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* From the Department of Clinical Bioethics (Dr. Miller), National Institutes of Health, Bethesda, MD; and Pulmonary and Critical Care Medicine (Dr. Shorr), Walter Reed Army Medical Center, Washington, DC.
Correspondence to: Franklin G. Miller, PhD, Department of Clinical Bioethics, Clinical Center, National Institutes of Health, Bldg 10, Room 1C118, Bethesda, MD 20892-1156; e-mail:fmiller{at}nih.gov
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Abstract |
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 TOP Abstract Trial Description and ResultsEthical AssessmentDiscussionReferences |
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Key Words: ethics • industry-sponsored clinical trials • placebo controls
During the past decade, pharmaceutical industry sponsorship of clinical trials has increased dramatically. Approximately 70% of funding for clinical trials now comes from pharmaceutical or biotechnology firms.1 In parallel, there have been striking changes in the conduct of randomized controlled trials (RCTs).2 Whereas 80% of industry funding for clinical research went to academic medical centers in 1991, by 1998 their share of industry funding had dropped to 40%.1 Increasingly, the pharmaceutical industry has turned to community physicians for access to patient volunteers to participate in studies coordinated by contract research organizations and site management organizations.1 2 3 These private physicians receive fees for each patient enrolled in an RCT.3 The demand for patients has led to increasing advertising to recruit volunteers and the offer of monetary compensation for trial participation.4 Typically, ethical review of industry-sponsored clinical trials conducted outside academic medical centers is undertaken by for-profit "noninstitutional" review boards.2 5 6 Concerns have been raised about the potential for this new system of managing clinical trials to compromise both the scientific quality of clinical research and the protection of research participants.1 2
In this article, we explore a range of ethical issues posed by industry-sponsored RCTs by examining in depth a case study of a single clinical trial—a placebo-controlled study of a new inhaled corticosteroid for the treatment of asthma. Certainly no single clinical trial is representative of the universe of industry-sponsored RCTs. However, the structure, design, and conduct of the clinical trial selected for our case study raise generic ethical issues. To guide our ethical analysis, we adopt a proposed ethical framework for evaluating clinical research focusing on seven ethical requirements: (1) scientific value, (2) scientific validity, (3) fair subject selection, (4) favorable risk/benefit ratio, (5) independent review, (6) informed consent, and (7) respect for enrolled subjects.7
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Trial Description and Results |
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TOPAbstractTrial Description and ResultsEthical AssessmentDiscussionReferences |
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12 years. Entry criteria required that patients have a history of asthma lasting at least 6 months and have been maintained on treatment with inhaled corticosteroids for at least 30 days prior to study enrollment. At baseline, these patient volunteers had a mean FEV1 of 76% of predicted. After an assessment phase of 1 to 2 weeks, the research participants discontinued their prescribed inhaled corticosteroids and were randomized to one of four study arms: MF, 100 µg bid (n = 57); MF, 200 µg bid (n = 56); BDP, 168 µg bid (n = 57); and placebo (n = 57). Patients were enrolled at 15 private-physician practice groups in the United States. The study was funded by a major pharmaceutical company, the manufacturer of both MF and BDP. One human subjects review board approved the study.
The primary efficacy variable evaluated in the trial was mean change in FEV1. Secondary outcome measures included asthma symptom scores, albuterol use, nocturnal awakening requiring albuterol treatment, and physician assessments of response to study treatment. The study was designed to have 90% power (at 
= 0.05) to detect a 12% difference in FEV1 between treatment arms.
The FEV1 and asthma symptom scores were significantly improved in all three active treatment arms as compared with placebo. Those patients randomized to placebo treatment on average experienced symptom worsening and had significantly greater albuterol use. Forty-four percent of the patients in the placebo arm were forced to discontinue study participation because of asthma worsening, as opposed to approximately 9% of those receiving inhaled corticosteroid. Physician investigators’ ratings of response to therapy indicated significant improvement in the three active treatment groups as compared with placebo. The percentage of patients rated much worse at the conclusion of the trial was 10% for those receiving MF at 100 µg, 11% for MF at 200 µg, 23% for BDP, and 63% for placebo. There was no significant difference between the three active-treatment arms with respect to study outcome variables, although the larger improvement in FEV1 in the group receiving the higher dose of MF, as compared with the other two active-treatment arms, "approached statistical significance."
