ETHIKasabati

Logistical and Ethical Considerations in HIV Vaccine Clinical Trials

By Jessica Ho, University of Pennsylvania, 2008

Between the laboratory and licensure, successful clinical trials are essential to any HIV vaccine candidate. In clinical trials, investigators administer a new intervention (such as a drug or vaccine) and measure its effects under controlled and monitored conditions. Typically, trials are divided into discrete phases, differing from each other in purpose and size. For vaccines, Phase I trials are usually small and meant to test for general safety. If results are favorable, larger Phase II trials are conducted, in which the vaccine must stimulate an immune response. In the largest pre-approval trials, Phase III, scientists strive to demonstrate efficacy – that the vaccine actually works in preventing the disease.1 Licensure is dependent on positive results in each phase with respect to both safety and efficacy.2 Lengthy and complex, clinical trials are the most costly and time-consuming steps in the development of any new pharmaceutical product. This has been particularly true for HIV vaccine research. It has been estimated that in the most optimistic scenario, six to nine years would elapse between the start of Phase I trials for an HIV candidate vaccine and reaching the results from Phase III trials.3 While numerous Phase I studies of HIV vaccine candidates have been conducted, very few have progressed to Phases II and III, and none produced positive results.

Causes of Delay in Clinical Trials

For those HIV candidate vaccines currently in development, scientific, logistical, political, and economic factors are slowing progression through Phase III trials.4 In order to test the efficacy of a vaccine, large populations with high incidence of the disease – primarily located in developing countries – are required.

Not only are there shortages of appropriate trial sites, but the areas where trials must take place are often quite poor and politically unstable.5 Meanwhile, developing countries lack research facilities and staff necessary for the successful coordination of a trial, meaning that trial staff must come from foreign countries. The Global HIV Vaccine Enterprise states that “the acute shortage of qualified personnel is a major bottleneck to the conduct of clinical trials in developing countries with severe or rapidly emerging HIV epidemics.”6 The scarcity of local investigators may be due to a lack of sufficient training and/or expertise to undertake the trials or to their commitments to other research projects.7 Additionally, it is widely acknowledged that strong political and community support is vital to conduct clinical trials successfully. Public awareness of AIDS, HIV, and the transmission of infectious diseases may be limited, with greater attention devoted, often justifiably, to meeting basic survival needs such as clean drinking water. Furthermore, international research often proves extremely burdensome for the trial communities and participants. Clinical trials impose inconvenience and uncertainty on research subjects.

They face possible threats to their health, stigma, time loss, and the risk of exploitation.8 For HIV trials in particular, other commonly cited reasons for refraining from enrollment include a fear of side effects from the vaccine, contracting HIV from the vaccine, and difficulties with obtaining insurance, and a distrust of drug companies, the government, researchers, and clinical research in general.9 Communities as a whole may suffer if research priorities dominate health services. In poverty-stricken areas, scarce health resources may be diverted for research purposes. Researchers may recruit skilled health personnel from community health centers, and once the trial ends, poorer overall access to care may result from this disruption to the local infrastructure.10 A complex ethical problem arises when there are individuals who want to participant in trials but are prevented from doing so if community leaders such as tribal leaders or village elders withhold their approval.11 In areas where clinical trials have already been held, researchers often have great difficulty convincing civic leaders that their communities should again enroll in clinical trials.12 This is understandable given the real possibility that these communities may not benefit from their contribution if a product is eventually developed. A prime example is that of the hepatitis B vaccine. As journalist Michael Specter relates, “Africans served as essential participants in trials for the principal vaccine now used against hepatitis B; yet when the vaccine finally arrived they could not afford it.”13

The Core Issue

Time and resources are not the only constraints in this stage of HIV vaccine development. Clinical trials of HIV vaccines have proven particularly controversial. A deceptively simple, one-line description of the third phase, “Phase III generally involves several thousand healthy volunteers at a relatively high risk of HIV infection,” instantly gives rise a number of ethical issues. A tension exists between the need to clearly and efficiently demonstrate vaccine efficacy and to protect trial subjects.14 In order to establish efficacy, new infections must occur among trial participants, if the results are to show a difference in incidence between the control and the treatment group.15 A conflict of interest arises between researchers, who need to prove efficacy, and trial participants, who naturally desire to protect themselves.16 However, research subjects may also be motivated by altruism, expecting no return or personal benefit from their participation. In this case, physicians have a duty to protect the subjects and prevent them from taking undue risks.

Scientists may also feel the need to minimize risk to study participants, and it has been proven that HIV can be prevented by reductions in high-risk behaviors. However, if the ethical imperative is followed and counseling and contraceptives provided, the study results could be jeopardized. If there is a decrease in the risk and incidence of HIV infection in the entire community, it can be difficult, costly, and time-consuming to determine whether the trial results were due to public health interventions or the efficacy of the vaccine candidate.17 The reality remains that the effectiveness of any vaccine cannot be determined unless some new infections occur within the study population.

