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Adaptive trial designs (instead of classic phase III randomized controlled trials) and the use of surrogate endpoints (instead of clinical endpoints) are intended to facilitate rapid gathering of meaningful data. Looking back at Emanuel and colleagues’ seven requirements for ethical clinical research , do novel designs and surrogate endpoints meet the Value and Validity criteria?
current as of June 4, 2008. Online article and related content http://jama.ama-assn.org/cgi/content/full/283/20/2701 . 2000;283(20):2701-2711 (doi:10.1001/jama.283.20.2701) JAMA Ezekiel J. Emanuel; David Wendler; Christine Grady What Makes Clinical Research Ethical? Correction Contact me if this article is corrected. Citations Contact me when this article is cited. This article has been cited 296 times. Topic collections Contact me when new articles are published in these topic areas. Statistics and Research Methods; Medical Practice; Medical Ethics the same issue Related Articles published in . 2000;283(20):2729.JAMA May 24, 2000 http://pubs.ama-assn.org/misc/permissions.dtl
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[email protected] http://jama.ama-assn.org SPECIAL COMMUNICATION What Makes Clinical Research Ethical? Ezekiel J. Emanuel, MD, PhD David Wendler, PhD Christine Grady, PhD WHAT MAKES RESEARCH IN-volving human subjectsethical? Informed con-sent is the answer most US researchers, bioethicists, and insti- tutional review board (IRB) members would probably offer. This response re- flects the preponderance of existing guidance on the ethical conduct of research and the near obsession with autonomy in US bioethics.1-4 While informed consent is necessary in most but not all cases, in no case is it suffi- cient for ethical clinical research.5-8 In- deed, some of the most contentious con- temporary ethical controversies in clinical research, such as clinical research in developing countries,9-13 the use of placebos,14-16 phase 1 re- search,17-19 protection for communi- ties,20-24 and involvement of chil- dren,25-29 raise questions not of informed consent, but of the ethics of subject se- lection, appropriate risk-benefit ratios, and the value of research to society. Since obtaining informed consent does not en- sure ethical research, it is imperative to have a systematic and coherent frame- work for evaluating clinical studies that incorporates all relevant ethical consid- erations. In this article, we delineate 7 require- ments that provide such a framework by synthesizing traditional codes, declara- tions, and relevant literature on the eth- ics of research with human subjects. This framework should help guide the ethi- cal development and evaluation of clini- cal studies by investigators, IRB mem- bers, funders, and others. THE 7 ETHICAL REQUIREMENTS The overarching objective of clinical re- search is to develop generalizable knowledge to improve health and/or in- crease understanding of human biol- ogy30,31; subjects who participate are the means to securing such knowledge.32 By placing some people at risk of harm for the good of others, clinical re- search has the potential for exploita- tion of human subjects.33,34 Ethical re- quirements for clinical research aim to minimize the possibility of exploita- tion by ensuring that research sub- jects are not merely used but are treated with respect while they contribute to the social good.30 For the past 50 years, the main sources of guidance on the ethical conduct of clinical research have been the Nurem- berg Code,35 Declaration of Helsinki,36 Belmont Report,37 International Ethical Guidelines for Biomedical Research In- volving Human Subjects,38 and similar documents (TABLE 1). However, many of these documents were written in re- sponse to specific events and to avoid fu- ture scandals.50,51 By focusing on the in- stigating issues, these guidelines tend to Many believe that informed consent makes clinical research ethical. How- ever, informed consent is neither necessary nor sufficient for ethical clinical research. Drawing on the basic philosophies underlying major codes, dec- larations, and other documents relevant to research with human subjects, we propose 7 requirements that systematically elucidate a coherent frame- work for evaluating the ethics of clinical research studies: (1) value— enhancements of health or knowledge must be derived from the research; (2) scientific validity—the research must be methodologically rigorous; (3) fair subject selection—scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine com- munities selected as study sites and the inclusion criteria for individual sub- jects; (4) favorable risk-benefit ratio—within the context of standard clini- cal practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks; (5) independent review— unaffiliated individuals must review the research and approve, amend, or terminate it; (6) informed consent—individuals should be informed about the research and provide their voluntary consent; and (7) respect for en- rolled subjects—subjects should have their privacy protected, the opportu- nity to withdraw, and their well-being monitored. Fulfilling all 7 require- ments is necessary and sufficient to make clinical research ethical. These requirements are universal, although they must be adapted to the health, economic, cultural, and technological conditions in which clinical research is conducted. JAMA. 2000;283:2701-2711 www.jama.com Author Affiliations: Department of Clinical Bioeth- ics, Warren G. Magnuson Clinical Center, National In- stitutes of Health, Bethesda, Md. Corresponding Author and Reprints: Christine Grady, PhD, Warren G. Magnuson Clinical Center, Bldg 10, Room 1C118, National Institutes of Health, Bethesda, MD 20892-1156 (e-mail:
