Research
Human Subjects’ Protections
Summary: The conceptual, empirical, and educational projects described here aim to improve the protection of human participants in research, the system and processes, as well as to provide a conceptual framework to be used by IRBs, researchers, bioethicists, regulators, and others to analyze and address ethical issues in human subjects research.
| Section: | Ethics of Human Subjects Research | ||||||||||||||
| Principal Investigators: | Ezekiel J. Emanuel, M.D., Ph.D. Christine Grady, R.N., Ph.D. Sara Hull, Ph.D. Reidar Lie, M.D., Ph.D. Franklin Miller, Ph.D. David Wendler, Ph.D. Alan Wertheimer, Ph.D. |
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Background: Clinical research ethics has been at the forefront of bioethics since its emergence as a field of inquiry. Despite an extensive literature on ethical principles governing clinical research, their application to particular studies, and oversight protections, theoretical and practical limitations attenuate the ethical analysis of issues in clinical research. For example, although several ethical requirements must be satisfied in order to make clinical research ethical, informed consent, which is neither sufficient to make clinical research ethical nor necessary in all clinical investigation, has been overemphasized as the key ethical requirement. Additionally, ethical norms and principles pertinent to patient care have been uncritically applied to clinical research without appreciating ethically significant differences between the pursuit of generalizable knowledge characteristic of clinical investigation and the personalized therapeutic attention characteristic of patient care. Third, ethical guidance has been promulgated without sufficient attention to the methodology of clinical research and the practical contexts in which studies are conducted.
The history of clinical research has been inextricable from consideration about its ethics. In the late 19th century, the work of Giuseppe Sanarelli, who induced yellow fever in five volunteers in an effort to understand its cause, was categorically condemned by many researchers, most importantly by William Osler, one of the world’s most prominent physicians. Half a century later there were the horrors of the Nazi medical experiments. Beginning in the early 1960s a series of research scandals occurred in the United States, and 22 questionable studies were delineated in Henry K. Beecher's landmark 1966 paper in the New England Journal of Medicine entitled “Ethics and Clinical Research.” The culminating scandal was the infamous USPHS Tuskegee Syphilis Study which came to the public's attention in 1972. More recently, in the early 1990s, spurred primarily by AIDS activists, the ethics and regulation of clinical research were again called into question. The deaths of Jesse Gelsinger and Ellen Roche, the burgeoning of financial interests in research, and the suspension of human participants' research at major medical facilities such as Duke and Johns Hopkins, among other things, provoked a sense of inadequacy and crisis in the research protection system. Additionally, the precipitous growth of international research and worry about exploitation of populations in resource poor countries ignited much ethical controversy about research.
In response to these controversies and scandals, a number of ethical guidelines were issued and/or revised, including the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, the Common Rule and CIOMS International Guidelines. Since many of these guidelines were “born in scandal” they focus on the ethical issues highlighted by the particular case(s) that served as an impetus for their creation and therefore are often neither comprehensive nor systematic. Furthermore, these guidelines seldom provide justification for their positions, sometimes contradict each other or take positions that seem indefensible. Finally, some of the guidelines are difficult to apply to protocol evaluation, a primary mechanism to ensure compliance with ethical principles.
The Department of Bioethics and NIH Intramural Research Activities
The Department of Bioethics as part of the NIH Clinical Center has close proximity to the design, review, and conduct of clinical investigation and therefore a unique opportunity to advance the understanding of the ethics of clinical research and rectify limitations of previous bioethics scholarship in clinical research. Department staff serve as members, and bioethics fellows as observers, on NIH Intramural Institutional Review Boards. IRB membership provides access to cutting edge research, familiarity with scientific methodology, and the opportunity to reflect on complex ethical issues in research. In addition, through the Department's Bioethics Consultation Service and participation in the Clinical Center's Ethics Committee, faculty and fellows grapple with challenging ethical dilemmas that arise in the conduct of clinical research, and with the development of policies related to research. Proximity to the enterprise of clinical research also facilitates collaboration with investigators who are interested in the ethics of clinical investigation.
