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Monash Bioethics Review Mar 2016The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of... (Review)
Review
The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of clinical equipoise have put forward alleged counter-examples to this restriction-describing instances of ethical placebo-controlled trials that apparently violate clinical equipoise. In this essay, we respond to these examples and show that clinical equipoise is not as restrictive of placebos as these authors assume. We argue that a subtler appreciation for clinical equipoise-in particular the distinction between de facto and de jure interpretations of the concept-allows the concept to explain when and why a placebo control may be necessary to answer a question of clinical importance.
Topics: Biomedical Research; Control Groups; Ethics, Research; Humans; Placebo Effect; Placebos; Randomized Controlled Trials as Topic
PubMed: 27188301
DOI: 10.1007/s40592-016-0057-z -
BMJ (Clinical Research Ed.) Jul 1996
Comparative Study
Topics: Clinical Trials as Topic; Control Groups; Controlled Clinical Trials as Topic; Ethics, Medical; Humans; Placebos; Therapeutic Human Experimentation
PubMed: 8664770
DOI: 10.1136/bmj.313.7048.3a -
Archives of Neurology Nov 1998Recent clinical trials of donepezil and vitamin E have produced active therapeutic drugs for the treatment of patients with Alzheimer disease (AD). The AD research... (Review)
Review
Recent clinical trials of donepezil and vitamin E have produced active therapeutic drugs for the treatment of patients with Alzheimer disease (AD). The AD research community is now in a gray zone between the absence of accepted therapies and the presence of completely effective therapies. How should these therapies guide the choice of the proper control for future AD clinical trials? The community equipoise principle can guide a process to answer this question. The principle is that a clinical trial should answer clinical questions that are valued by the community who will use the results of that trial. This means that the choice of the proper control for future AD clinical trials ought to be guided by the values of a community who will experience the results of those trials: physicians and patients or their representatives such as caregivers. The values of patients can be included by giving them a voice in the design and review of clinical trials. Community dialogue should be the norm for the design and review of AD clinical trials. We conclude with suggestions to foster this dialogue and issues that should be addressed.
Topics: Cognition Disorders; Control Groups; Controlled Clinical Trials as Topic; Donepezil; Ethics Committees, Research; Ethics, Medical; Federal Government; Government Regulation; Humans; Indans; Piperidines; Placebos; Research Design; Research Subjects; Risk Assessment; Therapeutic Human Experimentation; Vitamin E
PubMed: 9823825
DOI: 10.1001/archneur.55.11.1420 -
Seminars in Arthritis and Rheumatism Aug 2021To assess how patient characteristics and study design influence the effectiveness of control interventions in hand OA trials. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To assess how patient characteristics and study design influence the effectiveness of control interventions in hand OA trials.
METHODS
The study protocol was registered in PROSPERO (CRD42020163473). Two authors independently searched four electronic databases from their inception to December 31, 2019. Randomized and non-randomized controlled hand OA trials were included if pain intensity was assessed using a validated scale. We allocated control groups into one of the following: placebo, add-on treatment, no treatment, or active treatment. The standardized mean differences (d) of pain, as well as subjective function and hand strength, were pooled with 95% confidence intervals (CI) and 90% prediction intervals using random-effects models. Meta-regression and post-hoc subgroup analyses were performed to investigate which factors potentially impacted placebo analgesia and between-study heterogeneity.
RESULTS
Thirty-one placebo, 11 add-on, 12 no-treatment, and 10 active-treatment controls were included in meta-analyses. Effective pain relief was observed in placebo (d = -0.50, 95% CI -0.63 to -0.37), add-on (d = -0.35, 95% CI -0.59 to -0.12), and active-treatment (d = -0.92, 95% CI -1.35 to -0.48) groups. In subjective function, these treatments had smaller but beneficial effects; hand strength, contrastingly, was not improved. Placebo effects were larger when flare designs were used (d = -0.96) and more homogeneous when minimum pain thresholds were set (d = -0.46, 90% prediction intervals -0.79 to -0.14).
CONCLUSION
Placebo, add-on, and active control treatments were more effective than the no treatment control in relieving hand pain and improving subjective function. By choosing minimum pain thresholds and flare requirements at patient enrollment, moderate pain relief may be replicated among control participants in future randomized placebo-controlled trials.
Topics: Control Groups; Hand; Humans; Osteoarthritis; Pain; Randomized Controlled Trials as Topic
PubMed: 34146952
DOI: 10.1016/j.semarthrit.2021.04.006 -
JAMA Internal Medicine Nov 2013When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak.
OBJECTIVE
To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis.
DESIGN, SETTING, AND PARTICIPANTS
We searched relevant sources through February 2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes.
EXPOSURE
Active migraine treatment and the placebo control conditions.
MAIN OUTCOMES AND MEASURES
Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by the patients or their physicians.
RESULTS
Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P = .005 and P = .001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings.
CONCLUSIONS AND RELEVANCE
Sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities.
Topics: Acupuncture Therapy; Drug Administration Schedule; Humans; Migraine Disorders; Neurosurgical Procedures; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 24126676
DOI: 10.1001/jamainternmed.2013.10391 -
Epilepsia Oct 2010Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled... (Comparative Study)
Comparative Study Review
PURPOSE
Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled "withdrawal to monotherapy" in treatment-resistant patients, which employs a so-called "pseudo-placebo" as a comparator arm. The authors submitted a white paper to the FDA advocating use of a virtual placebo historical control as an alternative to pseudo-placebo. Such an approach reduces patient risk that would result from exposure to pseudo-placebo. In this article, we present the data submitted to the FDA to justify a historical control.
METHODS
We analyzed individual patient data from eight previously completed withdrawal to monotherapy studies, which we determined had similar design. All studies employed percent meeting predetermined exit criteria (denoting worsening of seizure control) as the outcome measure. Kaplan-Meier estimates of the percent exiting were calculated at 112 days.
