Correspondence
Protection of Research Subjects
N Engl J Med 2003; 349:188-192July 10, 2003
- Article
To the Editor:
Regarding the study by the Acute Respiratory Distress Syndrome (ARDS) Network, discussed by Steinbrook (April 3 issue),1 some may wonder whether the institutional review boards (IRBs) had enough information to evaluate the risks of this study properly. As a member of an IRB that reviewed this protocol, I want to assure readers that there was indeed a very diligent review. The local consent form carefully and properly represented the risks involved in the study. There was ongoing review of adverse events, which were assiduously reported by the investigators. The public overall and the research subjects in particular were protected as much as possible by the investigators and by their local IRBs. Despite the criticisms of this study, the process of conducting proper research involving human subjects did work here.
1 ReferencesJeffrey L. Kaufman, M.D.
Vascular Services of Western New England, Springfield, MA 01107
kaufman@massmed.org 1
Steinbrook R . How best to ventilate? Trial design and patient safety in studies of the acute respiratory distress syndrome. N Engl J Med 2003;348:1393-1401
Full Text | Web of Science | Medline
To the Editor:
In his Sounding Board article on research involving cognitively impaired adults, Dr. Karlawish (April 3 issue)1 argues for limits on the risks that proxies are allowed to accept on behalf of cognitively impaired subjects. In the case of experimental therapeutic interventions, he asserts that the risk associated with the procedure must be justified by its potential benefits. Although this standard is reasonable, its application requires difficult, value-laden decisions.
The fact that patients must be enrolled in studies without their direct consent necessitates an extraordinary certainty in the determination of allowable risk. Rather than leaving the medical investigator and IRB alone to shoulder the burden of making this determination, we recommend that a process of community consultation be required for all trials enrolling cognitively impaired subjects. Such a process is already mandated in the guidelines of the Food and Drug Administration (FDA) and the Department of Health and Human Services that govern emergency research conducted without informed consent.2-4
Community consultation serves to enlighten investigators and IRBs about the values that should inform the analysis of the risks and benefits of a proposed trial. Furthermore, this process helps to reduce the perception that vulnerable persons may be abused by the medical establishment.5
5 ReferencesBrian T. Bateman
Philip M. Meyers, M.D.
H. Christian Schumacher, M.D.
Columbia University, New York, NY 10032
btb2002@columbia.edu 1
Karlawish JHT . Research involving cognitively impaired adults. N Engl J Med 2003;348:1389-1392
Full Text | Web of Science | Medline2
21 CFR §50.24(a)(7)(i).
3
Santora TA ,Cowell V ,Trooskin SZ . Working through the public disclosure process mandated by use of 21 CFR 50.24 (Exception to informed consent): guidelines for success. J Trauma 1998;45:907-913
CrossRef | Web of Science | Medline4
Bateman BT ,Meyers PM ,Schumacher HC ,Mangla S ,Pile-Spellman J . Conducting stroke research with an exception from the requirement for informed consent. Stroke 2003;34:1317-1323
CrossRef | Web of Science | Medline5
Adams JG ,Wegener J . Acting without asking: an ethical analysis of the Food and Drug Administration waiver of informed consent for emergency research. Ann Emerg Med 1999;33:218-223
CrossRef | Web of Science | Medline
To the Editor:
I commend Karlawish for raising many important issues regarding research on cognitively impaired adults and would like to note several widely held related presuppositions. First, Karlawish recognizes that “most states have not addressed the question of who is legally authorized to provide consent.” However, the ethical basis for such authority is still inadequately accounted for in the bioethics literature.1-4 Second, Karlawish pragmatically recommends that subjects designate someone to serve as “proxy during the course of the research.” The use of proxies for research raises multiple unresolved ethical issues, including limits to the authority of the proxy and the fitness of burdened caregivers to serve in this nonessential role. Third, Karlawish notes that, in most situations, research proxies will decide “on the basis of the person's best interests.” Since research is intended to benefit future patients, many investigations serve subjects' best interests poorly. Finally, he suggests that “the core ethical challenge is to define the limits on the kinds of research risks that the proxy can accept.” Perhaps a more fundamental challenge is to develop a robust ethical framework for third-party consent in research.
4 ReferencesJeffrey T. Berger, M.D.
Winthrop University Hospital, Mineola, NY 11501
jberger@winthrop.org 1
World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. (Accessed June 20, 2003, at http://www.wma.net/e/policy/b3.htm.)
2
Informed consent for research on human subjects with dementia: AGS Ethics Committee, American Geriatrics Society. J Am Geriatr Soc 1998;46:1308-1310
Web of Science | Medline3
National Bioethics Advisory Commission. Research involving persons with mental disorders that may affect decisionmaking capacity. (Accessed June 20, 2003, at http://bioethics.georgetown.edu/nbac/capacity/TOC.htm.)
