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1 Temple University School of Medicine, and Temple University Hospital, Division of Pulmonary and Critical Care Medicine, Temple Lung Center, Philadelphia, Pennsylvania
Correspondence and requests for reprints should be addressed to Gerard J. Criner, M.D., FCCP, Division of Pulmonary and Critical Care Medicine, Temple Lung Center, Temple University Hospital, 777 Parkinson Pavilion, 3401 North Broad Street, Philadelphia, PA 19140. E-mail: crinerg{at}tuhs.temple.edu
ABSTRACT
Clinical research can create a conflict between the quest for science and the quest for individualized best patient care. The researcher must balance the degree of uncertainty about a particular treatment with the risk of patient exposure to control therapy. This is known as clinical equipoise. Clinical research and clinical care are intricately linked, yet they differ significantly from each other. This is an important distinction to make for both patients and physicians. This overview of ethics in clinical research will discuss some of the key contentious issues: informed consent (including payment for participation in a clinical trial, use of a placebo, and defining "standard of care"), research in critically ill patients, dissemination of study results, race issues, and financial disclosure. More research is being conducted by more investigators, in more organizations, in more disciplines than ever before. While this environment creates enormous opportunities for advances in healthcare, it also poses numerous challenges to the ethical conduct of clinical trials and raises numerous heretofore unconsidered issues.
Key Words: ethics • clinical trial • race • financial disclosure • informed consent
The question of what makes clinical research ethical is, perhaps, as old as medicine itself. Clinical investigators have long struggled with the balance of advancing medical science with the moral duties and Hippocratic oath of practicing medicine. Emanuel and colleagues offered an in-depth discussion of the requirements for ethical clinical research and they define seven requirements for research to be considered ethical (Table 1) (1). They note that "fulfilling all 7 requirements"—value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for enrolled subjects—"is necessary and sufficient to make clinical research ethical" (1).
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CLINICAL EQUIPOISE
Clinical research can create a conflict between the quest for science and the quest for individualized best patient care. The researcher must balance the degree of uncertainty about a particular treatment with the risk of patient exposure to control therapy. As reviewed by Grunberg and Cefalu, this balance (clinical equipoise) is reached when either the physician is unaware of the superiority of the treatments or the medical community as a whole legitimately disagrees on the best course of treatment, which then justifies random assignment to treatment (2). An example of the challenge of clinical equipoise, the National Emphysema Treatment Trial (NETT), is described in detail elsewhere in this issue (3–5).
CLINICAL RESEARCH VERSUS CLINICAL CARE
Clinical research and clinical care are intricately linked. Clinical trials are designed to improve outcomes for a population, not the individual patient (hence the avoidance of individualized care). However, the success of clinical studies is built upon success in individual patients. Also, clinical research institutions and researchers provide nonresearch clinical care. And, in many states, insurers must now pay for the standard care delivered to patients enrolled in cancer-related clinical research, even if the care is part of the study protocol (2).
Nonetheless, while clinical research is paramount to clinical medicine, they differ significantly from each other. This is an important distinction to make for both patients and physicians. For patients, there is the potential misperception or expectation (known as the therapeutic misconception) that their involvement in a study means that they will be receiving superior or even individualized medical care (6–8). In fact, the care they will be receiving will be standardized, not individualized, and may not be the most optimal care that they could receive. Their care will be dictated by the study protocol, and it is important that each participant understands that distinction. Similarly, physicians may believe that the patient's enrollment in a trial will allow the physician to provide superior medical care, or conversely, that the research project will interfere with the physician's ability to provide optimum patient care. Thus, the current standard of care and the study protocol must be clearly defined for all parties involved (2). This can prove challenging, given the existence of the therapeutic misconception and uncertainty over strategies to employ to reduce its occurrence.
INFORMED CONSENT
Patients must be clearly informed that they are subjects in the clinical trial (not patients) and thus are not receiving clinical care from the investigator. There are several contentious issues regarding informed consent, including, but not limited to, payment for participation in a clinical trial, use of a placebo, and defining "standard of care."
Should subjects be paid for participating in a clinical trial, to highlight the distinction between clinical care (as a patient) versus clinical research (as a subject)? Payment for clinical trial participation for healthy volunteers is common practice, and study grants often include funds to reimburse participants for travel costs and lodging. However, payment for participation can have the unintended consequence of coercing or persuading patients to participate, particularly poor patients or those afflicted by costly, life-threatening illnesses (2). At what point is the decision to participate made on the basis of financial need?