RESULTS
The percent meeting exit criteria were uniformly high, ranging from 74.9-95.9%. The eight studies appear to meet the criteria set forth for use of historical control. The estimate of the combined percent exit based on the noniterative mixed-effects model is 85.1%, with a lower bound of the 95% prediction interval of 65.3%, and 72.2% for an 80% prediction interval.
CONCLUSION
There is justification for proposing that these data can serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo-placebo arm in trials intended to demonstrate the efficacy of approved drugs as monotherapy in treatment-resistant patients.
Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Control Groups; Controlled Clinical Trials as Topic; Drug Resistance; Epilepsy; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Placebos; Randomized Controlled Trials as Topic; Research Design; United States; United States Food and Drug Administration
PubMed: 20561024
DOI: 10.1111/j.1528-1167.2010.02650.x -
JAMA Network Open Nov 2023Randomized clinical trials (RCTs) testing innovative drugs must strive to use optimal control groups to reflect the best available treatments. A comprehensive evaluation...
IMPORTANCE
Randomized clinical trials (RCTs) testing innovative drugs must strive to use optimal control groups to reflect the best available treatments. A comprehensive evaluation of the quality of control groups in pivotal RCTs supporting systemic rheumatic disease (SRD) drug approvals by the Food and Drug Administration (FDA) is lacking.
OBJECTIVE
To examine the proportion of pivotal RCTs that used optimal control groups among RCTs supporting newly approved SRD drugs in the US over the past decade.
DESIGN, SETTING, AND PARTICIPANTS
In this study, individual RCTs supporting SRD new drug approvals by the FDA between January 2012 and October 2022 were analyzed for design, study duration, control group, and primary end point. The quality of control groups was determined by comparison with published guidelines before and during the trial.
MAIN OUTCOMES AND MEASURES
The primary measure was the proportion of RCTs using optimal control groups. Differences in response rate between investigating and control groups and the response rate of placebo control groups were also examined.
RESULTS
Between January 2012 and October 2022, the FDA approved 44 SRD drugs, involving 65 pivotal RCTs. Overall, 16 RCTs used optimal control groups. In 55 trials, no active groups were used, and more than 80% of these trials were suboptimal (47 trials [85.5%]). Among 56 trials for systemic arthritis, 49 trials used suboptimal control groups, mainly placebo or dose-response controls (47 trials), with a few active controls (2 trials). Studies of other SRDs frequently used placebo or dose-response controls but were considered optimal controls (8 trials). There was significant improvement in response rates of investigating compared with placebo groups, with relative risk mostly exceeding 1.50 (range, 0.90; 95% CI, 0.69-1.17 for anifrolumab to 11.00; 95% CI, 2.69-44.96 for mepolizumab). In all placebo-controlled trials, the median (IQR) response rate in placebo groups was 26.0% (19.2%-32.3%).
CONCLUSIONS AND RELEVANCE
These findings suggest that the quality of control groups in RCTs leading to SRD drug approval needs improvement and that despite challenges in translating scientific theories to clinical scenarios, it is crucial to consistently prioritize efforts to promote appropriate control group selection to ensure the accurate assessment of innovative drug efficacy.
Topics: Humans; Arthritis; Control Groups; Drug Approval; Rheumatic Diseases; United States; United States Food and Drug Administration; Randomized Controlled Trials as Topic
PubMed: 37991756
DOI: 10.1001/jamanetworkopen.2023.44767 -
European Journal of Clinical... Nov 2019Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12-item Template for Intervention Description and...
BACKGROUND
Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12-item Template for Intervention Description and Replication (TIDieR) checklist was developed to improve the reporting of active interventions. The extent to which TIDieR has been used to improve description of placebo or sham control is not known.
MATERIALS AND METHODS
We systematically identified and examined all placebo/sham-controlled randomised trials published in 2018 in the top six general medical journals. We reported how many of the TIDieR checklist items were used to describe the placebo/sham control(s). We supplemented this with a sample of 100 placebo/sham-controlled trials from any journal and searched Google Scholar to identify placebo/sham-controlled trials citing TIDieR.
RESULTS
We identified 94 placebo/sham-controlled trials published in the top journals in 2018. None reported using TIDieR, and none reported placebo or sham components completely. On average eight TIDieR items were addressed, with placebo/sham control name (100%) and when and how much was administered (97.9%) most commonly reported. Some items (rationale, 8.5%, whether there were modifications, 25.5%) were less often reported. In our sample of less well-cited journals, reporting was poorer (average of six items) and followed a similar pattern. Since TIDieR's first publication, six placebo-controlled trials have cited it according to Google Scholar. Two of these used the checklist to describe placebo controls; neither one completely desribed the placebo intervention.
CONCLUSIONS
Placebo and sham controls are poorly described within randomised trials, and TIDieR is rarely used to guide these descriptions. We recommend developing guidelines to promote better descriptions of placebo/sham control components within clinical trials.
Topics: Checklist; Control Groups; Humans; Placebos; Randomized Controlled Trials as Topic; Research Report
PubMed: 31519047
DOI: 10.1111/eci.13169 -
Annals of Internal Medicine Jul 2001
Topics: Control Groups; Ethics, Medical; Humans; Informed Consent; Placebos; Randomized Controlled Trials as Topic; Research Design
PubMed: 11434741
DOI: 10.7326/0003-4819-135-1-200107030-00023 -
Annals of Internal Medicine Jul 2001
Topics: Control Groups; Ethics, Medical; Humans; Placebos; Randomized Controlled Trials as Topic; Uncertainty
PubMed: 11434740
DOI: 10.7326/0003-4819-135-1-200107030-00022