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A geocentric approach to sponsor conducted clinical trials
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Abstracts Imputing Missing Values Under Order Restrictions Bruce T h o m p s o n , Carol H a n d y , a n d Michael Terrin
Maryland Medical Research Institute, Baltimore, Maryland (68) The problem of excluding missing data from analyses can lead to substantial errors in estimations. Using actual data and simulations, we examine the bias in several models for imputing missing values. The situation of interest is when both the probability of being missing and the likelihood of a positive response change monotonically with respect to a covariate. The models examined are a ratio-allocation model, which imputes missing values on the basis of observed percentages, a logistic allocation model, which imputes missing values according to external covariates, and an order restricted model where the data are assumed to obey the above mentioned ordered relationships.
Analytic Aspects of Single-Subject Trials Robin Roberts, G o r d o n Guyatt, a n d Jana Keller
McMaster University, Hamilton, Ontario, Canada (69) Multiperiod crossover trials to determine efficacy in individual patients are popular at our institution. An N-of-1 service provides help to clinicians in randomization, outcome assessment, and analysis. Fifteen trials have been done to date in a variety of conditions. Typically a trial runs for 3-5 pairs of treatment periods with 3-6 measurements of functional status per period by questionnaire. Possible analytic approaches include ANOVA, time series, and randomization tests. We present data to show that autocorrelation is not a problem and thus repeated-measures ANOVA is appropriate. Usually there is a between period component of variance so that observations are essentially averaged within treatment period. Data on the presence of carry-over effects are presented. Randomization tests are less satisfactory with the relatively few treatment pairs available. Clinicians are often persuaded by the results before formal significance is achieved.
Experience with Distributed Data Analyses in the Cardia Study Gary Cutter, Laura Perkins, L y n n e W a g e n k n e c h t , D a v i d Martin, a n d S a m S h a n n o n for the C A R D I A S t u d y University of Alabama at Birmingham, Birmingham, Alabama (70) Low-cost PC hardware and analysis software has created the opportunity for collaborative studies to release the analysis process from centralized control. CARDIA has implemented a distributed data analysis system that permits each clinical center and coordinating center to perform primary analyses. This process has removed the coordinating center as the bottleneck in the initial writing phase. Responsibilities usually resident within a coordinating center have been distributed, such as outlier detection and documentation, choice of proper algorithms and statistical procedures, and complete programming documentation. Verification of final results has remained with the coordinating center using the official study database. Evolution of the process has led us to create a system that defines the degree of verification and the administrative process of conducting verification.
POSTER SESSION (P01-P81) A Geocentric Approach to Sponsor Conducted C l i n i c a l Trials L e o n a r d Jacob a n d Rita C a r e y
SK&F Labs, Philadelphia, Pennsylvania (POD A geocentric approach to clinical trials is being used to conduct drug development worldwide (WW). A WW Clinical R&D administration manages, coordinates, and supports all activities. Three units were established from which clinical investigations are conducted. These are North America, United Kingdom (Britain, Scandinavia, Australasia, South Africa), and the European Continent. A centrally located operations unit supports the clinical trials by preparing protocols and case report forms, managing clinical data, providing statistical services, monitoring safety information, and preparing clinical reports for registration to WW regulatory agencies. A WW Clinical R&D Executive Committee, composed of VPs from each clinical investigation unit and the VP of central operations, review Clinical Development Plans, monitor the progress of trials,
Abstracts
263
and facilitate the optimal use of WW facilities and personnel. This approach eliminates redundant research efforts, capitalizes on the WW economy of scale, minimizes the number of protocols carried out, and establishes a single WW database from which all data can be immediately accessed for efficient and consistent reporting WW.
Electronic Reconciliation Reporting J u d y Worth, Diane Seif, a n d D e n i s e H a r p e r
Marion Laboratories, Inc., Kansas City, Missouri (P02) A trial management system to electronically calculate and reconcile study drug inventory records was used in a large, long-term multicenter trial. The system generated reports for clinical supply, regulatory compliance, clinical research, and investigator study sites. Data presentation details the following reports: Final Comparison Report Discrepancy Report Case Report Form Detail Drug Log Detail Unassigned Patient Numbers Summary Report By Lot Number Clinical Supply Patient Detail Report Patient Reconciliation Status Report Used to document GCP compliance, detailed reports aided investigation and resolution of discrepancies. In addition, the system allowed a means to identify final reconciliation status of each patient in the study.
