410 Abstracts

A27 BETA ERRORS REVISITED

D. Moher, G.A. Wells and C.S. Dulberg Loeb Medical Research Institute

Ottawa, Canada

Randomized controlled trials (RCTs) have been accepted as the gold standard by which the medical community assesses the efficacy of interventions. Fifteen years ago, in a landmark study, Freiman and colleagues reviewed 71 "negative" RCTs: the vast majority had inflated Type II errors. We replicated and extended this study to assess whether the proportion of negative RCTs and inflated Type II errors had changed over time. A structured data collection form as well as guidelines to classify trials as positive or negative and to determine primary outcomes were developed. We reviewed all RCTs in three leading general medical journals (JAMA, Lancet, and NEJM), published in 1975, 1980, 1985 and 1990. Of the 383 RCTs, 102 (27%) were classified as negative: 22, 22, 21, and 37 over time. The number of RCTs nearly tripled from 1975 to 1990, with the proportion of negative trials remaining fairly stable. Only 15% and 34% of the negative two group parallel design trials (n=73) had sufficient statistical power (80%) to detect, respectively, a 25% or 50% relative difference. These results have not improved over time: 12%, 12%, 6%, 24% for a 25% relative difference; and 25%, 44%, 25%, 40% for a 50% relative difference. While overall, only 32 % of the negative trials reported sample size calculations, this percentage has improved significantly over time: 0%, 32%, 48%, 43%. The majority of these negative trials (70%) did not provide sufficient information to replicate sample size calculations. There is still much that needs improvement. One suggestion is to report RCTs using a structured format.

A28 SHOULD THERE BE RESTRICTIONS ON INDICATOR

LESIONS FOR PHASE II TRIALS IN ONCOLOGY?

Hilary Franklin on behalf of Early Clinical TriaLs Group of the EORTC

New Drug Development Office Amsterdam, The Netherlands

As tumor response is the main end point of phase II cancer clinical trials, it is essential that the chosen indicator lesions are reliable parameters for the activity of a potential anti-cancer drug. Recent proposals are to restrict the target groups of patients, for example to only those who have bi- dimensionally measurable disease of more than a certain diameter. Since these restrictions will inevitably decrease the rate of patient accrual, it is important to know whether they will in fact give a more reliable assessment of drug activity.

Over the last three years the Early Clinical Trials Group has gathered data on more than 750 patients in 27 multi-centric phase I1 trials concerning seven drugs and ten different tumor types. The following factors, besides the drug itself, which could influence the response of tumor lesions, have been recorded: site of lesion (primary, lung-, liver-, lymphnode-, soft tissue-, bone-metastasis), size of lesion, method of evaluation, tumor-type, prior irradiation, measurability (bi-, uni-dimensional), institution. Simulation of different groups of selection criteria was applied to these data to assess the "cost/benefit" in terms of loss of accrual/overall response rate in different situations, using multivariate techniques we could study the characteristics of an "optimal" balance between the speed/reliability of anti-cancer drug testing.

A29 OPTIMIZING PATIENT SELECTION IN

THERAPEUTIC EXPERIMENTS

K.G.M. Moons, G.A. van Es and D.E. Grobbee Erasmus UniversiLy

Rotterdam, Netherlands

To participate in a therapeutic experiment (trial) patients have to satisfy pre-defined inclusion and exclusion criteria. These criteria are often evaluated over a period of time, called selection period. The goal of this paper is to propose a methodology for optimizing the selection period in terms of efficiency, i.e., to obtain relevant information for recruitment with a minimum of measurements. The approach is to determine whether variables initially measured in the selection period have a predictive value for exclusions later on in this period, is evaluated by an univariate sensitivity and specificity analysis and subsequently by multivariate logistic regression models in

Abstracts 411

combination with ROC-curves. The methodology is illustrated by the ROtterdam CArdiovascular Risk Intervention (ROCARI) trial, which investigated the effect of cholesterol lowering on the risk of coronary heart disease in 9,000 men with primary hypercholesterolemia. For Otis study 62,000 men had to be screened. The selection period comprised 5 consecutive visits with a frequency of one per month. The present analysis is based on data of 30,300 screened men. Univariate analysis showed, that exclusion at average HDL cholesterol_>> 1.40 mmolfl at visit 3 (required of two consecutive HDL measurements at visit 2 and 3), could correctly be predicted by the first measurement with a sensitivity of 43% (95% Ch42-44), which by extrapolation to the final number of 62,000 would save the costs of visit 3 for 4600 men. The 1-specificity of 0.07 % (0.05-0.07) indicated an extrapolated number of 37 false predictions, which stands for loss in benefits since 37 potential randomizations are lost at visit 3 and therefore 111 men had to be screened extra to obtain the study population. Similarly though less efficient, exclusion because of total cholesterol (TC) outside the range of 6.0-8.5 mmol/l could truly be predicted in 2530 cases with 198 false predictions involving 595 extra screenings. In the multivariate analysis, the area under curve (AUC) of the model with all (15) variables measured at visit 1 and 2 to predict these criteria was 0.0977 (0.959-0.995) and 0.959 (0.937-0.981) respectively. However, the AUC's of the model with only the first HDL respectively TC measurement at visit 2, were not significantly lower. We conclude that the use of,t~t~ obtained early in a prolonged selection period to predict subsequent exclusions, utilizing the proposed methodology, could increase efficiency m the screening for ROCARI as well as in other trials.

A30 COMPUTERIZED AND CENTRALIZED PARTICIPANT ENTRY IN

LARGE-SCALE, MULTI-CENTERED CLINICAL TRIALS

Walter M. Cronin University of Pittsburgh

Pittsburgh, Pennsylvania

Recruitment into the Breast Cancer Prevention Trial (BCPT) will involve the generation of over 50,000 risk assessment profiles and randomization of 16,000 participants over a 2-year period, and the distribution of 64 million tablets of medication over 7 years. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has developed a computer-based system which generates individualized profiles of risks, screens for participant eligibility, assigns randomized treatments, initializes all d~t~ files, automatically processes orders for drug distribution, and creates participant schedules. Many aspects of this system are applicable for coordinating centers which are responsible for the conduct of large-scale clinical trials.

A31 REPRESENTATION OF WOMEN AND MINORITIES

IN PUBLISHED CLINICAL TRIALS

Barbara A. Duffy and Curtis L. Meinert The Johns Hopkins University

Baltimore, Maryland

All randomized clinical trials published in 1986 and 1991 in five peer review journals were selected and evaluated for their patient populations. The patient populations will be examined for their gender, racial, and age distributions. The gender distribution and racial distribution of the selected trials will be analyzed by the disease under study, sample size of the trial population, the phase of the trial, and the year of publication. Trials studying diseases that are primarily associated with a specific gender will be analyzed by frequency, sample size of the trial population, and the phase of the trial. From this analysis, conclusions will be drawn regarding the representation of women and minorities in trials for the subsets under review.