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Perceptions of the coordinating center
Perceptions of the Coordinating Center As V i e w e d b y a Project Officer Basil M. Rifkind From the Lipid Metabolism Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
ABSTRACT: From the perspective of the project officer of the multicenter, international
Lipid Research Clinics Program, some salient points in evaluating a coordinating center are discussed: assessment of its needs, appraisal of its quality-control methods, determination of the appropriate balance between active/passive participation in the study, judgment of its communication skills, and estimation of its ability to enhance data analysis and publication of research results. KEY WK)RDS: coordinating centers, clinical trials, epidemiology, data processing and storage
INTRODUCTION M y p e r c e p t i o n of the role of coordinating centers has b e e n d e r i v e d largely from m y e x p e r i e n c e as Project Officer of the Lipid Research Clinics (LRC) Program. This p r o g r a m embraces other collaborative studies in addition to the T y p e II C o r o n a r y P r i m a r y P r e v e n t i o n Trial, and thus it should be e m p h a s i z e d that the role of the LRC C o o r d i n a t i n g C e n t e r is even more complex t h a n that of centers serving only a clinical trial. An exhaustive r e v i e w of all facets of coordinating center activities is not possible here; rather, this p a p e r is i n t e n d e d to highlight some diverse topics that are g e r m a n e to the successful o p e r a t i o n of c o o r d i n a t i n g centers. A v e r y a b b r e v i a t e d r e v i e w of the LRC Program, and the role of the c o o r d i n a t i n g center w i t h i n it, m a y help the reader to u n d e r s t a n d some of the concerns facing the Project Officer responsible for such a program.
THE LRC P R O G R A M
The LRC Program, s p o n s o r e d b y the National Heart, Lung, and Blood Institute (NHLBI), consists of 12 clinics in N o r t h America and one in Israel; two additional clinics in the Soviet U n i o n have b e e n established u n d e r the Paper presented to The Fifth Annual Symposium on Coordinating Clinical Trials, Arlington, Virginia, May 25-26, 1978. Address reprint requests to Basil M. Rifkind, M.D., Lipid Metabolism Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20205. Received August 23, 1979; accepted November 9, 1979. Controlled Clinical Trials 1, 135-139 (1980)
© 1980 Elsevier N o r t h Holland, Inc., 52 Vanderbilt Avenue, New York, NY 10017
137 0197-2456/80/02013506502.25
138
Basil M. Rifkind U S - U S S R Joint P r o g r a m in C a r d i o v a s c u l a r Disease. Virtually all of the LRC's h a v e p a r t i c i p a t e d in o n e or m o r e aspects of the P o p u l a t i o n Studies; the 12 N o r t h A m e r i c a n clinics are p a r t i c i p a t i n g in the i n t e r v e n t i o n trial.
Population Studies T h e s e studies a i m to collect a d e q u a t e lipid a n d l i p o p r o t e i n data on the p r e v a l e n c e of different t y p e s of h y p e r l i p o p r o t e i n e m i a a n d on the distribution of lipids a n d l i p o p r o t e i n s in defined p o p u l a t i o n s , to relate diet to lipid a n d l i p o p r o t e i n levels, a n d to establish correlates w i t h c o r o n a r y heart disease.
Coronary Primary Prevention Trial This clinical trial w a s e s t a b l i s h e d to test the h y p o t h e s i s that l o n g - t e r m r e d u c t i o n of s e r u m cholesterol in h y p e r c h o l e s t e r o l e m i c m e n initially free of clinical c o r o n a r y heart disease (CHD) will lead to a l o w e r e d incidence of C H D . The 12 N o r t h A m e r i c a n clinical centers enrolled a total of 3810 m e n w i t h p r i m a r y T y p e II h y p e r l i p o p r o t e i n e m i a ; half the m e n h a v e b e e n rand o m l y p r e s c r i b e d a bile acid s e q u e s t r a n t a n d the other half a placebo, a n d all are b e i n g followed in a d o u b l e - b l i n d m a n n e r for a m i n i m u m of s e v e n years.