The Department has had the opportunity to provide education to the research community at the NIH about the ethics of clinical research. We developed a 7-week-long course entitled “Ethical and Regulatory Aspects of Human Subjects Research” that covers many important topics related to the ethics of clinical research and includes as speakers experts in the field from both within and outside the NIH. Now in its 8th year, the course receives overwhelmingly favorable evaluations and continues to enroll hundreds of participants each year. Although originally developed to serve the educational needs of the NIH community, each year there are many attendees from other institutions including from the FDA, National Naval Medical Center, Walter Reed, as well as private IRBs and remote sites in other parts of the United States and the world, such as Peru. Members of the department, in collaboration with colleagues from the University of Virginia, published an anthology of seminal articles on the ethics of clinical research based on the syllabus that was originally created for this course. The Department has adapted a shorter, more intensive course from this curriculum which has been offered in many countries around the world (see Multinational Research description). In addition, an “advanced” research ethics workshop has been developed and offered at the annual meeting of PRIM&R for 3 consecutive years.
Departmental Research Initiatives: The Department's conceptual and empirical work related to the ethics of clinical research over the last several years has focused primarily on the following areas:
- Articulation and application of an overall ethical framework for clinical research ethics;
- The quality of informed consent and efforts to improve it;
- Financial conflicts of interest in research; and
- Evaluation and improvement of oversight systems and protections.
Additional topics related to the ethics of research are summarized elsewhere in these materials. See especially the Ethics of Research Design, Ethical Issues in International Research, Vulnerable Populations, Ethical Issues related to Recruitment and Payment of Subjects, and Complementary and Alternative Medicine
1 Ethical Framework for Clinical Research Ethics
Departmental Research Initiatives: The Department began by focusing on a comprehensive and systematic conceptual framework for research ethics both for domestic and international research. Domestically, one motivation was to figure out how to evaluate Phase I oncology trials and, more broadly, to redress the imbalance of emphasis placed on informed consent as an ethical safeguard. Internationally, former NIH director, Dr. Varmus, asked for a framework for NIH researchers and program officers to evaluate international research proposals.
We began by stepping back from all existing guidelines and thinking through what principles research protocols should fulfill to be deemed ethical. The first product was a paper delineating seven principles that guide ethical clinical research, published in JAMA in 2000. This framework is: 1) comprehensive — taking into account the relevant ethical considerations; 2) systematic — has an order that reflects the process of designing, reviewing, and implementing a research protocol; 3) universal — applies to all types of clinical research across different countries and settings; but 4) sensitive to cultural, economic, health, and institutional differences in application in local settings.
We used this framework and our growing experience both in observing research studies and in conducting our own research projects in developing countries to elaborate an eighth principle — collaborative partnership. In the United States, there is an infrastructure for research and evidence based clinical care that forms a widespread foundation of collaboration and support for clinical research, and includes public support for research, organized advocacy groups, involvement of public members on IRBs, advisory boards to NIH and specific cooperative groups or protocols. In other settings, partnerships with local researchers and health care providers, government entities, members of the community, and others needed to be explicit for ethical collaborative research. More importantly, we further specified each principle with a set of benchmarks to help determine whether the principle is fulfilled. The goal was to provide specific guidance to researchers and reviewers and an even more comprehensive checklist for protocol evaluation. This framework was published in the Journal of Infectious Diseases in 2004.
Development of Books and Other Materials for Training and as References: We have developed three books using the framework. First, as described above, we developed an anthology of classic papers in research ethics with colleagues from University of Virginia, to be used in our annual research ethics course and as a basic educational text. In this book, we edited the collected papers and provided scholarly introductions to different sections. The first edition went to the publisher prior to completion of our framework, so its organization does not strictly follow the eight principles. However, the second edition of this textbook will follow the eight principles framework and is expected in 2007.
While it is important to provide classic articles, we also began work on an original, multi-authored textbook of research ethics. This was conceived as a comprehensive and systematic summary of all of the important topics in clinical research ethics. The core of this textbook, The Oxford Textbook of Research Ethics, is organized according to the eight principles. Some sections were added to address the history, as well as other topics such as industrialization of medical research, conflicts of interest, and misconduct. This textbook will be published by Oxford University Press in 2007. This book is intended to be a definitive textbook on research ethics.
Finally, we have developed a book of cases that pose complex ethical challenges in international research. Through our teaching and conducting research in developing countries we encountered a number of challenging cases. In collaboration with James Lavery then of the Fogarty International Center at NIH, we identified cases and organized them by defining which of the 8 principles was primarily implicated in the case. We then solicited two commentaries for each case. Our guiding philosophy was not only to include established commentators but to find new voices especially from developing countries. The book contains 21 cases with two commentaries on each case and is scheduled to be published by Oxford University Press in early 2007.