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Ethical Assessment |
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TOPAbstractTrial Description and ResultsEthical AssessmentDiscussionReferences |
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The lack of a clear research question and selection of study arms for this trial suggest that it was undertaken to serve marketing or licensing, rather than scientific, purposes. By evaluating MF at two escalating doses in comparison with placebo and a single dose of BDP, likely to be comparable to the lower dose of MF, the trial appears designed to showcase the sponsor’s newer drug.
Scientific Validity
Clinical trials must be designed with methodologic rigor sufficient to provide a scientifically valid test of study hypotheses. Placebo controls are often methodologically necessary or desirable to validate clinical trials comparing active treatments when these trials are designed to test equivalence rather than superiority.11
12
Without a placebo control, a finding of no difference between a new treatment and a standard active comparator does not demonstrate equivalence or the efficacy of the new treatment. It remains possible that neither of the two active treatments were superior to placebo in the study sample. Placebo controls are needed to validate treatment efficacy in such active-controlled trials enrolling patients with conditions known to have high rates of placebo response, or when existing treatments have not been shown to be consistently more effective than placebo in previous RCTs.
These methodologic criteria for the use of placebo controls to validate active-controlled trials do not hold in the case of patients with persistent asthma who have been receiving inhaled corticosteroids prior to trial participation. Historically, the placebo response rate in RCTs for asthma therapy is low.13 Moreover, with patients previously maintained on treatment with inhaled corticosteroids, there is a minimal chance of a positive placebo response. Indeed, as shown in previous placebo-controlled trials14 15 16 and further confirmed in this study,8 such patients typically experience symptom exacerbation when inhaled corticosteroids are withdrawn in the course of placebo assignment. Frequently, this leads to trial discontinuation. In addition, inhaled corticosteroids are highly effective, and have become the standard of care, in the treatment of moderate persistent asthma.17 It follows that use of a placebo control was not methodologically necessary to compare the efficacy of MF with BDP in this patient population. This conclusion is further supported by the fact that at the same time as it funded this trial, the industry sponsor also funded a considerably larger trial with similar entry criteria, study duration, and outcome variables in 20 countries, not including the United States, comparing MF in three escalating doses to a single dose of fluticasone propionate without a placebo arm.18
The article reporting trial results did not explain the rationale for a placebo control; however, considerations of efficiency, perceived methodologic rigor, and regulatory approval may have influenced trial design. Smaller study samples typically are required to demonstrate efficacy of a new treatment as compared with placebo than to demonstrate equivalence or superiority to an active comparator.19 Because the placebo-controlled RCT is widely regarded as the "gold standard" for testing treatment efficacy, clinical trials may be viewed as more rigorous when they include a placebo arm, regardless of whether use of placebo is necessary to answer valuable scientific questions. Moreover, the US Food and Drug Administration (FDA) favors, but does not necessarily require, placebo controls.20 Nonetheless, these considerations do not justify withholding proven effective treatment in RCTs when placebo controls are not needed to test study hypotheses.
Fair Subject Selection
Subject selection for clinical trials should be fair so that vulnerable or disadvantaged groups are not exploited. The inclusion of children in the placebo-controlled trial comparing MF with BDP raises a question of fair subject selection. At the time this trial was conducted, the FDA did not have specific regulations concerning the involvement of children in clinical trials. Recently, the FDA has issued an interim rule essentially incorporating the regulations governing research with children promulgated by the US Department of Health and Human Services.21
This trial would not be approvable under the US Department of Health and Human Services regulations,22
now applicable to research under the jurisdiction of the FDA.
The likelihood that children previously maintained on treatment with inhaled corticosteroids would get worse after having this treatment withdrawn in the context of receiving placebo14 15 16 would make this trial greater than minimal risk. It might be thought this study could be approved as "research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects,"22 because two thirds of the trial participants would receive inhaled corticosteroids. However, for this category of research, the regulations contain two requirements that this study would not satisfy: "(a) the risk is justified by the anticipated benefit to the subjects"; and "(b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches."22 Clearly, the trial did not offer direct medical benefits to the children randomized to placebo treatment that would justify the risks of withholding needed inhaled corticosteroid therapy; nor would they have a risk/benefit ratio just as favorable on placebo treatment in this trial as they would if they continued with their prescribed treatment.