Informed consent also involves the question of receiving placebo treatment. The ethics of placebo-controlled trials has been questioned, especially in the last 10 years. A review of the literature on this question points to a placebo-orthodoxy. The use of a placebo is ethical when: (1) no effective therapies exist; (2) its use poses no long-term adverse effects or morbidity or mortality; and (3) there are methodological limitations when active controls are used. However, placebo use is considered unethical when: (1) the criteria for ethical use are never well defined; (2) its use permits subject suffering (including mental suffering); or (3) when the clinical question should be whether the study treatment is better than current treatment, rather than if study treatment is better than placebo. However, some recent trials are now using a three-way design to compare study treatment versus current treatment versus placebo.
Finally, the terms "standard care," "usual care," and "best current care" are frequently used (sometimes interchangeably) without being well defined. As discussed by Dr. Henry Silverman in this issue, there are several well-known examples of a clinical study design being called into question when "standard care" was not used, or not even defined. "Standard care" or "standard of care" is, in fact, a legal term relating to medical malpractice (9). As reviewed by Miller and Silverman, "standard of care" is understood, in the legal community, to mean "the typical or customary practice of physicians in the professional community, as evidenced by the testimony of expert witnesses" (9, 10). Because randomized, controlled trials (involving either placebo or standard care) are designed to ask specific clinically valuable questions, deviations from standard care are not, by themselves, unethical.
RESEARCH IN CRITICALLY ILL PATIENTS
Ultimately, informed consent is designed to protect the research subjects. Several widely publicized cases of study subject deaths in recent years has led to increased scrutiny of the informed consent process, increased education of study investigators, a more rigorous consenting process with the Investigational Review Board (IRB), and overall oversight of clinical trial conduct, including establishment of the Office for Human Research Protections in 2000. All of these effects have triggered a dramatic increase in the number of IRBs at major research institutions over the past 10 years to handle these expanding regulatory and educational tasks, which ultimately protect human subject safety.
The issue of subject safety is especially important for those who are critically ill, because they rarely have the capacity to consent to research and need special protection. Also, critical illness carries a high mortality. The burden is increasing with extended life expectancies and soaring medical costs, so the demand for quality research is great. However, clinical research in the ICU is fraught with ethical issues. ICU patients are very ill, and may be vulnerable or even captive to their caregivers, which may affect their ability to give informed consent. Surrogates commonly are involved and may give consent for any of several reasons: guilt, hope for a cure, reduction of pain and suffering in their loved one, or extension of the patient's life (to be with the patient longer or even to continue collecting social security payments). In several important studies in critical care, written informed consent was not used in more than 50% of the patients enrolled—a surrogate was used (11–13).
Surrogates face significant difficulties in appropriately exercising their responsibilities to grant or deny consent to study participation. The underlying clinical circumstances in many critical care trials necessitate such consent, but the legal and ethical complexities of both identifying appropriate surrogates and ensuring that they understand how to responsibly employ their decision-making authority and discretion is still an evolving field. This area requires much more thought and discussion of how to appropriately study patients who are too ill to provide informed consent while simultaneously ensuring their rights to participate in a clinical study.
Requiring informed consent in severely ill patients can affect study outcomes. Tu and coworkers reported on the impracticability of informed consent in a registry of the Canadian Stroke Network (14). In this study, despite the use of nurse research coordinators at each site and a simple yes-no checklist for patients/surrogates to complete for informed consent, the participation rate (i.e., the number of patients who consented divided by the number of patients eligible for registry) was only 39% to 50%. Some of the most common reasons for nonparticipation included the patient leaving the hospital before they could be approached and unsuccessful attempts to contact the patient. As a result of the poor participation rate, an unintended patient selection bias was noted. The in-hospital mortality rate was much lower among enrollees versus those who were not enrolled (6.9% versus 21.7%; risk ratio [RR], 3.13; 95% confidence interval, 2.65–3.70, p< 0.001). Thus, the patients ultimately enrolled in the registry were not representative of the patients seen at the study institution. In addition, the investigators estimated that about CA $500,000 was spent on consent-related issues alone during the first 2 years of the study (14). Thus, study investigators need to monitor participation rates during study recruitment to ensure that the study population will be representative and therefore the study results will ultimately be generalizable.
DISSEMINATION OF STUDY RESULTS
Ethical clinical trial conduct also extends to dissemination of study results, to both the medical community and general public. Two recent studies provide useful examples of how this can be poorly or effectively accomplished.