4
Moorhouse A ,Weisstub DN . Advance directives for research: ethical problems and responses. Int J Law Psychiatry 1996;19:107-141
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Berger argues that third-party consent in research requires a robust ethical framework. Many would argue that 30 years of scholarship and debate have gotten us that. We just cannot agree on how to apply the framework. Tweaking it or creating a whole new one may not be the most productive way to achieve agreement. Instead, we should address an empirical deficit. Much of the disagreement may reflect our thin understanding of what matters to persons at risk for cognitive impairment and persons who would be their proxies. A core question to ask these persons in order to inform our framework and its application is “when, if ever, is proxy altruism acceptable?”
Bateman and colleagues suggest that all trials that use informed consent by proxies to enroll cognitively impaired persons should require community consultation modeled after the rules for the waiver of informed consent in emergency research.1 That is a tough position to defend. The justification for community consultation is that the absence of any informed consent warrants “consent” from the community of potential subjects. But proxy consent from a person who is close to the potential subject does offer some protection. Still, there is reason to question whether IRBs adequately take advantage of their ability to include representatives of vulnerable communities.2 But why wait for the finished protocol? A more rewarding approach would involve the community of potential subjects in the process of research design and planning.3 This is current practice among scientific review groups of the National Institute of Mental Health4 and selected FDA advisory committees.5
5 ReferencesJason H.T. Karlawish, M.D.
University of Pennsylvania, Philadelphia, PA 19104
jasonkar@mail.med. upenn. edu 1
Department of Health and Human Services, Food and Drug Administration 2
Department of Health and Human Services
Medline3
Karlawish JHT ,Lantos J . Community equipoise and the architecture of clinical research. Camb Q Healthc Ethics 1997;6:385-396
CrossRef | Web of Science | Medline4
Department of Health and Human Services, National Institute of Mental Health. Public participant membership on scientific review groups at the NIMH. (Accessed June 20, 2003, at http://grants1.nih.gov/grants/guide/notice-files/not98-167.html.)
5
Department of Health and Human Services, Food and Drug Administration. FDA patient representative program. (Accessed June 20, 2003, at http://www.fda.gov/oashi/patrep/patientrep.html.)
To the Editor:
In their discussion of the ethical problems with the therapeutic orientation of clinical trials, Miller and Rosenstein (April 3 issue)1 fail to acknowledge that all researchers must abide by the Declaration of Helsinki, the underlying principle of which is respect for the human subject. The obligations to a patient in a physician–patient relationship cannot be separated from those in a researcher–patient relationship, and the conflicts of interest cannot be removed. The solution lies in increased education and transparency of the process. Patients need to be educated about the different objectives of medical care and clinical trials. When, after explanation of a research study protocol, the patient says, “Doctor, you are asking me to be a guinea pig,” I know the patient understands what is being asked of him or her. The patient participates in the study as a collaborator in order to increase knowledge and to advance medical care. In addition, researchers need increased training and support to ensure that they remain aware of their conflicts of interest and their obligation to give the highest priority to the life, health, privacy, and dignity of the human subject.
1 ReferencesDuncan J. Campbell, M.D., Ph.D.
St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia
j.campbell@medicine. unimelb. edu. au 1
Miller FG ,Rosenstein DL . The therapeutic orientation to clinical trials. N Engl J Med 2003;348:1383-1386
Full Text | Web of Science | Medline
To the Editor:
Miller and Rosenstein argue that incorporating clinical trials as an integral part of ideal patient care “constitutes an ethical distortion that ought to be scrupulously resisted.” If pediatric oncologists shared this view, the dramatic advances in cancer care for children would not have happened. Cure rates for childhood lymphoblastic leukemia increased by 30 percent over three decades without the use of a single new therapeutic agent, because nearly all children with the disease were treated in carefully conducted clinical trials testing adjustments of the doses and schedules of administration of established agents.1 As an oncologist for adults, I strive to emulate my colleagues in pediatrics by recommending well-designed clinical trials as the best option for care for most of my patients. We train our fellows and nurses to make clinical trials “part of the fabric of both oncology education and practice”2 and to share Bernard Fisher's clear view: clinical trials are to oncology what sterile technique is to surgeons.3 Caring physician–patient relationships have been the most rewarding part of such a career in oncology.