The placebo intervention in this trial might be considered as posing greater than minimal risk without the prospect of direct benefit to the subjects. If so, it must meet three additional requirements: (1) that the risk of receiving placebo treatment for 12 weeks is no more than "a minor increase over minimal risk"; (2) that the experiences of children randomized to placebo treatment are comparable to those that children with moderate persistent asthma would typically encounter; and (3) that the use of the placebo control "is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition."22 This placebo-controlled trial would not satisfy this third requirement, because of its questionable scientific value and the lack of methodologic rationale for use of placebo. It follows that the inclusion of children in this trial was not justifiable under federal regulations.
Favorable Risk/Benefit Ratio
In discussing the inclusion of children in this trial, we have anticipated to some extent the discussion of risk/benefit assessment. Two types of benefits can potentially justify the risks of clinical trials. The potential medical benefits to individual participants may outweigh the risks posed by the research interventions. If the trial does not offer the prospect of medical benefit for some or all subjects that is adequate to justify the risks, then the risks may be justifiable by the scientific knowledge to be gained by the study. Clinical trials have a favorable risk/benefit ratio when risks are minimized, consistent with meeting the requirements of scientific value and validity, and justified by the benefits to subjects and/or the anticipated knowledge to be gained by the study.
For those patients randomized to placebo treatment in the case study, there was no favorable balance of potential medical benefits to risks, because medically indicated treatment with inhaled corticosteroids was discontinued for up to 12 weeks. The anticipated scientific knowledge to be gained by this study did not justify the risks to subjects receiving placebo, because the placebo control was neither necessary nor desirable for answering a valuable scientific question concerning the efficacy or safety of MF or its relative therapeutic value as compared with BDP.
Independent Review
To ensure the protection of human subjects, all clinical trials should be reviewed and approved prospectively by an independent review committee that examines a detailed protocol explaining the plan for conducting the study and the informed consent documents. Research review committees should assess and modify planned clinical trials in accordance with the other six substantive ethical requirements. According to the article reporting the results of this trial, "The protocol, case report form, and patient informed consent were reviewed by an institutional review board responsible for the study center."8
Nothing more is mentioned about the composition of the review board. We presume that a centralized, for-profit review board was used, in view of the fact that this trial was conducted by multiple groups of private physicians and funded by a pharmaceutical firm. Our assessment of the trial with respect to ethical considerations of scientific value, scientific validity, and favorable risk/benefit ratio raise doubts about the adequacy of independent review of this study.
Commercial review boards receive funding from research sponsors. This financial relationship poses the problem of conflict of interest, with the potential to bias review and approval of industry-sponsored clinical trials. Institutional review board (IRBs) at academic medical centers may also have conflicts of interest, in view of the financial benefits to the research institution that flow from the conduct of industry-sponsored clinical trials.
Informed Consent
Informed consent demands that potential study participants receive a thorough and understandable disclosure of the purpose of the clinical trial; basic design features, such as randomization, blinding, and placebo controls; risks and benefits of research procedures; and alternatives to research participation. Additionally, potential subjects should be free of coercion or undue influence and be informed that they have a right to withdraw from the study at any time without penalty. Although no valid inferences can be drawn about the quality of informed consent for participants from the article describing trial results, features of the study design and conduct suggest relevant ethical issues. To be adequate, disclosure to the potential subjects should have explained how participation in this placebo- controlled trial differs from routine treatment of asthma in clinical practice. Particularly important would be to inform prospective participants about the risks of symptom worsening for those randomized to placebo treatment. Additionally, emerging standards concerning the management of financial conflicts of interest suggest that the informed consent process for such an industry-sponsored clinical trial should disclose the source of funding for the trial and the amount of payment for recruiting individual subjects.23
24
The report of the trial does not describe the extent to which the participants were in a physician/patient relationship with the investigators prior to entry into the trial. The power dynamics of an ongoing clinical relationship may compromise patients’ voluntary choice to participate in a study recommended by their treating physicians.3 Undue financial inducement also has the potential to compromise voluntary choice of research participation. The article reporting this trial does not mention financial incentives, including free treatment and payment for participation.