Perhaps the most recent notorious example is the Vioxx Gastrointestinal Research (VIGOR) study, which ultimately led to the removal of rofecoxib from the market. Originally published in 2000, the concern was raised that the published study article did not fully disclose all of the thrombotic complications that were observed in the actively treated group (15). Merck and Co., Inc. (Whitehouse Station, NY) stated that the three acute myocardial infarctions were not included in the published paper because the events occurred after a prespecified cut-off point for data analysis. The events in question occurred 3 weeks after the cut-off point.
Conversely, the designers of the NETT (described in the DISCUSSION HIGHLIGHTS at the end of this article) recognized the potential for complications with the study treatment and defined criteria that would prompt an early study end for patients who met those criteria (4, 5). The NETT inclusion/exclusion criteria, because of the clinical equipoise for both the medical community and individual investigators who designed the trial, were purposely broad. The data and safety monitoring board (DSMB) met every 3 months and examined 12 variables to identify subgroups of patients who might not benefit or might be at risk from lung volume reduction surgery. In April 2001, the DSMB identified a set of clinical characteristics that resulted in a higher mortality rate and little benefit after LVRS. The researchers published those data in October of that year and the NETT protocol was modified to exclude those patients. This was possible because the results were disseminated quickly to the medical and lay press (5).
RACE ISSUES
Another contentious issue that has been brought to the forefront in recent years is the impact of race on healthcare delivery and disease outcomes. Race has been associated with a variety of factors that affect disease outcome, including preventive care, access to interventions, exposure to qualified physicians and specialized services, and access to high-quality clinical research. Some of the recent findings regarding medical interventions in African Americans are outlined in Table 2 (16–21). Race is an important consideration not only for medical care equity but also because race can affect clinical outcomes due to differences in genetics and environment. Genetic differences among races can influence susceptibility to disease and modulation of treatment (Table 3) (22–25). With regard to environmental influences, there are differences among races in typical dwelling locations, types of occupations, educational levels, socioeconomic class, and access to healthcare, all of which affect the health of each patient.
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One of the few ethical issues about which there is little conflict is financial disclosure. The boundary between clinical care and clinical research should be definite and clear. It is ethically inappropriate for investigators to achieve personal financial gain via trial conduct. This includes not being employed by the entity performing or funding the investigation, not owning equity in the entity conducting the clinical trial, and not using insider information to buy equity or to communicate with financial institutions prematurely the trial results.
While the integrity of industry-sponsored research has been focused mainly on financial conflicts of interest and study sponsors, other potential biases are not commonly addressed, such as the role of the sponsor in study design and the investigator's access to data and control over publication. In 2001, the International Committee of Medical Journal Editors (ICMJE) revised its "Uniform Requirements for Manuscripts Submitted to Biomedical Journals," which called for "full disclosure of the sponsor's role in the research, as well as assurances that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data, and control all editorial and publication decisions" (26–28). Schulman and coworkers conducted a survey of American medical schools to determine the number of provisions in clinical trial agreements between medical schools and industry sponsors, as an indirect measure of compliance to the ICMJE requirements. As shown in Table 4, the extent of these provisions varies widely and includes a wide range of possible roles involving trial design, access to data, and publication of results (26). Although they note particular limitations in their survey, the study authors conclude that "academic institutions routinely engage in research that fails to adhere to ICMJE guidelines for trial design, access to data, and publication rights. Our findings suggest that a reevaluation of the process of contracting for clinical research is urgently needed" (26).
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CONCLUSIONS
Clinical research is vital to clinical care. In modern medicine, more research is being conducted by more investigators, in more organizations, in more disciplines than ever before. While this environment creates enormous opportunities for advances in healthcare, it also poses numerous challenges to the ethical conduct of clinical trials and raises numerous heretofore unconsidered issues. Thus, we now have an ever-expanding need for the evaluation and treatment of ethical standards for the conduct of clinical trials.
DISCUSSION HIGHLIGHTS
The Ethics of Sponsoring a Clinical Trial
DR. ZAB MOSENIFAR (Cedars-Sinai Medical Center, Los Angeles, CA): Which entities should be sponsoring and conducting clinical trials? You can really exert equipoise when you have a removed and independent entity.
DR. CRINER: Good question, for which I have no answer. Even in the NETT trial, there was a lot of suspicion that Medicare had the most to gain by censuring a therapy that might be part of clinical practice to save money. If we only rely upon governmental funds [i.e., CMS] to do research, we're going to be very limited, especially with drug research, in getting important therapy out into practice. I hope that the resurgence of involvement by IRBs in the education/training of investigators, trial monitoring, design, and agreements [with universities] would help to counter that balance where the pharmaceutical industry, in some cases, might go astray.
