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A Framework for Biomarker and Surrogate Endpoint Use in Drug Development Janet Woodcock M.D. Acting Deputy Commissioner for Operations November 4, 2004.

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Presentation on theme: "A Framework for Biomarker and Surrogate Endpoint Use in Drug Development Janet Woodcock M.D. Acting Deputy Commissioner for Operations November 4, 2004."— Presentation transcript:

1 A Framework for Biomarker and Surrogate Endpoint Use in Drug Development Janet Woodcock M.D. Acting Deputy Commissioner for Operations November 4, 2004

2 Agenda Current Definitions Limitations of current conceptual and developmental framework Towards robust use of biomarkers in drug development Towards regulatory acceptance of surrogate endpoints

3 Definitions NIH Definitions Working Group Development of terms and definitions Overall conceptual model of biomarkers and surrogate EP Offshoot of FDA/NIH Consensus conference on topic Clin Pharm Thera 69:89, 2001

4 Biomarker Definition A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention FDA draft Pharmacogenomics Guidance further defines possible, probable and known valid biomarker categories depending on available scientific information on the marker

5 Clinical Endpoint Definition A characteristic or variable that reflects how a patient feels, functions or survives (Note that, except for survival, all these involve some sort of intermediary measurement)

6 Surrogate Endpoint Definition A biomarker intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence

7 Use of Biomarkers in Clinical Medicine Diagnosis Tool for staging disease Indicator of disease status Predict and/or monitor clinical response to an intervention

8 More at Stake than Efficient Drug Development Biomarkers are the foundation of evidence based medicine-who should be treated, how and with what Absent new markers, advances in more targeted therapy will be limited and treatment will remain largely empirical It is imperative that biomarker development be accelerated along with therapeutics

9 Examples of Biomarkers in Clinical Medicine Electrocardiogram PET brain image Serum chemistries Auto-antigens in blood Bone densitometric measurement Pulmonary function test Neonatal Apgar score

10 Use of Biomarkers in Early Drug Development and Decision Making Evaluate activity in animal models Bridge animal and human pharmacology via proof-of-mechanism or other observations Evaluate safety in animal models Evaluate human safety early in development

11 Examples of Biomarkers in Early Drug Development Serum chemistries Cell surface protein expression Drug pharmacokinetic measurements Drug metabolizing isoenzyme phenotype Serum transaminases Genomic expression profile Drug distribution or receptor occupancy via imaging

12 Use of Biomarkers in Later Drug Development and Decision Making Evaluate dose-response and optimal regimen for desired pharmacologic effect Use safety markers to determine dose- response for toxicity Determine role (if any) of differences in metabolism on above Rolan. Br J Phamacol 44: 219, 1997

13 Biomarkers in Later Clinical Development Psychometric testing Pain scales Imaging studies Culture status (antimicrobials) Pulmonary function tests Serum chemistries Electrocardiogram

14 Use of Surrogate Endpoints in Later Drug Development Efficacy: Use to asses whether drug has clinically significant efficacy Safety: Use to predict the safety profile when used in the “real world”

15 Surrogate Endpoints in Drug Development Blood pressure Intraocular pressure (glaucoma) HgB A1c Psychometric testing Tumor shrinkage (cancer) ACR criteria (rheumatoid arthritis) Pain scales (pain)

16 Limitations of Current Conceptual and Developmental Framework Biomarkers represent bridge between mechanistic understanding of preclinical development and empirical clinical evaluation Regulatory system has been focused on empirical testing: skewing overall clinical evaluation towards “all empirical” Early mechanistic clinical evaluation often lacking

17 Limitations of Current Conceptual and Developmental Framework Business model for biomarker development is lacking Consequence: no rigorous pursuit of evidence to “Qualify” marker or to assemble data for regulatory approval Exploration of clinical relevance is generally ad hoc

18 Urgent Need to Overcome Current Obstacles New opportunities to link biomarker development to the drug development process Requires clear regulatory framework for the technical evaluation that is required Need to spur new business models

