Declaration of Helsinki

Th is expanded requirement also highlights Justifi cation, Coherence and Consistency a tension with the DoH. On the one hand, it claims to explicitly address only physi- of Provisions in the Revised Declaration cians. But to the extent that its require- ments apply to every study involving hu- of Helsinki man subjects, they would apply to research covered by non-physicians as well. Limiting To make this argument, I provide a read- the scope of the provisions to only research ing of several revised passages in the 2013 with human subjects that is conducted by DoH. Th is reading draws on a normative physicians seems arbitrary, at best. More- framework that emphasizes a particular over, the requirement that research results view of the proper division of labor be- be published has been expanded to include tween research and medical and public “publication and dissemination” and this health systems and the threat that biased obligation is now ascribed to sponsors as or poor quality research poses to those well as researchers, authors and editors (par. systems. It also treats various provisions 36). Th e language of this paragraph has also of the DoH as helping to provide a pub- been strengthened from “should” to “must” lic assurance to stakeholders that the re- in several places, including the obligation to search enterprise functions as a system of publish negative and inconclusive fi ndings mutually benefi cial social cooperation in and to report confl icts of interest. which all parties are respected as free and equal contributors [1]. Although these Th ese concrete prescriptions assign poten- commitments are not expressed within tially costly duties to a range of stakeholders the DoH itself, this reading illustrates and their requirements are not limited by Alex John London strengths and weakness of the new docu- disciplinary orientation or by the degree of ment and highlights areas for improve- risk posed to study participants. It is some- Since the fi rst version of the Declara- ment. what surprising, therefore, that the DoH tion of Helsinki (DoH) was adopted in does not contain an explicit statement of 1964, it has been revised nine times and their normative grounding or justifi cation. numerous other bodies have promulgated Integrity of Scientifi c In particular, there have been a number of ethics guidance documents. During this Information proposals recently to titrate the level of re- same period, scientifi c research with hu- search oversight to risk as a way of reign- man subjects has dramatically increased in Th e 2013 version of the DoH contains ing in what is criticized as costly regulatory size, scope, and importance. If the DoH several changes that signifi cantly expand overreach [2, 3]. Th e only explicit discus- is to continue to play a signifi cant role in the scope of requirements relating to the sion of the “importance” of a “research ob- regulating the research enterprise, it must registration of research and the disclosure jective” in the DoH is to state that it must convincingly convey a coherent, if highly of fi ndings. For example, the requirement outweigh the risks and burdens imposed on general, view of the research enterprise for trial registration has been expanded participants (par. 16, 2013). If a study poses and the basic normative requirements nec- from “every clinical trial” in the 2008 ver- little to no risk to participants, there is no essary to preserve its integrity and protect sion to “every research study involving hu- independent ground stated in the DoH to the rights and welfare of participants. In man subjects” (par. 35). With this expanded justify requiring uniformly high oversight what follows, I argue that the emphasis in scope, this requirement now covers a wider for it and risker or more burdensome stud- the DoH on detailed prescriptive require- range of research activities. For example, ies. ments untethered from general justifi ca- the 2008 wording would not cover sub- tory grounds means that it is particularly studies carried out within larger trials, such Th e DoH would benefi t, therefore, from dependent on readers to supply underlying as biomarker studies, because these are not an explicit statement that these require- normative justifi cations. Without these separate clinical trials. Such sub-studies are ments are justifi ed because registration of normative grounds, its provisions might covered under the new language because studies and comprehensive reporting of all appear inconsistent, unfounded, or arbi- they are research studies involving human study data, including negative and incon- trary. subjects. clusive results, are necessary to ensure the