The Central Patient Registry (CPR) and Coordinating Center A m o n g the central s u p p o r t facilities that serve the v a r i o u s aspects of the LRC P r o g r a m , the CPR plays a key role in all the studies. O n e s i m p l e statistic will s u m m a r i z e the m a g n i t u d e of this task: In March 1979, the CPR received the 1,000,000th LRC f o r m for processing. The scope of the task facing the CPR is illustrated in the original R e q u e s t for Proposals issued b y the NHLBI: In order to achieve their goals many of the ventures of the Lipid Research Clinics will require common study protocols, comparable patients, random assignment, double-blind evaluation, placebo control, long-term observation and central collection, editing and monitoring of data. Thus the Central Patient Registry and Coordinating Center is vital to the coordinated functions of the Lipid Research Clinics. It will serve to plan and design all reporting forms, collect and store all data on patients with primary hyperlipoproteinemia, edit all data, and collaborate actively in the planning, data storage, monitoring and coordination of intervention trials.
VIEWS ON THE COORDINATING
CENTER
Evaluation of Coordinating Center Needs It is not u n d u l y difficult for a project officer to evaluate the resources r e q u i r e d b y the v a r i o u s clinical centers in a collaborative p r o g r a m , especially after the clinical trial c o m p o n e n t a n d related studies h a v e t a k e n shape. This
As Viewed by a Project Officer
139
evaluation is facilitated by the existence of multiple collaborating clinical centers, each with essentially similar needs. However, the evaluation of coordinating center needs is much more complex as it generally involves disciplines and activities more remote from the expertise of the typical project officer. It is rendered more difficult by the rapid developments in statistical and computer technology (i.e., the state of the art) and it is complicated by the lack of unanimity on what constitutes ideal data systems. Because a coordinating center is usually the single most costly component of a collaborative study, it is all the more important to develop better techniques to assess its needs. The coordinating center community can contribute to better assessment of needs and to economy by developing a cost-conscious approach, which provides a clear picture of the cost of various activities. In addition, needs should be clearly defined according to the changing phases of studies. Standardization of procedures between coordinating centers and agreement on optimum general procedures and specific systems should be sought.
Quality Control It is axiomatic that quality control is a major feature of a collaborative study and it is probable that many studies have been compromised by insufficient standardization of measurement. Nevertheless, quality control is extremely expensive in terms of the various procedures required to implement and monitor it. An attendant danger is that maintenance of high quality data might become a goal in itself, rather than being one of several important elements needed to conduct a successful study. Coordinating centers should be encouraged to evaluate the cost effectiveness of their quality control procedures. It may well be possible to demonstrate that less stringent and less costly quality control procedures would suffice for certain elements of studies without sacrificing anything of substance.
Activist Role of Coordinating Center In any collaborative program, a coordinating center must guard that its role does not follow either of two extremes. It should not become the passive servant of the clinical investigators or the project office. This is especially in danger of happening if the statistical and data management expertise is concentrated in the coordinating center and the medical scientific expertise is found outside of it. On the other hand, a coordinating center and the program of which it is part must ensure that the center does not dominate crucial activities, especially data analysis, by virtue of its unique position. Coordinating centers should be encouraged to show initiative in ensuring their representation and full participation in all key study committees. At the outset, senior staff of the coordinating center should develop a good understanding of the scientific and clinical issues upon which their study is built. As the study progresses, they should then stand back from the detailed activities of the center from time to time, evaluate key elements of the program and communicate their judgement and any recommendations to the appropriate program committees, the project office, and the individual
140
Basil M. Rifkind clinical centers. Furthermore, the coordinating center should share responsibility for assuring maximum utilization of the data being collected; for example, data collected to monitor ongoing performance should be used effectively.
Communication Perhaps the single biggest problem in a large-scale collaborative study involves the maintenance of adequate communication throughout its usually long course. Communication problems frequently occur among the various participating units and also within individual units. In the Lipid Research Clinics Program, we have placed considerable priority on ensuring good communication between the coordinating center and the project office. Monthly and quarterly reports, generated by the center, give details on the various facets of its activities and the program status as a whole. These reports are of considerable value to the program office, and they are also helpful to the coordinating center because they ensure a periodic and systematic review of many center activities. In addition, the project office receives an annual report and participates in the annual site visit to the coordinating center. As in many programs, there are frequent committee meetings at which the coordinating center and the project office are jointly represented. Of considerable importance is a bimonthly "joint meeting" providing a comprehensive routine review of the many elements of the program as well as problem areas. The joint meeting is attended by all the support facilities of the program, e.g., the coordinating center, the Program Office, the Central Exercise Laboratory, the Lipid Standardization Laboratory, and the Nutrition Coding Center. Informal modes of communication are also of considerable value and should be encouraged. In the LRC program they consist of frequent telephone conversations between the Project Officer and the Director of the Coordinating Center, and unstructured visits by the Project Officer to the facility, to permit a wide-ranging review of important topics.
