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The effect of between-group compliance rate differences on the results of the lipid research clinics coronary primary preventaion trial (CPPT)
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Abstracts The DATAGIPSY: Regional Multicentric Data Management Monique Konings
Comprehensive Cancer Center South, Tilburg, Netherlands (P05) In our center the data manager works in 12 different hospitals, located in various cities. The average traveling distance is 40 kilometers from our center. We have gained considerable experience in organizing our work efficiently in spite of these facts. I give an overview of the specific aspects of multicentric data management, e.g., traveling, working as a guest in the hospitals, not being allowed to take patient files out of the hospitals, and the fact that all these hospitals are different with regard to patient files, working methods, ways of storing the information etc. Emphasis is placed on the organizational consequences of working with 12 different hospitals and the solutions we have found in order to work efficiently and satisfy the various needs and wishes of the physicians. Advertising--A Tool for Patient Recruitment M.E. Vitek, S.G. F i s h e r , N. C o h e n , S. W a l t z m a n , W . G . H e n d e r s o n VA CSPCC, Hines, Illinois (P06) A Prospective Randomized Cooperative Study of Advanced Cochlear Implants, CSP #304, was initiated in January 1987. Funded by the VA Cooperative Studies Program and the VA Rehabilitation Research and Development Service, this trial involving seven VA medical centers will compare four cochlear implant devices. Cochlear implants electrically stimulate the auditory nerve to produce sound. A 3-year intake of 120 veterans with bilateral profound hearing loss is required. By April 1987, no patients were randomized and it became clear that an accrual problem existed. An intensive national advertising campaign was instituted with VA Central Office support. Veterans' magazines, medical journals, and UPI and AP wire services were used to inform the public of our research. In the 5 months following the first article 2702 telephone calls and letters were received; both qualified and unqualified candidates responded. Potential candidates were screened and forwarded for testing. As of October 1, 1987, 30 patients have been approved for randomization; 15 (50%) were as a result of the advertising campaign. It is expected that this percentage will increase as each center exhausts its own patient population.
Use of Nonstudy Drugs in Clinical Trials C.M. H a k e n s o n , C.L. Frye, M.R. S a t h e r , a n d C.L. Colling VA CSPCRPCC, Albuquerque, New Mexico (P07) With the general acceptance of the intent-to-treat principle in clinical trials, patients are seldom terminated from follow-up or excluded from analysis on the basis of concurrent use of nonstudy medications. Use of such drugs, however, can complicate the analysis unless consideration is given to this aspect during planning. Acceptable and unacceptable drug use should be defined to minimize use of drugs that can enhance or diminish the effect of the intervention or make evaluating adverse effects difficult. Forms for recording concurrent drug use should be simple and facilitate computer data entry. If only a few drugs are of concern, forms can be limited to questions about those specific drugs. If all drug use is to be recorded, a system for coding the drugs will be needed for data entry. The VA Cooperative Studies Program has developed a drug coding system for use in clinical trials. Each drug has been given a three-letter code and is listed by both generic and trade names. At each clinic visit, drug names are recorded and the appropriate computer codes assigned. This system has been employed in ten trials over the past 6 years and has provided a flexible system for forms completion, data entry, and data analysis of all medications taken by study patients.
The Effect of Between-Group Compliance Rate Differences on the Results of the Lipid Research Clinics Coronary Primary Prevention Trial (CPPT) K e n n e t h B. S c h e c h t m a n a n d M a e G o r d o n Washington University, St. Louis, Missouri (P08) Between-group differences in compliance (C) can have a major impact on the results of clinical trials. In the CPPT, C in the treatment (T) group (65.7%) was lower than in the placebo group (77.0%). Had C in the T group been as high as it was in the placebo group, the observed T group decrease of 13.7% in total cholesterol would have had an expected value of 15.9%. LDL decreases
Abstracts
265
are 20.6% (observed) and 23.8% (expected u n d e r equal C). There were 187 placebo events (9.8%) and 155 in the T group (8.1%). Equal C yields an expected 145 T group events, an increase of 31% in the observed between group difference. These event rates produce sample size requirements that would be 43% lower if C in the T group were as high as in the placebo. We believe that C differences are common in clinical trials involving treatments with important side effects. We conclude that between-group differences in C can dramatically increase sample size requirements and lead to underestimates of the efficacy of treatments with attributes that reduce C.
