Biomedical subjects
David L Sackett
Publications and source records attributed to David L Sackett.
A surrealistic mega-analysis of redisorganization theories.
BACKGROUND: We are sick and tired of being redisorganized. OBJECTIVE: To systematically review the empirical evidence for organizational theories and repeated reorganizations. METHODS: We did not find anything worth reading, other than Dilbert, so we fantasized. Unfortunately, our fantasies may well resemble many people's realities. We are sorry about this, but it is not our fault. RESULTS: We discovered many reasons for repeated reorganizations, the most common being 'no good reason'. We estimated that trillions of dollars are being spent on strategic and organizational planning activities each year, thus providing lots of good reasons for hundreds of thousands of people, including us, to get into the business. New leaders who are intoxicated with the prospect of change further fuel perpetual cycles of redisorganization. We identified eight indicators of successful redisorganizations, including large consultancy fees paid to friends and relatives. CONCLUSIONS: We propose the establishment of ethics committees to review all future redisorganization proposals in order to put a stop to uncontrolled, unplanned experimentation inflicted providers and users of the health services.
Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review.
BACKGROUND: Blinding is a cornerstone of therapeutic evaluation because lack of blinding can bias treatment effect estimates. An inventory of the blinding methods would help trialists conduct high-quality clinical trials and readers appraise the quality of results of published trials. We aimed to systematically classify and describe methods to establish and maintain blinding of patients and health care providers and methods to obtain blinding of outcome assessors in randomized controlled trials of pharmacologic treatments. METHODS AND FINDINGS: We undertook a systematic review of all reports of randomized controlled trials assessing pharmacologic treatments with blinding published in 2004 in high impact-factor journals from Medline and the Cochrane Methodology Register. We used a standardized data collection form to extract data. The blinding methods were classified according to whether they primarily (1) established blinding of patients or health care providers, (2) maintained the blinding of patients or health care providers, and (3) obtained blinding of assessors of the main outcomes. We identified 819 articles, with 472 (58%) describing the method of blinding. Methods to establish blinding of patients and/or health care providers concerned mainly treatments provided in identical form, specific methods to mask some characteristics of the treatments (e.g., added flavor or opaque coverage), or use of double dummy procedures or simulation of an injection. Methods to avoid unblinding of patients and/or health care providers involved use of active placebo, centralized assessment of side effects, patients informed only in part about the potential side effects of each treatment, centralized adapted dosage, or provision of sham results of complementary investigations. The methods reported for blinding outcome assessors mainly relied on a centralized assessment of complementary investigations, clinical examination (i.e., use of video, audiotape, or photography), or adjudication of clinical events. CONCLUSIONS: This review classifies blinding methods and provides a detailed description of methods that could help trialists overcome some barriers to blinding in clinical trials and readers interpret the quality of pharmacologic trials.
Applying a phase II futility study design to therapeutic stroke trials.
BACKGROUND AND PURPOSE: Most large, randomized phase III efficacy trials of therapeutic agents in ischemic stroke have failed to find treatment benefit. We determined whether some phase III studies could have been avoided if preceded by smaller single-arm phase II studies to evaluate the futility of proceeding to phase III. METHODS: To provide examples of the application of phase II methodology, we obtained primary outcome data for the active treatment group of 6 phase III ischemic stroke therapy trials. For each study, we estimated the sample size number required for a multistage single-arm study using parameters specified in the original study. We evaluated outcome data for the first number of subjects in the phase III study treatment arm ordered by enrollment dates. We compared the proportion of favorable outcomes to prespecified stopping criteria derived from a single-arm phase II futility design. If the observed proportion of favorable outcomes was less than the stopping criterion, we declared the treatment not sufficiently effective to warrant further evaluation in phase III. RESULTS: We identified 3 trials as futile in phase II; none of 3 showed treatment efficacy in phase III. In the 3 remaining phase II trials in which we did not show futility, one showed efficacy in phase III. CONCLUSIONS: Single-arm phase II futility studies have been underused in stroke research, but provide a strategy for discarding treatments likely to be ineffective in phase III trials.
Participants in research.
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Need for expertise based randomised controlled trials.
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A surrealistic mega-analysis of redisorganization theories.