188 Declaration of Helsinki

reliability, relevance, and validity of scien- Th e WMA may be uncomfortable stating Medical research with a vulnerable group is tifi c information. As the DoH states, the moral requirements for stakeholders beyond only justifi ed if the research is responsive to the primary purpose of research involving hu- physicians, but omitting the obligations of health needs or priorities of this group and the man subjects is “to understand the causes, others would either cripple the document’s research cannot be carried out in a non-vul- development and eff ects of diseases and ability to provide comprehensive ethical nerable group. In addition, this group should improve preventive, diagnostic and thera- guidance across the lifecycle of research or stand to benefi t from the knowledge, practices peutic interventions (methods, procedures it would lead to unfairly attributing to phy- or interventions that result from the research and treatments)” (par. 6). Reliable, rel- sicians responsibilities that vest in and must (par 20). evant, and valid data are essential to the be discharged by other parties. ability of the research enterprise to fulfi ll Although the responsiveness requirement this purpose. will undoubtedly be subject to further criti- Responsiveness and Benefi ts cism for vagueness, this language makes it In modern health systems and health pol- clear that the primary consideration in eval- icy, many forms of research with human In several places, the 2008 DoH states that uating research in vulnerable groups should subjects contribute data on which clini- populations in which research is carried out be the relationship of the questions being cians, patients, researchers, institutions, should stand to benefi t from the results of investigated, and the knowledge that is ex- policy makers, and others rely in making research. Paragraph 17 of the 2008 ver- pected to be generated, to the health needs decisions that aff ect the health and wel- sion reads, “Medical research involving a or health priorities of that group. fare of individuals and groups and the al- disadvantaged or vulnerable population or location of scarce resources [4]. Because community is only justifi ed if the research Th e current version of the DoH does not research data are the bedrock of evidence- is responsive to the health needs and pri- contain a justifi cation for this requirement, based health systems and social policy, the orities of this population or community and and some changes to the text obscure one quality and reliability of that information if there is a reasonable likelihood that this potential justifi catory ground. Th at is, in aff ects the health, welfare, and rights of the population or community stands to benefi t the 2008 version, the statement “Medical individuals who rely on those health sys- from the results of the research.” Paragraph progress is based on research that ultimate- tems to address their health needs. Even 33 of the 2008 version uses even broader ly must include studies involving human research that imposes little or no risk to language, “At the conclusion of the study, subjects” is followed immediately by the study participants can generate data that is patients entered into the study are entitled claim that “Populations that are underrep- biased or of poor quality. Concerns about to be informed about the outcome of the resented in medical research should be pro- the quality of low risk studies have sur- study and to share any benefi ts that result vided appropriate access to participation faced frequently in the context of postmar- from it, for example, access to interventions in research,” (par 5, 2008). Although both keting research, where decreased oversight identifi ed as benefi cial in the study or to claims are retained in the 2013 revision, removes incentives and safeguards against other appropriate care or benefi ts.” the second now appears as an independent using biased evidence to advance market- statement (par. 13), eight paragraphs after ing objectives, sometimes at the expense of Although the most direct result of research the former claim (par. 5). Separating these patient health [5,6]. Similar concerns have is new information and knowledge, re- claims severs the natural justifi catory link emerged recently in biomarker studies as search can also produce new interventions, that was at least implied in the previous well [7,8]. improved infrastructure, and potentially version. lucrative fi nancial rewards. If the core re- Strengthening registration, publication quirement for research in disadvantaged Th e link that is more clearly implied in the and reporting requirements is justifi ed by populations is that those populations ben- 2008 version is that inclusion in research their contribution to ensuring the quality efi t from participation, and if there are is necessary for vulnerable groups to share and reliability of research data. Ascribing myriad benefi ts that can fl ow from research, in medical progress. Excluding vulner- obligations for registration, reporting, and then critics might wonder why research able groups from research stifl es what is, dissemination of study fi ndings to a broad should be required to meet the responsive- if not the only, then the most effi cient, av- range of stakeholders is also warranted ness requirement at all [9]. enue through which their distinctive health because responsibility for ensuring the in- needs can be understood and addressed. If tegrity of the research enterprise must be Th e current revision of the DoH retains the fundamental purpose of research with shared by all of the parities that assert some responsiveness as a requirement and elimi- human subjects is to produce the evidence control over critical aspects of that process. nates this ambiguity: necessary to improve standards of care and