Education and Orientation of a Contract Research Group to Co-Monitor and Close Out a Multicenter Study Larry Dollar, Diane Seif, Sue Ruckh, Esam Sidarous, a n d J u d y W o r t h
Marion Laboratories, Inc., Kansas City, Missouri (P03) A need was identified for help in monitoring a 38-site multicenter trial as well as conduct study closure visits for the same trial. The use of a contract research group was deemed necessary to complete this task. This large multicenter trial had a patient enrollment of 2500, with an individual site enrollment range of 18 to 179. The primary research needs required by the sponsor of the contract group were as follows: (1) monitoring and maintenance of protocol compliance; (2) drug accountability and data integrity; (3) prompt and accurate reporting of events; (4) confidentiality; and (5) ethical practices in clinical research. The training and orientation process was effectively accomplished and the needs of the sponsor were deafly defined using a two-step approach: (1) day-long workshops and (2) co-monitoring. This presentation addresses the development of these study management processes.
Microcomputer-Based Data Management and Statistical Analysis in a VA Cooperative Study D o m e n i c J. Reda, Yui-Li H s u , D o r o t h y H o n g , a n d the VA Cooperative TURP Group Hines VA Cooperative Studies Program Coordinating Center, Hines, Illinois (P04) Advances in hardware design and the conversion of mainframe database management and statistical analysis software packages to the microcomputer environment have made it possible to perform all data processing for large clinical trials on a microcomputer. VA Cooperative Study #246 is designed to compare TURP surgery to medical follow-up in men over age 55 with moderately symptomatic benign prostatic hyperplasia. The study is being conducted at nine VA urology departments with a target sample size of 526 patients. The medical database will grow to 25,000 records. A medical resource utilization database is also being maintained for a costeffectiveness subprotocol and will contain over 50,000 records. All data processing, including data entry, database management and interim statistical analyses are being conducted on an IBM PC AT. This presentation focuses on the selection of hardware and software, systems design, and problems encountered that are unique to the microcomputer environment.
Abstracts Imputing Missing Values Under Order Restrictions Bruce T h o m p s o n , Carol H a n d y , a n d Michael Terrin
Maryland Medical Research Institute, Baltimore, Maryland (68) The problem of excluding missing data from analyses can lead to substantial errors in estimations. Using actual data and simulations, we examine the bias in several models for imputing missing values. The situation of interest is when both the probability of being missing and the likelihood of a positive response change monotonically with respect to a covariate. The models examined are a ratio-allocation model, which imputes missing values on the basis of observed percentages, a logistic allocation model, which imputes missing values according to external covariates, and an order restricted model where the data are assumed to obey the above mentioned ordered relationships.
Analytic Aspects of Single-Subject Trials Robin Roberts, G o r d o n Guyatt, a n d Jana Keller
McMaster University, Hamilton, Ontario, Canada (69) Multiperiod crossover trials to determine efficacy in individual patients are popular at our institution. An N-of-1 service provides help to clinicians in randomization, outcome assessment, and analysis. Fifteen trials have been done to date in a variety of conditions. Typically a trial runs for 3-5 pairs of treatment periods with 3-6 measurements of functional status per period by questionnaire. Possible analytic approaches include ANOVA, time series, and randomization tests. We present data to show that autocorrelation is not a problem and thus repeated-measures ANOVA is appropriate. Usually there is a between period component of variance so that observations are essentially averaged within treatment period. Data on the presence of carry-over effects are presented. Randomization tests are less satisfactory with the relatively few treatment pairs available. Clinicians are often persuaded by the results before formal significance is achieved.
Experience with Distributed Data Analyses in the Cardia Study Gary Cutter, Laura Perkins, L y n n e W a g e n k n e c h t , D a v i d Martin, a n d S a m S h a n n o n for the C A R D I A S t u d y University of Alabama at Birmingham, Birmingham, Alabama (70) Low-cost PC hardware and analysis software has created the opportunity for collaborative studies to release the analysis process from centralized control. CARDIA has implemented a distributed data analysis system that permits each clinical center and coordinating center to perform primary analyses. This process has removed the coordinating center as the bottleneck in the initial writing phase. Responsibilities usually resident within a coordinating center have been distributed, such as outlier detection and documentation, choice of proper algorithms and statistical procedures, and complete programming documentation. Verification of final results has remained with the coordinating center using the official study database. Evolution of the process has led us to create a system that defines the degree of verification and the administrative process of conducting verification.