The VIGOR Trial
DR. CRINER: From personal experience, the pharmaceutical industry has been careful to separate themselves from an economic gain in most cases. But, with case of the VIGOR trial, it's hard to know what Merck was thinking when they didn't include all the adverse events that occurred.
DR. ROBERT R. FENICHEL (Independent Consultant, Washington, DC): A recently published response from non-Merck authors spelled out why those cases weren't included (29). They said that prior to breaking the blind, they settled upon the protocol as to which events would count. The most solid interpretations of any data are built around protocols that were frozen before the blind is broken, and that is the approach that the VIGOR investigators tried to take. So, I don't know how to interpret that case, but to say that it is a simple case of the sponsor's malfeasance I think is an extraordinarily facile approach.
DR. MOSENIFAR: I have significant issues with that. There are degrees of cutoffs and boundaries of reasonableness. April 15th is the cutoff for the IRS. It is defined by tradition. But, if, in a clinical trial, three patients die 5 days or 1 week after the cutoff, I have issues with the definition of "cutoff" because the deadlines are somewhat artificial. Although they're agreed upon, but if events of such magnitude happen a few days or a few weeks after that preordained dateline, then people just ignore that?
DR. FENICHEL: No, of course not. But we have to see if the outcomes numbers change with those data. Suppose during the whole trial that there was virtually no difference between the two treatment groups, but 1 week after the cutoff half of the patients taking rofecoxib died. If that had been the case, then no reasonable description of the trial could have ignored the post-cutoff data; but that's a very different story from what happened. In the VIGOR study, the adverse event ratio was about 4.25:1, and with three additional deaths, it increased to 5:1 (30). The overall message did not change. If the message is not changing, it's appropriate to say protocols matter, the rules matter, and the best description is the description based upon the pre-agreed criteria.
DR. HENRY SILVERMAN (University of Maryland School of Medicine, Baltimore, MD): In the spirit of increased scrutiny, there should be more sensitivity and a lower threshold to report all the data, irrespective of whether they are in the protocol. Having said all that, I'm not trying to explain the intent as to why the data were not reported.
ACKNOWLEDGMENTS
The technical assistance provided for this symposium by Mary Gabb, M.S., is gratefully appreciated.
FOOTNOTES
This article was funded by Boehringer Ingelheim and by Pfizer, Inc.
Conflict of Interest Statement: G.J.C. has received research grants from Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Schering-Plough, Emphasys, and Aeris. He has also participated on Advisory CTES of Otsuka, Ortho Biotech, and Schering-Plough. None of these activities are related to the subject matter of this manuscript. Z.M. has received $4,500 in 2004, 2005, and 2006 from Boehringer-Ingelheim and $4,000 from Pfizer in 2006 for speaking at conferences organized by these companies. He is an investigator in the Uplift trial. The amount of this grant is $11,000 over a period of 4 years. Z.M. received no salary or consulting fees, however. R.R.F. has served as a consultant to AVEO Pharmaceuticals, Abbott Laboratories, BioCryst Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Bracco Diagnostics, Bristol-Myers Squibb, CV Therapeutics, CoTherix, Corgentech, Daiichi Sankyo Pharma, Eli Lilly & Company, Eyetech Pharmaceuticals, Forest, H. Lundbeck A/S, Hope Medical Enterprises, Idun Pharmaceuticals, Janssen Pharmaceuticals, Johnson & Johnson, KAI Pharmaceuticals, King Pharmaceuticals, Laboratoires Fournier, Lifescape BioSciences, Luitpold Pharmaceuticals, LungRx, MDS Pharma, MedImmune, Medtronic, Merck, Mylan-Bertek Pharmaceuticals, Navitas Pharma, Neurochem, NicOx, NovaCardia, Orion Pharma, Otsuka America Pharma, Prestwick Pharmaceuticals, Reliant Pharmaceuticals, Roxane Laboratories, Sanofi-Aventis, Schwarz BioSciences, Scios, Servier Canada, Shire Development, Solvay, TAP Pharmaceutical Products, Teijin America, Vanda Pharmaceuticals, Watson Pharma, Wyeth-Ayerst, and Yamanouchi Pharma America. H.S. received $2,000 from Boehringer-Ingelheim in 2006 for a presentation at a workshop.
(Received in original form January 3, 2007; accepted in final form February 22, 2007)
REFERENCES
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