[email protected]). ©2000 American Medical Association. All rights reserved. (Reprinted) JAMA, May 24/31, 2000—Vol 283, No. 20 2701 at Wake Forest Univ Sch of Med on June 4, 2008 www.jama.comDownloaded from http://jama.ama-assn.org emphasize certain ethical requirements while eliding others. For instance, the Nuremberg Code35 was part of the judi- cial decision condemning the atrocities of the Nazi physicians and so focused on the need for consent and a favorable risk- benefit ratio but makes no mention of fair subject selection or independent re- view. The Declaration of Helsinki36 was developed to remedy perceived lacunae in the Nuremberg Code, especially as re- lated to physicians conducting research with patients, and so focuses on favor- able risk-benefit ratio and independent review; the Declaration of Helsinki also emphasizes a distinction between thera- peutic and nontherapeutic research that is rejected or not noted by other docu- ments.30,52 The Belmont Report37 was meant to provide broad principles that could be used to generate specific rules and regulations in response to US re- search scandals such as Tuskegee53 and Willowbrook.54,55 It focuses on in- formed consent, favorable risk-benefit ra- tio, and the need to ensure that vulner- able populations are not targeted for risky research. The Council for International Organizations of Medical Sciences (CIOMS) guidelines38 were intended to apply the Declaration of Helsinki “in de- veloping countries . . . [particularly for] large-scale trials of vaccines and drugs.” The CIOMS guidelines lack a separate section devoted to risk-benefit ratios, al- though the council considers this issue in commentary on other guidelines. It also includes a section on compensa- tion for research injuries not found in other documents. Because the Advisory Committee on Human Radiation Experi- ments was responding to covert radia- tionexperiments, avoidingdeceptionwas among its 6 ethical standards and rules; most other major documents do not highlight this.56 This advisory commit- tee claims that its ethical standards are general, but acknowledges that its choices were related to the specific cir- cumstances that occasioned the re- port.56 Finally some tensions, if not outright contradictions, exist among the provisions of the various guide- lines.5,19,30,51,52,57,58 Absent a universally ap- plicable ethical framework, investiga- tors, IRB members, funders, and others lack coherent guidance on determining whether specific clinical research pro- tocols are ethical. There are 7 requirements that pro- vide a systematic and coherent frame- work for determining whether clinical re- search is ethical (TABLE 2). These requirements are listed in chronologi- cal order from the conception of the re- search to its formulation and implemen- tation. They are meant to guide the ethical development, implementation, and review of individual clinical proto- cols. These 7 requirements are in- tended to elucidate the ethical stan- dards specific for clinical research and assume general ethical obligations, such as intellectual honesty and responsibil- ity. While none of the traditional ethi- cal guidelines on clinical research ex- plicitly includes all 7 requirements, these requirements systematically elucidate the fundamental protections embedded in the basic philosophy of all these docu- ments.30 These requirements are not lim- ited to a specific tragedy or scandal or to the practices of researchers in 1 coun- try; they are meant to be universal, al- though their application will require ad- aptation to particular cultures, health conditions, and economic settings. These Table 1. Selected Guidelines on the Ethics of Biomedical Research With Human Subjects* Guideline Source Year and Revisions Fundamental Nuremberg Code35 Nuremberg Military Tribunal decision in United States v Brandt 1947 Declaration of Helsinki36 World Medical Association 1964, 1975, 1983, 1989, 1996 Belmont Report37 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979 International Ethical Guidelines for Biomedical Research Involving Human Subjects38 Council for International Organizations of Medical Sciences in collaboration with World Health Organization Proposed in 1982; revised, 1993 Other 45 CFR 46, Common Rule8 US Department of Health and Human Services (DHHS) and other US federal agencies DHHS guidelines in 1981; Common Rule, 1991 Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products42 World Health Organization 1995 Good Clinical Practice: Consolidated Guidance44 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 1996 Convention on Human Rights and Biomedicine43 Council of Europe 1997 Guidelines and Recommendations for European Ethics Committees45 European Forum for Good Clinical Practice 1997 Medical Research Council Guidelines for Good Clinical Practice in Clinical Trials46 Medical Research Council, United Kingdom 1998 Guidelines for the Conduct of Health Research Involving Human Subjects in Uganda47 Uganda National Council for Science and Technology 1998 Ethical Conduct for Research Involving Humans48 Tri-Council Working Group, Canada 1998 National Statement on Ethical Conduct in Research Involving Humans49 National Health and Medical Research Council, Australia 1999 *CFR indicates Code of Federal Regulations. More extensive lists of international guidelines on human subjects research can be found in Brody39 and Fluss.40 An extensive summary of US guidelines can be found in Sugarman et al.41 ETHICAL REQUIREMENTS FOR CLINICAL RESEARCH 2702 JAMA, May 24/31, 2000—Vol 283, No. 20 (Reprinted) ©2000 American Medical Association. All rights reserved. at Wake Forest Univ Sch of Med on June 4, 2008 www.jama.comDownloaded from http://jama.ama-assn.org 7 requirements can be implemented well or ineffectively. However, their system- atic delineation is important and con- ceptually prior to the operation of an en- forcement mechanism. We need to know what to enforce. Value To be ethical, clinical research must be valuable,4,35 meaning that it evaluates a diagnostic or therapeutic interven- tion that could lead to improvements in health or well-being; is a prelimi- nary etiological, pathophysiological, or epidemiological study