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Background: Ankylosing spondylitis (AS) is a rheumatic and autoimmune disease associated with a chronic inflammatory response, mainly characterized by pain, stiffness, or limited mobility of the spine and sacroiliac joints. Severe symptoms can lead to joint deformity, destruction, and even lifelong disability, causing a serious burden on families and society as a whole. A large number of clinical studies have been published on AS over the past 20 years. This study aimed to summarize the current research status and global trends relating to AS clinical trials through a bibliometric analysis. Methods: The Web of Science Core Collection database was searched for publications related to AS clinical trials published between January 2003 and June 2023. Bibliometric analysis and web visualization were performed using CiteSpace, VOSviewer, and a bibliometric online analysis platform (https://bibliometric.com), which included the number of publications, citations, countries, institutions, journals, authors, references, and keywords. Results: 1,212 articles published in 201 journals from 65 countries were included in this study. The number of publications related to AS clinical trials is increasing annually. The United States and the Free University of Berlin, the countries and institutions, respectively, that have published the most articles on AS, have made outstanding contributions to this field. The author with the most published papers and co-citations over the period covered by the study was Desiree Van Der Heijde. The journal with the most published and cited articles was Annals of the Rheumatic Diseases. The keywords: "double-blind," "rheumatoid arthritis," "efficacy," "placebo-controlled trial," "infliximab," "etanercept," "psoriatic arthritis" and "therapy" represent the current research hotspots regarding AS. Discussion: This is the first study to perform a bibliometric analysis and visualization of AS clinical trial publications, providing a reliable research focus and direction for clinicians. Future studies in the field of AS clinical trials should focus on placebo-controlled trials of targeted therapeutic drugs. [ABSTRACT FROM AUTHOR]

Background: The effects of tenapanor in reducing serum phosphorus in hemodialysis patients with hyperphosphatemia are uncertain and no relevant meta‐analysis has been conducted. We performed a meta‐analysis of randomized placebo‐controlled trials to evaluate the efficacy and safety of tenapanor. Methods: All randomized controlled trials of tenapanor were searched up to 1 August 2022. The primary endpoint was the change in serum phosphorus level from baseline with tenapanor and placebo. Data on drug‐related adverse events (AEs), gastrointestinal AEs and diarrhea were collected to determine the safety of tenapanor. Results: There were 533 patients throughout five trials that were eligible. Tenapanor significantly lowered blood phosphorus level by 1.79 mg/dl in the mean difference than the placebo. Diarrhea, gastrointestinal AEs, and drug‐related AEs were more severe than placebo. Conclusions: This meta‐analysis showed that although drug side effects were common, tenapanor significantly reduced serum phosphorus level in hemodialysis patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fluoxetine was approved for depression in children and adolescents based on two placebo-controlled trials, X065 and HCJE, with 96 and 219 participants, respectively. OBJECTIVE: To review these trials, which appear to have been misreported. METHODS: Systematic review of the clinical study reports and publications. The primary outcomes were the efficacy variables in the trial protocols, suicidal events, and precursors to suicidality or violence. RESULTS: Essential information was missing and there were unexplained numerical inconsistencies. (1) The efficacy outcomes were biased in favour of fluoxetine by differential dropouts and missing data. The efficacy on the Children's Depression Rating Scale-Revised was 4% of the baseline score, which is not clinically relevant. Patient ratings did not find fluoxetine effective. (2) Suicidal events were missing in the publications and the study reports. Precursors to suicidality or violence occurred more often on fluoxetine than on placebo. For trial HCJE, the number needed to harm was 6 for nervous system events, 7 for moderate or severe harm, and 10 for severe harm. Fluoxetine reduced height and weight over 19 weeks by 1.0 cm and 1.1 kg, respectively, and prolonged the QT interval. CONCLUSIONS: Our reanalysis of the two pivotal trials showed that fluoxetine is unsafe and ineffective. [ABSTRACT FROM AUTHOR]

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo‐controlled trials, and we explore the fundamental ethical and scientific complexities involved with each. [ABSTRACT FROM AUTHOR]