Thus, by 2007 we will have completed three books — an international case book with commentaries, a book of classic articles in research ethics, and a definitive textbook of new chapters on research ethics — all organized according to and reinforcing the eight principles approach to ethical clinical research.
Applications: Members of the Department have also applied the framework both by applying the entire framework to specific kinds of research, such as research with healthy volunteers, research on complementary and alternative medicine, or research with vaccines, and by further analyzing and applying one or more of the principles that make up the framework, such as risk-benefit assessment, or respect for enrolled participants.
Impact of Research: This framework — the seven and now eight principles framework — has been tremendously influential. The original framework article published in JAMA has had more than 200 citations in just five years. Furthermore the framework has been explicitly adopted by numerous IRBs, some have even created a form with the seven principles that investigators and IRB members use to evaluate protocols.
At least three countries — Kenya, Nigeria, and Sri Lanka — have revised their regulations regarding clinical research explicitly adopting the seven principle framework in their national regulations. The 2004 Kenyan “Guidelines for Ethical Conduct of Biomedical Research Involving Human Subjects in Kenya,” for example, has a section entitled “A systematic and coherent framework for determining whether clinical research is ethical” which lists our seven principles and virtually quotes verbatim the explanation of each one.
Ethical and Regulatory Aspects of Clinical Research: Readings and Commentaries (Johns Hopkins Press 2003) has sold over 4,000 copies, is used in numerous courses, such as the research ethics course at Johns Hopkins School of Public Health, and has received excellent reviews. Its second and extensively revised edition will be published in 2007.
In 2005, the Department was recognized with the Award for Excellence in Human Research Protection by the Health Improvement Institute for their Framework and Benchmarks for the Evaluation of Clinical Research.
The NIH Office of Communications is in the process of developing a public website about clinical research and will utilize the seven principle framework to educate the public about the ethics of clinical research.
Future Research Initiatives: We expect that the book of international research cases with commentaries will be revised and expanded with more cases by 2010. Both textbooks — the one of classic papers and the Oxford Textbook — we plan to regularly revise on a 4 to 5 year cycle. These works will continue to reinforce and refine the conceptual framework.
In addition, members of the Department are continuing to subject ethical canons of research to philosophical analysis. In one project, for example, Dr. Alan Wertheimer, has identified an apparent phenomena in research that he calls the "Interaction Principle," namely that people have special obligations to those with whom they interact in mutually beneficial and consensual transactions that they would not have if they had chosen not to interact with them. Such claims are often made about clinical researchers, both with respect to treatment of the disease under investigation and provision of ancillary care. Dr. Wertheimer argues that the interaction principle is deeply problematic and its acceptance may be counter-productive. He intends to combine this analysis with others (described later) into a book.
Members of the department also will continue to examine specific issues in clinical research through the lens of the ethical framework and pursue deeper analysis of each of the principles.
Publications:
Framework
Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000;283:2701-11.
Emanuel EJ, Wendler D, Killen J, Grady C. What makes clinical research in developing countries ethical? The benchmarks of ethical research. Journal of Infectious Diseases. 2004;189;130-37.
Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C. Ethical and Regulatory Aspects of Clinical Research (Baltimore: Johns Hopkins University Press 2003).
Lavery J, Grady C, Wahl E, Emanuel EJ. Ethical Issues in International Biomedical Research: A Casebook (New York: Oxford University Press 2006).
Emanuel EJ, Crouch RA, Grady C, Lie R, Miller F, Wendler D. The Oxford Textbook of Research Ethics (New York: Oxford University Press 2007).
Grady, C. Chapter 2: Ethical Principles in Clinical Research, pp 15-26 in Principles and Practice of Clinical Research; John Gallin, Ed. (New York: Academic Press, January 2002). Revised chapter for 2nd edition (in press).
Application of the Framework
Grady, C. Ethics of Vaccine Research. Nature Immunology. 2004;5(5):465-468
Miller FG, Emanuel EJ, Rosenstein DL, Straus SE. Ethical issues concerning research on complementary and alternative medicine. JAMA. 2004;291:599-604.
Miller, FG. Clinical Research with Healthy Volunteers. Journal of Investigative Medicine. 2003;51(Suppl 1.):S2-S5.
Miller FG, Shorr AF. Ethical Assessment of Industry-Sponsored Clinical Trials: A Case Analysis. Chest. 2002;121:1337-1342.
