major milestones in the history of ethical issues in research

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The 50th Anniversary of the Declaration of Helsinki Progress but Many Remaining Challenges

Since 1964, through 7 revisions, the World Medical Association’s (WMA’s) Declaration of Helsinki has stood as an important statement regarding the ethical prin- ciples guiding medical research with human partici- pants. The declaration is consulted by ethics review com- mittees, funders, researchers, and research participants; has been incorporated into national legislation; and is routinely invoked to ascertain the ethical appropriate- ness of clinical trials.

There is much to praise about the revision process and the latest revision, which coincides with the decla- ration’s 50th anniversary. The Working Group exten- sively consulted stakeholders and justified the pro- posed revisions. The result is a declaration that is better organized into clear sections, more precise, and likely to be more effective at protecting research participants.

For the first time, the declaration requires compen- sation and treatment for research-related injuries (para- graph 15), an explicit recognition that research partici- pants should not bear the costs of research gone wrong.1

The revised declaration’s emphasis on the dissemina- tion of research results, including studies with negative results, should increase the value of medical research (paragraphs 23, 35, and 36).

Nevertheless, the proposed declaration contains per- sistent flaws. While the document purports to be a state- ment of enduring ethical principles, the nearly continu- ous process of revision undermines its authority.2

Moreover, the declaration continues to assert that “con- sistent with the mandate of the WMA,” its primary audi- ence is physicians (paragraph 2). This is a mistake. In- deed, the document then offers recommendations for other health professionals (paragraph 9), research ethics committees (paragraph 23), sponsors and governments (paragraph34),andeditorsandpublishers(paragraph36). It is time for the WMA to recognize that the Declaration of Helsinkishouldaddressphysiciansaswellotherhealthpro- fessionals and personnel involved in research. A state- ment of ethical principles does not require a mandate from the people who ought to follow those principles.2

The revised declaration’s treatment of informed con- sent remains inadequate. It fails to recognize the possibil- ity of waiving consent for some research involving com- petent adults, even though such research is common and widely endorsed. Similarly, the declaration avoids provid- ing guidance on when it can be appropriate to ask partici- pants to give broad consent for their biological samples to be used in a wide range of future studies, rather than seek- ing consent for each specific study. This is a pressing issue on which researchers need clear guidance. In addition, the declaration prohibits individuals who cannot consent from

participating in research that does not address the condi- tion that caused their incapacity (paragraph 30), even when the research offers participants the potential for im- portant medical benefit and there are no—or few— potential participants who can consent. This approach transforms a protection into a barrier.

Problems With Research Posing Net Risks Research studies and interventions that pose risks with- out compensating benefits to participants—“nonben- eficial” studies—are crucial to improving medical care. Yet the revised declaration offers conflicting and problem- atic guidance on this topic. It rejects placing partici- pants at any net risk to collect data, no matter how valu- able: “While the primary purpose of medical research is to generate new knowledge, this goal can never take pre- cedence over the rights and interests of individual re- search subjects” (paragraph 8, emphasis added).

Similarly, the declaration permits research com- bined with medical care—an increasingly important cat- egory of research— only to the extent that “this is justi- fied by its potential preventive, diagnostic or therapeutic value,” leaving it unclear whether individuals may be ex- posed to any net risks in this context (paragraph 14). Even more puzzling, the declaration seems to allow nonben- eficial research only with individuals who are unable to give informed consent (paragraph 28).

Clearly, the goal of generating new knowledge must not take precedence over the rights of individual re- search participants. Research participants should not be exposed to high net risks. Yet nonbeneficial research can be ethical when the net risks to participants’ interests are low and the benefits to society are sufficiently large. In- deed, in apparent conflict with paragraphs 8 and 14, para- graphs 16 and 28 seem to affirm that ethical research can pose some net risks to participants: “Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and bur- dens to the research subjects” (paragraph 16).

The declaration’s lack of clear and consistent guid- ance regarding when net risks are acceptable creates un- necessary confusion and fuels the unfounded concern that all medical research is inherently exploitative.

Problems With Research in Poor Communities The declaration rightly recognizes the importance of pro- tecting the worst off, including populations who lack ac- cess to adequate health care. The revised declaration calls for special protection for groups and individuals who are “vulnerable and may have an increased likelihood of being wronged or of incurring additional harm” (paragraph 19).3

VIEWPOINT

Joseph Millum, PhD Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, Maryland, and Fogarty International Center, National Institutes of Health, Bethesda, Maryland.

David Wendler, PhD Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, Maryland.

Ezekiel J. Emanuel, MD, PhD Office of the Provost, University of Pennsylvania, Philadelphia, and Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Viewpoint page 2145

Related article page 2191

Corresponding Author: Ezekiel J. Emanuel, MD, PhD, Department of Medical Ethics and Health Policy, University of Pennsylvania, 122 College Hall, Philadelphia, PA 19104 (vp-global@upenn .edu).

