Optimal adaptive randomized designs for clinical trials

Optimal decision-analytic designs are deterministic. Such designsare appropriately criticized in the context of clinical trialsbecause they are subject to assignment bias. On the other hand,balanced randomized designs may assign an excessive number ofpatients to a treatment arm that is performing relatively poorly.We propose a compromise between these two extremes, one thatachieves some of the good characteristics of both. We introducea constrained optimal adaptive design for a fully sequentialrandomized clinical trial with k arms and n patients. An r-designis one for which, at each allocation, each arm has probabilityat least r of being chosen, 0 r 1/k. An optimal design amongall r-designs is called r-optimal. An r₁-design is also an r₂-designif r₁ r₂. A design without constraint is the special case r = 0and a balanced randomized design is the special case r = 1/k.The optimization criterion is to maximize the expected overallutility in a Bayesian decision-analytic approach, where utilityis the sum over the utilities for individual patients over a‘patient horizon’ N. We prove analytically thatthere exists an r-optimal design such that each patient is assignedto a particular one of the arms with probability 1 – (k – 1)r,and to the remaining arms with probability r. We also show thatthe balanced design is asymptotically r-optimal for any givenr, 0 r < 1/k, as N/n  . This implies that everyr-optimal design is asymptotically optimal without constraint.Numerical computations using backward induction for k = 2arms show that, in general, this asymptotic optimality featurefor r-optimal designs can be accomplished with moderate trialsize n if the patient horizon N is large relative to n. We alsoshow that, in a trial with an r-optimal design, r < 1/2,fewer patients are assigned to an inferior arm than when followinga balanced design, even for r-optimal designs having the samestatistical power as a balanced design. We discuss extensionsto various clinical trial settings.     

Community-equipoise and the ethics of randomized clinical trials

This paper critically examines a particular strategy for resolving the central ethical dilemma associated with randomized clincial trials (RCTs) -- the "community equipoise" strategy (CE). The dilemma is that RCTs appear to violate a physician's duty to choose that therapy which there is most reason to believe is in the patient's best interest, randomizing patients even once evidence begins to favor one treatment. The community equipose strategy involves the suggestion that our judgment that neither treatment is to be preferred (that there obtains a state of "equipoise") is to be assessed according to a community rather than an individual standard. Thus, though a physician may personally believe that there is some reason to prefer one treatment, patients can legitimately be randomized if there remains disagreement in the community of medical professionals. Rationales in favor of this conception include the following: (i) medical knowledge is best understood as residing in the community, (ii) the judgments of others count as evidence, and so should change one's own opinion, (iii) subjects would not be better off outside the trial, and (iv) the point of any trial is the resolution of dispute in the medical community. I critically examine these rationales and argue that they are insufficient. Amongst the problems are tensions between various of these underlying rationales, and important ambiguities in just what the CE criterion is to amount to. Finally, I argue that even if use of CE was justified, it would not justify carrying out RCTs anywhere near long enough to discharge our duty to gain reliable knowledge on which to base safe and effective medical practice. Hence, we need some different justification for carrying out RCTs.     

Discontinuation rates in clinical trials in musculoskeletal pain: meta-analysis from etoricoxib clinical trial reports

Introduction

Patient adherence to therapy in clinical practice is often low, and the difference between efficacy measured in clinical trials and effectiveness in clinical practice is probably a function of discontinuation of therapy because of lack of efficacy or because of unmanageable or intolerable adverse events. Discontinuation is frequently measured in clinical trials but is not usually described in detail in published reports, often because of limitations in the size of publications. By contrast, company clinical trial reports include much more detail.

Methods

We examined company clinical trial reports of trials involving etoricoxib in four musculoskeletal conditions: osteoarthritis, rheumatoid arthritis, chronic low back pain and ankylosing spondylitis. Information was available from 18 randomized trials (10,143 patients) lasting 4 to 12 weeks (one 4 weeks, three 6 weeks, one 8 weeks and seven 12 weeks) and from three trials with a mean duration of about 80 weeks (34,695 patients). These clinical trial reports contain over 73,000 pages of information.

Results

Over 12 weeks, lack of efficacy and adverse event discontinuations were similar between osteoarthritis, rheumatoid arthritis and back pain, with lack of efficacy discontinuation rates some three times higher than for adverse events. All-cause and lack of efficacy discontinuations were lower with etoricoxib (all doses combined) and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) than with placebo, although NSAIDs produced higher rates of clinical adverse events and gastrointestinal discontinuations than did placebo. Etoricoxib had fewer discontinuations than NSAIDs for lack of efficacy, clinical adverse events, and laboratory and gastrointestinal adverse events, but with more discontinuations because of hypertension and oedema. Comparison with two similar meta-analyses of other cyclo-oxygenase-2 selective inhibitors (more than 80,000 patients in total) revealed consistency between analyses.

Conclusion

Examining discontinuation data from clinical trials, even when the numbers of patients are very large, does not necessarily predict what will happen in the real world, where clinical effectiveness may differ from clinical efficacy assessed in trials. Data from these analyses appears to agree with findings from real world practice.     