Miller F, Grady C. The Ethical Challenge of Infection-Inducing Challenge Experiments. Clinical Infectious Diseases. 2001;33:1028-1033.
Analysis of Principles
Wendler D, Miller F. Assessing research risks systematically: the net risks test. Journal of Medical Ethics. 2006 (In Press).
Gross CP, Krumholz HM, Van Wye G, Emanuel EJ, Wendler D. Does Random Treatment Assignment Cause Harm to Research Participants? PLoS Medicine. 2006;3(6):e188.
Shalowitz DI, Miller FG. Disclosing Individual Results of Clinical Research: The Implications of Respect for Participants. JAMA. 2005;294:737-740.
Rajczi, A. Making Risk-Benefit Assessments of Medical Research Protocols. Journal of Law, Medicine, and Ethics. 2004;32(2):327-337.
Churchill LR, Nelson DK, Henderson GE, King NMP, Davis AM, Leahey E, Wilfond BS. Assessing Benefits in Clinical Research: Why Diversity in Benefit Assessment Can Be Risky. IRB: Ethics and Human Research. 2003;25(3):1-3.
2. The Quality of Informed Consent
Background: Informed consent is a fundamental protection for human research. While its importance may be overstated, it is essential in most clinical research. Yet empirical data suggest that the informed consent of research participants is imperfectly realized. Many fail to understand critical aspects of research, such as randomization or the purpose of research. Furthermore, there is a widespread perception that understanding is worse in developing countries than in developed countries. In addition, many commentators claim that research participants are pressured, coerced, or unduly influenced to participate in studies.
Departmental Research Initiatives: The Department has conducted several empirical studies looking at the quality of informed consent (Pace et al. 2005, Pace et al. 2005) and the practices of investigators regarding consent (Sabik et al. 2005). In addition, members of the Department have examined the process of ongoing consent (Wendler, Rackoff), and the meaning of a signature on a consent document. (Wendler, Rackoff).
Members of the Department have also studied the “therapeutic misconception” in research, and introduced a distinction between a therapeutic misconception and a therapeutic misestimation. (Horng, Grady 2003; Miller, Joffe 2006).
A comprehensive analysis of existing literature on interventions to improve informed consent was undertaken to determine what interventions might improve research participants' understanding (Flory, Emanuel 2004). This analysis of 42 studies conducted between 1966 and 2004 identified four types of interventions: 1) multimedia interventions — videos or interactive computer programs; 2) enhanced forms — shorter forms or more graphics; 3) extended human discussion time — calls by nurses or others; and 4) test-feedback. Statistically significant improvements of understanding were found in: only 3 of 12 trials of multimedia interventions; 6 of 15 enhanced consent form interventions (although 5 of the 6 were tested in hypothetical research studies); 3 of 5 extended human discussion interventions (the other 2 trended toward improvement); and 5 of 5 test-feedback intervention studies — although all of the latter used the same questions for repeat tests so improvement may actually be memorization rather than understanding. Another finding was that some of these interventions, such as shorter consent forms and test-feedback, have not been subjected to rigorous well designed evaluations.
Based on these data, the Department developed several intervention studies to evaluate the impact of improved consent documents on understanding. We developed a technique for shortening consent forms to about one third the original length — mainly by eliminating repetition and providing information about risks in tables. We began five different studies, two of which progressed to full protocols and evaluation survey instruments. Unfortunately, even after passing IRB approval at multiple institutions both protocols were terminated. One was a study in Rakai, Uganda appended to a circumcision study for HIV prevention. The Division of AIDS stopped the consent study because not all participants would be required to be informed of their HIV status. The second was a study of adjuvant treatment of colon cancer being coordinated by the North Central Cooperative Group. The drug company sponsoring the study opposed the informed consent evaluation fearing that the FDA might void the study if it revealed that some of the participants were not fully informed.
Impact of Research: There has been considerable interest in our studies on the quality of informed consent, and we have received requests from investigators in Zambia, Zimbabwe, and the US to use our survey instruments. In addition, the review of research on interventions to improve consent has had almost 50 citations. Our work on therapeutic misconception and misunderstanding has been described anecdotally as helpful to others interested in the therapeutic misconception.
Future Research Initiatives: Alan Wertheimer and Frank Miller are beginning a project to reframe the way in which bioethics thinks about the principle of informed consent. The goal is to broaden and deepen the approach to informed consent by examining a wide variety of contexts in which people give consent such as sexual consent, contracts, marriage, jobs, and gambling. They reject the prevailing “autonomous authorization” model of consent used in biomedical research defend an alternative, “fair transaction” model, and argue that by understanding consent in this way, the therapeutic misconception need not entail that research is unethical. They are also co-editing an anthology examining the concept of consent in various contexts.