While the degree of COVID-19 vaccine accessibility and uptake varies at both national and global levels, increasing vaccination coverage raises questions regarding the standard of prevention that ought to apply to different settings where COVID-19 vaccine trials are hosted. A WHO Expert Group has developed guidance on the ethical implications of conducting placebo-controlled trials in the context of expanding global COVID-19 vaccine coverage. The guidance also considers alternative trial designs to placebo controlled trials in the context of prototype vaccines, modified vaccines, and next generation vaccines. [ABSTRACT FROM AUTHOR]

The article presents the discussion on debate about placebo comparators in COVID-19 vaccine trials. Topics include fundamental guiding principle in the cooperation between the sponsor and local stakeholders with full community partnership and engagement throughout; and adult populations being the main problem of many low and middle-income countries regarding the COVID-19 pandemic.

Background and Hypothesis There is limited evidence guiding clinicians and patients on how long to continue antipsychotic medication beyond the first 1–2 years of treatment. Data from long-term (beyond 2 years) placebo-controlled trials would be informative but would be resource-intensive and technically difficult to obtain. Philosophy and history offer perspective on whether schizophrenia researchers should invest in such trials. Study Design Essay. Results In Descartes' model of science, knowledge grows by accumulation and evolves from simpler toward more complex areas. From this perspective, the most important questions are when and how to build this evidence base. In Kuhn's model of science, paradigm shifts can occur that reframe which questions and answers are meaningful. From this perspective, the question of whether to invest in long-term placebo-controlled trials is especially important. An historical review of schizophrenia over the past century indicates that major paradigm shifts have occurred regarding schizophrenia treatments, what counts as evidence, and the definition of schizophrenia. Conclusions While long-term placebo-controlled trials would add value within the current paradigm, if a paradigm shift occurs there is a risk that this value would not be maintained in the new paradigm. [ABSTRACT FROM AUTHOR]

BACKGROUND: Antidepressants are much used and have been tested for many conditions. OBJECTIVE: To investigate the type of diagnoses in placebo-controlled trials apart from depression and anxiety. METHODS: This was a systematic review. RESULTS: We downloaded 5471 records from PubMed and excluded 3017 that contained depression or anxiety. After exclusion of non-eligible studies, meta-analyses and reviews, and records that were unclear, 1273 records remained. We counted 214 unique diagnoses, of which the most common were abuse of drugs or substances (227 records), pain or neuropathy (170), obesity (125), other eating disorders (45), obsessive compulsive disorder (66), sexual dysfunction (41), gastrointestinal disorders (40), menopausal symptoms/hot flashes (36), premenstrual dysphoric disorder (27), urinary incontinence (21), post-traumatic stress disorder (38), schizophrenia (31), dementia or cognition problems (25), insomnia (19), ADHD (17), autism spectrum disorders (14), and stroke or traumatic brain injury (15). CONCLUSIONS: Trials of antidepressants may be driven mainly by commercial interests, focusing on prevalent diseases and everyday problems. No one can live a full life without experiencing several of the problems for which these drugs were tested. Antidepressants, sometimes called happy pills, could be seen as the modern version of Aldous Huxley's soma pill intended to keep everyone happy in the "Brave New World". [ABSTRACT FROM AUTHOR]

BackgroundA typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant.ObjectiveTo assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size.Study Design and SettingWe performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively.ResultsWe identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6–179) in placebo-controlled trials testing conventional drugs, 107 (8–237) in such trials testing atypical drugs, and 104 (95–115) in such trials testing both drug types; it was 31 (10–88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size.ConclusionSample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered.