The prevention of emesis in plastic surgery: a randomized,prospective study

Perhaps the most unpleasant experience following outpatient plastic surgery procedures is postoperative nausea and vomiting. Postoperative nausea and vomiting often results in delayed recovery time and unintended admission, and it can be a contributing factor to the formation of hematoma following rhytidectomy. Ondansetron (Zofran) has proven benefit in preventing postoperative nausea and vomiting if given before general anesthesia in a variety of surgical procedures. Its utility in cases performed under conscious sedation has not been determined. The purpose of this study was (1) to test the ability of prophylactic ondansetron to prevent postoperative nausea and vomiting in plastic surgery cases performed under conscious sedation, and (2) to determine relative risk factors for postoperative nausea and vomiting and a selection policy for the administration of antiemetic prophylaxis. This was a prospective, randomized, double-blind study. One hundred twenty patients were enrolled after giving informed consent. Patients received a single dose of either placebo or ondansetron (4 mg intravenously) before administration of sedation. Sedation administration followed a standardized institutional protocol, using midazolam and fentanyl. Data were recorded from a series of three questionnaires: preoperatively, immediately postoperatively, and at the time of the first office return. Data were confirmed by means of telephone interview, chart analysis, and nursing documentation. Multivariate analysis was conducted. Nausea and emesis occurred with an overall frequency of 33 percent and 22 percent, respectively. Postoperative nausea and vomiting was associated with statistically longer recovery periods. The incidence of emesis was statistically higher among women, among those undergoing facial rejuvenation, and among those with a history of opioid-induced emesis or postoperative nausea and vomiting following a previous operation (p < 0.05). The incidence of postoperative nausea and vomiting paralleled increases in case duration; the incidence of emesis was zero in cases less than 90 minutes in duration. Ondansetron significantly reduced the incidence of emesis overall (placebo, 30 percent; ondansetron, 13 percent; p < 0.05). Postoperative perception of nausea was significantly lower among those who had received ondansetron (p < 0.05). These results confirm the efficacy of ondansetron for the prevention of postoperative nausea and vomiting in plastic surgery cases under conscious sedation. In those who are at increased risk, prophylaxis should be considered. Such risks include female gender, facial rejuvenation procedures, and a patient history of opioid-induced emesis or postoperative nausea and vomiting following a prior operation. The zero incidence of emesis in cases less than 90 minutes does not support the routine use of prophylaxis in such cases. Patient satisfaction in plastic surgery is derived from the overall subjective experience of the event as much as by the final result. By remaining attentive to patient concerns and optimizing perioperative care, we can improve the subjective experience for our patients.     

Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners

Recent developments in group sequential methods have had a great impact on the design and analysis of randomized clinical trials. The consequences for both planned and unplanned interim analyses are discussed using several real trials as illustrations. Guidelines for the conduct of interim analysis are given, including tables of nominal significance levels and required sample sizes for several group sequential plans. Areas in need of further theoretical advance include multiple endpoints, estimation of treatment differences, stratification, and design of multiple-armed trials.     

Assessing the quality of reports about randomized controlled trials of acupuncture treatment on mild cognitive impairment

Objective

To evaluate the reports'' qualities which are about randomized controlled trials (RCTs) of acupuncture treatment on Mild Cognitive Impairment (MIC).

Methods

Nine databases including the Cochrane Central Register of Controlled Trials (CENTRAL,2010), PUBMED (1984-5/2010), EMbase (1984-5/2010), MEDLINE (1984-5/2010), CINAL (1984-5/2010), China National Knowledge Infrastructure (CNKI, 1980-5/2010), China Biomedicine Database disc (CBMdisc, 1980-5/2010), VIP (a full text issues database of China, 1989-5/2010) were searched systematically. Hand search for further references was conducted. Language was limited to Chinese and English. We identified 14 RCTs that used acupuncture as an intervention and assessed the quality of these reports against the Consolidated Standards for Reporting of Trials (CONSORT) statement and Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA).

Results

In regard to the items in the CONSORT statement, 13(92.86%) RCTs described baseline demographic and clinical characteristics in each group. 7 (50.0%) mentioned the method of generating the random sequence, only 2 (14.3%) RCTs had adequate allocation concealment. No RCTs used blinding. RCTs reported the sample size calculation. In regard to the items in STRICTA, 10 (71.43%) mentioned the depths of insertion, 6 (42.86%) reported acupuncture response, 11 (78.57%) mentioned the technique of acupuncture, 12 (85.71%) recorded the time, and only 3 (21.43%) RCTs reported the numbers of needles inserted. No RCTs reported the background of the acupuncture practitioners and professional title of practitioners.

Conclusion

The reporting quality of RCTs of acupuncture for mild cognitive impairment was moderate to low. The CONSORT statement and STRICTA should be used to standardize the reporting of RCTs of acupuncture in future.     

Priorities in plastic surgery

The study of historical priorities in plastic surgery must be based on established principles in the field instead of mere chronology. Examples of application of these principles to two landmarks in plastic surgery are given. The reader is commended to adhere to these principles in the study of other developments in plastic surgery.     

Advances in plastic surgery

The influence of the war period has been reflected in an active trend toward the conservation of time in the execution of reconstructive operations. The myriad improvements in the technique of tissue transplantation and the use of large flaps rather than tubed pedicles have been in keeping with this trend. The goal of the complete restoration of function and appearance applies not only to the correction of post-traumatic defects but also to the cosmetic repair of defects created by the surgical excision of malignant tumors and to correction of congenital anomalies.     

Thromboembolism in plastic surgery

Thromboembolism is a dreaded complication of surgery in multiple disciplines, including plastic surgery, and deep venous thrombosis and pulmonary embolus cause significant morbidity, even death. This article provides methods for understanding and preventing deep venous thrombosis and pulmonary embolus in plastic surgery.