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COMMENTARY Ethics of research

Christine Grady

Vaccination has attracted controversy at every stage of its development and use. Ethical debates should consider its basic goal, which is to benefit the community at large rather than the individual.

accines truly represent one of the mira- include value, validity, fair subject selection, the context in which it will be used and Vcles of modern science. Responsible for favorable risk/benefit ratio, independent acceptable to those who will use it. This reducing morbidity and mortality from sev- review, informed consent and respect for assessment considers details about the pub- eral formidable , have made enrolled participants. Applying these princi- lic health need (such as the , bur- substantial contributions to global public ples to vaccine research allows consideration den and natural history of the , as health. Generally very safe and effective, vac- of some of the particular challenges inherent well as existing strategies to prevent or con- cines are also an efficient and cost-effective in testing vaccines (Box 1). trol it), the scientific data and possibilities way of preventing disease. Yet, despite their Ethically salient features of clinical vac- (preclinical and clinical data, expected brilliant successes, vaccines have always been cine research include the fact that it involves mechanism of action and immune corre- controversial. Concerns about the safety and healthy subjects, often (or ultimately) chil- lates) and the likely use of the vaccine (who untoward effects of vaccines, about disturb- dren and usually (at least when testing effi- will use and benefit from it, safety, cost, dis- ing the natural order, about compelling indi- cacy) in very large numbers. Furthermore, tribution, political will, acceptability and so viduals to be vaccinated for the public good in vaccine research, individuals are asked to on). An important consideration is the and the injustices of uneven access to the accept risk for the public good and the value of the research for those participating http://www.nature.com/natureimmunology benefits of vaccines have been interwoven prospect of ‘provisional’ benefit. Finding in the vaccine testing and how it will be throughout the history of vaccines and safe and effective vaccines benefits the pub- maximized through dissemination of remain controversial today1–3. Such contro- lic health through reducing the burden of knowledge gained, product development, versies and the scientific complexities and disease among individual members of the long-term research collaboration and/or successes that fuel them raise considerable public and indirectly protecting unvacci- improvements. No judgment of ethical challenges in the development, public nated members of the public through ‘herd value is straightforward or immune from crit- health use and social acceptability of vac- ’. Individual benefit is ‘provi- icism, however, as illustrated by the following cines. This commentary will broadly con- sional’, however, because individuals benefit example in which the value of vaccine sider one aspect of these ethical challenges in directly from investigational vaccines only if research was in dispute. An effective rotavirus the clinical testing of vaccines. they are sufficiently exposed to the infec- vaccine was pulled from the US market Vaccine development is a lengthy, expen- tious agent at some future time, had because of a high of intussuscep- sive and multifaceted process of basic and received the active vaccine and had been tion in vaccinated children. Consequently, , production, licensing and sufficiently protected. debates ensued about proceeding with large © 2004 Nature Publishing Group marketing. Clinical testing, usually with large trials planned in developing countries numbers of healthy subjects, is an integral Value where and and essential part of the process. Principles, According to the framework, the first ethi- might differ. Debates highlighted differing codes and norms of ethics guiding the ethical cal requirement is that the research ques- risk-benefit calculations in developing conduct of all clinical research apply to vac- tion have potential social or scientific value countries in which childhood deaths from cine research, yet most such guidance con- to justify exposing individuals to research rotavirus were high, as well as how accep- centrates on therapeutic clinical trials of risks and inconvenience. Research that can tance of vaccine might be compromised by interventions for individuals seeking treat- improve health or increase useful knowl- the US decision6,7. Assessing the value of ment. Little specific attention has been given edge has value. Determining the value of a this research was clearly, and appropriately, to how the ethics of vaccine trials differ. calls for an understanding that context dependent. “…the major purpose is to determine Applying a framework for ethical research whether a vaccine is of use as a public Validity One framework for ethical clinical research health tool. This is in contrast to the many A valuable research question ethically synthesizes and simplifies guidance found in large scale therapeutic trials where the requires a valid research design and imple- existing codes and regulations and describes objective is to determine what is best for mentation. Carefully chosen and rigorous seven principles universally applicable to eth- individuals. Yet, our ethical system is built study design, methodology and implemen- ical clinical research4. The seven principles around individuality…”5. tation strategies appropriate to the research Although vaccines have considerable question, and likely to provide interpretable value, it does not necessarily generalizable data, also are balanced by con- Christine Grady is in the Department of Clinical follow that every vaccine research proposal siderations of fairness and minimizing risk. Bioethics, Warren Grant Magnuson Clinical Center, has social or scientific value. A specific vac- In ensuring that the scientific design of a National Institutes of Health, Building 10/1C118, cine study or program’s value depends on its vaccine trial realizes social value for the pri- Bethesda, Maryland 20892-1156, USA. contribution to the goal of finding a safe, mary beneficiaries, several controversial e-mail: [email protected] effective and available vaccine useful within design and methodological issues can arise.