Background: A typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant. Objective: To assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size. Study Design and Setting: We performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively. Results: We identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6–179) in placebo-controlled trials testing conventional drugs, 107 (8–237) in such trials testing atypical drugs, and 104 (95–115) in such trials testing both drug types; it was 31 (10–88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size. Conclusion: Sample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance: Shuganjianpi Therapy (SGJP), Jianpi Therapy (JP), Shugan Therapy (SG), Jianpiwenshen Therapy (JPWS), and Shuganjianpiwenshen Therapy (SGJPWS), consisting of formulas from Chinese herbal medicine (CHM), have been tremendously applied to irritable bowel syndrome (IBS). However, it remains uncertain when exploring the preferable option among different CHM therapies for diarrhea-predominant irritable bowel syndrome (IBS-D). Aim of the study : To compare and rank the efficacy and safety of different CHM therapies for IBS-D. Materials and methods: We searched randomized, double-blinded, placebo-controlled trials through mainstream databases from their inception to October 31, 2022. Eligible randomized controlled trials (RCTs) applied one of the CHM therapies as the experimental group and placebo as the control group. Two authors independently extracted data into a form and evaluated the quality of the retrieved articles by the Cochrane Risk of Bias Tool. At least one of the following outcomes was assessed: Serotonin, Neuropeptide Y (NPY), Incidence of Adverse Events (AE), and Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS) with its subscales of Severity of Abdominal Pain (SAP), Frequency of Abdominal Pain (FAP), Severity of Abdominal Distension (SAD), Dissatisfaction with Bowel Habits (DBH), and Interference with Quality of Life (IQOL). A Bayesian network meta-analysis on a random-effect model was conducted using R 4.2.2 software. Results: 1367 records were retrieved from databases in an initial search. Fourteen studies involving six interventions with 2248 participants were identified. Provided pairwise comparisons, the surface under the cumulative ranking curve (SUCRA) ranking, and cluster analysis, JPWS was the best option for ameliorating clinical symptoms simultaneously, which included IBS-SSS, SAP, FAP, SAD, DBH, and IQOL. As for AE, JPWS contributed to fewer adverse events than others as well. In respect of serum indicators, we noticed the dominance of SGJP in regulating both serotonin and NPY. Conclusions: JPWS and SGJP were the most prominent CHM therapies for IBS-D in terms of clinical symptoms, including abdominal pain, distension, bowel habits, and improvement of quality of life. The effect of JP and SG for IBS-D required further investigation. As a potential candidate, SGJP may well treat IBS-D by mediating dysmotility, visceral hypersensitivity, and the gut-brain axis with an increase of NPY and a reduction of serotonin. For safety, JPWS was ideal for the fewest adverse events in the treatment of IBS-D. On account of a small sample size and possible geographical publication bias, more double-blinded and placebo-controlled trials with larger samples worldwide would be necessary for strengthening current evidence. [Display omitted] [ABSTRACT FROM AUTHOR]

Keywords: AstraZeneca vaccine; COVID-19; efficacy; elderly; placebo-controlled trials; SARS-CoV-2 EN AstraZeneca vaccine COVID-19 efficacy elderly placebo-controlled trials SARS-CoV-2 2405 2406 2 04/30/21 20210501 NES 210501 The UK MHRA granted emergency authorization to the AstraZeneca COVID-19 vaccine on December 30, 2020. Will AstraZeneca be able to provide clinical trial data on its COVID-19 vaccine efficacy in older adults? However, vaccine effectiveness in the real world - that could be shown in observational studies conducted in countries where this vaccine is being rolled out10 - will shed light on this weak point of this, otherwise, cheap and useful vaccine to address this pandemic. [Extracted from the article]

