A model for the development, conduct, and monitoring of multicenter clinical trials in the veterans administration

A Model for the Development, Conduct, and Monitoring of Multicenter Clinical Trials in the Veterans Administration Kenneth E. James From the Cooperative Studies Program, Coordinating Center, Veterans Administration Medical Center, Palo Alto, California

ABSTRACT: In the past 20-30 years, increased interest on the part of biostatisticians and medical investigators has been exhibited in clinical trial research. In the mid-1940's, the Veterans Administration Hospital system was recognized as an ideal environment for the conduct of multicenter clinical trials, with the initiation of a study to determine the effectiveness of chemotherapy in the treatment of tuberculosis, in a joint effort with the United States Armed Forces. This research effort later evolved into what is presently known as the Cooperative Studies Program of the Medical Research Service. Within the past seven years, this program has undergone considerable growth and reorganization. This paper describes a system for the review, operation, and conduct of multicenter clinical research in a wide variety of medical specialty areas. In particular, it stresses the importance of core biostatistical coordinating centers where biostatisticians and other key support personnel constitute an integral part of the planning and development, implementation, conduct, and reporting of many cooperative studies in diverse disciplines. The paper also describes the interaction of various review bodies and a check and balance system to promote sound management and opportunity for the exchange of clinical and biostatistical methodology in the cooperative study setting.

INTRODUCTION AND BACKGROUND The identification of effective a p p r o a c h e s to health care and medical research r e q u i r i n g large n u m b e r s of patients and diverse p o p u l a t i o n s has precipitated increasing interest in cooperative clinical trials. M a n y medical issues cannot be resolved in the single hospital/investigator setting because a d e q u a t e n u m b e r s of qualifying patients are not available to p r o d u c e statistically reliable results. Thus, a multicenter trial, with each center p e r f o r m i n g the same protocol in the same way, becomes necessary. H a g a n s [1] presents a general o v e r v i e w of the process involved in the p l a n n i n g , evaluation, initiation, and final analysis of a cooperative trial and briefly describes the role of the biostatistician in each of these phases. He Address requests for reprints to Kenneth E. James, Chief, Cooperative Studies Program, Coordinating Center, Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304 Received October 31, 1979; accepted March 28, 1980.

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K. f"2.James notes that cooperative research requires detailed specification of methodology (both medical and biostatistical) and a willingness and dedication on the part of the medical and biostatistical investigators to pursue vigorously one common goal. This paper addresses a model for the conduct of clinical trials that facilitates the interchange between biostatisticians and medical investigators in the cooperative research environment and details ways by which the productivity of such research can be maximized. The backbone of this model in the Veterans Administration Cooperative Studies Program is the Cooperative Studies Program Coordinating Centers.

THE ROLE OF THE B I O S T A T I S T I C I A N IN THE VA C O O P E R A T I V E STUDIES PROGRAM

The biostatistician can make a major contribution in the development and conduct of clinical research, be it individual or cooperative. In cooperative research, this person provides valuable input, along with the other members of the planning group, in identifying the experimental design; defining hypotheses, determining endpoints and variables to be collected; specifying inclusion/exclusion criteria; computing the sample size; developing the randomization process; and projecting methods for analyzing, reporting, and monitoring the data as it is collected. Biostatisticians with experience in clinical trials can be especially helpful in defining operational procedures of data collection, data flow, the quality control processes, and final analysis. One of the major strengths of the VA Cooperative Studies Program (VACSP) is the early and continuous involvement of the biostatistician with the researchers. After the protocol has been approved and the study funded, the biostatistician plays a definitive role in the implementation, ongoing, final analysis, and publication stages of the clinical trial. Within the VACSP, four Cooperative Studies Program Coordinating Centers (CSPCC) have been established to coordinate these biostatistical and data processing activities and to provide the necessary administrative and operational support. These centers receive administrative and budgetary support from the VA Medical Research Service through the Office of the Chief, Cooperative Studies Programs. Studies are proposed by medical investigators within the VA system, reviewed by one or more discipline specialists, and by a triage committee consisting of five to seven high ranking officials in Research and Development and Professional Services in the Veterans Administration. Based on assigned priorities and funding availability, the approved proposals are released for planning and are assigned to one of the four Coordinating Centers. This begins the development phase of the cooperative study. Each center operates essentially independently of the others and is wholly responsible for the studies assigned to it. Thus, the Coordinating Center constitutes the first component of our model as shown in Figure 1. Each center supports studies (15-18 per center) representing diverse medical disciplines. As stated earlier, a major effort of the CSP has been devoted to the development of the coordinating centers, to provide tile proper staffing and

