The history of research involving human subjects includes instances of unethical practices and, consequently, the advent of guidelines and regulations to ensure the p

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The Declaration of Helsinki, 50 Years Later

Fifty years and 7 revisions later, the 2013 version of the Declaration of Helsinki includes several important changes. By changing the format and including several subsections, the revised declaration enhances and im- proves clarity regarding specific issues. By having spe- cific issues covered under these subsections, the dec- laration is now “ bolder” in the way it addresses specific issues. The new formatting will also be welcomed by readers because the subsections improve the readabil- ity of the document. By so doing, the Declaration of Helsinki is a better and more important authority at what it is aimed at achieving—providing guidance on conduct- ing medical research involving humans.

The increase in international studies over the past few decades has contributed to serious debate about the ethics of research conducted in various settings. Most of the debate centered on issues related to limited re- sources and justice: use of placebo and posttrial access to interventions. Through this and previous revisions, the World Medical Association (WMA) has demonstrated that the declaration is a living document that considers current issues in medical research. Important docu- ments such as the declaration are expected to respond to new areas of need or areas that require revision.

The Declaration of Helsinki was born from the his- tory of abuses of human research subjects. Over the years, research oversight has improved but has led to the underrepresentation of certain groups in research investigations.1 This has disadvantaged such groups because they have not benefitted from some advances that others have experienced from the conduct of research. The new version of the declaration addresses this development in paragraph 13 by recommending that access to clinical trials for underrepresented groups needs be increased so these groups also can benefit from research. Instead of excluding groups that have been ordinarily excluded from research, such as minority groups, women, and children, researchers need to clearly justify why these groups have been excluded from research.

There are current discussions about compensa- tion and treatment for individuals who are harmed as a result of their participation in research. Some funders of research have been unwilling to address this topic over the years.2 However, India has issued a law that re- quires all trial participants to receive treatment and fi- nancial compensation for trial-related injuries or death. The law has disrupted the conduct of clinical trials sup- ported by one of the major funders of medical research in that country.3 The issues of compensation and ac- cess to treatment for research-related injuries are im- portant for limited-resource settings in which the ma- jority of trial participants are not insured. By clearly stating that trial participants need to be treated and com- pensated for trial-related injuries, the new declaration

is likely to lead to further discussions by certain re- search funders who would like to avoid the cost of in- suring trial participants. In the past some important stakeholders in medical research have preferred to ad- here to older versions of the declaration as a way of avoiding dealing with certain provisions included in newer versions.4

ThenewversionoftheDeclarationofHelsinki ismore relevant to countries with limited resources because it in- cludes clear terms that address issues of importance in these settings, such as posttrial access to interventions and care for participants from limited-resource settings. In limited-resource countries, there have been concerns that communities may be used for testing interventions that will not be accessible to their citizens because of high costs and other reasons such as logistical challenges in de- livering the new interventions outside the research envi- ronment. The new version of the declaration is clear on the requirement to have plans for ensuring access to an intervention if it is proven to be effective. This require- ment serves to recognize that research can play an addi- tional role of improving access to care in limited- resource settings. In further recognition of the role of research in improving access to care in limited-resource settings, the new version of the declaration also ad- dresses the issue of use of unproven interventions. The 2013 version of the Declaration of Helsinki recommends use of unproven interventions in cases for which proven interventions do not exist, after the physician has sought expert advice as well as the patient’s informed consent.

The new version also addresses several issues re- lated to the dissemination of health research informa- tion, including registration of trials in publicly acces- sible databases and publication of negative, inconclusive, and positive results. The nonpublication of research with inconclusive or negative findings is concerning and must be discouraged by all who sanction research. The scien- tific enterprise must acknowledge openly that science improves through failures and successes.

Informed consent is one of the hallmarks of ethical research and ensures that individuals can make deci- sions that are in their best interests. The new version of the declaration acknowledges that in some cases, such as in close-knit societies, informed consent needs to in- volve others such as community leaders and significant others. Community leaders can serve as additional lay- ers of protection that researchers need to pass through before they reach the potential participants. By address- ing this reality, the new version is emphasizing respect for culture and community norms as part of the re- search process.

With respect to individual participants in research, several studies have illustrated that individuals often agree to participate in clinical trials without full knowledge or un- derstanding of the studies.5 The new version of the dec-

VIEWPOINT

Paul Ndebele, PhD Medical Research Council of Zimbabwe, Causeway, Harare, Zimbabwe.

Viewpoint page 2143

Related article page 2191

Corresponding Author: Paul Ndebele, PhD, Medical Research Council of Zimbabwe, Cnr J. Tongogara/Mazowe St, PO Box CY573, Causeway, Harare, Zimbabwe (pndexas @yahoo.com).

Opinion

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laration encourages researchers to explain their studies using inno- vative ways, such as video and vignettes. The declaration also encourages that researchers need to assess understanding of the re- search interventions and purpose by potential research participants before engaging those individuals in their studies.

The issue of providing feedback to research participants after termination of study activities is part of respecting individuals who participate in research and also is part of demystifying research. Fail- ure to provide feedback contributes to research fatigue in commu- nities and perhaps lack of trust in research in other communities. The new version encourages researchers to plan for provision of feed- back to participants and their communities.

Research ethics committees are recognized as an important part of research oversight systems. The new version of the declaration addresses many points that are of relevance to these committees. Paragraph 23 clearly articulates that all research protocols have to be reviewed by a well-constituted and competent committee be- fore studies begin. Paragraph 23 further emphasizes that ethics com- mittees should be transparent and should follow standards, poli- cies, and national laws in performing their functions. This is consistent with the standards for research committees that were issued by the World Health Organization in 2011.6 Paragraph 23 is also clear on the need for research ethics committees to monitor ongoing research.