Studies on the acute treatment of migraine in children and adolescents are rare and difficult to design. In particular, the high placebo response in some trials makes it difficult to prove efficacy of a verum drug. All available placebo-controlled trials on the acute migraine treatment in children and adolescents with a triptan were analyzed with respect to different end points (rate of pain free and pain relief at 2 hours; rate of adverse events). We identified 6 crossover and 11 parallel group trials. Although the trials were heterogenous with respect to the triptans and the dosage, pooled data were calculated. The pooled responder rate of triptans for 2 hours pain free was 36.0 % in crossover trials (significant difference to placebo with 17.7 %) and 32.5 % in parallel group trials (significant difference to placebo with 26.3 %). Triptans also showed a significantly higher pain relief rate at 2 hours than placebo both in crossover and parallel group trials. The rate of adverse events was significantly higher after triptans than after placebo. However, triptans were well tolerated in all trials. At least 1 trial with significant efficacy was found for sumatriptan (10-20 mg nasal spray), zolmitriptan (2.5-5 mg tablet), rizatriptan (5-10 mg tablet), and almotriptan (12.5-25 mg tablet). Placebo rates for efficacy were considerably lower in crossover trials than in parallel group trials. This analysis suggests that parallel group trials on the acute treatment of migraine in children and adolescents with a triptan show a very low therapeutic gain because of a high placebo rate. The verum response rates, however, are very similar to those seen in adulthood trials. However, there is sufficient evidence that at least some triptans are efficacious even in childhood and adolescence. [ABSTRACT FROM AUTHOR]

The oral assumption of lactotripeptides Valine-Proline-Proline (VPP) and Isoleucine-Proline-Proline (IPP) as nutraceuticals or functional foods is supposed to improve blood pressure (BP) control by angiotensin-converting enzyme-inhibition. However, data derived from clinical trials have reached conflicting conclusions. To perform a meta-analysis of placebo-controlled clinical trials evaluating the anti-hypertensive effect of lactotripeptides assumed as nutraceuticals or functional foods. Trials identified using a defined search strategy in PubMed were included in the meta-analysis, and their pooled effect was estimated with a random effects model, weighting for the inverse of the variance. Heterogeneity, publication bias, subgroup and meta-regression analyses were performed. A total of 18 trials have been identified, the clinical data of which have been clearly reported. Pooled effect of peptides was a reduction of −3.73 mm Hg (95% CI: −6.70, −1.76) for systolic blood pressure (SBP) and 1.97 mm Hg (95% CI: −3.85, −0.64) for diastolic blood pressure (DBP). The effect was more evident in Asian patients (SBP=−6.93 mm Hg (95% CI: −10.95, −2.94); DBP=−3.98 mm Hg(95% CI: −5.38, −2.44)) than in Caucasian ones (SBP=−1.17 mm Hg (95% CI: −2.82, 0.72); DBP=−0.52 mm Hg (95% CI: −1.39, 0.13)), and apparently not related to age, baseline BP values, dose of lactotripeptides assumed or length of the treatment. VPP and IPP lactotripeptides assumed as functional foods may significantly reduce SBP particularly in Asian subjects. The relevance of this findings in other ethnicities or associated with different dietary pattern should to be further investigated. [ABSTRACT FROM AUTHOR]

Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression. [ABSTRACT FROM AUTHOR]

OBJECTIVE. Desmopressin is an approved medical therapy for the treatment of mono- symptomatic primary nocturnal enuresis. In cases of limited response to desmopressin, we have added anticholinergic therapy to desmopressin (combination therapy). To evaluate this treatment strategy, we examined the efficacy of combination therapy for primary nocturnal enuresis in desmopressin-nonresponders. METHODS. Only patients with primary nocturnal enuresis refractory to the maximal dosage of desmopressin were enrolled. Children with lower urinary tract symptoms or bowel dysfunction were excluded, on the basis of a 3-day, 24-hour, frequency- volume chart and elimination record. Children continued to take desmopressin and were assigned randomly, in a double-blind manner, to receive either extended- release anticholinergic medication or placebo. Patients were reassessed after 1 month of therapy, with a 1-week nocturnal record. RESULTS. Forty-one desmopressin-nonresponders were enrolled, and 7 patients were excluded because of noncompliance. The treatment groups were equally matched with respect to age, gender, functional bladder capacity, and number of wet nights per week. After 1 month of treatment, there was a significant reduction in the mean number of wet nights in the combination therapy group, compared with the placebo group. With a generalized estimating equation approach, there was a significant 66% decrease in the risk of a wet episode, compared with the placebo group. CONCLUSIONS. This study represents the first prospective, placebo-controlled trial examining the effect of desmopressin in combination with long-acting, anticholinergic, bladder-relaxing therapy for monosymptomatic primary nocturnal enuresis. [ABSTRACT FROM AUTHOR]