Analysis of Large Data Sets It is a characteristic of large-scale collaborative studies that they generate a considerable quantity of data, much of which is never adequately analyzed or published. There are special problems in coping with the volume and in establishing an organization that is both democratic and efficient to analyze the data and prepare it for publication. In the Population Studies component of the LRC program, a complex set of "guidelines for analysis" has evolved which outlines the organizational structure and process for analyzing the data and publishing the findings. Although it is comprehensive and democratic, it suffers the danger of being rather rigid and overwhelming in its scope. To balance this, the program has had to inject an element of pragmatism by identifying and assisting the more productive and competent investigators, wherever they happen to be located in the program. The coordinating center obviously has an important role in this collaborative
As Viewed by a Project Officer
141
analysis area, including development of systems to monitor the status of analysis, and to ensure adequate statistical input into the various topics under consideration.
Publications and Abstracts Although m a n y collaborative programs have produced outstanding contributions to the literature, it is by no means u n c o m m o n to encounter publications whose quality is not commensurate with that of the preceding design and data collection phases. This problem relates to the special difficulties in identifying qualified individuals who work effectively in the collaborative mode and who can adequately focus on appropriate topics. A coordinating center and the other program elements have a definite responsibility to ensure that the results, which after all are the ultimate product of any collaborative activity, will be delivered to the community in a timely and high quality manner. These then are some of the problems that face collaborative programs in general, and coordinating centers in particular. Consideration of their existence and their resolution should not obscure the fact that the new discipline of "Coordinating Center Science" has advanced considerably in the past decade. The clinical science community is indeed fortunate in the quality of the coordinating centers that are presently in its midst.
ABSTRACT: From the perspective of the project officer of the multicenter, international
Lipid Research Clinics Program, some salient points in evaluating a coordinating center are discussed: assessment of its needs, appraisal of its quality-control methods, determination of the appropriate balance between active/passive participation in the study, judgment of its communication skills, and estimation of its ability to enhance data analysis and publication of research results. KEY WK)RDS: coordinating centers, clinical trials, epidemiology, data processing and storage
INTRODUCTION M y p e r c e p t i o n of the role of coordinating centers has b e e n d e r i v e d largely from m y e x p e r i e n c e as Project Officer of the Lipid Research Clinics (LRC) Program. This p r o g r a m embraces other collaborative studies in addition to the T y p e II C o r o n a r y P r i m a r y P r e v e n t i o n Trial, and thus it should be e m p h a s i z e d that the role of the LRC C o o r d i n a t i n g C e n t e r is even more complex t h a n that of centers serving only a clinical trial. An exhaustive r e v i e w of all facets of coordinating center activities is not possible here; rather, this p a p e r is i n t e n d e d to highlight some diverse topics that are g e r m a n e to the successful o p e r a t i o n of c o o r d i n a t i n g centers. A v e r y a b b r e v i a t e d r e v i e w of the LRC Program, and the role of the c o o r d i n a t i n g center w i t h i n it, m a y help the reader to u n d e r s t a n d some of the concerns facing the Project Officer responsible for such a program.
THE LRC P R O G R A M
The LRC Program, s p o n s o r e d b y the National Heart, Lung, and Blood Institute (NHLBI), consists of 12 clinics in N o r t h America and one in Israel; two additional clinics in the Soviet U n i o n have b e e n established u n d e r the Paper presented to The Fifth Annual Symposium on Coordinating Clinical Trials, Arlington, Virginia, May 25-26, 1978. Address reprint requests to Basil M. Rifkind, M.D., Lipid Metabolism Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20205. Received August 23, 1979; accepted November 9, 1979. Controlled Clinical Trials 1, 135-139 (1980)
© 1980 Elsevier N o r t h Holland, Inc., 52 Vanderbilt Avenue, New York, NY 10017
137 0197-2456/80/02013506502.25
138
Basil M. Rifkind U S - U S S R Joint P r o g r a m in C a r d i o v a s c u l a r Disease. Virtually all of the LRC's h a v e p a r t i c i p a t e d in o n e or m o r e aspects of the P o p u l a t i o n Studies; the 12 N o r t h A m e r i c a n clinics are p a r t i c i p a t i n g in the i n t e r v e n t i o n trial.
