Determining an Adaptive Exclusion Procedure following Discovery of an Association between the Whole Genome and Adverse D
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Ting-Li Su, PhD Medical and Pharmaceutical Statistics Research Unit. Department of Mathematics and Statistics. Luncaster University, UK Helene Thygosen, PhD Medical and Pharmaceutical StatisticsResearch Unit. Department of Mathematics and Statistics, Lancaster University, UK
John Whitebeod, PbD Medical and Pharmaceutical StatisticsResearch Unit. Department of Mathematics and Statistics. Luncaster University, UK
Clive Bowmon, MSc School of Biological Sciences, University of Reading, UK
Determining an Adaptive Exclusion Procedure Following Discovery of an Association Between the Whole Genome and Adverse Drug Reactions This article concerns the identification of associations between the incidence of adverse drug reactions and features appmcnt h r n whde genome scans of patients together with the subsequent implementation of an adaptive exclusion procGdure within a drug devdopment program. Our context is not a retrospective assessment of a large and complete database: instead we are concerned with identifvingsuch a relationship during a drug deveZopment program and the consequences for the fiture conduct of that progmm. In particular, we seek
Key Words Adverse drug reactions; Clinical trial; Drug development; Genotyping; Pharmacogenomics; Pharmacovigilance;SNP
Correspondence Address ring-Li Su, PhD. Medical and Pharmaceutical Statistics Research Unit. Department of Mathematics and Statistics. Fylde College, Lancaster University, LuncasterL41 4YF. OK (email: [email protected]).
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INTRODUCTION The recent publication of the PREDICT-1 study (1,2) has underlined the prospective practical relevance of pharmacogenetic determinants of adverse reactions to drugs. The study concerned patients treated with the drug abacavir, which is commonly used in the combination treatment of HIV-1 infection. Although abacavir is associated with little toxicity in the long term, clinical trial evidence shows that about 5% of "allcomer" patients who receive the drug will suffer a hypersensitivity reaction (HSR) to the drug within the first 6 weeks of treatment, leading to fever, rash, and gastrointestinal and/or respiratory symptoms. Mallal et al. (1) describe how an association between the incidence of HSR and possession of the HLA-B*57 allele was reported by several researchers between 2002 and 2006. This led to PREDICT-1, a trial in which patients were randomized between prescreening for HLA-B*57 (with a negative finding being necessary for administration of abacavir) and a conventional control policy of abacavir administration without prescreening for HLA-B'57. Screening reduced the incidence of clinically diagnosed HSR from 7.8%in
methods for identifving changes to the exclusion criteria that lvillpreventfirturcpatientsat high risk of an adverse reaction h m continuing to be recruited. We discuss the levels of evidence needed to amend an existing recruitment pdiq, how this cun be done, and how to evaluate and revise the refonnlclated rmitment policy as the trials continue. f i e appmch will be illustrated using clinical t
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