189 Declaration of Helsinki

prevention, then exclusion from research deavor for a variety of reasons. Some may tions for confi dentiality) can then be seen creates or perpetuates evidence gaps. Th is seek profi t, career advancement, access to as special requirements necessary to ensure means that health systems have fewer eff ec- medical care, prestige, or some mixture of proper respect for study participants as free tive interventions for the distinctive health these and other motives. Th ese parochial and equal. needs of excluded groups and that patients motives alone cannot justify social sup- from these groups are exposed to elevated port for the research enterprise, since not Th e 2013 DoH contains a new provision risk when they access those health systems all parties seek the same parochial goals, that can be read as trying to ensure that [10]. there are often other means of advancing participant interests are not compromised these ends, and because pursuit of these through research participation. It holds that, Although the DoH is not explicit about the goals can sometimes come at the expense “Appropriate compensation and treatment relationship between the requirements that of other parties. for subjects who are harmed as a result of have been discussed so far, there is a read- participating in research must be ensured” ing on which they can be seen as playing In contrast, research is often the only way (par. 15). If the legitimate social purpose of a crucial role in the social justifi cation of to produce the evidence base necessary research is to generate a public good – the research. On this view, the purpose of re- for health systems to eff ectively and ef- evidence base for eff ective and equitable search is to produce a unique social good, fi ciently meet the diverse health needs of health systems – then compensation for namely, the information necessary to en- the individuals that they serve. Because study-induced harms can be grounded in able health systems to better understand community members must rely on medical reciprocity. Th e DoH does not specify who and address the health needs of the people and public health services to address their bears this obligation and it would seem un- they serve [1, 4, 6]. Th is good is unique, basic health needs, ensuring equity in their reasonable to saddle researchers alone with because unlike other benefi ts that stake- capacity to fulfi ll this mission can be seen it since other stakeholders who contribute holders seek from research participation, as a legitimate focus for social support and to and benefi t from the enterprise are better it often cannot be produced in any other the use of social resources. When there is situated to eff ectuate it. way. Promoting access to research among credible public assurance that the research underrepresented groups is thus necessary system is designed to advance this goal, Similarly, the new paragraph 34 holds that, to promote equity in the capacity of health all of the necessary stakeholders can par- “In advance of a clinical trial, sponsors, re- systems to meet the needs of the diverse ticipate with the warranted belief that even searchers and host country governments communities that they serve. Th e respon- if they each contribute in order to pursue should make provisions for post-trial access siveness requirement, and the requirements some parochial interest, the system will not for all participants who still need an inter- relating to registration and publication are be coopted so as to siphon social support vention identifi ed as benefi cial in the trial. necessary to ensure that when individuals and social resources simply to advance the Th is information must also be disclosed to and groups participate in research, they parochial interests of some at the expense participants during the informed consent have public assurance that they are help- of the others. process.” Th is duty is ascribed to multiple ing to generate information that is likely to stakeholders and the more general language strengthen and improve the health systems I am suggesting that it is useful to view the of benefi t sharing from the 2008 version on which they depend. provisions discussed so far as helping to has been replaced with specifi c emphasis on provide a public assurance to stakeholders participants who need access to study inter- Th is kind of social justifi cation is impor- that the research enterprise functions as a ventions. tant because it legitimates social and indi- system of mutually benefi cial social coop- vidual support for the research enterprise eration in which all parties are respected On the reading I have been proposing, as a collaborative undertaking [1]. In par- as free and equal contributors [1]. Because this provision fi ts into a larger view of the ticular, medical and public health research study participants are the most at risk of proper division of labor between research require the support of diverse stakeholders, having their status as free and equal per- and medical and public health systems. Th e from researchers and institutions of scien- sons compromised in research participation, social function of research is to generate the tifi c advancement, to public and private they require special assurance that their evidence necessary to improve the standard sponsors, participants, policy makers, and rights and welfare will be respected. Ethi- of care and prevention and it falls to medi- the community in whose name research cal principles that are traditionally viewed cal and public health systems to provide ac- is often conducted and whose interests as forming the moral core of research ethics cess to this improved care on a large-scale it is supposed to advance. Many of these (such as informed consent, the minimiza- basis. When research is contemplated in parties may contribute to the research en- tion and justifi cation of risk, and protec- places where this division of labor may not

