 Source: NIAID 2017

18 HIV Vaccine Trial Phase III Trial in South Africa Blinded, randomized controlled trial Subjects randomized to receive vaccine or placebo All subjects counseled to prevent HIV infection Condom/lubricant use STD prevention Information/referral medical male circumcision Information/referral for PrEP Source: NIAID 2017

19 HIV Vaccine Trial In order to determine efficacy of vaccine, need individuals to engage in risky behavior Need to test in population where HIV infection is not rare event and/or have very large sample Low/middle income country setting Need to provide standard-of-care regarding prevention Concern about behavioral dis-inhibition

20 Ebola: 2014 Outbreak West Africa Initial case report from Guinea - January, 2014 Subsequent spread to Liberia, Sierra Leone, Nigeria, Senegal and Mali Effective transmission in densely populated areas

21 Ebola Vaccine Trial Should we adjust our commitments to the welfare of human subjects in the face of a public health emergency?

22 Ebola Vaccine Trial Randomized Clinical Trial Placebo Controlled? What level of protection do we provide to those in control arm? Who ought to be approached to enroll in such a trial? Who is at highest risk of infection? Health care worker willingness to respond

23 Ebola Vaccine Trial Ring Vaccination: A ring vaccination trial tracks the epidemic, recruiting individuals at raised risk of infection due to their connection to a case: this design may both contribute to transmission interruption and have a higher power to detect vaccine efficacy than other study designs. Source: Henao-Restrepo et al BMJ 2015

24 Source: Henao-Restrepo et al BMJ 2015; Lancet 2017

25 Ebola Vaccine Trial Randomized controlled trial Immediate/delayed vaccination Product rvsv-zebov Phase I/II trials had been completed; NOT first-inhuman trials Approved by multiple IRBs in March 2015 DMC halted trial January 2016

26 Ebola Vaccine Trial groups (total n = 2,014) were compared beginning 10 days after they entered the study, to give the vaccine time to set off an immune response, and because some of the contacts might already have been incubating the virus After 10 days, none of those in the immediate vaccination group subsequently contracted Ebola (n=2,014), whereas 16 of the people eligible for the study who were not immediately vaccinated came down with the disease (n=2380). Source: Fink, NYT 7/31/15

27 Ebola Vaccine Trial In order to determine efficacy of vaccine, need individuals to engage in risky behavior Need to test in population where Ebola infection is not rare event and/or have very large sample Low/middle income country setting Need to provide standard-of-care regarding prevention Concern about behavioral dis-inhibition

28 Summary Ethics of conducting vaccine research Complexity of/knowledge about virus Mode of transmission Morbidity/mortality of disease Character of the epidemic Social justice concerns