Controlled Clinical Trials 

Abstract: This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.

Abstract: It has been suggested that the quality of clinical trials should be assessed by blinded raters to limit the risk of introducing bias into meta-analyses and systematic reviews, and into the peer-review process There is very little evidence in the literature to substantiate this This study describes the development of an instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research and its use to determine the effect of rater blinding on the assessments of quality A multidisciplinary panel of six judges produced an initial version of the instrument Fourteen raters from three different backgrounds assessed the quality of 36 research reports in pain research, selected from three different samples Seven were allocated randomly to perform the assessments under blind conditions The final version of the instrument included three items These items were scored consistently by all the raters regardless of background and could discriminate between reports from the different samples Blind assessments produced significantly lower and more consistent scores than open assessments The implications of this finding for systematic reviews, meta-analytic research and the peer-review process are discussed

Abstract: In recent years quality of life instruments have been featured as primary outcomes in many randomized trials. One of the challenges facing the investigator using such measures is determining the significance of any differences observed, and communicating that significance to clinicians who will be applying the trial results. We have developed an approach to elucidating the significance of changes in score in quality of life instruments by comparing them to global ratings of change. Using this approach we have established a plausible range within which the minimal clinically important difference (MCID) falls. In three studies in which instruments measuring dyspnea, fatigue, and emotional function in patients with chronic heart and lung disease were applied the MCID was represented by mean change in score of approximately 0.5 per item, when responses were presented on a seven point Likert scale. Furthermore, we have established ranges for changes in questionnaire scores that correspond to moderate and large changes in the domains of interest. This information will be useful in interpreting questionnaire scores, both in individuals and in groups of patients participating in controlled trials, and in the planning of new trials.

Abstract: The primary objective of a phase II clinical trial of a new drug or regimen is to determine whether it has sufficient biological activity against the disease under study to warrant more extensive development. Such trials are often conducted in a multi- institution setting where designs of more than two stages are difficult to manage. This paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the regimen has low activity subject to constraints upon the size of the type 1 and type 2 errors. Two-stage designs which minimize the maximum sample size are also determined. Optimum and "minimax" designs for a range of design parameters are tabulated. These designs can also be used for pilot studies of new regimens where toxicity is the endpoint of interest.

Abstract: The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.