190 Declaration of Helsinki

take place, requiring strong assurance that and it would strengthen the DoH if it con- Th e language form the 2008 version may research is relevant to health needs or pri- tained a statement to the eff ect that research strike readers as too simplistic since, for orities of the less-advantaged increases the conducted in resource scarce environments example, it may be diffi cult in practice to likelihood that information and interven- must mitigate the prospect of these delete- know when the results of a single study tions will later be integrated into the health rious eff ects and should make positive con- represent “conclusive proof.” Th e new ver- systems that serve those populations. How- tributions to strengthen the capacity of local sion retains this language, however, and ever, the time horizon for the process of health systems. reads, “When the risks are found to out- integrating new fi ndings or interventions weigh the potential benefi ts or when there into health systems can be protracted. Th e is conclusive proof of defi nitive outcomes, requirement in paragraph 34 ensures that Reasonable Risk physicians must assess whether to contin- there is some meaningful continuity in the ue, modify or immediately stop the study” care that is provided to participants whose In the previous section I suggested that (par. 18, 2013). If the risks of participation health depends on access to study interven- standard research ethics requirements re- are found to outweigh potential benefi ts tions until the responsibility for providing garding informed consent and the reason- or there is conclusive proof of defi nitive access to an improved standard of care can ableness of risk can be seen as helping to outcomes, on what basis would a trial be be eff ectively discharged within the regular provide public assurance to potential par- continued? Where the 2008 version states health system. ticipants that their moral status and their a condition for stopping studies based on interests will be respected in the course of confi rmation of risks and benefi ts, the pro- Critics may counter that even if these con- research participation. Th e 2013 revision of posed revision opens the possibility that ditions are met, there is no guarantee that the DoH includes a new provision in para- studies could continue after these issues host communities will receive a fair level graph 17 that adds to this assurance, namely, have been conclusively established with- of benefi t from hosting research. After all, that “Measures to minimise the risks must out providing substantive guidance about most studies do not vindicate successful be implemented. Th e risks must be continu- how clinicians should make such decisions. interventions. Th ree brief points about this ously monitored, assessed and documented Moreover, continuing a study once “risks objection are worth considering. First, it by the researcher.” However, other revisions are fond to outweigh the potential ben- is not at all clear what a fair level of ben- are somewhat puzzling. efi ts” seems to undermine any public assur- efi t is for hosting a research study and the ance to participants that their interests will most prominent accounts of this matter Th e 2013 DoH retains language from the not be knowingly compromised through are underdeveloped, at best, and internally 2008 version to the eff ect that physicians study participation. inconsistent at worst [11]. Second, rigor- must not be involved in research unless ously designed and well-executed trials that they are confi dent that the risks have been To avoid inconsistency, either the old lan- produce negative fi ndings do contribute “adequately assessed and can be properly guage should have been retained or the new to the evidence base necessary to improve managed.” Th e 2008 version then states language should have been be clarifi ed. For the standard of care – if they are published. that, “Physicians must immediately stop example, it might be revised to say that as Granted, this is not an immediate benefi t a study when the risks are found to out- evidence mounts to indicate that poten- to communities. But compliance with the weigh the potential benefi ts or when there tial benefi ts do not outweigh risks or that requirements discussed above increases is conclusive proof of positive and benefi - confi rms benefi cial results, physicians must the prospect that host communities will cial results” (par. 20, 2008). Th e claim that assess whether to continue, modify or im- have access to the long-term benefi ts that studies must be stopped when fi ndings mediately stop the study. come from increased understanding and the of benefi t or lack thereof are conclusive eventual development of interventions that seems to follow directly from the scien- can bridge health gaps. tifi c purpose of research and from concern Conclusion for the welfare of study participants. Once Th ird, there is a genuine concern that stud- there is conclusive proof that risks of an I have tried to provide a reading of the ies might be carried out in ways that divert intervention outweigh its benefi ts, or its 2013 DoH that integrates some of its key local resources from other health priorities, benefi cial eff ects have been confi rmed, provisions within a coherent, general view consume scarce resources, or otherwise bur- the study question has been answered and of the research enterprise and the central den members of communities that already there is no longer a social purpose that ethical challenges that it has to address. suff er from problems rooted in poverty and justifi es exposing participants to study- Although this analysis draws heavily on deprivation. Th ese are legitimate concerns related risks. normative foundations not explicitly stated