POSTER SESSION (P01-P81) A Geocentric Approach to Sponsor Conducted C l i n i c a l Trials L e o n a r d Jacob a n d Rita C a r e y
SK&F Labs, Philadelphia, Pennsylvania (POD A geocentric approach to clinical trials is being used to conduct drug development worldwide (WW). A WW Clinical R&D administration manages, coordinates, and supports all activities. Three units were established from which clinical investigations are conducted. These are North America, United Kingdom (Britain, Scandinavia, Australasia, South Africa), and the European Continent. A centrally located operations unit supports the clinical trials by preparing protocols and case report forms, managing clinical data, providing statistical services, monitoring safety information, and preparing clinical reports for registration to WW regulatory agencies. A WW Clinical R&D Executive Committee, composed of VPs from each clinical investigation unit and the VP of central operations, review Clinical Development Plans, monitor the progress of trials,
Abstracts
263
and facilitate the optimal use of WW facilities and personnel. This approach eliminates redundant research efforts, capitalizes on the WW economy of scale, minimizes the number of protocols carried out, and establishes a single WW database from which all data can be immediately accessed for efficient and consistent reporting WW.
Electronic Reconciliation Reporting J u d y Worth, Diane Seif, a n d D e n i s e H a r p e r
Marion Laboratories, Inc., Kansas City, Missouri (P02) A trial management system to electronically calculate and reconcile study drug inventory records was used in a large, long-term multicenter trial. The system generated reports for clinical supply, regulatory compliance, clinical research, and investigator study sites. Data presentation details the following reports: Final Comparison Report Discrepancy Report Case Report Form Detail Drug Log Detail Unassigned Patient Numbers Summary Report By Lot Number Clinical Supply Patient Detail Report Patient Reconciliation Status Report Used to document GCP compliance, detailed reports aided investigation and resolution of discrepancies. In addition, the system allowed a means to identify final reconciliation status of each patient in the study.
Education and Orientation of a Contract Research Group to Co-Monitor and Close Out a Multicenter Study Larry Dollar, Diane Seif, Sue Ruckh, Esam Sidarous, a n d J u d y W o r t h
Marion Laboratories, Inc., Kansas City, Missouri (P03) A need was identified for help in monitoring a 38-site multicenter trial as well as conduct study closure visits for the same trial. The use of a contract research group was deemed necessary to complete this task. This large multicenter trial had a patient enrollment of 2500, with an individual site enrollment range of 18 to 179. The primary research needs required by the sponsor of the contract group were as follows: (1) monitoring and maintenance of protocol compliance; (2) drug accountability and data integrity; (3) prompt and accurate reporting of events; (4) confidentiality; and (5) ethical practices in clinical research. The training and orientation process was effectively accomplished and the needs of the sponsor were deafly defined using a two-step approach: (1) day-long workshops and (2) co-monitoring. This presentation addresses the development of these study management processes.
Microcomputer-Based Data Management and Statistical Analysis in a VA Cooperative Study D o m e n i c J. Reda, Yui-Li H s u , D o r o t h y H o n g , a n d the VA Cooperative TURP Group Hines VA Cooperative Studies Program Coordinating Center, Hines, Illinois (P04) Advances in hardware design and the conversion of mainframe database management and statistical analysis software packages to the microcomputer environment have made it possible to perform all data processing for large clinical trials on a microcomputer. VA Cooperative Study #246 is designed to compare TURP surgery to medical follow-up in men over age 55 with moderately symptomatic benign prostatic hyperplasia. The study is being conducted at nine VA urology departments with a target sample size of 526 patients. The medical database will grow to 25,000 records. A medical resource utilization database is also being maintained for a costeffectiveness subprotocol and will contain over 50,000 records. All data processing, including data entry, database management and interim statistical analyses are being conducted on an IBM PC AT. This presentation focuses on the selection of hardware and software, systems design, and problems encountered that are unique to the microcomputer environment.