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Summary: Neurological disease has been a central focus in the ongoing ethical debate over the use of invasive placebo controls, especially sham surgery. The risk to research subjects and necessary use of deception involved in these procedures must be balanced against the methodological need to control for bias and the placebo effect. We review a framework formulated for the ethical assessment of sham surgery in the context of research evaluating novel procedures for neurological conditions. Special issues raised include the growing evidence of expectation and conditioning effects in a number of neurological diseases, the escalating scale of risk from different types of invasive placebo interventions, and the increasing use of cross-over designs, which allow a switch from placebo to active intervention without additional procedures. [Copyright &y& Elsevier]

There is significant debate on the nature of the active therapeutic ingredient in homeopathic medicines and whether the effect of homeopathic medicines is exerted locally. This paper accepts that there is an active therapeutic ingredient in homeopathic medicines that acts pharmacologically in the body and proposes a possible receptor site. The vomeronasal organ (Jacobson''s organ) is the receptor site for the detection of non-odorant molecules, eg pheromones, in reptiles, amphibians and mammals. The organ forms the main part of a chemoreceptor system known as the vomeronasal system. This paper proposes that it is this system that constitutes the receptor for homeopathic medicines in both animal and human subjects. [Copyright &y& Elsevier]

The article discusses that the infectious diseases therapeutic area bears many similarities to the political process, specifically that "only the ideas that are considered and evaluated can generate clinical evidence; and mentions about many principles of antibiotic use have been generated and enshrined by expert opinion, thereby limiting openness to new approaches.

Chronic daily headache (CDH), a heterogeneous group of headache disorders occurring on at least 15 days per month, affects up to 4% to 5% of the general population. CDH disorders include transformed (or chronic) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Patients with CDH have greater disability and lower quality of life than episodic migraine patients and often overuse headache pain medications. To date, only topiramate, gabapentin, tizanidine, fluoxetine, amitriptyline, and botulinum toxin type A (BoNTA) have been evaluated as prophylactic treatment of CDH in randomized, double-blind, placebo-controlled, or active comparator-controlled trials. The evidence supporting the use of BoNTA as prophylaxis of CDH is composed of larger and longer trials, as over 1000 patients were evaluated for up to 11 months duration. Compared with placebo BoNTA has significantly reduced the frequency of headache episodes, a recommended efficacy measure for headache trials and has been demonstrated to be safe and very well tolerated with few discontinuations due to adverse events. Side effects are generally transient, mild to moderate, and nonsystemic. The results of clinical trials using traditional oral pharmacotherapy, while supportive of their use as prophylactic treatment of CDH, are limited by several factors, including small numbers of patients, the choice of efficacy measures, and short treatment periods. The use of oral agents was associated with systemic side effects, which may limit their effectiveness as prophylactic treatment of CDH. [ABSTRACT FROM AUTHOR]

Empirical research related to ethical issues in clinical research has grown dramatically in recent years. However, little attention has been devoted to the ethical relevance of the findings from this research. In order to examine the value and limitations of ethics-related empirical research, we discuss 3 case studies involving research with stored biological samples, placebo-controlled trials, and the idea of the therapeutic misconception. [ABSTRACT FROM PUBLISHER]

The ability of randomized, clinical trials (RCTs) to produce unbiased estimates of an intervention''s specific (i.e., innate pharmacologic or physiologic) effect rests on at least two assumptions. First, other prognostic effects (such as disease severity or the psychologic effects of treatment) are assumed to be evenly distributed across treatment groups, and second, it is assumed that these other effects do not interact with the intervention''s specific effect. This essay shows how the effect of patients'' preferences for treatments may interact with an intervention''s specific effect to bias the trial''s results. Earlier mathematical descriptions of how preference effects may produce bias in nonblinded trials are extended to the case of (presumably) blinded RCTs. The extent to which preference effects may confer bias in partially unblinded placebo-controlled vs. active-controlled drug trials are considered. Finally, methods for estimating preference effects in partially unblinded RCTs are provided. It is concluded that investigators could use these methods to quantify potential preference effects in partially unblinded RCTs, and thereby more accurately estimate the specific effects of treatments. [Copyright &y& Elsevier]