191 Declaration of Helsinki

in the DoH, it is clear that those concerns 4. A. J. London, J. Kimmelman, M. E. Emborg, 10. Jeff rey P. Kahn, Anna C. Mastroianni, and Jer- are not alien to the document. Th is analysis Research ethics. Beyond access vs. protection emy Sugarman eds. Beyond Consent: Seeking highlights ways in which many proposed in trials of innovative therapies. Science 328, 829 Justice in Research New York: Oxford Univer- (May 14, 2010). sity Press, 1998. changes increase the coherence and com- 5. J. Hasford, T. Lamprecht, . Company observa- 11. London AJ, Zollman KJS. 2010. Research at prehensives of the document while indicat- tional post-marketing studies: drug risk assess- the Auction Block: Some Problems for the Fair ing particular areas where diffi culties and ment and drug research in special populations- Benefi ts Approach to International Research. inconsistencies remain. Because the DoH is -a study-based analysis. Eur J Clin Pharmacol Th e Hastings Center Report 40(4):34-45. not explicit about these foundational issues, 53, 369 (Jan, 1998). however, it is vulnerable to appearing incon- 6. London AJ, Kimmelman J, Carlisle B. 2012. Interest Disclosure: I was an invited speaker at sistent, unfounded, or arbitrary to readers Rethinking Research Ethics: Th e Case of Post- three WMA consultations regarding proposed who approach it with diff erent interpretive marketing Trials. Science 336 (May 4):544-545. revisions to the Declaration of Helsinki. 7. Tzoulaki I, Siontis KC, Evangelou E, Ioannidis starting points. JA. Bias in Associations of Emerging Biomark- ers With Cardiovascular Disease. JAMA Intern Acknowledgement: I thank Jonathan Kimmel- Med. 2013;173(8):664-671. doi:10.1001/ja- man and Danielle Wenner for their feedback on References mainternmed.2013.3018. a draft of this manuscript. 1. London AJ. 2012. A Non-Paternalistic Model 8. Nissen SE. Biomarkers in Cardiovascular Medi- of Research Ethics and Oversight: Assessing the cine: Th e Shame of Publication Bias Comment Benefi ts of Prospective Review. Journal of Law, on “Bias in Associations of Emerging Biomark- Alex John London, PhD Medicine, and Ethics 40(4):930-944. ers With Cardiovascular Disease”. JAMA In- Professor of Philosophy and Director, 2. U.S. Department of Health and Human Ser- tern Med. 2013;173(8):671-672. doi:10.1001/ Center for Ethics and Policy, vices, Fed. Regist. 76, 44512 (2011). jamainternmed.2013.4074. 3. Federman DD, Hanna KE, Rodriguez LL, eds, 9. Rebecca Wolitz, Ezekiel Emanuel, Seema Shah. Carnegie Mellon University. Responsible Research: A Systems Approach to Pro- 2009. Rethinking the responsiveness require- 5000 Forbes Avenue tecting Research Participants. (National Academ- ment for international research. Lancet 374: Pittsburgh, ics Press, Washington, DC, 2002). 847–49 E-mail: [email protected]

From Justifying Inclusion to Justifying Exclusion of Study Populations: Strengths and Limitations

Rieke van der Graaf Rolf HH Groenwold Shona Kalkman Diederick E Grobbee Johannes JM van Delden

Since the 2000s, international ethical guide- should ensure that study populations are in- sion of study populations in ethical guide- lines for human subjects research increas- clusively selected. lines on human subjects research. ingly emphasize that exclusion from research participation must be justified. Despite increased use of inclusive selection require- Methods Results ments for the choice of study populations, it has so far not been evaluated what the moral We analysed inclusive selection require- We found that most ethical guidelines fo- strength of these requirements is and who ments or statements on justifying the exclu- cus on inclusive selection requirements

192 COUNTRYG20438World Medical Journal

Official Journal of the World Medical Association, INC Nr. 5, October 2013 vol. 59

• 64rd WMA General Assembly and 195th/196th Council Sessions • Declaration of Helsinki