Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2).

BACKGROUND: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. METHODS/DESIGN: We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. DISCUSSION: A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.

Collection and use of cancer family history in primary care.

OBJECTIVES: This systematic review was undertaken to: (1) evaluate the accuracy of patient reporting of cancer family history, (2) identify and evaluate tools designed to capture cancer family history that are applicable to the primary care setting, and (3) identify and evaluate risk assessment tools (RATs) in promoting appropriate management of familial cancer risk in primary care settings. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Cochrane Central from 1990 to July 2007. REVIEW METHODS: Standard systematic review methodology was employed. Eligibility criteria included English studies evaluating breast, colorectal, ovarian, or prostate cancers. All primary study designs were included. For family history tools (FHxTs) and RATs, studies were limited to those applicable to primary care settings. RATs were excluded if they calculated the risk of mutation only, required specialist genetics knowledge, or were stand-alone guidelines. RESULTS: Reporting Accuracy: Of 19 eligible studies, 16 evaluated the accuracy of reporting family history and three on reliability. Reporting accuracy was better for relatives free of cancer (specificity) than those with cancer (sensitivity). Accuracy was better for breast and colorectal than for ovarian and prostate cancers. Family History Tools: Of 40 eligible studies, 18 FHxTs were applicable to primary care. Most collected information on more than one cancer, employed self-administered questionnaires, and favored paper-based formats to collate family information. Details collected were often focused on specific conditions and affected relatives. Eleven tools were evaluated relative to current practice and seven were not. Irrespective of study design, compared to best current practice (genetic interviews) and standard primary care practice (family history in medical records) the FHxTs performed well. Risk Assessment Tools: Of 15 eligible studies, three RATs were identified for patient use and eight for use by professionals. They were presented in a range of computer-based and paper-based formats, and preliminary evidence indicated potential efficacy, but not definitive effectiveness in practice. CONCLUSIONS: Although limited in generalizability, informants reporting their cancer family history have greater accuracy for relatives free of cancer than those with cancer. Reporting accuracy may vary among different cancer types. FHxTs varied in the extent of family enquiry depending on the tool's purpose. These tools were primarily developed as an integral part of risk assessment. The few tools that were evaluated performed well against both best and standard clinical practice. A number of RATs designed for primary care settings exist, but evidence is lacking of their effectiveness in promoting recommended clinical actions.