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K.t.:.. James resources necessary for the management of cooperative research. Although the role of the biostatistician has been emphasized, the remarks may be aptly applied to other members of the coordinating center staff as well--the systems and statistical programmers, the forms design specialist, the data coordinators and transcribers, and the administrative assistants and secretaries. Each makes a vital contribution to the success of the Coordinating Center and the studies that it supports.

THE COOPERATIVE STUDY PLANNING COMMITTEE When a cooperative study is approved for planning, the study chairperson (principal proponent) identifies a committee composed of the chairperson (co-chairpersons), two or three potential participating investigators, the biostatistician, a clinical research pharmacist, consultants, and, if required, representatives of central laboratory facilities. This committee shares responsibility for the development of the research proposal and constitutes the second component of our model (Figure 2). The study chairperson (co-chairpersons) is, in most cases, the originator of the proposal for the cooperative study and is primarily responsible for the planning and development of the protocol. The biostatistician represents the Coordinating Center and works with the Study Chairman in setting up planning meetings and providing the necessary biostatistical and administrative input. Consultants may be engaged to provide expertise in a discrete area of medicine, biostatistics, or clinical trial methodology. The potential participating investigators serve on the Planning Committee to provide medical and operational input. If the cooperative study is to involve a laboratory for central readings of specific clinical endpoints (e.g., blood samples, x-ray, EKG readings, etc.), a representative from the laboratory usually attends the Planning Committee meetings to provide details on the collection of specimens, reading procedures, and shipment of samples to the central facility. These laboratories are study-specific and established separately from the Coordinating Center. In addition, the CSP has established a Clinical Research Pharmacy Coordinating Center (CSPCRPCC) to monitor the handling and distribution of drugs, cosmetics or medical devices that may be involved in a cooperative study. If the study involves any of these items, a clinical research pharmacist from the CSPCRPCC attends the planning meeting to provide input on dosage and dosage forms, applications for Investigation New Drugs (IND), Investigational Device Exceptions (IDE), and other appropriate FDA approvals; and details for packaging and distribution of the study materials to the participating medical centers. THE C O O P E R A T I V E S T U D I E S P R O P O S A L REVIEW PROCESS

Upon completion of planning, a research proposal (individual or cooperative) is almost always evaluated by a review body prior to funding. Because clinical trials tend to be large and require substantial sums of money, the review of such studies by funding organizations is quite extensive.

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K.E. /ames In the VACSP there are four steps to the review process, as shown schematically in [:igure 3. After the final draft of the protocol has been completec~, the ethical aspects are reviewed by the CSPCC Human Rights Committee. This committee consists of nonphysician members who have the responsibility of assessing the cooperative study in the proposal stage with respect to patients' rights and welfare. The medical, scier~tific, and professional issues involving ethics are addressed later by the Cooperative Studies Evaluation Committee (CSEC). When the proposal has been reviewed by the Center Chief and study biostatistician, and approved by the Human Rights Committee, it is submitted to the Chief of the CSP for review by three referees who provide written critiques. These critiques and the completed proposal are reviewed by the Cooperative Studies Evaluation Committee (CSEC) for scientific merit and relevancy to the Veterans Administration. The study chairperson (cochairpersons) and the biostatistician appear before CSEC to defend the proposed cooperative study. The budgetary aspects of the proposal are reviewed by the Budget Review Group that meets concurrently with CSEC. The CSEC rnakes recommendations and sets priorities with regard to VA funding and scientific merit. The final decision for funding is given by the Director of Medical Research Service who has, in most cases, accepted the recommendations of CSEC. Past experience indicates that approximately 70% of the studies that progress through the planning and evaluation stages are ultimately approved and funded.