19 Limitation of Current Conceptual Framework for Development of Surrogate Endpoints Current model for surrogacy based largely on cardiovascular and HIV experiences in the 1990’s CAST outcome: Surrogate: suppression of VBP’s Mortality increased in treatment arms Temple. “A regulatory authority’s opinion about surrogate endpoints”. Clinical Measurement in Drug Evaluation. Wiley and Sons. 1995

20 Surrogate Endpoint Development HIV epidemic in 1990’s spurred evaluation of the use of surrogate endpoints Rigorous statistical criteria for assessing correlation of candidate surrogate with clinical outcome* No surrogate EP has met these criteria *Prentice. Stat in Med 8: 431, 1989

21 Surrogate Endpoint Development HIV RNA copy number is now used as early drug development tool, surrogate endpoint in trials, and for clinical monitoring of antiviral therapy Lack of complete correlation with clinical outcomes has not compromised utility Successful development of antiretrovirals and control of HIV infection

22 More Fundamental Problems with the Current Framework for Surrogate Endpoints There is no “gold standard” clinical outcome measurement Survival: data show that desirability of longer survival dependent on quality of life, in many individuals’ estimation Generalizability of any single outcome measure can be limited by trial parameters

23 More Fundamental Problems with Current Framework for Surrogate Endpoint Development Many clinical outcomes are multidimensional—a single outcome measure may miss domains of interest Very difficult to capture both benefit and harm within a single measure—very unlikely for a biomarker. The concept of “ultimate clinical outcome” includes parameters such as duration of observation that are important dimensions. However, knowledge about these dimensions could be acquired outside of the biomarker measurement

24 Problems with Surrogate Endpoint Framework Per-patient view of outcomes very different from population mean view of outcomes. Newer (and older, e.g., metabolizing enzymes) biomarkers provide information at the individual level

25 Problems with Surrogate Endpoint Framework For above reasons, should view drug development as “progressive reduction of uncertainty” about effects—or “increasing level of confidence” about outcomes Multidimensional NOT binary information set

26 Problems with Surrogate Endpoint Framework No single measurement contributes all knowledge Population mean findings may not be valid for any given individual

27 Future of Surrogate Endpoint Development Composite outcome measurements Responder rather than population mean analyses Individualized therapy

28 Future of Surrogate Endpoint Development With these evaluations, also will require larger treatment effects to provide face validity Basic problem is that drugs don’t work very well on a population basis right now

29 Towards Robust Use of Biomarkers in Drug Development Biomarkers must be USED to be accepted Add-on costs in clinical trials have been a significant barrier Requires government-academic- industry collaboration and focus

30 Towards Robust Use of Biomarkers in Drug Development Diagnostic and imaging industry sector needs to be fully engaged FDA must provide regulatory framework

31 Development of New Biomarkers New biomarkers can revolutionize both development and use of therapeutics and preventatives Requires commercial development of the particular biomarker technology Regulatory pathways for efficient development of therapeutic/biomarker pair also needed

32 Towards the Regulatory Acceptance of Surrogate Endpoints Further exploration of conceptual framework needed: re-assessment of the idea of “validation”; perhaps adoption of new nomenclature More emphasis on multidimensional approach to efficacy Greater emphasis on safety biomarkers

33 Towards the Regulatory Acceptance of Surrogate Endpoints Replace idea of “validation” with understanding of degree of certainty in various dimensions Usefulness of any surrogate will be disease-, context-, and to some extent intervention-specific. Develop framework for understanding usefulness of surrogate as evidence of effectiveness (or safety) in a context-specific manner

34 Summary Important public health need for development of additional biomarkers to target and monitor therapy This requires use in clinical trials during drug development Business model/regulatory path for such markers is not clear to industry Clarification and stimulus required

35 Summary Definitions for biomarkers, clinical outcomes and surrogate endpoints have been developed Further development of the model needed in order to increase use and utility of markers in drug development Single measurements will rarely capture all dimensions of clinical outcomes

36 Summary A multidimensional and continuous model needs to replace the current single dimension, binary model of clinical effect Outcomes happen to people, not populations. In order to target therapy, individual outcomes, (e.g. responder analyses, individual AEs etc.) will need to be correlated with biomarker status

37 Summary FDA is considering development of these concepts as part of its “Critical Path” Initiative. Development would include process for refining general framework as well as individual projects on biomarker and surrogate endpoint development

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