Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 1: Ethical and Scientific Issues

Placebo-controlled trials are used extensively in the development of new pharmaceuticals. They are sometimes challenged as unethical in settings in which patients could be treated with an existing therapy (1-7). The issues of when placebo controls are ethically acceptable and when they are scientifically necessary are important and worthy of discussion. The Ethics of Placebo Controls The Declaration of Helsinki The Declaration of Helsinki (8) is an international document that describes ethical principles for clinical investigation. Those who contend that placebo controls are unethical whenever known effective therapy exists for a condition usually cite the following sentence in the Declaration as support for that position: In any medical study, every patientincluding those of a control group, if anyshould be assured of the best proven diagnostic and therapeutic method. We believe that an interpretation of this sentence as barring placebo controls whenever an effective treatment exists is untenable. First, the requirement that all patients receive the best proven diagnostic and therapeutic method would bar not only placebo-controlled trials but also active-control and historically controlled trials. When effective treatment exists, the patient receiving the investigational treatment instead of the established therapy is clearly not getting the best proven treatment. Second, it does not seem reasonable to consider as equivalent all failures to use known effective therapy. Historically, concerns about placebo use have usually arisen in the context of serious illness. There is universal agreement that use of placebo or otherwise untreated controls is almost always unethical when therapy shown to improve survival or decrease serious morbidity is available. But in cases in which the treatment does not affect the patient's long-term health, an ethical imperative to use existing therapy is not plausible. Can it be, for example, that because topical minoxidil or oral finasteride can grow hair, a placebo-controlled trial of a new remedy for baldness is unethical? Is it really unethical to use placebos in short-term studies of drugs for allergic rhinitis, insomnia, anxiety, dermatoses, heartburn, or headaches in fully informed patients? We do not believe that there is a reasonable basis for arguing that such studies and many other placebo-controlled studies of symptom relief are unethical and that an informed patient cannot properly be asked to participate in them. Third, there is good reason to doubt that the cited phrase was intended to discourage placebo-controlled trials. The phrase under discussion was not part of the original 1964 Declaration but was added in 1975 to reinforce the idea that the physicianpatient relationship must be respected just as it would be in a purely therapeutic situation not involving research objectives (8). In the explanation accompanying the 1975 change, the issue of placebo-controlled trials was not even mentioned (9). The American Medical Association (10), the World Health Organization (11), and the Council for International Organizations of Medical Sciences (12) have rejected the position that the Declaration uniformly bars placebo-controlled trials when proven therapy is available. Informed Consent in Placebo-Controlled Trials Patients asked to participate in a placebo-controlled trial must be informed of the existence of any effective therapy, must be able to explore the consequences of deferring such therapy with the investigator, and must provide fully informed consent. Concern about whether consent to participate in trials is as informed as we would like to believe is valid, but these concerns apply as much to the patient's decision to forgo known effective treatment and risk exposure to a potentially ineffective or even harmful new agent in an active-control trial as to a decision to accept possible persistence of symptoms in a placebo-controlled trial. Thus, this problem is not unique to placebo-controlled trials. For the above reasons, we conclude that placebo-controlled trials may be ethically conducted even when effective therapy exists, as long as patients will not be harmed by participation and are fully informed about their alternatives. Although in many cases application of this standard will be fairly straightforward, in others it will not, and there may be debate about the consequences of deferring treatment (13). Assessment of Effectiveness with Active-Control Trials Clinical trials that, because of deficiencies in study design or conduct, are unlikely to provide scientifically valid and clinically meaningful results raise their own ethical concerns (12, 14). The remainder of this paper will address the inability of commonly proposed alternatives to placebo-controlled trials to evaluate the effectiveness of new treatments in many medical settings. Active-Control Equivalence Trials (Noninferiority Trials) The ability to conduct a placebo-controlled trial ethically in a given situation does not necessarily mean that placebo-controlled trials should be carried out when effective therapy exists. Patients and physicians might still prefer a trial in which every participant is given an active treatment. What remains to be examined is why placebo-controlled trials (or, more generally, trials intended to show an advantage of one treatment over another) are frequently needed to demonstrate the effectiveness of new treatments and often cannot be replaced by active-control trials showing that a new drug is equivalent or noninferior to a known effective agent. The limitations of active-control equivalence trials (ACETs) that are intended to show the effectiveness of a new drug have long been recognized and are well described (15-33) but are perhaps not as widely appreciated as they should be. A recent proposed international guideline on choice of control group addresses this issue in detail (33). The Fundamental Problem: Need for Assay Sensitivity There are two distinct ways to show that a new therapy is effective. One can show that the new therapy is superior to a control treatment, or one can show that the new therapy is equivalent to or not worse by some defined amount than a known effective treatment. Each method can be valid, but each requires entirely different inferential approaches. A well-designed study that shows superiority of a treatment to a control (placebo or active therapy) provides strong evidence of the effectiveness of the new treatment, limited only by the statistical uncertainty of the result. No information external to the trial is needed to support the conclusion of effectiveness. In contrast, a study that successfully shows equivalencethat is, little difference between a new drug and known active treatmentdoes not by itself demonstrate that the new treatment is effective. Equivalence could mean that the treatments were both effective in the study, but it could also mean that both treatments were ineffective in the study. To conclude from an ACET that a new treatment is effective on the basis of its similarity to the active control, one must make the critical (and untestable within the study) assumption that the active control had an effect in that particular study. In other words, one must assume that if a placebo group had been included, the placebo would have been inferior to the active control (15-33). Support for this assumption must come from sources external to the trial. Although it might appear reasonable to expect a known active agent to be superior to placebo in any given appropriately designed trial, experience has shown that this is not the case for many types of drugs. The ability of a study to distinguish between active and inactive treatments is termed assay sensitivity. If assay sensitivity cannot be assumed, then even if the new and standard treatments appear virtually identical and the confidence interval for their comparison is exquisitely narrow, the study cannot demonstrate effectiveness of the new drug. (Note that in practice, ACETs are not designed simply to show lack of a statistically significant difference between treatments. Rather, such trials are designed to show noninferioritythat the new treatment is not inferior to the control by more than a specified margin. This approach is described in the Appendix.) The best evidence that an active drug would have an effect superior to that of placebo in a given study would be a series of trials of similar design in which the active drug has reliably outperformed placebo. The ACET thus requires information external to the trial (the information about past placebo-controlled studies of the active control) to interpret the results. In this respect, an ACET is similar to a historically controlled trial. In some settings, such as highly responsive cancers, most infectious diseases, and some cardiovascular conditions, such external information is available and ACETs can and do provide a valid and reliable basis for evaluating new treatments. In many cases, however, the historically based assumption of assay sensitivity cannot be made; for many types of effective drugs, studies of apparently adequate size and design do not regularly distinguish drugs from placebo (16-18, 25, 34). More than 20 years ago, Lasagna (19) described this difficulty particularly well (reflecting long recognition of the problem among analgesiologists): a comparison between new drug and standard is convincing only when the new remedy is superior to standard treatment. If it is inferior, or even indistinguishable from a standard remedy, the results are not readily interpretable. In the absence of placebo controls, one does not know if the inferior new medicine has any efficacy at all, and equivalent performance may reflect simply a patient population that cannot distinguish between two active treatments that differ considerably from each other, or between active drug and placebo. Certain clinical conditions, such as seri