Susan S. Ellenberg

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

Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials.

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.

A randomized trial of adenotonsillectomy for childhood sleep apnea.

BACKGROUND Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes. METHODS We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months. RESULTS The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [±SD] improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%). CONCLUSIONS As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.).

Considerations in the evaluation of surrogate endpoints in clinical trials : Summary of a National Institutes of Health Workshop

We report on recommendations from a National Institutes of Health Workshop on methods for evaluating the use of surrogate endpoints in clinical trials, which was attended by experts in biostatistics and clinical trials from a broad array of disease areas. Recent advances in biosciences and technology have increased the ability to understand, measure, and model biological mechanisms; appropriate application of these advances in clinical research settings requires collaboration of quantitative and laboratory scientists. Biomarkers, new examples of which arise rapidly from new technologies, are used frequently in such areas as early detection of disease and identification of patients most likely to benefit from new therapies. There is also scientific interest in exploring whether, and under what conditions, biomarkers may substitute for clinical endpoints of phase III trials, although workshop participants agreed that these considerations apply primarily to situations where trials using clinical endpoints are not feasible. Evaluating candidate biomarkers in the exploratory phases of drug development and investigating surrogate endpoints in confirmatory trials require the establishment of a statistical and inferential framework. As a first step, participants reviewed methods for investigating the degree to which biomarkers can explain or predict the effect of treatments on clinical endpoints measured in clinical trials. They also suggested new approaches appropriate in settings where biomarkers reflect only indirectly the important processes on the causal path to clinical disease and where biomarker measurement errors are of concern. Participants emphasized the need for further research on development of such models, whether they are empirical in nature or attempt to describe mechanisms in mathematical terms. Of special interest were meta-analytic models for combining information from multiple studies involving interventions for the same condition. Recommendations also included considerations for design and conduct of trials and for assemblage of databases needed for such research. Finally, there was a strong recommendation for increased training of quantitative scientists in biologic research as well as in statistical methods and modeling to ensure that there will be an adequate workforce to meet future research needs.

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

Effects of Testosterone Treatment in Older Men

BACKGROUND Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

&NA; There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

Data monitoring committees in clinical trials

Data monitoring committees in clinical trials , Data monitoring committees in clinical trials , کتابخانه دیجیتال جندی شاپور اهواز

Leukemia and Preleukemia after Adjuvant Treatment of Gastrointestinal Cancer with Semustine (Methyl-CCNU)

We evaluated the risk of acute nonlymphocytic leukemia, acute myelodysplastic syndrome, and preleukemia in 3633 patients with gastrointestinal cancer who were treated in nine randomized clinical trials. Among 2067 patients given semustine (methyl-CCNU) as adjuvant therapy, leukemic disorders developed in 14, whereas only one leukemic disorder (acute nonlymphocytic leukemia) occurred among 1566 patients given other therapies (relative risk = 12.4; 95 per cent confidence interval = 1.7 to 250). The six-year cumulative mean risk (+/- S.E.) of acquiring a leukemic disorder after treatment with semustine was 4.0 +/- 2.2 per cent; the incidence rate was 2.3 cases per 1000 persons per year. Risk increased significantly with time after treatment. The risk of leukemic disorders did not differ according to sex, race, age at treatment, or initial tumor type, nor was it enhanced by concomitant radiotherapy or immunotherapy. In addition, no excess of acute nonlymphocytic leukemia was seen in 44,370 patients treated for gastrointestinal cancer in Connecticut during the period 1935 to 1974, before the advent of nitrosourea chemotherapy. This study provides quantitative evidence that nitrosoureas are leukemogenic in human beings and confirms previous observations that adjuvant chemotherapy with alkylating agents may increase the risk of leukemia.

Review and recommendationsResearch design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations

&NA; There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.