In collaboration with a research group in Japan, we are comparing participant understanding and satisfaction between short consent forms and traditional consent forms in a large cohort study. In addition to understanding and satisfaction, we will compare enrollment and retention in the two groups with the hypothesis that enrollment, retention and satisfaction will be higher in the short form group, and understanding will be the same or better. Data is currently being analyzed.
Drs. Wendler and Grady and Sumeeta Varma are beginning a study to look at the process of parental permission and child assent in adolescents participating in oncology clinical trials. In addition to examining the process, this study will analyze how parents and adolescents understand and trade off risks and benefits, and how they make decisions about research participation
Published Papers:
Flory J, Emanuel EJ. Interventions to improve research participants' understanding in informed consent for research: a systematic review. JAMA. 2004;292:1593-1601.
Pace C, Talisuna A, Wendler D, Maiso F, Wabwire-Mangen F, Bakyaita N, Okiria E, Garrett-Mayer E, Emanuel E, Grady C. Quality of Parental Consent in a Ugandan Malaria Study. American Journal of Public Health. 2005;95(7):1184-1189.
Pace C, Emanuel E, Chuenyam T, Duncombe C, Bebchuk JD, Wendler D, Tavel JA, McNay LA, Phanuphak P, Forster HP, Grady C, for the ESPRIT Group. The Quality of Informed Consent in a Clinical Research Study in Thailand. IRB: Ethics and Human Research. 2005;27(1):9-17.
Sabik L, Pace CA, Forster HP, Wendler D, Bebchuk JD, Tavel JA, McNay LA, Killen J, Emanuel EJ, Grady C. Informed Consent: Practices and Views of Investigators in a Multinational Clinical Trial. IRB: Ethics and Human Research. 2005;27(5):13-18.
Miller FG , Kaptchuk TJ. Acupuncture trials and informed consent. Journal of Medical Ethics. 2006. (In Press).
King NMP, Henderson G, Churchill LR, Davis AM, Hull SC, Nelson DK, Parham-Vetter C, Rothschild BB, Easter MM, Wilfond BS. Consent Forms and the Therapeutic Misconception: The Example of Gene Transfer Research. IRB: Ethics and Human Research . 2005;27(1):1-8.
Wendler D . Can We Ensure All Research Subjects Give Valid Consent? Archives of Internal Medicine. 2004;164:2201-2204.
Agrawal, M. Voluntariness in Clinical Research at the End of Life. Journal of Pain and Symptom Management. 2003;25(4):S25-S32.
Horng S, Grady C. Misunderstanding in Clinical Research Subjects: Distinguishing the Therapeutic Misconception from the Therapeutic Misestimation. IRB: Ethics and Human Research. 2003;25(1):11-16.
Miller FG, Joffe S. Evaluating the therapeutic misconception. Kennedy Institute of Ethics Journal. (In Press).
Lie RK . The Absolute Ethical Requirement of Individual Informed Consent: A Commentary on Barrett and Parker. Monash Bioethics Review. 2003;22(3):18-22.
Pace C, Grady C, Emanuel E. What we don’t know about informed consent. SciDevNet. 2003:August 28, http://www.scidev.net/dossiers/ethics/.
Wendler D, Prasad K, Wilfond B. Does the Current Consent Process Minimize the Risks of Genetics Research? American Journal of Medical Genetics. 2002;113:258-262.
Wendler D, Rackoff J. Consent for Continuing Research Participation: What Is It and When Should It Be Obtained? IRB: Ethics and Human Research. 2002;24(3):1-6.
Wendler D, Rackoff J. Informed Consent and Respecting Autonomy: What’s a Signature Got to Do With It? IRB: Ethics and Human Research. 2001;23(3):1-4.