Population Studies T h e s e studies a i m to collect a d e q u a t e lipid a n d l i p o p r o t e i n data on the p r e v a l e n c e of different t y p e s of h y p e r l i p o p r o t e i n e m i a a n d on the distribution of lipids a n d l i p o p r o t e i n s in defined p o p u l a t i o n s , to relate diet to lipid a n d l i p o p r o t e i n levels, a n d to establish correlates w i t h c o r o n a r y heart disease.
Coronary Primary Prevention Trial This clinical trial w a s e s t a b l i s h e d to test the h y p o t h e s i s that l o n g - t e r m r e d u c t i o n of s e r u m cholesterol in h y p e r c h o l e s t e r o l e m i c m e n initially free of clinical c o r o n a r y heart disease (CHD) will lead to a l o w e r e d incidence of C H D . The 12 N o r t h A m e r i c a n clinical centers enrolled a total of 3810 m e n w i t h p r i m a r y T y p e II h y p e r l i p o p r o t e i n e m i a ; half the m e n h a v e b e e n rand o m l y p r e s c r i b e d a bile acid s e q u e s t r a n t a n d the other half a placebo, a n d all are b e i n g followed in a d o u b l e - b l i n d m a n n e r for a m i n i m u m of s e v e n years.
The Central Patient Registry (CPR) and Coordinating Center A m o n g the central s u p p o r t facilities that serve the v a r i o u s aspects of the LRC P r o g r a m , the CPR plays a key role in all the studies. O n e s i m p l e statistic will s u m m a r i z e the m a g n i t u d e of this task: In March 1979, the CPR received the 1,000,000th LRC f o r m for processing. The scope of the task facing the CPR is illustrated in the original R e q u e s t for Proposals issued b y the NHLBI: In order to achieve their goals many of the ventures of the Lipid Research Clinics will require common study protocols, comparable patients, random assignment, double-blind evaluation, placebo control, long-term observation and central collection, editing and monitoring of data. Thus the Central Patient Registry and Coordinating Center is vital to the coordinated functions of the Lipid Research Clinics. It will serve to plan and design all reporting forms, collect and store all data on patients with primary hyperlipoproteinemia, edit all data, and collaborate actively in the planning, data storage, monitoring and coordination of intervention trials.
VIEWS ON THE COORDINATING
CENTER
Evaluation of Coordinating Center Needs It is not u n d u l y difficult for a project officer to evaluate the resources r e q u i r e d b y the v a r i o u s clinical centers in a collaborative p r o g r a m , especially after the clinical trial c o m p o n e n t a n d related studies h a v e t a k e n shape. This
As Viewed by a Project Officer
139
evaluation is facilitated by the existence of multiple collaborating clinical centers, each with essentially similar needs. However, the evaluation of coordinating center needs is much more complex as it generally involves disciplines and activities more remote from the expertise of the typical project officer. It is rendered more difficult by the rapid developments in statistical and computer technology (i.e., the state of the art) and it is complicated by the lack of unanimity on what constitutes ideal data systems. Because a coordinating center is usually the single most costly component of a collaborative study, it is all the more important to develop better techniques to assess its needs. The coordinating center community can contribute to better assessment of needs and to economy by developing a cost-conscious approach, which provides a clear picture of the cost of various activities. In addition, needs should be clearly defined according to the changing phases of studies. Standardization of procedures between coordinating centers and agreement on optimum general procedures and specific systems should be sought.