Objective: To evaluate physicians' preferences for referring patients to, and using information from, active-controlled trials (ACTs) versus placebo-controlled trials (PCTs) of new antihypertensive drugs.Design and Setting: Nationwide mailed survey, with telephone contact of nonresponders to assess nonresponse bias.Participants: One thousand two hundred primary care physicians randomly selected from the American Medical Association's Master File. Of 1,154 physicians eligible to respond, 651 (56.4%) returned completed questionnaires.Measurements and Main Results: We measured physicians' stated willingness to encourage hypertensive patients to enroll in ACTs and PCTs of new antihypertensive drugs, their views of the relative merits of ACTs versus PCTs, their stated willingness to prescribe new drugs tested in ACTs or PCTs, and their views regarding the overall justifiability of the 2 designs. Physicians were significantly more likely to indicate they would encourage their patients to enroll in ACTs than in PCTs (P <.0001). Physicians thought ACTs provided more valuable information for their practices, were more likely to lead to a public health benefit, offered enrolled patients greater opportunity for personal benefit, and were less likely to expose enrolled patients to unnecessary risks (all P <.0001). Physicians were more likely to prescribe new drugs that had been compared in ACTs (P <.0001), and viewed ACTs as a more justifiable method for testing new antihypertensive drugs (P <.0001). There was no evidence of nonresponse bias for these main results.Conclusions: Although PCTs remain the standard method for testing new antihypertensive drugs, physicians strongly prefer ACTs. Using ACTs to test new antihypertensive drugs may enhance the efficiency of patient recruitment and more strongly influence physicians' prescribing practices. [ABSTRACT FROM AUTHOR]

: The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate since proven treatments are available. In this review we argue that, if new agents are to be developed, there is still a place for the placebo-controlled trial. A move to studies of equivalence or non-inferiority raises more problems than it resolves. [ABSTRACT FROM AUTHOR]

A critical review is provided of the available research evidence concerning the efficacy and effectiveness of lithium prophylaxis in bipolar disorder. It is emphasized that, in spite of the limitations of available placebo-controlled trials and naturalistic studies, lithium is the only drug whose prophylactic activity in bipolar disorder is convincingly proved, and remains the first-choice medication in the long-term treatment of bipolar patients. The impact of lithium prophylaxis is likely to be less significant on atypical and comorbid cases of bipolar disorder than in typical manic–depressive illness, but the superiority of other medications over lithium in the long-term treatment of those cases is at present not convincingly proved by research. Currently available research evidence does not seem to support the idea that lithium exerts its prophylactic effect on relapses but not on recurrences of bipolar disorder. Clinicians should be aware of the fact that the drop-out rate in bipolar patients receiving long-term lithium prophylaxis is high even if treatment surveillance is accurate, and that complete suppression of recurrences is a relatively rare outcome of prophylaxis. [ABSTRACT FROM AUTHOR]

In order to test hypotheses prospectively with hard data and against placebo, the scientific method of clinical trials has been developed. The present paper focuses on specific problems associated with the use of a placebo control group. (a) The placebo highlights the ethical dilemma that a controlled clinical trial can place us in. (b) Also, in a trial an atmosphere is created of enhanced risks of placebo effects. (c) 'Significantly different from placebo' does not necessarily mean clinically relevant. (d) A biased placebo period due to carry-over effect is a common problem of controlled trials with a cross-over or self-controlled design. (e) Likewise an asymmetric placebo group is also a common problem in parallel-group designs. (f) The response to a placebo is generally small in comparison with the response to active treatment and is therefore sometimes more susceptible to bias. It is emphasized that routinely accounting for such problems may further improve the powerful method of controlled clinical trials. [ABSTRACT FROM AUTHOR]