3. Financial Conflicts in Research
Background: Financial relationships between biomedical researchers and research institutions and for-profit companies have significantly increased over the last two decades and currently exist in a variety of forms (per capita payments, consulting fees, etc.). As awareness of those relationships becomes more widespread, managing them so that they do not threaten or compromise scientific objectivity, the safety of research participants, evidence-based patient care, and the public's trust in the integrity of clinical research has become a major priority. Professional organizations and institutions have developed policies and mechanisms to deal with financial conflicts of interest. Many have advocated disclosure as an important way to manage financial conflicts of interest in biomedical research, including disclosure to audiences, journal editors, readers, institutional administrators and increasingly research participants. Many questions have surrounded the recommendation to disclose financial interests to research participants and little is known about what participants actually think. Are research participants aware of financial conflicts of interest in biomedical research, do they want to be informed about them, how will information about investigators' or institutions' financial relationships influence their decisions and willingness to participate in clinical research? Moreover, disclosure is a limited tool as it does not prevent bias in research related to financial relationships.
Departmental Research Initiatives: The department conducted two empirical studies investigating the views of research participants about financial conflicts of interest. One was a qualitative study of research participants at the NIH, using a semi- structured instrument that included vignettes in which investigators had different types of financial relationships with the company making the investigational drug. Research participants were asked to describe their views about each of the vignettes, what they would want to know about such relationships, and the extent to which knowing might influence their willingness to participate in research. Although most said they would want to know, very few said it would influence their participation decision. Reasons given for why such information would have no influence included that it just didn't matter, that other things were more important to them, or that it was private information. The results suggest that although making financial information available might be important, the value of disclosing such information to subjects is limited; they would rarely use it in making research decisions, sometimes find it burdensome, and instead rely on institutional mechanisms to monitor financial relationships (Grady et al., 2006).
The second study investigated the views of participants in oncology trials regarding both investigator and institutional financial interests and also institutional mechanisms to handle such interests. Participants in all phases of oncology research at five different sites were invited to participate in face-to-face interviews. The study found that most respondents were not aware of researcher COI and more importantly were not worried about them and found them acceptable, the majority thought there was an oversight system in place to monitor financial interests, most said knowing that financial interests existed would not have changed their decision to participate in research study. Approximately 1/3 wanted disclosure of all financial interests, 40 percent wanted disclosure about the oversight system, and 17 percent thought no disclosure was required (Hampson et al., 2006).
In addition to this empirical research, the ethics of academic physicians participating in industry-sponsored clinical trials has been analyzed from the perspective of professional integrity (Miller and Brody, 2005).
Future Research Initiatives: A manuscript reporting on the results of a third survey of patients' attitudes (n=1193) regarding sponsorship and investigator's financial interests in genetic research is currently in progress. Patients expressed a preference for government or advocacy group sponsorship over private industry. The majority of respondents said that the prospect of a researcher making money from patents would not make a difference in their willingness to participate in a study, yet nearly half felt that such a financial interest would influence the researcher's interpretation of study results. This finding will be further explored.
Publications:
Hampson L, Agrawal M, Joffe S, Gross C, Verter J, Emanuel E. Patients’ Views on Financial Conflicts of Interest in Cancer Research Trials. New England Journal of Medicine. 2006;355:2330-2337.
Grady C, Horstmann E, Sussman J, Hull S. The Limits of Disclosure: What Research Subjects Want to Know About Investigator Financial Interests Journal of Law, Medicine, and Ethics. 2006;34(3):592-599.
Miller FG, Brody H. Professional integrity in industry-sponsored clinical trials. Academic Medicine. 2005;80:899-904.
4. Evaluation and Suggestions for Improving the Human Protections System
Background: The federal regulations and other guidance for the protection of human subjects in research focus largely on IRB review of research and the informed consent of participants. In recent years because of perception that the system was in jeopardy, reforms to the human protection and regulatory system have been suggested. Legislation to reform the human research protection system was introduced in Congress. The National Bioethics Advisory Commission under President Clinton examined and opined about several controversial issues in research ethics. A voluntary system of accreditation for Human Participant Protection Programs was initiated. The Institute of Medicine was asked to investigate the problem and issue recommendations. Professional societies and others examined the problems and issued their own recommendations. The Doris Duke Foundation supported Dr. Emanuel and Dr. Sugarman (currently at Johns Hopkins University) with a grant to create the Consortium to Evaluate Clinical Research Ethics (CECRE), comprised of individuals with broad experience in clinical research oversight to study how the protection system could be improved.