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BOX 1 FRAMEWORK APPLIED TO VACCINE RESEARCH is used in some places but not others, the jus- tification for and choice of a control can be Elements of ethical research Specific considerations more difficult. The use of placebo controls Value • Public health need in one arm of National Institutes of •Scientific possibility Health–sponsored acellular pertussis vac- • Social acceptability cine trials in Sweden and Italy, for example, • Political will was criticized despite a previous decision by Validity • Endpoints and measurement of efficacy the Swedish and Italian governments not to • Choice of control (such as placebo) routinely use the available whole killed per- • Randomization tussis vaccine10. These trials could not have •Feasibility of recruitment and follow-up been done in the US, where Fair subject selection • Large numbers of healthy subjects, is required for children to go to school. often including children Randomization, a powerful research tool • Participants in developing countries used to balance comparison groups, is a common feature of vaccine trials. Favorable risk/benefit ratio • Risks to individuals: physical, social, Randomization raises ethical questions confidentiality, future trials about participant autonomy, especially as • Risk of no protection empirical data show that randomization is •Provisional benefit to individual • Benefits to community and public good poorly understood by research subjects. • Fair benefit evaluations Although most phase 3 vaccine efficacy trials randomize individuals to demonstrate the Independent review • Familiarity with vaccine research direct protective effects of vaccine, some • International settings studies use cluster randomization or ran- Informed consent • Misconceptions about vaccines domization by community or group. http://www.nature.com/natureimmunology • Cultural and social differences Although often justified by the need to eval- • Community permission uate and indirect as well as Respect for enrolled participants • Monitoring welfare direct protection from a vaccine, community • Right to withdraw randomization could be seen as jeopardizing •Treatment and/or compensation for the autonomy rights of individuals within vaccine-induced injury randomized communities. Ethically, it is necessary to ensure that a research study is feasible given the social, polit- Carefully defined endpoints, for example, serve many important scientific and public ical and cultural environment. In this regard, a are essential for high-quality science as well health purposes, addressing questions about feasible strategy for recruiting a large sample as ethical science. Although some vaccines etiology, pathogenicity, pathogenesis, and following them over time is essential. prevent , many alter the course of immune response and protection9. Although infection and have their protective effect on challenge studies can be scientifically valu- Fair subject selection © 2004 Nature Publishing Group clinical disease. In vaccine trials, surrogate able and efficient, there is something disqui- Fairness in subject selection is realized when endpoints can sometimes be accurately used eting about deliberately infecting someone, subjects are chosen mainly because of their to measure efficacy, but more often clinical potentially causing considerable discomfort scientific appropriateness for a study, bal- endpoints are necessary. A vaccine trial eval- in the process. Thus, microbes amenable to anced by considerations of risk, benefit and uating clinical outcomes requires consider- challenge studies are carefully selected when vulnerability. Fairness in the processes and able time, resources and careful planning for the rationale is strong, the risk is low and outcomes of subject selection prevent statistical power and long-term follow-up. symptoms or effects of the challenge are self- exploitation of vulnerable individuals and Furthermore, apparent conflicts can arise limiting or reversible or can be treated easily. populations. Scientifically, those most appro- between the interventional care of those who The voluntary informed consent of the vol- priate for vaccine efficacy studies are popula- become infected and the measurement of unteer is also essential. tions with a sufficient and predictable critical clinical endpoints. For a placebo- The choice of an appropriate control in incidence of the disease in question to be able controlled trial of an experimental vaccine any randomized , including vac- to show the effect of the vaccine. The sample against in bacillus Calmette- cine trials, can be contentious. Tension can size needed to demonstrate vaccine efficacy is Guerin–naive people, for example, a deci- exist between the need to ensure that the usually large and is calculated in part on sion about purified protein derivative testing design realizes the scientific objectives while expected incidence, taking into account pre- and prophylactic treatment of those found still guaranteeing research participants the vious and evolving incidence of infection, positive would have to be balanced against health care interventions to which they are demographics of the target population and the need to determine the efficacy of the vac- entitled. A placebo control is acceptable characteristics of those who are likely to vo- cine against clinical disease8. Shorter trials when no effective vaccine is available, lunteer. Historically, vaccines were often using surrogate endpoints to measure out- although it is ethically important to inte- tested in ‘vulnerable’ and captive popula- comes are attractive, but can in some cases, grate other known preventive strategies, tions, such as prisoners and the institutional- provide misleading results. such as , into both arms of a ized mentally impaired. At present, inclusion Challenge studies in which volunteers are vaccine trial. When a partially effective vac- of these vulnerable groups is restricted by deliberately infected with a microbe can cine is available or a known effective vaccine specific and protective regulations.