I M P L E M E N T A T I O N OF THE COOPERATIVE S T U D Y

Upon recommendation by the CSEC and approval for funding, the implementation phase of the cooperative study begins. This process constitutes the fourth component of the Cooperative Study model as depicted in Figure 4. All activities in this process are closely coordinated by the CSPCC and the Study Chairperson's Office. The necessity for carefully controlled medical treatment and data collection procedures for the successful conduct of multicenter clinical trials is well recognized. Because of its administrative structure, the VA provides an environment that is uniquely suited to this type of research. Each participating facility is funded by one control point for the entire period of the study, and the VA Medical Center system provides a structure in which a relatively high degree of medical, scientific, and administrative control can be exercised. This same degree of control is often more difficult to obtain in studies that involve a number of individual institutions that may have widely diverse administrative structures. The Coordinating Center recommends funding levels and monitors the performance of the individual medical centers. This information is reviewed regularly by the study biostatistician and center chief and, on a semiannual basis, by the Executive and Operations Committees whose functions will be described later. This integrated monitoring of scientific, biostatistical, and administrative aspects by the CSPCC provides a comprehensive ap-

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proach to the management of multicenter clinical trials, in contrast to many other clinical trial mechanisms that are responsible only for the analytical and data processing aspects and exercise no fiscal control. The Research and Development Committee ~of each participating medical center must review and approve a cooperative study before it can be implemented in that facility. Furthermore, the Cooperative Studies Program requires a uniform consent form and procedures. While this occasionally presents some difficulty, on the whole such a procedure has been implemented in virtually all cases. Included in the implementation component of a cooperative study is the establishment of the Executive and Operations Committees who share responsibility for the conduct and monitoring of the cooperative study in the ongoing phase. The Executive Committee, which often includes several members of the original Planning Committee, consists of the study chairperson (co-chairpersons), the study biostatistician, the research pharmacist, two or three participating investigators, and one or two consultants. This committee is responsible for the detailed operational aspects of the study during its ongoing phase and insures adherence to the study protocol, including aspects relating to patient recruitment, treatment, laboratories, data collection and submission, biostatistical analysis, data processing, and reporting. The Operations Committee consists of individuals who have not been involved in the planning and development of the proposal, and includes a biostatistician and two or more subject matter experts in the field(s) of the cooperative study. This committee is charged with the responsibility of monitoring and determining the course of the ongoing study and considers such questions as: Should the study continue unchanged or be terminated or modified? What data reports and statistical analyses are necessary to properly monitor the study? Is each participating center entering sufficient numbers of patients and adhering to the protocol? Although the primary responsibility of the Operations Committee is one of monitoring the study, the opportunity exists for an exchange of medical and biostatistical methodology. Ideally, members of the Operations Committee will have had substantial exposure to cooperative research and can contribute significantly to the success of the trial. The study chairperson (co-chairpersons) and biostatistician act as liaison representatives to the Operations Committee. They meet with the Committee to present data on the progress of the study but do not vote. Much controversy exists in medical research over the necessity for and ethical considerations of prospective randomized clinical trials. Chalmers, et al. [2] have addressed this issue; as proponents of randomization, they discuss the need for a monitoring committee or advisory board to review the masked 2 data during the course of the study. In the CSP, this function 'Each VA Medical C e n t e r has its o w n Research a n d D e v e l o p m e n t C o m m i t t e e that is r e s p o n s i b l e for the a p p r o v a l and control of research c o n d u c t e d at that center. 2Masked data in the context of the C o o p e r a t i v e S t u d i e s P rogra m p e r t a i n s to data i d e n t i f i e d w i t h a specific or coded t r e a t m e n t or m e d i c a l proc e dure .