Departmental Research Initiatives:
The department also undertook a series of projects evaluating the current human protections system and suggesting ways to improve it. One effort was to identify the actual problems with the oversight system. Most commentators focused on three problems: 1) researchers’ conflicts of interest, 2) lack of IRB resources, and 3) increasing volume of clinical research. In our view, this mischaracterized or underrepresented problems with the current system. And by mischaracterizing the problems, proposed solutions also seemed inadequate. First, we endeavored to create an exhaustive characterization of the problems of the human research participants' oversight system. The initial review was undertaken primarily by Wood, Grady, and Emanuel and presented to CECRE. A list of 15 problems categorized into three broad groups was revised, as follows:
Specific Problems |
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Structural Problems |
1) Federal regulations do not apply to all research. |
2) Inconsistencies in FDA and NIH regulations of human participants research. |
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3) No effective mechanism for IRBs to address major, recurrent ethical issues such as payment to research subjects or use of placebos. |
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4) Inherent institutional conflict of interest with institutions regulating their own IRBs responsible for reviewing research protocols from the institution itself. |
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5) No systematic consistent management of individual researcher conflicts of interest. |
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6) Repetitive IRB reviews of multi-site research protocols. |
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7) Absence of resources devoted to IRB review. |
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8) Inadequate education of clinical investigators and IRB members with a requirement but no specification of curricular content. |
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Procedural Problems |
9) Time consuming review process with multiple reviews and the need for revisions to be reviewed by the entire IRB. |
10) Poor quality control of IRB reviews. |
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11) Inadequate guidance on IRB operations such as selection of members, how decisions are made etc. |
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12) Excessive focus on informed consent forms rather than other aspects of protection such as risk-benefit ratio. |
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13) Ineffective and inefficient adverse event reporting, with vague definitions and time requirements and repetitive reporting of minor issues. |
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Performance Assessment Problems |
14) No validated measures of IRB performance or systematic collection of measures of the quality of IRB reviews. |
15) No systematic collection of data on clinical research performance such as deaths or serious harms from clinical research. |
After listing the problems, we evaluated how each proposed solution, from accreditation of IRBs, to centralizing IRBs to several legislative proposals, addressed these problems. A paper summarizing the problems and the evaluation of the proposed solutions was published in the Annals of Internal Medicine (Emanuel et al., 2004).
The Consortium proposed five aspects of reform, such as having a single federal office with regulatory authority over all human participants' research and a permanent advisory committee to systematically address ethical issues. However, it could not agree on a comprehensive reform proposal for protection of research participants. Consequently, Wood, Grady and Emanuel proposed comprehensive reform based on a system of regional ethics organizations. In a paper in Nature Medicine, they delineated a proposal for regional ethics organizations to oversee all human participants’ research and include responsibility for prospective and continuing review of protocols, education of researchers, development of ethics policies, and collection of performance data. They analyzed how such a proposal would likely be the best solution for the 15 problems identified by the consortium, such as inherent institutional conflict of interest.
To examine the claims about insufficient resources for IRBs, the Consortium developed a survey of IRBs to determine the actual cost of IRB review. The survey was sent to all 121 medical schools with active IRBs — 63 responded. The Consortium was able to determine the staffing levels, total costs and costs per protocol, and found a strong association of costs with volume demonstrating that there are economies of scale. This report was published in the New England Journal of Medicine (Sugarman et al., 2005).
As a follow up, Sobolski and Emanuel tried to estimate cost savings if the multiple reviews currently done for most multi-site protocols were eliminated and only one site reviewed the protocol, by re-surveying the 121 IRBs to determine what proportion of their new protocols were multi-site and, on average, how many other sites were involved in the protocol. Interestingly, most of the IRBs did not record whether a protocol was multi-site and those that did rarely knew how many other sites were on the protocol. Using data from the few IRBs that did record the information on multi-site review, it is estimated that 10 to 35 percent of IRB review costs could be saved by eliminating repetitive reviews. This paper has been accepted at Annals of Internal Medicine.
Because there exists controversy in the research community about for-profit IRBs, Emanuel engaged in a point-counter-point discussion with Lemmens and Elliot about the benefits and problems with for-profit IRBs. Emanuel argued that profit status is not a key indicator of anything relevant to IRB functioning, and that we should measure quality directly. Furthermore, the purported conflict of interest of for-profit IRBs is not unique — academic IRBs also have a conflict of interest.