BACKGROUND: We are sick and tired of being redisorganized. OBJECTIVE: To systematically review the empirical evidence for organizational theories and repeated reorganizations. METHODS: We did not find anything worth reading, other than Dilbert, so we fantasized. Unfortunately, our fantasies may well resemble many people's realities. We are sorry about this, but it is not our fault. RESULTS: We discovered many reasons for repeated reorganizations, the most common being "no good reason". We estimated that trillions of dollars are being spent on strategic and organizational planning activities each year, thus providing lots of good reasons for hundreds of thousands of people, including us, to get into the business. New leaders who are intoxicated with the prospect of change further fuel perpetual cycles of redisorganization. We identified eight indicators of successful redisorganizations, including large consultancy fees paid to friends and relatives. CONCLUSIONS: We propose the establishment of ethics committees to review all future redisorganization proposals in order to put a stop to uncontrolled, unplanned experimentation inflicted on providers and users of the health services.
Editorial independence at the BMJ:.and the author apologises unreservedly.
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Campaign to revitalise academic medicine: don't believe us.
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Turning a blind eye: why we don't test for blindness at the end of our trials.
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HARLOT plc: an amalgamation of the world's two oldest professions.
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Effect of awareness of a randomized controlled trial on use of experimental therapy.
CONTEXT: Use of experimental therapies during but outside of randomized controlled trials (RCTs) has not been studied. OBJECTIVE: To determine whether initiation of an RCT leads to increased use of the experimental therapy outside the trial. DESIGN AND SETTING: Data on national apheresis use during 3 Canadian RCTs for multiple sclerosis (1986-1988), thrombotic thrombocytopenic purpura (1982-1988), and myeloma cast nephropathy (1998-2000) were obtained from 19 major medical centers in Canada. The multiple sclerosis and myeloma cast nephropathy trials had data on apheresis use for 3 years prior to and during the trials, which permitted a time-series analysis to determine the impact of the RCTs on the use of apheresis. The ongoing myeloma cast nephropathy trial provided data on the number of patients inside and outside of the RCTs in trial and nontrial centers. Initial and follow-up questionnaires were sent to 24 Canadian physicians in trial and nontrial centers to determine if they had noted an increase in apheresis activity during the trials and, if so, their explanation for it. MAIN OUTCOME MEASURE: Change in number of patients undergoing apheresis for thrombotic thrombocytopenic purpura, multiple sclerosis, and myeloma cast nephropathy prior to and during the respective RCTs compared with all patients undergoing apheresis during the same periods. RESULTS: During all 3 RCTs, there were large increases in use of apheresis. The majority of the increased use of apheresis was outside of the trials: for multiple sclerosis, 30 of 49 patients per year (61% of increase); thrombotic thrombocytopenic purpura, 49 of 56 patients per year (72% of increase); and myeloma cast nephropathy, 60 of 72 patients per year (57% of increase). The myeloma cast nephropathy study noted that this increase occurred in both nontrial and trial centers. Among questionnaire respondents (n = 22; 92% response rate), most physicians noted an increase in apheresis activity during the trials and attributed it to a "jumping-the-gun" phenomenon. CONCLUSIONS: During 3 Canadian RCTs, apheresis increased, but most of the increase occurred outside the trials. This behavior during an RCT, in the absence of clear efficacy, can be termed jumping the gun.
Analysis and reporting of factorial trials: a systematic review.
