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UNC-Chapel Hill ENVR 442 - Strategic paths for biomarker qualification

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Strategic paths for biomarker qualificationIntroductionContext-independent qualificationContext-dependent qualificationA Context-dependent biomarker qualification processConsortia and qualificationDefinition of context dependence for exploratory biomarkersCollaboration with regulatory agencies in the development of a process for biomarker qualificationUniform interpretation of biomarker qualification context by reviewers across regulatory agenciesContribution by multiple pharmaceutical companies with data and samples for biomarker qualificationConclusionReferencesAvailable online at www.sciencedirect.comToxicology 245 (2008) 219–223Strategic paths for biomarker qualificationFederico M. Goodsaida,∗, Felix W. Frueha, William MattesbaGenomics Group, Office of Clinical Pharmacology, Office of Translational Science,Center for Drug Evaluation and Research, FDA, United StatesbCritical Path InstituteReceived 13 November 2007; accepted 17 December 2007Available online 6 January 2008AbstractBiomarkers may be qualified using different qualification processes. A passive approach for qualification has been to accept the end of discussionsin the scientific literature as an indication that a biomarker has been accepted. An active approach to qualification requires development of acomprehensive process by which a consensus may be reached about the qualification of a biomarker. Active strategies for qualification includethose associated with context-independent as well as context-dependent qualifications.© 2007 Elsevier Ireland Ltd. All rights reserved.Keywords: Biomarkers; Consortia1. IntroductionSeveral definitions have been published for what a biomarkeris (Lesko and Atkinson, 1999; Lee et al., 2006) and also forhow to qualify exploratory biomarkers (Goodsaid and Frueh,2006; Wagner et al., 2007). The focus of this review is on strate-gies developed to qualify biomarkers, and how these strategiesare encouraging new biomarkers in drug development. Inde-pendently of the definitions we use for biomarkers and theirqualification, the urgent need to improve tools available toaccelerate development of new and better drugs (Orr et al.,2007; Goodsaid and Frueh, 2007a) is reflected in the inten-sive research on biomarkers within the pharmaceutical industryand in academic and government labs. Biomarker use requiressome level of biomarker consensus, whether this consensusis generated internally within pharmaceutical companies forinternal decision-making or externally among scientists andclinicians.Acceptance of biomarkers has often not been linked to a com-prehensive process for qualification. A lack of a comprehensiveprocess for qualification results in some biomarkers in use today∗Corresponding author at: Genomics Group, Office of Clinical Pharmacology,Office of Translational Science, Center for Drug Evaluation and Research, FDA,10903 New Hampshire Avenue, MD 20903-0002, United States.Tel.: +1 301 796 1535.E-mail address: [email protected] (F.M. Goodsaid).that have not been qualified in the specific context they are tobe used. Different strategies have been proposed (Stokes et al.,2002, 2006; Wagner et al., 2007; Goodsaid and Frueh, 2007b)for biomarker qualification. Some of these propose context-independent (Stokes et al., 2002, 2006), while others proposecontext-dependent (Wagner et al., 2007; Goodsaid and Frueh,2007b) qualification paths.Current practice in biomarker acceptance is closely associ-ated with professional debate often initiated at the level aboutwhether qualification for specific biomarkers should be dis-cussed at all. While a biomarker must be defined both as a testmeasurement as well as a preclinical or clinical interpretationof the result from this measurement, professional debate oftenconfounds measurement with interpretation. For example, thedetection of a specific molecular species is often discussed inisolation from the interpretation of this detection in a specificpreclinical or clinical context.The unstructured process by which biomarkers are currentlyaccepted has lead to a common perception that biomarker qual-ification is a process that is both hopelessly complex and poorlyunderstood. A biomarker qualification regulatory process mustbe clearly defined, with explicit metrics for incremental successas qualification data is generated and interpreted. New biomark-ers cannot be efficiently developed and employed if biomarkerdata introduced through and IND or an NDA can be potentiallyinaccurately interpreted by regulatory reviewers. A uniform,consistent and explicit interpretation of a biomarker measure-0300-483X/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.tox.2007.12.023220 F.M. Goodsaid et al. / Toxicology 245 (2008) 219–223ment in a specific context must be an integral part of biomarkerqualification. Finally, biomarker qualification is easily justifiedin drug-test co-development, but efforts by individual compa-nies to qualify biomarkers may often run into untenable costsassociated with these efforts.2. Context-independent qualificationBiomarkers are currently accepted through professional pre-clinical or clinical consensus, often after many years of debateand discussions that may focus less on the actual scientific andclinical data supporting qualification than in the complex needsof organizations, scientists and clinicians proposing their use. Aqualification model independent of specific contexts required indifferent organizations was developed by the Interagency Coor-dinating Committee for the Validation of Alternative Methods(ICCVAM) (Stokes et al., 2002, 2006).ICCVAM evolved to encourage the development and quali-fication of test methods to replace animal testing in toxicology.These test methods cover a range of biomarkers in toxicology.A model was developed by ICCVAM for test method quali-fication on the basis of a public process through which testmethod data can be shared. The results of this process arecommunicated to the 15 Federal agencies that are currentlymembers of ICCVAM, and these agencies are then responsi-ble for communicating the results to their respective regulatedindustries. This process is context-independent: qualificationrequires a consensus over applications for these biomarkersthroughout different regulatory agencies. It is important for thereplacement of animal testing in toxicology, where the pro-posed test method can be qualified across multiple contexts ofuse.Much of the data


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