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Considerations of who might benefit from of harm to a few for the benefit of the many. understanding in clinical trials have consis- the vaccine are central to subject selection. For example, 40,000 children were vacci- tently demonstrated poor comprehension The World Medical Association Declaration nated in the hepatitis A trial mentioned of randomization and placebo design15. of Helsinki states that “ is above; efficacy was determined based on 38 Although little is known about the degree only justified if there is a reasonable likeli- cases of hepatitis A in the control group and 2 to which participants understand that some hood that the populations in which the in the vaccine group. Perhaps a clearer utili- of them or their children will (must) get the research is carried out stand to benefit from tarian justification exists for research with disease or infection to prove efficacy, this the results of the research” (Ethical principles the -blocking vaccine for knowledge is likely to be low. for medical research involving human sub- malaria. Individuals given only the transmis- Most agree that individual informed con- jects; http://www.wma.net/e/policy/b3.htm). sion-blocking vaccine would not themselves sent is necessary for vaccine trial participa- This has important implications when devel- be protected from malaria, but would inter- tion, even when community permission is oping country populations are involved in rupt the transmission cycle, protecting others indicated16. Some studies use a ‘staged con- vaccine research. in close contact with them14. Infectious chal- sent’ that may include seeking permission Some have argued that phase 1 vaccine lenge studies are another example of individ- from community leaders, providing infor- studies for diseases or conditions prevalent uals accepting some risk for benefit to society mation to community members through in the developing world, such as malaria or and no expected benefit to themselves. group meetings or public media, providing HIV infection, should be undertaken first in An ethical requirement of all clinical more detailed information to interested indi- the sponsor’s country, to minimize the pos- research is to minimize risk and maximize viduals, allowing time for deliberation or sibility of exploiting vulnerable populations benefit. In HIV vaccine trials, for example, consultation with family or health care in resource-poor countries11. Thinking is careful counseling and education about risk providers and ultimately obtaining voluntary shifting, however, because studies should be reduction strategies are an essential part of authorization from the person to be vacci- responsive to the health needs of popula- minimizing risk, as participants may incor- nated (or their parent or guardian). tions and there are good reasons to bring rectly assume they are protected by an exper- Information should be disclosed in culturally vaccine trials, even at early stages, to popula- imental vaccine and may actually increase and linguistically appropriate ways, and cre- http://www.nature.com/natureimmunology tions that will benefit most. On the other risky behavior that exposes them to HIV. ative strategies for educating participants hand, communities may be vulnerable to about vaccine trials are often warranted, exploitation if fair benefits from the research Independent review especially in populations unfamiliar with are not negotiated12. IRBs or research ethics committees with research or with high rates of illiteracy. Vaccine trials eventually enroll large num- varied expertise and no personal or busi- Another debated issue is the extent to which bers of healthy children or infants because ness interests in the research evaluate said participants in vaccine trials should be com- many vaccines are ultimately used in chil- research for adherence to established ethi- pensated for their participation. Because atti- dren. The amount of research risk to which cal guidelines. However, there are certain tudes about compensation vary considerably, children can be exposed without correspond- issues that may make review of vaccine it is important to involve the local commu- ing benefit is limited by regulation in US- studies more difficult. Some IRBs may sim- nity in establishing recruitment procedures sponsored research. Because children cannot ply lack expertise related to the science of and compensation schemes. When an entire protect their own interests through informed vaccines and the structure of vaccine stud- community is randomized to receive an consent, parents and guardians are asked for ies such as challenge studies or 50,000- investigational vaccine, strategies for uphold- © 2004 Nature Publishing Group permission to enroll their children in vaccine person efficacy field trials. Similarly, ing the right of individuals to refuse partici- research. Investigators and institutional because many vaccine trials involve popula- pation or to withdraw from the research review boards (IRBs) should ensure that par- tions in developing countries, IRBs need while ‘saving face’ should be sought. ents and guardians are well informed and information and sensitivity to both the make decisions compatible with the interests context in which a study will be done and Respect for enrolled participants of the child. In trials in current guidance and controversies in the Research participants deserve continued northern Thailand, parents gave permission ethics of international research. respect, through continuous monitoring of for their children to have both hepatitis A their welfare, maintaining confidentiality of and as part of the trial in a Informed consent private information, allowing withdrawal cross-over design13. Once a proposal is deemed valuable, valid without penalty and assuring access to suc- and acceptable with respect to risks, benefits cessful interventions or new information gen- Risks and benefits and subject selection, individuals are erated by the study. Large vaccine efficacy A favorable risk/benefit ratio exists when recruited and asked for informed consent. trials often include a cross-over design or risks are justified by benefits and research is Although widely valued, informed consent is other mechanism for ensuring that the con- designed so that risks are minimized and imperfectly realized in clinical research. trol group receives vaccine if it is found to be benefits to subjects and society are maxi- Because massive public education campaigns protective. Less settled are questions regard- mized. In vaccine research, most risk accrues promote the use of vaccines for public health, ing the circumstances, if any, in which study to individual participants and benefits accrue individuals may not appreciate how experi- participants can ethically remain untreated mainly to the community in finding a safe mental vaccines differ in the context of after they become infected. Although this was and protective vaccine. Individuals may research. Two other important aspects of vac- heavily debated in a series of global meetings receive provisional or future benefit from cine trials may be difficult for individuals to sponsored by UNAIDS, no consensus was vaccine trials, but most benefit only indi- understand: randomization and determina- reached for HIV vaccine trials by the time the rectly. A utilitarian calculation justifies both tion of vaccine efficacy. Studies of informed UNAIDS guidelines were published. the testing and use of vaccines, accepting risk consent that have measured participant Although most agree there is need to ensure