CONTEXT: Although factorial trials have become common, standards for the analysis and reporting of such trials have not been established and, despite concerns about the possibility of unrecognized interactions between therapies in factorial trials, the magnitude of this potential problem is unknown. OBJECTIVE: To examine the rationale, methods, and analysis of randomized factorial trials. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register using the terms factorial, interaction, 2 x 2, 2 by 2, and incremental to identify factorial randomized trials published from January 2000 to July 2002. To identify trials missed by the electronic search, we performed a hand search of English-language trials in a defined topic area (using the term myocardial ischemia [exp]) listed in MEDLINE (1966-2002), EMBASE (1980-2002), and the Cochrane Controlled Trials Register, as well as all trials in any topic area published in December 2000, excluding trials reporting only continuous surrogate end points. The final set of 33 eligible publications described 29 unique trials. DATA EXTRACTION: Two investigators independently identified factorial trials, generated a list of items affecting validity of results, and abstracted these items from each trial. DATA SYNTHESIS: The sensitivity of electronic searching for identifying factorial trials was 76%. Our 3-pronged search strategy identified 44 factorial trials with clinically important binary outcomes: 36 (82%) were done for reasons of efficiency (testing 2 interventions in the same patient population), and 8 (18%) were done to assess the incremental benefits of combining the 2 treatments. All but 1 of the trials reported treatment effects by comparing all patients who received treatment A (ie, those receiving either A alone or both A and B) vs all those not receiving treatment A (ie, those receiving either B alone or neither A nor B). Twenty-nine of the 44 trials (66%) reported the data from each of the treatment groups separately; 26 trials (59%) reported testing for interactions between the treatments. Only 2 of 31 (6%) comparisons demonstrated a statistically significant interaction between the 2 treatments. CONCLUSIONS: Accurate interpretation of factorial trials depends on the transparent reporting of data for each treatment cell. Despite concerns about unrecognized interactions, our findings suggest that investigators are appropriately restricting their use of the factorial design to those situations in which 2 (or more) treatments do not have the potential for substantive interaction.
The arrogance of preventive medicine.
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Clinical epidemiology. what, who, and whither.
Clinical epidemiology, the what, was introduced by John Paul in 1938, as a new basic science for preventive medicine. Its definition subsequently took on a more bedside tone, but continues to be adapted to the needs of its practitioners. Clinical epidemiology, the who, centers on Alvan Feinstein and the way that he led the field and nurtured so many of its practitioners. Clinical epidemiology, the whither, describes its more recent development and its impact on five evolutions and revolutions: in evidence generation, its rapid critical appraisal, its efficient storage and retrieval, evidence-based medicine, and evidence synthesis.
Accuracy of history, wheezing, and forced expiratory time in the diagnosis of chronic obstructive pulmonary disease.
OBJECTIVE: To determine the accuracy of the history and selected elements of the physical examination in the diagnosis of chronic obstructive pulmonary disease (COPD). DESIGN: Independent blind comparison of the standard clinical examination (evaluating the accuracy of history, wheezing, and forced expiratory time [FET]) with spirometry. The gold standard for diagnosis of COPD was a forced expiratory volume at 1 second (FEV1) below the fifth percentile (adjusted for patient height and age). SETTING: Seven sites in 6 countries, including investigators from primary care and secondary care settings. PARTICIPANTS: One hundred sixty-one consecutive patients with varying severity of disease (known COPD, suspected COPD, or no COPD) participated in the study. MAIN RESULTS: One hundred sixty-one patients (mean age 65 years, 39% female, 41% with known COPD, 27% with suspected COPD, and 32% normal) were recruited. Mean (+/-SD) FEV1 and forced vital capacity were 1,720 (+/-830) mL and 2,520 (+/-970) mL. The likelihood ratios (LR) for the tested elements of the clinical examination (and their P values on chi2 testing) were: self-reported history of COPD, 5.6 (P <.001); FET greater than 9 seconds, 6.7 (P < 0.01); smoked longer than 40 pack years, 3.3 (P =.001); wheezing, 4.0 (P <.001); male gender, 1.6 (P <.001); and age over 65 years, 1.6 (P =.025). The accuracy of these elements was not appreciably different when reference standards other than FEV1 below the 5th percentile were applied. Only 3 elements of the clinical examination were significantly associated with the diagnosis of COPD on multivariate analysis: self-reported history of COPD (adjusted LR 4.4), wheezing (adjusted LR 2.9), and FET greater than 9 seconds (adjusted LR 4.6). Area under the receiver operating characteristic curve for the model incorporating these 3 factors was 0.86. CONCLUSIONS: Less emphasis should be placed on the presence of isolated symptoms or signs in the diagnosis of COPD. While numerous elements of the clinical examination are associated with the diagnosis of COPD, only 3 are significant on multivariate analysis. Patients having all 3 of these findings have an LR of 33 (ruling in COPD); those with none have an LR of 0.18 (ruling out COPD).
Superiority trials, noninferiority trials, and prisoners of the 2-sided null hypothesis.
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