3 ReferencesAnand Karnad, M.D.
East Tennessee State University, Johnson City, TN 37604
karnad@mail.etsu. edu 1
Simone JV ,Lyons J . The evolution of cancer care for children and adults. J Clin Oncol 1998;16:2904-2905
Web of Science | Medline2
Cassileth BR . Clinical trials: time for action. J Clin Oncol 2003;21:765-766
CrossRef | Web of Science | Medline3
Fisher B . On clinical trial participation. J Clin Oncol 1991;9:1927-1930
Web of Science | Medline
To the Editor:
Miller and Rosenstein stress the ethical imperative for investigators to counteract therapeutic misconceptions about clinical trials and promote the scientific goal of improved medical care for future patients. The results of rigorously conducted clinical trials make up the foundation for what we like to term “evidence-based medicine.” However, even though almost two thirds of new cases of cancer occur among the elderly,1 with a median age of approximately 68 years for patients with lung cancer,2 recent studies indicate that less than 1 percent of patients participating in clinical cancer trials are older than 68 years of age.3 The possible toxicity of treatment because of organ-system abnormalities and functional-status limitations explain the underrepresentation of the elderly in clinical trials.1 Thus, the “evidence” on which we base our future treatment may not apply to most of the patients we will serve in the future — the growing population of elderly persons.4 Consequently, physicians may decide not to offer a treatment because the evidence does not support its use in clinical circumstances such as advanced age.5 This matter, too, merits ethical consideration.
5 ReferencesJon Sudbo, D.D.S., M.D., Ph.D.
Norwegian Radium Hospital, 0310 Oslo, Norway
jon.sudbo@rh. uio. no 1
Lewis JH ,Kilgore ML ,Goldman DP , et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003;21:1383-1389
CrossRef | Web of Science | Medline2
Bunn PA Jr ,Lilenbaum R . Chemotherapy for elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2003;95:341-343
CrossRef | Web of Science | Medline3
Balducci L ,Beghe C . Prevention of cancer in the older person. Clin Geriatr Med 2002;18:505-528
CrossRef | Web of Science | Medline4
Trends in aging -- United States and worldwide. MMWR Morb Mortal Wkly Rep 2003;52:101-4, 106
Medline5
Bickell NA ,McEvoy MD . Physicians' reasons for failing to deliver effective breast cancer care: a framework for underuse. Med Care 2003;41:442-446
CrossRef | Web of Science | Medline
Author/Editor Response
The objectives of research ethics are to promote valuable clinical research and to protect research subjects. We agree with Sudbo that greater inclusion of elderly research subjects in clinical trials is needed to improve medical care. Campbell faults us for not recognizing that clinical research must be conducted in accordance with the Declaration of Helsinki. Although this code of ethics has many sound provisions, it is morally problematic, in part because it fosters the therapeutic orientation to clinical trials that we criticized in our article. We disagree that the relationship between the physician-investigator and the patient-subject cannot be separated from the therapeutic relationship between physician and patient. We do agree, however, that conflicts of interest in research cannot be eliminated entirely and thus must be recognized and managed with integrity.1
Karnad recommends “well-designed clinical trials as the best option for care for most of my patients.” In many cases, participation in a trial may be the best option, all things considered, for patients with a given disorder.2 Nonetheless, sound research ethics depends on recognizing the ethically significant differences between research and therapy and between the obligations of the treating physician and those of the investigator conducting research.
(The views expressed in this letter are those of the authors and do not necessarily represent the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services.)
2 ReferencesFranklin G. Miller, Ph.D.
Donald L. Rosenstein, M.D.
National Institutes of Health, Bethesda, MD 20892-1156
fmiller@nih.gov 1
Miller FG ,Rosenstein DL ,DeRenzo EG . Professional integrity in clinical research. JAMA 1998;280:1449-1454
CrossRef | Web of Science | Medline2
Chen DT ,Miller FG ,Rosenstein DL . Clinical research and the physician-patient relationship. Ann Intern Med 2003;138:669-672
Web of Science | Medline
To the Editor:
I disagree with Drazen's assertion in his editorial (April 3 issue)1 that the assessment of the scientific merit of a study is outside the purview of the Office of Human Research Protections (OHRP). IRBs are empowered by the federal government to review research in accordance with the Belmont report.2 The OHRP requires IRBs to determine whether the risks are reasonable in relation to the anticipated benefits.3 Indeed, the risks cannot be assessed without judgment of the science, since no level of risk is justifiable if the scientific design is unsound.
Drazen also criticizes the OHRP for taking excessive time to collect data and make a decision, yet any scientist would be remiss in drawing a conclusion without seeing the data. Speed and efficiency are not virtues of either high-quality research or the protection of human research subjects.
The OHRP and IRBs should not be damned for doing precisely what they were created to do. Impatience to get on with clinical research must be tempered with cautious review to ensure the safety of research subjects. Like democracy, the process is inefficient but effective.
