Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 2: Practical Issues and Specific Cases

In clinical trials conducted in settings where no proven effective therapy exists, the use of placebo controls (or untreated controls, where blinding of therapy is not feasible) is routine and generally uncontroversial. Two concerns about use of placebo controls arise when effective therapy is available (1). An ethical concern is that use of placebos may deny patients potentially helpful treatment. A practical concern is that placebo-controlled trials in this setting may be of little interest or value to patients or investigators and that only a comparison of the new treatment with existing treatment will provide useful data. In our accompanying paper (2), we concluded that placebo controls are ethical when delaying or omitting available treatment has no permanent adverse consequences for the patient and as long as patients are fully informed about their alternatives. We also showed why such controls are often scientifically necessary. Application of these basic principles, however, is not straightforward in every research situation. Ethical Acceptability of Placebo Controls Few would consider problematic the use of placebo-controlled trials to study treatments that relieve minor symptoms or enhance enjoyment of life. Placebo-controlled trials in these situations pose no greater risk than do the regular decisions by many patients and physicians not to use drug therapy in similar circumstances for a wide variety of reasons. In contrast, in the treatment of many serious diseases, consensus would be almost universal that placebo-controlled trials in which some patients would not receive available therapy would be unethical. We do not, for example, omit use of proven therapy in trials of new antiretroviral treatments in patients with AIDS or of new thrombolytics in patients with recent myocardial infarction. There are other situations, however, in which researchers may disagree about the acceptability or unacceptability of placebo-controlled trials. These can be categorized into several types: 1. Documented evidence of effectiveness of existing therapy is limited to effects on symptoms, but concern exists that treatment may have more important, albeit undemonstrated, long-term effects as well. 2. There is evidence of benefit of long-term treatment on mortality or major morbidity, but the effect of a shorter period of treatment on these outcomes is uncertain. 3. Some evidence of efficacy of the treatment exists but is not universally considered persuasive or sufficient to outweigh the perceived risks. 4. The effective treatment may not be available in many settings, generally because of cost considerations. Unmeasured Effects on Long-Term Outcomes The study of new antidepressants illustrates concerns about potentially important but undemonstrated treatment effects. Depression is a well-documented example of a setting in which active control trials are unreliable in assessing efficacy (2-4). Although participants in a given trial might not respond to active agents or might show a good response to placebo, it can be expected that patients receiving the placebo will have, on average, delayed or decreased relief of depression compared with patients treated with a known active agent. If a short delay (no more than a few weeks) in relieving symptoms of depression were the only consideration, there should be no ethical objection to placebo-controlled trials of new antidepressants (2). Concern might arise, however, about the possibility of increased risk for suicide in patients receiving placebo (5). Suicide is a rare event in clinical trials because patients deemed at high risk for suicide are excluded from outpatient trials of new antidepressants and trial participants are closely monitored for suicidal thoughts; a small increase in rates would therefore be difficult to detect. An evaluation of almost 2500 patients in placebo-controlled and active-control studies of the popular selective serotonin reuptake inhibitor fluoxetine, however, revealed no increase in suicides or suicide attempts among placebo-treated patients (6). Another review analyzed data on suicide and suicide attempts from all controlled trials of all antidepressants approved for marketing between 1981 and 1997 for which data on these end points were available. This review, which included almost 20 000 patients, found no difference between placebo-treated and drug-treated groups for either outcome (7). Furthermore, a recent review of data on national suicide rates showed no indication that current treatments have reduced rates of suicide in depressed or psychotic patients (8). Similar issues have arisen with respect to placebo-controlled trials in schizophrenia. Because patients treated for schizophrenia are, on average, more seriously ill than those treated for depression, the level of debate in this area has been more intense (9-12). Even so, a recent comprehensive review concluded that medication-free psychotropic research can be conducted safely if appropriate patient selection criteria and monitoring procedures are implemented (13). One specific criticism of placebo-controlled trials is the need to withdraw effective therapy from patients. Such withdrawal of therapy to allow recurrence of depression, as required before entering a study of a new agent, is not inconsistent with the current practice of withdrawing antidepressant therapy after a period of apparently successful treatment (14). Of course, withdrawal of therapy would be equally necessary in active-control studies if acute antidepressant effects were to be measured in any patients except those with newly diagnosed depression. In addition, although concerns about informed consent in patients with mental or emotional problems are legitimate (15), they are no less relevant to active-control studies (in which patients may receive an ineffective or even harmful experimental therapy) than to placebo-controlled studies. Short-Term Studies of Treatments with Known Long-Term Benefits In some cases, the ethical acceptability of placebo controls may depend on aspects of trial design, such as the duration of treatment or the population to be studied. For example, a short-term (for example, 8-week) placebo-controlled trial in patients with mild to moderate hypertension without end-organ damage might be considered acceptable, whereas a longer trial or one that enrolled patients with known hypertensive end-organ damage would be unacceptable. Although the precise length of time for which one can delay treatment without increasing the risk for cardiovascular events is not known, delaying treatment of patients with mild disease for periods at least as long as the typical clinical trial of new agents is consistent with the common practice of following patients with newly diagnosed disease for some months to confirm that hypertension persists. During this time, such nonmedical approaches as weight reduction and increased exercise are generally recommended, even though success rates with these approaches are low compared with medical treatment (16). Nonetheless, although the effect of a short delay in treatment must be small, it is not possible to establish zero risk, and some patients and physicians may even consider this short delay a concern. Lack of Universally Persuasive Data on Efficacy or RiskBenefit Ratio In some cases, identifying known effective therapy is not straightforward. A possible approach in the United States might be to use the availability of therapy approved by the U.S. Food and Drug Administration (FDA) for treatment of the condition of interest as the basis for this determination. It should be recognized, however, that FDA marketing approval does not establish treatment as standard of care, even in the United States and certainly not in other countries. An example is use of tissue plasminogen activator (tPA) in acute ischemic stroke. Tissue plasminogen activator received FDA approval in 1996 on the basis of trials conducted by the National Institute of Neurological Disorders and Stroke demonstrating a decrease in stroke-related disability (17). Even though tPA was the first approved treatment for acute stroke, many physicians remained reluctant to use it, largely because of concerns about increased risk for intracerebral hemorrhage (18, 19). In these circumstances, sponsors, clinical investigators, institutional review boards, and the FDA agreed that placebo-controlled trials of new agents to treat stroke remained appropriate as long as patients were fully informed about tPA as an available treatment option outside the trial. Three years after the reporting of the tPA trials, a large European trial in an overlapping but not identical patient population reported essentially negative results for tPA treatment of acute stroke (20), increasing the uncertainty surrounding riskbenefit considerations for this agent. Thus, even though tPA was approved by the FDA and was the only treatment marketed for acute stroke, placebo-controlled trials of new agents to treat stroke continued to be conducted (21, 22). International differences exist in the acceptability of available treatments. For example, some trials of second-line treatments for cancer conducted in Europe with untreated controls could not be carried out in the United States (23, 24), reflecting differences in criteria for determining effectiveness of cancer drugs. Tumor response rates that are considered acceptable initial evidence of effectiveness in refractory cancer in the United States (25) would not ordinarily be acceptable to European authorities, who generally have asked for evidence of clinical benefit, such as prolonged survival or symptom relief. Similar differences in international perspectives have been seen in the field of HIV infection. The Concorde trial (26), a placebo-controlled trial of zidovudine treatment in early HIV infection sponsored by the U.K. Medical Research Council, is a well-known example. This trial continued