The Declaration of Helsinki is an international document that influ- ences how research is conducted in all countries. By stating expec- tations for ethics committees, it is hoped that these committees will be further strengthened.

Recent years have seen increased international debate about the ethics of conducting medical research in developing countries. From a limited-resource setting perspective, the Council for Inter- national Organizations of Medical Sciences (CIOMS) guidelines7

were viewed more favorably than those of the Declaration of Helsinki because the CIOMS addresses issues of relevance to resource-limited settings. The new version of the Declaration of Helsinki has addressed many of the important issues relevant to conducting research in developing countries, such as the need to include underrepresented groups in research, the importance of effective research ethics committees, posttrial access to care, use of unproven interventions, and improving informed consent. By addressing these issues, the declaration has recognized the role of limited-resource settings in generating research data. The influ- ence of the declaration in serving as an important international document for stakeholders in limited-resource settings should increase. For research ethics committees, funders, and participants in research, this version of the Declaration of Helsinki should be empowering given its emphasis on issues of justice.

ARTICLE INFORMATION

Published Online: October 19, 2013. doi:10.1001/jama.2013.281316.

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

REFERENCES

1. Sherwin S. Women in clinical studies: a feminist view. In: Mastriani A, Faden R, Federman D, eds. Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies. Institute of Medicine; 1994.

2. Mamotte N, Wassenaar D, Singh N. Compensation for research-related injury in NIH-sponsored HIV/AIDS clinical trials in Africa. J Empir Res Hum Res Ethics. 2013;8(1):45-54. doi:10.1525/jer.2013.8.1.45.

3. Bhattacharjee Y. Public health: clinical trials paused as India adopts new rules. Science. 2013;341(6144):327. doi:10.1126 /science.341.6144.327.

4. Plomer A. In defence of Helsinki and human rights. S Afr J Bioethics Law. 2012:83-86.

5. Mandava A, Pace C, Campbell B, Emanuel E, Grady C. The quality of informed consent: mapping the landscape—a review of empirical data from

developing and developed countries. J Med Ethics. 2012;38(6):356-365.

6. World Health Organization. Standards and Operational Guidance for Ethics Review of Health-Related Research With Human Participants. Geneva, Switzerland: World Health Organization; 2011.

7. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research Involving Human Subjects. http://www.cioms.ch/images/stories/CIOMS /guidelines/guidelines_nov_2002_blurb.htm. Published 2002. Accessed October 13, 2013.

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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.

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Corresponding Author: Ezekiel J. Emanuel, MD, PhD, Department of Medical Ethics and Health Policy, University of Pennsylvania, 122 College Hall, Philadelphia, PA 19104 ([email protected] .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.

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P A R T 1 : E T H I C A L I S S U E S

6310-WEEK 2

LEARNING OBJECTIVES

• Identify ways to address ethical issues in human subjects research

• Define evidence-based practice • Identify and apply the steps in the evidence-based

practice process • Identify resources that support evidence-based

practice

OUTLINE OF WEEK 2

• Ethical issues • Evidence-based practice

ETHICAL ISSUES IN RESEARCH

RESEARCH ETHICS

• Research priorities versus subjects’ rights • Ethical Principles • History • Human subjects protection • Institutional Review Board (IRB) • Informed consent

RESEARCH PRIORITIES VERSUS SUBJECTS’ RIGHTS

• Primary ethical responsibility is to research subjects • Other responsibilities to:

• Colleagues: provide feedback on research • Sponsoring body: final report • Profession: publication of findings

• Moral responsibility to publicize results, even if negative findings or inconclusive findings

ETHICAL PRINCIPLES

Three ethical principles guide research with human subjects: • Respect: requires investigators to obtain informed and

voluntary consent from research participants, to allow them to discontinue participation in research at any time, and to protect participants with impaired decision- making capacity.

• Beneficence: requires that the scientific knowledge to be gained from a study must outweigh the risk and inconvenience experienced by research participants, and that risks be minimized.

• Justice: requires that the benefits and burdens of research be distributed fairly . It also requires equitable access to the benefits of research.

HISTORY

• The history of research involving human subjects includes instances of unethical practices and, consequently, the advent of guidelines and regulations to ensure the protection of human subjects’ participation in research.

INSTITUTIONAL REVIEW BOARD (IRB) (1)

• An IRB is a review committee established to ensure that the research is ethically acceptable and that the welfare and rights of research participants are protected.

• Members: Researchers, community members, legal and ethical experts.

• While federal regulations use the term IRB, institutions may choose other names for the review committee, such as: • Research Ethics Board • Independent Ethics Committee • Human Subjects Committee

• UTRGV’s Institutional Review Board website link available here.

INSTITUTIONAL REVIEW BOARD (IRB) (2)

• IRB responsibilities include: reviewing protocols and consent forms, tracking progress annually, reviewing changes in protocol.

• Before approving a research study, the IRB must determine that: • Risks to participants are minimized • Risks are reasonable in relation to anticipated benefits and

the importance of the knowledge that is expected to be obtained

• Selection of participants is equitable • Informed consent will be obtained from participants or their

legally authorized representatives • Confidentiality is adequately maintained

HUMAN SUBJECT TRAINING

• To ensure human subjects protection, all research team members must complete a course on human subjects protection. Examples of such courses include: • National Institutes of Health (NIH) web course link • UTRGV requirement is to complete CITI (Collaborative

Institutional Training Initiative) course available at this link