Finally, Emanuel and Grady delineated four paradigms that characterize our understanding of clinical research and its oversight since World War II. For hundreds of years before that time, research was sporadic and often unsystematic, and sometimes dangerous. Centralization of research activities and increasing fiscal and public support catapulted clinical research into a formidable and continually expanding enterprise. The first paradigm, characterized as one of researcher paternalism, was one in which few checks and balances were built into the system of clinical research because research was conducted by physicians- who were trusted to be committed to the safety and welfare of their patients. Scandals and abuses shifted this paradigm to one emphasizing protection of participants, especially the vulnerable, from the risks and burdens of research. In the 1980s and 1990s, largely spurred by AIDS activism, the paradigm shifted again to emphasize individual autonomy in accepting risks, and demanding the benefits of access to research. A fourth paradigm emphasizing the ethical importance of community partnership has evolved along with an increase in international research and genetics research. This paper appears in the Cambridge Quarterly (Emanuel, Grady 2006).
Impact of Research: The Department’s review of the current human protections system has helped to shape discussion of the adequacy and efficiency of oversight of human participants’ research. The article diagnosing the problems with the human research participants’ oversight system in the Annals of Internal Medicine has been recognized as a comprehensive and systematic appraisal and elevated the discussion beyond conflict of interest, resources, and workload.
The work on IRB costs and potential cost savings from re-structuring multi-center protocol reviews was an effort to provide data that would inform the discussions about IRBs. It has been used by several groups including AAMC in their consideration of proper support for IRBs.
The proposal for regional ethics organizations has also expanded the discussion of reform possibilities beyond central IRBs and more resources. Notably, reform on this scale would require legislation and Congressional action and legislation. Currently there is no momentum in that direction. The point of the paper was to elaborate an alternative policy, to add it to the policy options under consideration, for a time when efforts at comprehensive reform might occur. Another scandal or tragedy like the Gelsinger case is likely to re-focus attention on the need for reform of the human participants protection system. When this happens, regional ethics organizations will likely be one of the policy options to be considered.
Future Research Initiatives: Wertheimer and Miller have recently co-authored a paper on paternalism in research ethics that is under review. This paper argues that the current system of regulating human subjects' research with competent adults places a variety of restrictions on permissible research beyond the requirement of obtaining informed consent, making it fundamentally paternalistic. This argument forces society to explain when paternalism is justifiable and when it is not, and suggests that contrary to the usual rhetoric of bioethics, paternalism can be justified.
Publications:
Sobolski GK, Flores L, Emanuel EJ. Reforming IRB review of multicenter studies. Annals of Internal Medicine. (In press).
Emanuel E, Grady C. Four Paradigms of Clinical Research and Research Oversight. Cambridge Quarterly of Health Care Ethics. 2006;16:82-96.
Emanuel EJ, Lemmens T, Elliot C. Should Society Allow Research Ethics Boards to Be Run As For-Profit Enterprises? PLoS Medicine. 2006;3(7):e309.
Sugarman J, Getz K, Speckman JL, Byrne MM, Gerson J, Emanuel EJ for the Consortium to Examine Clinical Research Ethics. The Cost of Institutional Review Boards in Academic Medical Centers. New England Journal of Medicine. 2005;352(17):1825-1827.
Emanuel E, Wood A, Fleischman A, Bowen, A, Getz KA, Grady C, Levine C, Hammerschmidt DE, Faden R, Eckenwiler L, Tucker C, Sugarman J. Oversight of Human Participants Research: Identifying Problems to Evaluate Reform Proposals. Annals of Internal Medicine. 2004;141:282-291.
Levine C, Faden R, Grady C, Hammerschmidt D, Eckenwiler L, Sugarman J. Special Scrutiny: A More Targeted Form of Protocol Review to Protect Research Participants. Annals of Internal Medicine. 2004;140:220-223.
Wood A, Grady C, Emanuel E. Regional Ethics Organizations for Protection of Human Research Participants. Nature Medicine. 2004;10(12):1283-1288.
Davis AM, Hull SC, Grady G, Wilfond BS, Henderson GE. The Invisible Hand in Clinical Research: The Study Coordinator's Critical Role in Human Subjects Protection. Journal of Law Medicine and Ethics. 2002;30(3):411-419.
Sugarman J, Eckenwiler L, Emanuel E. Research Oversight through New Lenses: The Consortium to Examine Clinical Research Ethics. IRB: Ethics and Human Research. 2003;25(1):9-10.
Emanuel, EJ. Institutional Review Board Reform. New England Journal of Medicine. 2002;347(16):1285-1286.
Silverman H, Hull SC, Sugarman J. Variability among Institutional Review Boards’ Decisions within the Context of a Multicenter Trial. Critical Care Medicine. 2001;29(2):235-241.