Opinion

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It then delineates 3 conditions for research with vulnerable groups: (1) the research must be responsive to their health needs; (2) it must be impossible to carry out with nonvulnerable groups; and (3) the group should stand to benefit from the knowledge, practices, or interven- tions that result from the research (paragraph 20).

The declaration is confused and mistaken about vulnerability and appropriate protections.4,5 First, the group the declaration has in mind that is in need of special protections is vulnerable because they are poor and have limited access to medical services, not because they are at higher risk of harms. Failure to make this clear undermines the protections. What is necessary to protect poor populations is very dif- ferent from what is necessary to protect participants who are at higher risk of harm, cannot consent, or, because of their position, eg, being a student, are at increased risk of coercion.

Second and more importantly, the declaration is confused about what constitutes appropriate protections and the appropriate means to achieve those protections.

To be clear and comprehensive, the declaration should state that populations who are vulnerable to exploitation should always re- ceive a fair level of benefits. Providing fair benefits is the goal. The means to achieve it vary. In only a limited number of clinical trials, the requirement that vulnerable groups should benefit “from the knowledge, practice, or interventions that result from the re- search” (paragraph 20) along with the requirement that partici- pants have posttrial access to interventions identified as beneficial (paragraph 34) can provide fair benefits, but only with respect to phase 3 trials in which an experimental intervention is found to be more effective. When research does not prove an intervention ef- fective—phase 1 and 2, and negative phase 3 research trials— participants from poor countries with limited access to medical ser- vices are unlikely to benefit at all from these requirements. In these cases, a research project might supply clean water, new clinics, or build local medical and research capacity. If this level of benefits is fair, then the research will not be exploitative.

Problems With Placebos The revised declaration fails to address the testing of interventions that may be beneficial to some groups but are expected to be less effective than interventions that are available elsewhere—“the best proven interventions.” It asserts that placebos may be used only when the “patients” who receive them “will not be subject to addi- tional risks of serious or irreversible harm as a result of not receiving the best proven intervention” (paragraph 33, emphasis added). How to interpret this last clause is unclear. The danger is that it may pre- clude vital research that promises to improve the condition of the worst off. For example, past trials of single-dose nevirapine given to mothers during labor and their infants within 72 hours of birth dem- onstrated that this approach was a highly cost-effective means of reducing mother-to-child-transmission of HIV.6 However, it was known at the time that single-dose nevirapine would not be as ef- fective as more comprehensive and much more expensive treat- ment regimens that also targeted transmission during pregnancy. Yet trials that used less than the best-known treatment were ethi- cal and had the potential to benefit mothers who otherwise would receive nothing. A future and better declaration should allow such trials under strict conditions, especially when no patients are de- prived of treatment they would otherwise receive and the re- search has the potential to save lives and improve the care of poor populations.7

Conclusion The revised Declaration of Helsinki represents a significant improve- ment over previous versions. Creating an international document to guide research around the world is an enormously difficult and complicated task. Nevertheless, important problems and some con- fusion remain in this 50th-anniversary declaration. The definitive guidance on research ethics and even better protection for re- search participants await responses to the Declaration of Helsinki’s remaining challenges.

ARTICLE INFORMATION

Published Online: October 19, 2013. doi:10.1001/jama.2013.281632.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Emanuel reported receiving payment for speaking engagements unrelated to this work.

Disclaimer: The views expressed are the authors’ own. They do not represent the position or policy of the National Institutes of Health, US Public Health Service, or the Department of Health and Human Services.

REFERENCES

1. Moral science: protecting participants in human subjects research. Presidential Commission for the Study of Bioethical Issues. http://bioethics.gov/sites /default/files/Moral%20Science%20June %202012.pdf. Accessed October 9, 2013.

2. Emanuel EJ. Reconsidering the Declaration of Helsinki. Lancet. 2013;381(9877):1532-1533.

3. Hurst SA. Vulnerability in research and health care; describing the elephant in the room? Bioethics. 2008;22(4):191-202.

4. Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Moral standards for research in developing countries:

from “reasonable availability” to “fair benefits.” Hastings Cent Rep. 2004;34(3):17-27.

5. Millum J. Sharing the benefits of research fairly: two approaches. J Med Ethics. 2012;38(4):219-223.

6. Marseille E, Kahn JG, Mmiro F, et al. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet. 1999;354(9181):803-809.

7. Wendler D, Emanuel EJ, Lie RK. The standard of care debate: can research in developing countries be both ethical and responsive to those countries’ health needs? Am J Public Health. 2004;94(6):923-928.

Opinion Viewpoint

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