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K.E. James is served by the Operations Committee and the Human Rights Committee, and these are the only bodies that see such data. The Executive Committee is not privy to the masked data because of the potentially biasing effect it could have on the participating investigators who serve on this committee. Although the biostatistician, and, in most cases, the Study Chairperson see the masked data, these data are not discussed by the Executive Committee. The third body involved in the conduct of the cooperative study is the Study Group that consists of all participating investigators, the study chairperson (co-chairpersons), biostatistician, clinical research pharmacist, and consultants. This body meets once annually to consider the progress of the study and to resolve problems which may arise in the participating centers.

THE O N G O I N G PHASE OF THE COOPERATIVE STUDY With the beginning of patient intake for the clinical trial, close exchange between the various component groups defined thus far is essential, as shown in Figure 5. Within the Coordinating Center, the biostatistician heads a team of programming and data management personnel that provides regular monitoring of the study. Reports on patient intake and demographic characteristics are sent to the Executive and Operations Committee at regular intervals. Data on treatment endpoints and toxicity are sent only to the Operations Committee. These committees convene at six month intervals and the Study Group meets yearly. The CSPCC | | u m a n Rights Committee reviews the ethical and human rights issues yearly in joint session with the Operations Committee. Site visits are made by the l | u m a n Rights Committee members to interview patients participating in the cooperative study. If patient intake extends beyond three years, the study is reviewed in depth at three year intervals by the CSEC. FINAL ANALYSIS AND PUBLICATION PHASE

Upon completion of patient intake and follow-up, the study enters the final analysis and publication phase (Figure 6). If the Executive Committee, the Coordinating Center, and the study biostatisticians have performed their tasks well, this phase should be quite straightforward. It requires an updating of all study files and the processing and analysis of the complete data set. The interval statistical analyses that were run during the ongoing phase of the study are now executed on the complete data. In addition, some analyses may point to additional questions that would be of interest; however, it is anticipated that the majority of final analyses and interpretation of results will occur within 6 to 12 months after study termination. All publications emanating from the cooperative study must be approved by the Executive Committee. Although the responsibility of the Operations Committee terminates at the end of patient intake, the Committee is at times requested to review manuscripts and give advice prior to submission for publication.

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COMBINING THE COMPONENTS IN THE COOPERATIVE STUDIES MODEL In previous sections we considered the individual components--planning, evaluation, implementation, ongoing analysis and reporting, and final analysis/publication--that comprise the cooperative study model in the Veterans Administration Cooperative Studies Program. Each component plays an essential role in contributing to the success of the study. The overall integration of these components is shown in Figure 7. While the model described in this paper may seem somewhat complex, it offers a number of advantages in the clinical trial environment. 1. The biostatistician is integrally involved in all phases of the cooperative study, from beginning to end.

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K.t... lames 2. The CSPCC's responsibili W goes b e y o n d that of the biostatistical and data processing aspects of the study and includes coordination of the administrative, b u d g e t a r y , and operational activities that are essential to the successful conduct of a cooperative study. 3. The Veterans Administration Medical Center system provides an envir o n m e n t w h e r e tight control and coordination of clinical trials can be exercised. 4. The evaluation process involves a t h o r o u g h review of the medical, professional, scientific, and h u m a n rights aspects, both at the time of initial s t u d y review and d u r i n g the ongoing phase. Beyond review and monitoring, an e n v i r o n m e n t is created for the exchange of advice in medical and biostatistical m e t h o d o l o g y , particularly in the o n g o i n g phase. 5. While m a n y biostatistical coordinating centers are established to support a specific clinical trial and/or medical speciality, such as cancer or h y p e r t e n s i o n , the CSPCC's s u p p o r t a wide range of disciplines.