Costs and Benefits of Electronic Mail for Clinical Trial Communication Bruce A. B a r t o n
Maryland Medical Research Institute, Baltimore, Maryland (P09) It is clear that timely communication in the management of clinical trials, especially during the planning phase, is important, if not critical, to the success of the study. Frequently, the investigators at the clinical centers are difficult to reach and a n u m b e r of return telephone calls are necessary to establish contact. Electronic mail has been proposed as an answer to this problem. During the planning phase and the feasibility phase of the Dietary Intervention Study in Children (DISC), two different electronic mall systems were utilized to facilitate communication. The first was based on a central mainframe-class computer with the electronic mail system accessed through remote terminals or microcomputers. The second system had a central post office implemented on a microcomputer at the Coordinating Center accessed by microcomputers at each clinical center using the same software as the central post office. A comparison of the features of each system, such as ease of use, speed of transmission, cost of use, and cost of the hardware and software, is presented. In addition, a comparison with normal telephone communication and FAX communication is made. Training costs and startup time are also considered.
The Importance of a Central Institutional Review Board in Multicenter Clinical Trials R i c h a r d D. N e w m a n a n d D a v i d C. G i l s o n G.D. Searle & Co., Skokie, Illinois (P10) A major consideration in the timely management of any clinical trial is the review and approval of the study by an Institutional Review Board (IRB). When managing a multicenter trial, the challenge of obtaining IRB approval is strongly related to the n u m b e r of participating study sites. Many physicians in private practice or associated with small local practices may not even have familiarity with the IRB requirements. In such cases, the use of a central IRB may afford several benefits: (1) safety oversight for all patients and investigators; (2) uniform and carefully reviewed informed consents; (3) timely review of both protocol and study sites; and (4) procedures and structure of the central IRB that conform to FDA requirements. In a phase III multicenter study conducted in 1987, more than 400 study sites needed and received central IRB approval within a 3-month period. Where necessary, as dictated by local practice or hospital policy, a local IRB also reviewed and approved the study. However, during the period of study enrollment only 25% of the sites requiring a local IRB received a timely review and approval.
Expert System for Problem Diagnosis of Distributed Data Processing Systems Ellis C l a r k e
Maryland Medical Research Institute, Baltimore, Maryland ( P l l ) An expert system was developed for use on a microcomputer to diagnose problems arising from data entry, security system conflicts, database integrity, and electronic communications in a distributed data processing system. This expert system interactively diagnoses a problem and either proposes a solution or refers the problem to a programmer at the coordinating center. The rules used by this diagnostic expert system were developed from actual problems arising from a clinical trial using microcomputer-based distributed processing. If the problem set eventually contains many problems that could be resolved at a clinic, the system would be installed at each clinic in the trial to advise on problems without first consulting a programmer at the coordinating center. The diagnostic system's use is expected to reduce the time and the costs necessary for maintenance of the distributed data processing system.
Abstracts The DATAGIPSY: Regional Multicentric Data Management Monique Konings
Comprehensive Cancer Center South, Tilburg, Netherlands (P05) In our center the data manager works in 12 different hospitals, located in various cities. The average traveling distance is 40 kilometers from our center. We have gained considerable experience in organizing our work efficiently in spite of these facts. I give an overview of the specific aspects of multicentric data management, e.g., traveling, working as a guest in the hospitals, not being allowed to take patient files out of the hospitals, and the fact that all these hospitals are different with regard to patient files, working methods, ways of storing the information etc. Emphasis is placed on the organizational consequences of working with 12 different hospitals and the solutions we have found in order to work efficiently and satisfy the various needs and wishes of the physicians. Advertising--A Tool for Patient Recruitment M.E. Vitek, S.G. F i s h e r , N. C o h e n , S. W a l t z m a n , W . G . H e n d e r s o n VA CSPCC, Hines, Illinois (P06) A Prospective Randomized Cooperative Study of Advanced Cochlear Implants, CSP #304, was initiated in January 1987. Funded by the VA Cooperative Studies Program and the VA Rehabilitation Research and Development Service, this trial involving seven VA medical centers will compare four cochlear implant devices. Cochlear implants electrically stimulate the auditory nerve to produce sound. A 3-year intake of 120 veterans with bilateral profound hearing loss is required. By April 1987, no patients were randomized and it became clear that an accrual problem existed. An intensive national advertising campaign was instituted with VA Central Office support. Veterans' magazines, medical journals, and UPI and AP wire services were used to inform the public of our research. In the 5 months following the first article 2702 telephone calls and letters were received; both qualified and unqualified candidates responded. Potential candidates were screened and forwarded for testing. As of October 1, 1987, 30 patients have been approved for randomization; 15 (50%) were as a result of the advertising campaign. It is expected that this percentage will increase as each center exhausts its own patient population.