Quality Control It is axiomatic that quality control is a major feature of a collaborative study and it is probable that many studies have been compromised by insufficient standardization of measurement. Nevertheless, quality control is extremely expensive in terms of the various procedures required to implement and monitor it. An attendant danger is that maintenance of high quality data might become a goal in itself, rather than being one of several important elements needed to conduct a successful study. Coordinating centers should be encouraged to evaluate the cost effectiveness of their quality control procedures. It may well be possible to demonstrate that less stringent and less costly quality control procedures would suffice for certain elements of studies without sacrificing anything of substance.
Activist Role of Coordinating Center In any collaborative program, a coordinating center must guard that its role does not follow either of two extremes. It should not become the passive servant of the clinical investigators or the project office. This is especially in danger of happening if the statistical and data management expertise is concentrated in the coordinating center and the medical scientific expertise is found outside of it. On the other hand, a coordinating center and the program of which it is part must ensure that the center does not dominate crucial activities, especially data analysis, by virtue of its unique position. Coordinating centers should be encouraged to show initiative in ensuring their representation and full participation in all key study committees. At the outset, senior staff of the coordinating center should develop a good understanding of the scientific and clinical issues upon which their study is built. As the study progresses, they should then stand back from the detailed activities of the center from time to time, evaluate key elements of the program and communicate their judgement and any recommendations to the appropriate program committees, the project office, and the individual
140
Basil M. Rifkind clinical centers. Furthermore, the coordinating center should share responsibility for assuring maximum utilization of the data being collected; for example, data collected to monitor ongoing performance should be used effectively.
Communication Perhaps the single biggest problem in a large-scale collaborative study involves the maintenance of adequate communication throughout its usually long course. Communication problems frequently occur among the various participating units and also within individual units. In the Lipid Research Clinics Program, we have placed considerable priority on ensuring good communication between the coordinating center and the project office. Monthly and quarterly reports, generated by the center, give details on the various facets of its activities and the program status as a whole. These reports are of considerable value to the program office, and they are also helpful to the coordinating center because they ensure a periodic and systematic review of many center activities. In addition, the project office receives an annual report and participates in the annual site visit to the coordinating center. As in many programs, there are frequent committee meetings at which the coordinating center and the project office are jointly represented. Of considerable importance is a bimonthly "joint meeting" providing a comprehensive routine review of the many elements of the program as well as problem areas. The joint meeting is attended by all the support facilities of the program, e.g., the coordinating center, the Program Office, the Central Exercise Laboratory, the Lipid Standardization Laboratory, and the Nutrition Coding Center. Informal modes of communication are also of considerable value and should be encouraged. In the LRC program they consist of frequent telephone conversations between the Project Officer and the Director of the Coordinating Center, and unstructured visits by the Project Officer to the facility, to permit a wide-ranging review of important topics.
Analysis of Large Data Sets It is a characteristic of large-scale collaborative studies that they generate a considerable quantity of data, much of which is never adequately analyzed or published. There are special problems in coping with the volume and in establishing an organization that is both democratic and efficient to analyze the data and prepare it for publication. In the Population Studies component of the LRC program, a complex set of "guidelines for analysis" has evolved which outlines the organizational structure and process for analyzing the data and publishing the findings. Although it is comprehensive and democratic, it suffers the danger of being rather rigid and overwhelming in its scope. To balance this, the program has had to inject an element of pragmatism by identifying and assisting the more productive and competent investigators, wherever they happen to be located in the program. The coordinating center obviously has an important role in this collaborative
As Viewed by a Project Officer
141
analysis area, including development of systems to monitor the status of analysis, and to ensure adequate statistical input into the various topics under consideration.
Publications and Abstracts Although m a n y collaborative programs have produced outstanding contributions to the literature, it is by no means u n c o m m o n to encounter publications whose quality is not commensurate with that of the preceding design and data collection phases. This problem relates to the special difficulties in identifying qualified individuals who work effectively in the collaborative mode and who can adequately focus on appropriate topics. A coordinating center and the other program elements have a definite responsibility to ensure that the results, which after all are the ultimate product of any collaborative activity, will be delivered to the community in a timely and high quality manner. These then are some of the problems that face collaborative programs in general, and coordinating centers in particular. Consideration of their existence and their resolution should not obscure the fact that the new discipline of "Coordinating Center Science" has advanced considerably in the past decade. The clinical science community is indeed fortunate in the quality of the coordinating centers that are presently in its midst.