Respect for Enrolled Subjects
Enrolled subjects must be respected and protected by careful monitoring of their conditions during trial participation, by measures to maintain privacy and confidentiality, and by informing them both of any new information about risks and potential benefits of research interventions and what was learned by the study in general and with respect to their own participation. We see nothing in the design or conduct of this study, as reported in the article describing its results, that raises ethical questions about protecting the welfare and rights of subjects during study enrollment. The article described clear and reasonable criteria for withdrawing participants from the study in the event of "clinically significant worsening of asthma."8
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Discussion |
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TOPAbstractTrial Description and ResultsEthical AssessmentDiscussionReferences |
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Most of the ethical questions raised by this trial concern the use of a placebo control without its being necessary to answer a valuable scientific question or to ensure the scientific validity of the study findings. This unnecessary design feature posed risks to trial participants not justified by potential medical benefits to the research participants or the potential knowledge to be gained by the study.
The systematic ethical framework that we deployed for this case study7 offers a valuable tool for IRB members in reviewing clinical research protocols and for peer reviewers and journal editors reviewing manuscripts describing the results of clinical research. IRBs should demand that sponsors and investigators justify the use of placebo controls whenever they involve withdrawal or withholding of proven effective therapy, and they should not approve placebo-controlled trials under these conditions without an adequate rationale. In some cases, as in trials of new treatments for moderate allergic rhinitis, the risks to subjects randomized to placebo treatment may be minimal, thus permitting placebo controls as long as they are useful to promote scientific value or validity. As the risks to trial participants from placebo assignment increase, the methodologic rationale for justifying placebo controls must be more compelling. Scientific journals should also require authors to justify the use of placebo controls whenever patients randomized to placebo treatment must forgo receiving either proven effective therapy or promising investigational treatment.
No single clinical trial can be representative of industry-sponsored RCTs. However, the ethically questionable features of this case study, especially the use of placebo controls in the face of known effective treatment without a solid methodologic rationale, are not unique to this trial.14 15 In addition, all industry-sponsored trials conducted by private physicians raise issues of informed consent comparable to those discussed here. Industry-sponsored clinical trials conducted by investigators at academic medical centers and government-funded clinical trials may also have ethical problems. Empirical research is needed that compares industry-sponsored and government-sponsored clinical trials with respect to key ethical requirements. The findings of such systematic research could provide valuable guidance on the adequacy of the current regulatory system and whether additional safeguards should be implemented.
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Acknowledgements |
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Footnotes |
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The opinions expressed are those of the authors and do not necessarily represent the position or policy of the National Institutes of Health, the Public Health Service, the Department of Health and Human Services, the Department of the Army, or the Department of Defense.
Dr. Shorr is a member of the speaker’s bureau for Glaxo-Smith-Kline.
Received for publication July 25, 2001. Accepted for publication November 29, 2001.
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References |
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This article has been cited by other articles:
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  D. L. Helman Jr, A. W. Brown, J. L. Jackson, and A. F. Shorr Analyzing the Short-term Effect of Placebo Therapy in Pulmonary Arterial Hypertension: Potential Implications for the Design of Future Clinical Trials Chest, September 1, 2007; 132(3): 764 - 772. [Abstract] [Full Text] [PDF]
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 M. J. Coffey, B. Wilfond, and L. F. Ross Ethical Assessment of Clinical Asthma Trials Including Children Subjects Pediatrics, January 1, 2004; 113(1): 87 - 94. [Abstract] [Full Text] [PDF]
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 M. J. Tobin Conflicts of Interest and AJRCCM: Restating Policy and a New Form to Upload Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1161 - 1164. [Full Text] [PDF]
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G. B. Fromm End-of-Life Care and Eudaemonia Chest, January 1, 2003; 123(1): 16 - 18. [Full Text] [PDF]
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B. G. Bigby and T. D. Bigby What About the Role of the US Food and Drug Administration? Chest, November 1, 2002; 122(5): 1869 - 1870. [Full Text] [PDF]
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