THE FUTURE

The foregoing is a description of one model for the d e v e l o p m e n t , conduct, and m o n i t o r i n g of multicenter clinical trials. O v e r the past eight years, the VA Cooperative Studies Program, u n d e r the able direction of Dr. James Hagans, Chief of the CSP, has c o n t i n u e d to grow and expand to meet the needs of advances in medical t e c h n o l o g y and the increased interest in health care delivery. While this model is t h o u g h t to p r o v i d e an effective combination of coordination, evaluation, and scientific/biostatistical interchange, it may not be applicable to e v e r y clinical trial setting. Also, there are several areas in which the present Program might be strengthened. 1. Most initial planning requests could benefit by a more precise statement of the p r o p o s e d study's objectives, e.g., more careful definition of the questions to be addressed by the protocol, the population to be studied, and a brief description of the research procedures. This would, in m a n y cases, facilitate protocol d e v e l o p m e n t . 2. At present, there is v e r y little incentive for investigators to participate in a cooperative s t u d y b e y o n d their general interest in research and the specific problems in the subject matter area to be addressed by that study. Because the success of cooperative research d e p e n d s heavily on the dedication of the investigators in the participating hospitals, some added incentives, like the o p p o r t u n i t y to attend professional meetings on an annual basis, might be beneficial. 3. In recruiting medical centers for participation in a cooperative study, the p r i m a r y emphasis focuses on potential patient yield per hospital. Additional factors such as experience and past participation of potential investigators in cooperative studies, investigator interest, and an indication of the Medical Center's willingness to s u p p o r t the research might be e m p h a s i z e d to a greater extent as the criteria for selecting hospitals: 4. Because ongoing studies require close m o n i t o r i n g by the CSPCC to assure that patient intake is a d e q u a t e and data is being collected in

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a c c o r d a n c e w i t h p r o c e d u r e s set forth in t h e p r o t o c o l , m o r e f r e q u e n t s i t e v i s i t s m i g h t i m p r o v e t h e q u a l i t y of t h e s t u d y , t ' I o w e v e r , at p r e s e n t , o n l y a m i n i m u m n u m b e r of s i t e v i s i t s a r e i n c l u d e d b e c a u s e of f u n d i n g constraints. 5. W h i l e C S P C C b i o s t a t i s t i c i a n s a r e e n c o u r a g e d to e n g a g e in t h e d e v e l o p m e n t of i n n o v a t i v e t e c h n i q u e s in s t a t i s t i c a l t h e o r y a n d c l i n i c a l trial m e t h o d o l o g i e s , t i m e a n d f u n d i n g c o n s t r a i n t s o f t e n l i m i t t h i s activity. While the points mentioned above might improve the present program, t h e m o s t i n p o r t a n t f a c t o r in t h e s u c c e s s f u l c o n d u c t of VACSP r e s e a r c h is t h e i n t e g r a t e d o p e r a t i o n of e a c h c o m p o n e n t p a r t a n d t h e d e d i c a t i o n a n d c o o p e r a t i o n of t h e i n d i v i d u a l s w h o p a r t i c i p a t e in t h e r e s e a r c h . T h i s p a p e r p r e s e n t s a g e n e r a l o v e r v i e w of t h e C o o p e r a t i v e S t u d i e s P r o g r a m . P r e c i s e d e t a i l s c o n c e r n i n g t h e P r o g r a m a n d c o m p a r i s o n to o t h e r c l i n i c a l trial s y s t e m s h a v e b e e n o m i t t e d a n d will b e a d d r e s s e d in f u t u r e publications. ACKNOWLEDGMENTS l)r. James ttagans, as Chief of the Cooperative Studies Programs, deserves malor credit for its accomplishments, t tis wealth of experience in clinical trials and the support of ideas described in this paper have contributed immeasurably to the success of this research effort. It also is appropriate that I recognize the contributions and critiques of the other Coordinating Center Chiefs--Dr. Yick-Kwong Chan, West Haven, Connecticut, Dr. William Henderson, ftines, Illinois, Dr. C. James Klett, Perry Point, Maryland, and Mr. Mike Sather, Albuquerque, New Mexico and the contributions of Dr. Pingl|uang, V.A. Central Office, Washington, l).C.,and the editorial assistance of Ms. Betty Maxwell, Palo Alto CSPCC.

REFERENCES I. t tagans JA: The design and methodology of cooperative drug trials. Dru~ lntell Clin Pharm 8:531-534, 1974. 2. Chalmers TC, Block JB, and Lee S: Controlled studies in clinical cancer research. N Engl ] Med 287:75-78, 1972.