Use of Nonstudy Drugs in Clinical Trials C.M. H a k e n s o n , C.L. Frye, M.R. S a t h e r , a n d C.L. Colling VA CSPCRPCC, Albuquerque, New Mexico (P07) With the general acceptance of the intent-to-treat principle in clinical trials, patients are seldom terminated from follow-up or excluded from analysis on the basis of concurrent use of nonstudy medications. Use of such drugs, however, can complicate the analysis unless consideration is given to this aspect during planning. Acceptable and unacceptable drug use should be defined to minimize use of drugs that can enhance or diminish the effect of the intervention or make evaluating adverse effects difficult. Forms for recording concurrent drug use should be simple and facilitate computer data entry. If only a few drugs are of concern, forms can be limited to questions about those specific drugs. If all drug use is to be recorded, a system for coding the drugs will be needed for data entry. The VA Cooperative Studies Program has developed a drug coding system for use in clinical trials. Each drug has been given a three-letter code and is listed by both generic and trade names. At each clinic visit, drug names are recorded and the appropriate computer codes assigned. This system has been employed in ten trials over the past 6 years and has provided a flexible system for forms completion, data entry, and data analysis of all medications taken by study patients.
The Effect of Between-Group Compliance Rate Differences on the Results of the Lipid Research Clinics Coronary Primary Prevention Trial (CPPT) K e n n e t h B. S c h e c h t m a n a n d M a e G o r d o n Washington University, St. Louis, Missouri (P08) Between-group differences in compliance (C) can have a major impact on the results of clinical trials. In the CPPT, C in the treatment (T) group (65.7%) was lower than in the placebo group (77.0%). Had C in the T group been as high as it was in the placebo group, the observed T group decrease of 13.7% in total cholesterol would have had an expected value of 15.9%. LDL decreases
Abstracts
265
are 20.6% (observed) and 23.8% (expected u n d e r equal C). There were 187 placebo events (9.8%) and 155 in the T group (8.1%). Equal C yields an expected 145 T group events, an increase of 31% in the observed between group difference. These event rates produce sample size requirements that would be 43% lower if C in the T group were as high as in the placebo. We believe that C differences are common in clinical trials involving treatments with important side effects. We conclude that between-group differences in C can dramatically increase sample size requirements and lead to underestimates of the efficacy of treatments with attributes that reduce C.
Costs and Benefits of Electronic Mail for Clinical Trial Communication Bruce A. B a r t o n
Maryland Medical Research Institute, Baltimore, Maryland (P09) It is clear that timely communication in the management of clinical trials, especially during the planning phase, is important, if not critical, to the success of the study. Frequently, the investigators at the clinical centers are difficult to reach and a n u m b e r of return telephone calls are necessary to establish contact. Electronic mail has been proposed as an answer to this problem. During the planning phase and the feasibility phase of the Dietary Intervention Study in Children (DISC), two different electronic mall systems were utilized to facilitate communication. The first was based on a central mainframe-class computer with the electronic mail system accessed through remote terminals or microcomputers. The second system had a central post office implemented on a microcomputer at the Coordinating Center accessed by microcomputers at each clinical center using the same software as the central post office. A comparison of the features of each system, such as ease of use, speed of transmission, cost of use, and cost of the hardware and software, is presented. In addition, a comparison with normal telephone communication and FAX communication is made. Training costs and startup time are also considered.
The Importance of a Central Institutional Review Board in Multicenter Clinical Trials R i c h a r d D. N e w m a n a n d D a v i d C. G i l s o n G.D. Searle & Co., Skokie, Illinois (P10) A major consideration in the timely management of any clinical trial is the review and approval of the study by an Institutional Review Board (IRB). When managing a multicenter trial, the challenge of obtaining IRB approval is strongly related to the n u m b e r of participating study sites. Many physicians in private practice or associated with small local practices may not even have familiarity with the IRB requirements. In such cases, the use of a central IRB may afford several benefits: (1) safety oversight for all patients and investigators; (2) uniform and carefully reviewed informed consents; (3) timely review of both protocol and study sites; and (4) procedures and structure of the central IRB that conform to FDA requirements. In a phase III multicenter study conducted in 1987, more than 400 study sites needed and received central IRB approval within a 3-month period. Where necessary, as dictated by local practice or hospital policy, a local IRB also reviewed and approved the study. However, during the period of study enrollment only 25% of the sites requiring a local IRB received a timely review and approval.
Expert System for Problem Diagnosis of Distributed Data Processing Systems Ellis C l a r k e
Maryland Medical Research Institute, Baltimore, Maryland ( P l l ) An expert system was developed for use on a microcomputer to diagnose problems arising from data entry, security system conflicts, database integrity, and electronic communications in a distributed data processing system. This expert system interactively diagnoses a problem and either proposes a solution or refers the problem to a programmer at the coordinating center. The rules used by this diagnostic expert system were developed from actual problems arising from a clinical trial using microcomputer-based distributed processing. If the problem set eventually contains many problems that could be resolved at a clinic, the system would be installed at each clinic in the trial to advise on problems without first consulting a programmer at the coordinating center. The diagnostic system's use is expected to reduce the time and the costs necessary for maintenance of the distributed data processing system.