Ethical Issues in Enrolling Women and Adolescents

Research can be hampered by the need to enroll certain groups which may be difficult to reach or whose involvement raises ethical issues which are difficult to resolve. For example, it has been stated that because the number of HIV-infected women is increasing worldwide, “enrolling women in HIV trials... must be fulfilled in order to conduct ethical, valid, and generalizable trials.”18 However, this is difficult in areas where women facing social, cultural, or economic constraints lack the freedom to make decisions autonomously.

Enrolling in a clinical trial, particularly one that addresses a sexually-transmitted disease, exposes women to a number of stresses. For example, women may encounter discrimination from their families and from their communities if they are viewed as or discovered to be infected with HIV. Researchers consider other potential barriers to trial participation to include women’s fears of contracting HIV from the vaccine, testing positive for antibodies to HIV, the effects of the vaccine on future pregnancies, experiencing difficulty with immigration if they test positive for HIV, and receiving a placebo.19 Trial participation may have other negative effects on a woman’s social and cultural standing. Trials that require women to refrain from breast-feeding or becoming pregnant are problematic in cultures in which women’s fertility has a high social value. In addition, trials may recommend condom usage, which is perceived by some communities to promote extramarital relationships. Lastly, some logistical barriers include time taken away from household duties and childrearing, inconvenient clinic hours for mothers and sex workers, potential job loss, and lack of transportation to the trial site.20 All of these factors may have a significant impact on trial participation, and researchers must weigh the ethical imperatives of enrolling women in trials against exposing them to risk from their partners, families, communities, and the vaccine itself.

Another elusive target group for clinical trials is adolescents. As demonstrated by the current experiences with the human papillomavirus (HPV) vaccine, future vaccination strategies for HIV may need to reach adolescents prior to initial sexual activity. As a result, scientists need information on immune responses and disease progression in African adolescents to develop safe and effective vaccines. However, adolescent participation in clinical trials is complicated by the need to obtain parental consent and unique family units. Researchers have found it difficult and sometimes impossible to attain parental consent in sub-Saharan Africa. In addition, studies that examine adolescent beliefs and behavior regarding sexuality and recreational drug use may place adolescents at risk from their parents.21 Given that many children now serve as the heads of their households in regions where the epidemic has been particularly devastating, the age requirements for parental consent may not be applicable in all parts of the world. Researchers must therefore decide whether it is ethically justifiable to enroll adolescents in HIV research without seeking parental consent.22

International Conflicts

A disconnect between foreign and local priorities can lead to accusations of paternalism or exploitation. Ethical dilemmas begin long before the start of clinical trials, when the specific HIV subtypes for vaccine candidates are selected. Developed and developing countries have different priorities for a vaccine depending on which strains are most prevalent in their regions. Since vaccines against certain subtypes may not prevent infection by other subtypes, it makes sense for the strains included in candidate vaccines to be those which are most prevalent in the trial population. However, this may prove problematic in some African countries where circulating recombinant forms (CRFs) exist.23 CRFs develop when different subtypes of the HIV virus recombine to create new, infectious hybrid viruses.24 When a developed country enters a developing country to conduct a clinical trial, its actions are closely and justly scrutinized because of the disparities which exist between the home nation of the researchers and the local trial population. If regulatory authorities and institutional review boards (IRBs) are not well-developed in host countries, political and economic interests can influence which vaccines proceed in clinical trials. For example, after failing to secure the support of local AIDS researchers, a U.S.-based company offered the president of South Africa a free license to test its vaccine.25

It is clear that developing countries may be averse to trusting pharmaceutical companies and researchers from sponsoring countries as well as their governments. Lawrence Corey, the principal investigator of the HIV Vaccine Trials Network, has identified another dimension to the situation: “We are asking the Third World to take risks that we have actually never taken ourselves. Every other time that we have gone in with a vaccine – whether polio, measles, and mumps – we have been able to say, ‘It works on our people. ’With AIDS, we can’t say that.”26

Other sources of friction include differing ethical standards for holding clinical trials. The CIOMS Guidelines (formally the International Ethical Guidelines for Biomedical Research Involving Human Subjects) lay out a set of ethical principles for human experimentation. The guidelines state that when research is externally sponsored, it must be reviewed by both the sponsoring and the host countries.27 This leads to the question: if the ethical norms and standards of care differ between countries, whose rules prevail – those of the country which has developed the vaccine and is holding the clinical trial, or those of the host country?28 Researchers differ on how to resolve a situation in which the review board of the host country permits the research but the sponsoring nation fails to approve.29 Despite well-meaning intentions to prevent the exploitation of host countries, the CIOMS Guidelines have at times caused confusion and conflict in the international arena. For example, Guideline 8 recommends that Phase I and II trials should only be conducted in developed communities of the sponsor country. While this specification aims to protect developing countries, recruitment for Phase I and II trials is a time-consuming process and may take over a year to complete, causing frustration among researchers. In their eyes, these ethical standards can be seen as paternalistic or imperialistic and detrimental to the search for an HIV vaccine.30

Conclusion

All parties involved in the development and testing of candidate HIV vaccines encounter logistical and ethical challenges during their work. These include resource shortages, barriers to individual and community trial participation, enrolling women and adolescents, proving vaccine efficacy, and upholding ethical standards. The task may seem difficult, if not impossible: accelerating vaccine development while simultaneously safeguarding the rights and welfare of communities and individuals participating in clinical trials.31 However, researchers in individual countries and international collaborations, such as the Jointed United Nations Programme on HIV/AIDS (UNAIDS)’s international consultation in 1997 and the World Health Organization Initiative for Vaccine Research (WHO/IVR)’s regional consultations in 2005 and 2006, are already examining these and other potent issues.32, 33 Their research and recommendations have the potential to guide and facilitate the development of an HIV vaccine.