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that vaccine trial participants who become vaccine trials. Careful attention to ethical 5. Hall, A. Int. J. Tuberc. Lung Dis. 3, 745 (1999). 6. Weijer, C. Br. Med. J. 321, 525–526 (2000). infected with HIV will receive treatment, the issues is essential to the successful develop- 7. Melton, L. Lancet 356, 318 (2000). challenge is determining how this should ment of vaccines as invaluable public 8. Snider, D.E. Clin. Inf. Dis. 30, S271–S275 (2000). happen17. Providing treatment and compen- health interventions. 9. Levine, M.M. Dev. Biol. Stand. 95, 169–174 (1998). 10. Edwards, K. & Decker, M. N. Eng. J. Med. 334, sation for vaccine-related injury is consistent 391–392 (1996). ACKNOWLEDGMENTS with respect for the vaccinee. In the US, the 11. Macklin, R. & Greenwood, B. in The Vaccine Book The views expressed here are the author’s and do (eds. Bloom, B. & Lambert, P.) 123 (Elsevier National Vaccine Injury Compensation not necessarily reflect those of the Clinical Center, Science, San Diego, 2003). Program provides compensation for certain the National Institutes of Health, the Public 12. Participants in the 2001 Conference on Ethical injuries deemed related to licensed childhood Health Service or the Department of Health and Aspects of Research in Developing Countries. . Science 298, 2133–2134 (2002). vaccines, but no such mechanism exists for 13. Innis, B. et al. J. Am. Med. Assoc. 271, 1363–1364 injuries sustained in clinical trials of vaccines. 1. Spier, R.E. Vaccine 16, 1788–1794 (1998). (1994). 2. Macklin, R. & Greenwood, B. in The Vaccine Book 14. Hoffman, S. & Richie, T. in The Vaccine Book (eds. (eds. Bloom, B. & Lambert, P.) 119–127 (Elsevier Bloom, B. & Lambert, P.) 291–306 (Elsevier Conclusion Science, San Diego, 2003). Science, San Diego, 2003). A framework for ethical research is helpful 3. Ulmer, J.B. & Liu, M. Nat. Rev. Immunol. 2, 15. Leach, A. et al. Soc. Sci. Med. 48, 139–149 (1999). 291–294 (2002). 16. UNAIDS. Ethical considerations in HIV preventive in identifying ethical challenges common 4. Emanuel, E., Wendler, D. & Grady, C. J. Am. Med. vaccines (UNAIDS, Geneva, 2000). to all research as well as those unique to Assoc. 283, 2701–2711 (2000). 17. Berkley, S. Lancet 362, 992 (2003). http://www.nature.com/natureimmunology © 2004 Nature Publishing Group

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