3 ReferencesWilliam J. Tremaine, M.D.
Mayo Foundation Office of Human Research Protection, Rochester, MN 559051
Drazen JM . Controlling research trials. N Engl J Med 2003;348:1377-1380
Full Text | Web of Science | Medline2
The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Washington, D.C.: Government Printing Office, 1978. (DHEW publication no. (OS) 78-0012.)
3
Code of Federal Regulations, title 45A, part 46.111: criteria for IRB approval of research. (Accessed June 20, 2003, at http://www4.law.cornell.edu/cfr/45p46.htm.)
To the Editor:
Drazen takes great pains to lay out the seemingly meticulous process of design, review, and approval of clinical trials that would appear to validate whatever decisions the National Institutes of Health (NIH) make about the direct conduct or funding of such trials. His strong suggestion that the OHRP should back off from questioning an ARDS study sponsored by the National Heart, Lung, and Blood Institute is nothing short of astonishing. The historical and recent records demonstrate that clinical trials approved by the NIH have not always satisfied the tenets of medical ethics and, therefore, are very much in need of independent monitoring and supervision.1 Checks and balances are at the heart of the U.S. system of governance. If the OHRP's independent oversight authority2,3 were to be disregarded, how could citizens participating — consciously or unconsciously — in biomedical research feel secure about their lives and safety?
3 ReferencesJohn H. Noble, Jr., Ph.D.
Vera H. Sharav, M.L.S.
Alliance for Human Research Protection, New York, NY 10023
veracare@ahrp.org 1
Marshall E . NIMH to screen studies for science and human risks. Science 1999;283:464-465
CrossRef | Web of Science | Medline2
Department of Health and Human Services, Health Resources and Services Administration 3
Department of Health and Human Services
To the Editor:
Drazen's criticism of the OHRP (formerly the Office for Protection from Research Risks [OPRR]) for excessive meddling in clinical research contrasts with our own experience. The OPRR on two occasions failed to address complaints from IRB members about financial conflicts of interest in a clinical trial at the Fred Hutchinson Cancer Research Center, in Seattle, in which it appears that all 85 patients died, including many who were told they had a 50 percent chance of cure. Research was conducted without IRB approval, NIH rules were ignored, IRB minutes were forged, IRB requests were ignored, the IRB was lied to by top staff members of the research center, patients were deceived, and known risks were ignored. The Seattle Times published a detailed, documented, award-winning series on this abuse in March 20011 showing that the OPRR never conducted an investigation when it issued a report stating that no wrongdoing by the research center was substantiated. Even now, the OHRP refuses to investigate. The NIH has many rules for protecting patients involved in research. However, like speed limits without police, they are blatantly ignored by some researchers. Physicians do themselves no favors by continuing to pretend that all is well.
1 ReferencesJohn M. Pesando, M.D., Ph.D.
Pacific Technology Associates, Seattle, WA 98102Author/Editor Response
Pesando cites an example of a case in which the now-closed OPRR of the NIH failed, in his opinion, to intervene in a situation in which there was blatant disregard for the process of appropriate oversight of protections for human research subjects. This office has been replaced by the OHRP, which is not part of the NIH. The OHRP has established a record of enforcing strict compliance with regulations concerning the performance of trials involving human subjects.
Tremaine takes issue with both my position that the OHRP does not have the resources to review the scientific merits of a clinical trial and my concern about the timeliness of the OHRP response. Noble and Sharav argue that there needs to be oversight of clinical research. It is in everyone's best interest to have redundant and complementary checks and balances in clinical research. However, as I stated in the last paragraph of my editorial, the process needs to be responsive and open. If the common goal is to fulfill the key tenet of the Belmont report that the risks involved in research are reasonable in relation to the anticipated benefits, then there must be a mechanism for rendering a final decision on a trial in question in an open, appropriate, and timely fashion.
In a given research trial, if there is concern that the standard of reasonable risk is not met, then it stands to reason that experts in the field of study who are not associated with the trial — that is, those who are familiar with both the risks and the benefits of the research and who are dispassionate with respect to the specific performance of the research trial — are those best qualified to make this determination. As detailed by Steinbrook, this was the procedure followed by the NIH with the advice and consent of the OHRP. Despite the unanimous opinion of the panel that the standard had been met, the OHRP has decided to ignore the view of those who are most qualified to judge the risks and benefits of the research and has continued to prevent this critical work from going forward. The tragedy is that physicians caring for many patients, such as those infected by the severe acute respiratory syndrome (SARS)–associated coronavirus, are continuing to base their care on guesses rather than facts. Who are we protecting and from what risk?
Jeffrey M. Drazen, M.D.
