Addressing the Ethical Problems of Randomized and Placebo-Controlled Trials of CPAP

Jason H. T. Karlawish and Allan I. Pack

University of Pennsylvania, Philadelphia, Pennsylvania

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In the February 2001 issue of the Journal, (pp. 344-348) Faccenda and colleagues describe results of a randomized placebo-controlled trial of continuous positive airway pressure (CPAP) on blood pressure in the sleep apnea/hypopnea syndrome (1). The study's results are provocative. They show that CPAP causes normotensive patients with sleep apnea to experience small but significant decreases in 24-h diastolic blood pressure. To obtain these useful data, the investigators employed a placebo capsule comparison groupa technique they have used previously (2). The subjects of this ethics committee approved study were told that this capsule might improve the tone in their upper airway muscles, thereby potentially alleviating their disorder. This design raises two significant questions: Why are investigators using placebo controls to test the efficacy of nasal CPAP to treat sleep apnea? When is it ever appropriate to deceive a patient in research?

Why are investigators using placebo controls to test the efficacy of nasal CPAP to treat sleep apnea? Wright and colleagues' (3) review of CPAP argued that treatment with nasal CPAP could not be justified without evidence from randomized controlled clinical trials. Absent such evidence, they argued that health authorities should not pay for this treatment. Their call for evidence-based medicine, therefore, had the potential to deny many patients this from of therapy. New evidence has fortunately been rapidly forthcoming (4, 5), and there is now consensus that data for severe sleep apnea meets the level of evidence (6, 7) required by Wright and coworkers, although data are not as convincing for more mild disease.

Currently, placebo-controlled trials to test the efficacy of nasal CPAP in treatment of sleep apnea employ one of two approaches. One approach, pioneered by the Oxford group in England, is to use sham CPAP. In its original formulation, the applied pressure was at low level (subtherapeutic) (4, 5). There is a more recently described sham CPAP that has essentially zero nasal pressure while avoiding reinhalation (8). The alternative placebo approach that Faccenda and colleagues (1) employ involves administering a capsule that has no likelihood of improving upper airway motor tone, but subjects are told that it might.

Faccenda and coworkers argue that sham CPAP has potential problems as a placebo (1). But their arguments are not supported by current data. In particular, the major study using this approach showed a surprisingly small difference in average nightly nasal CPAP use between active and sham CPAP (5.4 h compared to 4.6 h), and no evidence that using sham CPAP during sleep made subjects excessively during the daytime (4).

Regardless of which comparison group is chosen, an additional ethical and scientific issue remains in the conduct of controlled trials in CPAP research. This involves deception. Faccenda and colleagues told the subjects that the placebo pill might improve their upper airway tone. Trials using sham CPAP may also need to withhold that the subject might receive a sham intervention. The concerns here are that disclosure will influence a subject's perception of the benefit of the intervention and will allow them to unblind their intervention.

Clearly, the choice of control to design trials to settle Wright's call for an evidence-based practice raises interrelated issues of ethics and science. These issues involve the potential research risks to subjects and the value of the knowledge gained. The clinically valuable knowledge clinicans, patients, and healthcare authorities need is to know how well CPAP works. Perhaps the study that needs to be done to settle these issues is a comparison of CPAP with all scientifically and ethically viable comparison groups: sham CPAP, placebo pills, and even no intervention. Investigators should also test whether disclosing that the CPAP may be a sham intervention affects enrollment and retention, and the results of primary endpoints. In summary, there are several testable hypotheses about the "placebo effect" in CPAP research and results from studies that can answer them will help to definitively settle the issue of what is the appropriate comparison group.

When is it ever appropriate to deceive a patient in research? The problem with deception is that it is a research risk. It is a "risk" not in the traditional sense of physical or psychological harm. Rather, it is an affront to the dignity of an individual. In this sense, deception is like a violation of confidentiality or privacy. To deceive or breach confidentiality is to disrespect a person.

Investigators have two ways to justify research risks: (1) obtain a subject's informed consent, and (2) assure, based on the United States Common Rule, that the "research risks should be reasonable with respect to the potential benefits, if any, to the subjects and the importance of the knowledge that may reasonably be expected to result (9)[45CFR46.111)(a)(2)]." True, Faccenda's study was not conducted in the United States, so the U.S. Common Rule does not apply. But regardless of the statutory reach of the Common Rule, reasonable people would agree with this general point that is derived from the principle of beneficence.

In a case of deception, a full and free informed consent is not possible because, by definition, the subject is not receiving a disclosure of the relevant facts he or she needs to make an informed consent. In such a case, respect for persons through the mechanism of informed consent cannot serve as the means to justify research risks. Thus, a risk-benefit and risk-knowledge balance solely justifies research risks.

The charge to the investigators is to justify deception on the basis of the benefits to the subjects and the importance of the knowledge to be gained. Faccenda and colleagues (1) make a case that is largely based on the importance of the knowledge to be gained from this research. Having completed this study they are publishing the knowledge so that people may benefit from it. But they need to return to the issue of protecting human subjects. Did the 68 subjects benefit from the knowledge that was gained? One way to achieve this is to feed the research results back to the subjects. Specifically, after the study is over to tell the subjects what their individual results were, the group results, and the truth about the pill that was advertised as a safe and potentially effective treatment.

The Common Rule recognizes this requirement to feedback results. The Rule states that in cases when informed consent is waived or modified, such as in deception, "whenever appropriate, the subjects will be provided with additional pertinent information after participation (9)[45CFR46116(d)(4)]." In short, the investigators, using the approach adopted in this study, should be advised to sit down one-on-one and debrief each subject.

Empirical research supports the theory that people enroll in research for three reasons: they hope to benefit themselves, they want to contribute to knowledge, and they trust the investigator who is running the study (10). Deception without proper amends to provide information to the subjects might significantly undermine their desire to contribute to important knowledge and the trust they place in investigators.

Faccenda and coworkers, and others, are to be congratulated for responding to the challenge laid down by Wright and colleagues (3). As medicine uses research to gain this valuable knowledge, it needs to assure our patients and research subjects that this research is ethical. Deception can only be appropriate if there is full debriefing to the research subjects after completion of the study and efforts to assure that they benefit from the knowledge gained. Finally, we need a definitive trial to establish what is the proper comparison group for CPAP research: sham CPAP or pills and whether deception is even necessary to produce valid and valuable knowledge. Consensus on this matter has both a scientific and an ethical warrant. Our patient and research subjects trust us to do this.

	References

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1. Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 2001; 63: 344-348 .

2. Engleman HM, Kingshott RN, Wraith PK, Mackay TW, Deary IJ, Douglas NJ. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159: 461-467 [Abstract/Free Full Text].

3. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. BMJ 1997; 314: 851-860 [Abstract/Free Full Text].

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7. Wright J, Sheldon T. The efficacy of nasal continuous positive airway pressure in the treatment of obstructive sleep apnea syndrome is not proven. Am J Respir Crit Care Med 2000; 161: 1776-1778 [Free Full Text].

8. Farre R, Hernandez L, Ontserrat JM, Rotger M, Ballester E, Navajas D. Sham continuous positive airway pressure for placebo-controlled studies in sleep apnoea [letter]. Lancet 1999; 353: 1154 [Medline].

9. Department of health and Human Services. Common Rule, 45 CFR 46. Federal policy for the protection of human subjects; Notices and rules. Fed Reg. 1991;56:28003-28032.

10. Karlawish JHT, Casarett D, Klocinksi, J, Sankar P. How do AD patients and their caregivers decide whether to enroll in a clinical trial? (In press)