Robert Temple

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 patients 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 patients 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

Drug interaction studies: study design, data analysis, and implications for dosing and labeling.

One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose‐response studies, and drug‐drug interactions.

Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration

Objective To examine the risk of suicidal behaviour within clinical trials of antidepressants in adults. Design Meta-analysis of 372 double blind randomised placebo controlled trials. Setting Drug development programmes for any indication in adults. Participants 99 231 adults assigned to antidepressants or placebo. Median age was 42 and 63.1% were women. Indications for treatment were major depression (45.6%), other depression (4.6%), other psychiatric disorders (27.6%), and non-psychiatric disorders (22.2%). Main outcome measures Suicidal behaviour (completed suicide, attempted suicide, or preparatory acts) and ideation. Results For participants with non-psychiatric indications, suicidal behaviour and ideation were extremely rare. For those with psychiatric indications, risk was associated with age. For suicidal behaviour or ideation and for suicidal behaviour only, the respective odds ratios were 1.62 (95% confidence interval 0.97 to 2.71) and 2.30 (1.04 to 5.09) for participants aged <25, 0.79 (0.64 to 0.98) and 0.87 (0.58 to 1.29) for those aged 25-64, and 0.37 (0.18 to 0.76) and 0.06 (0.01 to 0.58) for those aged ≥65. When age was modelled as a continuous variable, the odds ratio for suicidal behaviour or ideation declined at a rate of 2.6% per year of age (−3.9% to −1.3%, P=0.0001) and the odds ratio for suicidal behaviour declined at a rate of 4.6% per year of age (−7.4% to −1.8%, P=0.001). Conclusions Risk of suicidality associated with use of antidepressants is strongly age dependent. Compared with placebo, the increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents. The net effect seems to be neutral on suicidal behaviour but possibly protective for suicidal ideation in adults aged 25-64 and to reduce the risk of both suicidality and suicidal behaviour in those aged ≥65.

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

New Era in Drug Interaction Evaluation: US Food and Drug Administration Update on CYP Enzymes, Transporters, and the Guidance Process

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administrations (FDAs) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP‐based and transporter‐based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDAs current understanding of drug interactions (http:www.fda.govcderdrugdrugInteractionsdefault.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling.

Anticoagulant Options — Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran

Last fall, the FDA approved dabigatran, in a 150-mg dose only, for reducing risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. A 110-mg regimen was also effective, but the agency believes that patients should receive the higher dose.

Erythropoiesis-Stimulating Agents — Time for a Reevaluation

Randomized trials have endeavored to show that using ESAs to raise hemoglobin concentrations to higher targets improves clinical outcomes in patients with anemia associated with chronic kidney disease. Dr. Ellis Unger and FDA colleagues describe the trial results, which have suggested the opposite.

The FDA's Critique of the Anturane Reinfarction Trial

The Food and Drug Administration recently refused to approve a claim that sulfinpyrazone (Anturane) was effective in the prevention of sudden death during the first six months after myocardial infa...

Is This the Drug or Dose for You?: Impact and Consideration of Ethnic Factors in Global Drug Development, Regulatory Review, and Clinical Practice

Differences in response to medical products have been observed in racially and ethnically distinct subgroups of the US population.1,2 These differences may be attributable to intrinsic ethnic factors (e.g., genetics, metabolism, and elimination), extrinsic ethnic factors that are associated with environment and culture (e.g., medical practice, diet, use of alcohol, and concomitant drug use), or interactions among these factors (Figure 1).3 Behind these “ethnic” factors, of course, are individual differences that may be more common in particular subgroups but are generally present in all groups, albeit with different frequencies. Although subgroup differences are of great therapeutic and scientific interest, the ultimate goal is to understand these differences so that treatments can be truly individualized. In order to foster a better understanding of how medical products might differ in their performance in individual patients, the US Food and Drug Administration (FDA) requires tabulation in New Drug Applications (NDAs) of the numbers of participants in clinical trials by age group, gender, and race, as well as any Extrinsic

Therapeutic Protein–Drug Interactions and Implications for Drug Development

Many intrinsic and extrinsic factors can affect an individual patients drug exposure and response. 1 The US Food and Drug Administration (FDA) has published a number of guidances that recommend how and when to evaluate these factors during drug development. 2 The most recent FDA draft guidance on drug interactions 3 provides advice for in vitro and in vivo drug interaction studies, including suggestions for study design, dosing strategies and analysis, and interpretation of data for medical product labels. The draft guidance 3 updated the FDAs recommendations on the evaluation of important cytochrome P450 (CYP) enzyme‐ and transporter‐based drug interactions during drug development.