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Issues in effeciency and reliability in trials using surrogate endpoints
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Abstracts Forms Reports. Since the Query, DB contains the data of each DCC question and CC answer, response times can be calculated and summarized. The Query DB allows for efficient monitoring of types of data problems and rates of outstanding queries, and it ensures DCC follow up of all discrepancies detected.
D i f f e r e n c e s in C a t e g o r i z a t i o n of Morbidity and M o r t a l i t y E v e n t Variables Between Study Coordinators and E n d p o i f l t R e v i e w S u b c o m m i t t e e s i n the Multicenter
Diltiazem Post-lnfarction Trial (MDPIT) M a r y W. B r o w n , Robert P. A n n e c h i a r i c o , A r t h u r J. M o s s Universzty Of Rochester, Rochester, New York (37) l h e MDPIT was a double blind placebo-controlled study which enrolled 2466 post-Ml patients from 38 enrolling centers (EC) in the United State~ antt Canada. The purpose of the trial was to determine the effects of diltiazem on first cardiac events and mortality. In order to provide maximum uniformity and continuity in the review and categorization of endpoint events (total mortality, death from cardiac causes, and non-fatal reinfarction), mortality and non-fatal reinfarction (morbidity) review subcommittees were formed to review and categorize all endpoint event data based on event information received from the EC. Common variables for each event were categorized independently by both the endpoint subcommittees (ES) and the EC study coordinators (SC). Common variables included location, cause, and mechanism of mortality events and determination of chest pain, enzyme criteria, type, and cause of morbidity e v e n t s The purpose of this presentation is to report the similarities and differences between the SC and ES categorization of common endpnint variables. A total of 333 mortality events and 256 morbidity events were categorized by the SC and ES. For all of the major endpoints the differences between the categorizations of the SC and the ES were <15%; for mechanism of death, the difference was 41ok. Detailed analyses of the findings of the ES and the SC will be provided for each variable. The specific steps of the endpoint categorization process will also be presented. These findings present important issues regarding the need for ES in future clinical trials.
Issues in Efficiency and Reliability in Trials Using Surrogate Endpoints K. Teo, P. H e l d , S. Y u s u f
National Heart Lung and Blood Institute, Bethesda, Maryland (38) Although the use of surrogate endpoints to replace mortality or morbidity has sometimes been employed to improve efficiency, and decrease costs, such studies may have important limitations. First, if the endpoint measurement is expensive, invasive, applicable in only a restricted proportion of patients or only available in specialized centers, such studies may be difficult and expensive to conduct. Second, biases in endpoint ascertainment and availability may cloud the interpretation of results. Although imputations for missing values may be attempted, if a large proportion of measures are missing, the validity of the study may be in question. Third, since surrogate endpoint studies are usually small, they are unlikely to detect infrequent but important adverse effects (e.g., intracranial hemorrhage or cancers). Fourth, much emphasis has been placed in the past on standardization and improving the precision of endpoints. While reasonable efforts in these directions are warranted, increasing the precision with which endpoints are measured beyond what is easily achieved might not necessarily confer increased power on the study. Conversely, comparable efforts in decreasing biases and missing data usually lead to greater improvements in study validity, value and persuasiveness.
Development of a Composite Index as a Primary Outcome Measure i n a C l i n i c a l Trial William G. H e n d e r s o n , S u s a n G. Fisher, N o e l C o h e n , S u s a n W a l t z m a n , Laura W e b e r Hines VA Cooperative Studies Program Coordinating Center, Hines, Illinois (39) VA Cooperative Study No. 304 is a cooperative clinical trial comparing three cochlear implant devices in bilaterally profoundly deaf veterans. Planners of this trial selected a battery of 30 different quantitative audiologic tests to evaluate the implant devices. However, no single audio]ogic test or small subset of tests could be designated as the primary outcome measure(s).
Abstracts Forms Reports. Since the Query, DB contains the data of each DCC question and CC answer, response times can be calculated and summarized. The Query DB allows for efficient monitoring of types of data problems and rates of outstanding queries, and it ensures DCC follow up of all discrepancies detected.
D i f f e r e n c e s in C a t e g o r i z a t i o n of Morbidity and M o r t a l i t y E v e n t Variables Between Study Coordinators and E n d p o i f l t R e v i e w S u b c o m m i t t e e s i n the Multicenter
Diltiazem Post-lnfarction Trial (MDPIT) M a r y W. B r o w n , Robert P. A n n e c h i a r i c o , A r t h u r J. M o s s Universzty Of Rochester, Rochester, New York (37) l h e MDPIT was a double blind placebo-controlled study which enrolled 2466 post-Ml patients from 38 enrolling centers (EC) in the United State~ antt Canada. The purpose of the trial was to determine the effects of diltiazem on first cardiac events and mortality. In order to provide maximum uniformity and continuity in the review and categorization of endpoint events (total mortality, death from cardiac causes, and non-fatal reinfarction), mortality and non-fatal reinfarction (morbidity) review subcommittees were formed to review and categorize all endpoint event data based on event information received from the EC. Common variables for each event were categorized independently by both the endpoint subcommittees (ES) and the EC study coordinators (SC). Common variables included location, cause, and mechanism of mortality events and determination of chest pain, enzyme criteria, type, and cause of morbidity e v e n t s The purpose of this presentation is to report the similarities and differences between the SC and ES categorization of common endpnint variables. A total of 333 mortality events and 256 morbidity events were categorized by the SC and ES. For all of the major endpoints the differences between the categorizations of the SC and the ES were <15%; for mechanism of death, the difference was 41ok. Detailed analyses of the findings of the ES and the SC will be provided for each variable. The specific steps of the endpoint categorization process will also be presented. These findings present important issues regarding the need for ES in future clinical trials.
Issues in Efficiency and Reliability in Trials Using Surrogate Endpoints K. Teo, P. H e l d , S. Y u s u f
National Heart Lung and Blood Institute, Bethesda, Maryland (38) Although the use of surrogate endpoints to replace mortality or morbidity has sometimes been employed to improve efficiency, and decrease costs, such studies may have important limitations. First, if the endpoint measurement is expensive, invasive, applicable in only a restricted proportion of patients or only available in specialized centers, such studies may be difficult and expensive to conduct. Second, biases in endpoint ascertainment and availability may cloud the interpretation of results. Although imputations for missing values may be attempted, if a large proportion of measures are missing, the validity of the study may be in question. Third, since surrogate endpoint studies are usually small, they are unlikely to detect infrequent but important adverse effects (e.g., intracranial hemorrhage or cancers). Fourth, much emphasis has been placed in the past on standardization and improving the precision of endpoints. While reasonable efforts in these directions are warranted, increasing the precision with which endpoints are measured beyond what is easily achieved might not necessarily confer increased power on the study. Conversely, comparable efforts in decreasing biases and missing data usually lead to greater improvements in study validity, value and persuasiveness.
Development of a Composite Index as a Primary Outcome Measure i n a C l i n i c a l Trial William G. H e n d e r s o n , S u s a n G. Fisher, N o e l C o h e n , S u s a n W a l t z m a n , Laura W e b e r Hines VA Cooperative Studies Program Coordinating Center, Hines, Illinois (39) VA Cooperative Study No. 304 is a cooperative clinical trial comparing three cochlear implant devices in bilaterally profoundly deaf veterans. Planners of this trial selected a battery of 30 different quantitative audiologic tests to evaluate the implant devices. However, no single audio]ogic test or small subset of tests could be designated as the primary outcome measure(s).