1 Specter, Michael. “The Vaccine.” The New Yorker 78.45(2003):57.

2 Esparza, José, and Natth Bhamarapravati. “Accelerating the Development and Future Availability of

HIV-1 Vaccines: Why, When, Where, and How?” The Lancet 355.9220(2000):2062.

3 Esparza, José. “AN HIV Vaccine: How and When?” Bulletin of the World Health Organization 79.12(2001):1135.

4 Guenter, Dale, Jose Esparza, and Ruth Macklin. “Ethical Considerations in International HIV Vaccine Trials: Summary of a Consultative Process Conducted by the Joint United Nations Programme on HIV/AIDS (UNAIDS).” Journal of Medical Ethics 26.37(2000):37.

5 WHO-UNAIDS HIV Vaccine Initiative and the Quality Assurance and Safety of Biologicals Team of the World Health Organization. “Scientific Considerations for the Regulation and Clinical Evaluation of HIV/AIDS Preventive Vaccines: Report from a WHO-UNAIDS Consultation 13-15 March 2001, Geneva, Switzerland.” AIDS 16.10(2002): W22.

6 Coordinating Committee of the Global HIV/AIDS Vaccine Enterprise. “The Global HIV/AIDS Vaccine Enterprise: Scientific Strategic Plan.” PLoS Medicine 2.2(2005):0116.

7 WHO-UNAIDS. “Scientific Considerations for the Regulation and Clinical Evaluation of HIV/AIDS Preventive Vaccines,” p. W22.

8 Shapiro, K, and SR Benatar. “HIV Prevention Research and Global Inequality: Steps Towards Improved Standards of Care.” Journal of Medical Ethics 31(2005):42.

9 Mills, Edward, et al. “Barriers to Participating in an HIV Vaccine Trial: a Systematic Review.” AIDS 18(2004):2239.

10 Shapiro, K, and SR Benatar. “HIV Prevention Research and Global Inequality,” p. 42.

11 Bayer, Ronald. “Ethical Challenges of HIV Vaccine Trials in Less Developed Nations: Conflict and Consensus in the International Arena.” AIDS 14.8(2000):1053.

12 Specter, M. “The Vaccine,” p. 57.

13 Ibid.

14 Bayer, R. “Ethical Challenges of HIV Vaccine Trials in Less Developed Nations,” p. 1051-1052.

15 Guenter, D, et al. “Ethical Considerations in International HIV Vaccine Trials,” p. 40.

16 Ibid.

17 Bayer, R. “Ethical Challenges of HIV Vaccine Trials in Less Developed Nations,” p. 1051-1052.

18 Mills, Edward, et al. “Enrolling Women into HIV Preventive Vaccine Trials: An Ethical Imperative but  a Logistical Challenge.” PLoS Medicine 3.3(2006):0308.

19 Ibid.

20 Ibid, p. 0308-9.

21 Singh, Jerome A, et al. “Enrolling Adolescents in Research on HIV and Other Sensitive Issues: Lessons from South Africa.” PLoS Medicine 3.7(2006):0984.

22 Singh, JA, et al. “Enrolling Adolescents in Research on HIV and Other Sensitive Issues,” p. 0987.

23 Esparza, J, and Bhamarapravati N. “Accelerating the Development and Future Availability of HIV-1

Vaccines,” p. 2063.

24 Esparza, J. “AN HIV Vaccine: How and When?” p. 1134.

25 Abdool Karim, SS. “Globalization, Ethics, and AIDS Vaccines,” p. 2129.

26 Specter, M. “The Vaccine,” p. 64.

27 Bayer, R. “Ethical Challenges of HIV Vaccine Trials in Less Developed Nations,” p. 1055.

28 Bloom, Barry R. “The Highest Attainable Standard: Ethical Issues in AIDS Vaccines.” Science 279.5348(1998): 188.

29 Bayer, R. “Ethical Challenges of HIV Vaccine Trials in Less Developed Nations,” p. 1055

30 Bloom, BR. “The Highest Attainable Standard,” p. 188.

31 Guenter, D, et al. “Ethical Considerations in International HIV Vaccine Trials,” p. 39.

32 Guenter, D, et al. “Ethical Considerations in International HIV Vaccine Trials,” p. 37-43.

33 Tarantola, D, et al. “Ethical Considerations Related to the Provision of Care and Treatment in Vaccine Trials.” Vaccine 25.26(2007):4863-4874.

Cet article est disponible à l’adresse suivante :

http://www.vaccineethics.org/issue_briefs/HIV_clinical_trials.php