Surrogate Endpoints in Aids Drug Development: Current Status
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0092-8615/98 Copyright 0 1998 Drug Information Association Inc.
SURROGATE ENDPOINTS IN AIDS DRUG DEVELOPMENT: CURRENT STATUS CHRISTYCHUANG-STEIN Director, Clinical Development Biostatistics I, Pharmacia & Upjohn Company, Kalamazoo, Michigan
RALPHDEMASI Senior Statistician, Department of Clinical Statistics, Glaxo Wellcome Inc., Research Triangle Park,North Carolina
During the past several years, signifcant efforts have been devoted to searching for surrogate endpoints to evaluate AIDS treatments. Efforts were made in theform of research sponsored b y the government and trials conducted by the pharmaceutical industry. Rapidly changing treatment strategies, low incidences of clinical endpoints due to prophylactic drug usage for AIDS-defining illness, and poor patient compliance have made long-term large trials to evaluate the clinical benefits of AIDS drugs impossible. The latter has intensified the need for surrogate endpoints. This paper shares with readers activities that have taken place in the search process and what medical, statistical, regulatory, and patient advocacy groups as a whole have accomplished so far: Some results from the collaborative effort to validate CD4 count and H N - I viral load as surrogates for the clinical endpoints will be presented using data from AIDS clinical trials. The ultimate question this paper seeks to answer is: Are researchers likely to be misled in their pursuit of surrogate endpoints for AIDS trials? Key Words: Clinical endpoints; Surrogate Marker Collaborative Group; Validation of surrogate markers; Vial load reduction
INTRODUCTION THE CONCEPT OF surrogate endpoints or biologic markers has been around for a long time. Health care professionals frequently urge people to monitor their cholesterol levels to reduce the risk of coronary heart disease. The female population is constantly reminded of the importance of maintaining bone mineral density to reduce the risk of
Part of this paper was presented at the DIA 33rd Annual Meeting “Optimizing Pharmaceutical Development: The Global Experience,” June 22-26, 1997, Montreal, Canada. Reprint address: Christy Chuang-Stein, Director, Clinical Development Biostatistics I, 9 1 6 2 - 2 2 7 4 . Pharmacia & Upjohn Company, Kalamazoo, MI 49001.
hip fractures. In the development of treatments for insulin-dependent diabetes mellitus, it is a common practice to use blood glucose level as an indicator for a regimen’s efficacy. In the area of anesthesia, EEG spectral edge is used as a marker for a patient’s autonomic or somatic response to surgical stress. Other well-known surrogate endpoints include blood pressure for myocardial infarction and tumor response for survival among cancer patients. These relationships are summarized in Table 1. In chronic disease, death is the primary (and ultimate) endpoint. It is well accepted, however, that an endpoint that measures the morbidity of a disease directly is an important secondary clinical endpoint. By contrast, a surrogate disease marker is used to predict
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