Guidelines for monitoring company sponsored clinical trials in the pharmaceutical industry

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P122 QUALITY CONTROL IN THE DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT) Walter Owen, Patrlcle Cleary, F. John Service and Rodney Lorenz

The George Washington University Biostatis~cs Center Rockville, Maryland The DCCT is a controlled clinical tdal designed to study the effects of intensive insulin therapy on diabetes complications. Samples collected at 29 centers in the U.S. and Canada are analyzed by a central biochemistry laboratory (CBL), an ophthalmologic reading unit, ECG and neurology reading units and nutritional and neurobehavioral coding units. Study personnel are trained and certified in the collection of data. Data quality is assured by a multicomponent system: (1) data are double keyed; (2) edit messages are mailed monthly; (3) precision of central unit measurements is monitored by an external quality surveillance system. For example, masked split duplicates of 10% of all laboratory specimens are analyzed by the CBL to assess the entire process of collection, analysis and reporting of biochemical data. The hemoglobin AIc data is critical to the DCCT, therefore special measures are used to monitor precision over time. Annual rereadings of fundus photographs check for potential drift in the grading system. Comparable mechanisms of QC have been initiated at the other units. The results of QC monitoring systems are reviewed by internal study committees. Although minor irregularities have been detected by the system, such as a correctable problem in patient collected home blood profilsets, overall performance has been excellent. P123 DEVELOPING A QUALITY CONTROL (QC) PROGRAM FOR BONE DENSITY MEASUREMENTS IN A MULTICENTER TRIAL: THE POSTMENOPAUSAL ESTROGEN/PROGESTIN INTERVENTIONS (PEPI) EXPERIENCE Carol H. Wasllauskas and H. Bradley Wells

Bowman Gray School of Medicine Winston-Salem, North Carolina Bone density measurements have become an increasingly important end-point in many clinical trials. Onsite, rather than central, measurements present several challenges for QC in the collection and processing of scans. The PEPI Tdal requires bone density measurements of lumbar spine and hip at Baseline, 12 and 36 months on women at 7 clinical centers. To control for variation inherent in measurements done with different instruments and operators, at different sites and over time, the PEPI Coordinating Center has implemented a QC program which includes: • • • • • •

Central Purchase of Equipment Special Training of Instrument Operators A Manual of Procedures for PEPI Bone Scans Repeated (Duplicate) Hip and Spine Scans Special Data Forms A Bone Scan Quality Control Center to: Review scans and calibration data Reenalyze and correct scans Circulate a =Gold Standard" Phantom Provide technical assistance to clinics

This presentation reviews the development and implementation of the various aspects of the QC program. Preliminary QC data indicate that the coefficient of variation in the error of measurement, based on repeated scans, is 1.6% for the spine and 1.7% for the hip scans. P124 GUIDELINES FOR MONITORING COMPANY SPONSORED CLINICAL TRIALS IN THE PHARMACEUTICAL INDUSTRY P.L.C. Banks

Adria Laboratodes Dublin, Ohio Phase III clinical tdals in oncology frequently require ongoing monitoring of the data to satisfy both ethical demands end efficiency considerations. Standard statistical practices exercised in cooperative groups to evaluate interim results are steadily becoming commonplace in the pharmaceutical industry. That is, group

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sequential test designs are used to establish a stopping rule. However, the decision to terminate a study prematurely is a complex process, with other factors needing to be considered in addition to the evidence provided from the group sequential guideline. Company sponsored studies are usually monitored in-house to address management concerns regarding efficient allocation of resources. Given the vested interest the company has in the likely success of the trial, the potential for biased decisions are increased. To overcome this dilemma, interim results should be reported to an independent Data Monitoring Committee (DMC) with little or no company involvement in the group's deliberations. Here, guidelines are presented to outline the interaction between the sponsor and the DMC so as to maintain the integrity of the trial's results and yet, provide assurance to the sponsor that resources are being properly spent. P 125 ELECTRONIC COMPLIANCE MONITORING IN CLINICAL TRIALS: BENEFITS AND RISKS J. Todd Sahlroot and Gordon W. Pledger

Epilepsy Branch National Institutes of Health Bethesda, Maryland It is generally agreed that clinical trial designs should provide for assessing the extent of compliance with the protocol. Traditionally patient compliance with prescribed drug treatment regimens has been assessed by pill counts, patient reports or blood levels. Each method has its shortcomings. Smart pill boxes that electronically record the time of each opening and closing offer the potential to collect more complete and more accurate compliance data. For chronic disorders such as epilepsy it would be particularly useful to be able to relate missed doses to disease flaraups, e.g., increased seizure activity. The Epilepsy Branch of the NIH has used electronic monitoring in a randomized, double-blind, six-period crossover trial with 16 patients at two centers. This experience has revealed various practical problems that require attention before electronic monitoring could be recommended for large-scale trials with complicated dosing regimens. These problems relate to the limited capabilities of the specific devices used and, more importantly, to the possible undesirable effects on compliance itself. In some circumstances, the attempt to measure compliance more accurately may reduce compliance. P 126 A COMPARISON OF COMPUTER AND HUMAN CORONARY ANGIOGRAPHIC END-POINT MEASURES Wendy Mack, Janlce Pogoda, Stanley Azen, and David Blankenhorn

University of Southern California Los Angeles, California CLAS, a randomized angiographic clinical trial, has demonstrated the beneficial effect of niacin/colestipol therapy on coronary atherosclerosis using a panel-determined consensus score evaluating global change in lesions determined angiographically. Computerized edge-tracking (CET) estimates of lesion change were also made. We present a comparison of human panel with CET evaluations in 85 baseline/2-year film pairs. Parameters included presence of lesions, lesion size, and change in lesion size. Lesions evaluated by CET but not by the panel were principally early lesions where information on treatment effect is of particular value for primary atherosclerosis prevention. Lesions evaluated by humans but not by CET were principally advanced lesions which lacked an appropriate segment of uninvolved vessel for CET assessment. For lesions evaluated by both panel and CET, the correlation between the CET and panel estimates of lesion size was 0.70 (p < 0.0001), and for changed lesions was 0.28 (p = 0.002). We conclude that film evaluation by human panel readers and CET are complementary procedures which assess information in different but overlapping sets of lesions. P127 DATA MANAGEMENT CONCEPTS AT THE EPIDEMIOLOGY DATA CENTER Polly Swanson, Diane Hurah, Janlce Murphy, and Nancy Remaley

University of Pittsburgh Pittsburgh, Pennsylvania The Epidemiolegy Data Center (EDC), at the Graduate School of Public Health, coordinates data management and analysis for 21 sponsored research studies, including the Bypass Angioplasty Revascularization Investigation (BARI), the Liver Transplantation Database (LTD), and the Percutaneous Transluminal Coronary