1. Transition of Biomarkers to Surrogate Endpoints: A Critical Path Initiative….. …..Introduction Clinical Pharmacology Subcommittee of ACPS November 4, 2004 Lawrence J. Lesko, Ph.D., FCP Director, Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research Food and Drug Administration

2. Biomarkers: The Fear Factor Biologisk markor Biomarqueur Biologische merker Marcatore biologico Biologischer marker Marcador biologico Biological marker

3. Definitions Biomarker (Biological Marker): A characteristic that is measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Surrogate Endpoint: A biomarker intended to substitute for a clinical endpoint.

4. The Problem: Pace of Biomarker Discovery Keeps Increasing Without Measurable Improvements in Predicting Success Past focus and overemphasis on biomarkers as surrogates has yielded only few successes Past focus and overemphasis on biomarkers as surrogates has yielded only few successes –Numerous workshops, symposia and publications –Conditions favoring/against surrogate status –Exposure-response guidance –Only general validation specifications linked to use –Resistance stemming from past failures –Paralysis related to statistical rigor –Fragmented into therapeutic area specific –Unrealistic expectations Surrogates aside, begin enhancing the integration and use of biomarkers over the entire course of drug development Surrogates aside, begin enhancing the integration and use of biomarkers over the entire course of drug development

5. Biomarkers: A Lot Has Happened But How Can Things be Improved?.....Have we been settling for less?.....Have we been settling for less? – –Biomarkers are extremely relevant to efficacy and safety, aside from being surrogates – –Do not need surrogate markers to gain the full impact of biomarkers Iressa ~ EGFR mutations in tumor tissue from patients with NSCLC defined 8 of 9 responders …..Can we more fully work-up biomarkers from discovery to clinical outcomes? – –Reducing uncertainty in the gray zone between preclinical biomarker discovery and phase 3 clinical outcomes may naturally lead to more acceptable surrogate endpoints

6. Critical Path Initiative: A Call to Action "Critical Path" Paper Calls for Academic Researchers, Product Developers, and Patient Groups To Work With FDA To Help Identify Opportunities to Modernize Tools for Speeding Approvable, Innovative Products To Improve Public Health www.fda.gov/oc/initiatives/criticalpath/ whitepaper.html

7. The Biomarker Vision “Adopting a new biomarker or surrogate endpoint for effectiveness standards can drive clinical development. For example, FDA adoption of CD4 cell counts and, subsequently, measures of viral load as surrogate markers for anti-HIV drug approvals allowed the rapid clinical workup and approval of life-saving antiviral drugs…..” From “Innovation/Stagnation – Challenge and Opportunity on the Critical Path to New Medical Products” (2004), p. 21.

8. The Biomarker Challenge “Additional biomarkers (quantitative measures of biological effects that provide informative links between mechanism of action and clinical effectiveness) and additional surrogate markers (quantitative measures that can predict effectiveness) are needed to guide product development.” From “Innovation/Stagnation – Challenge and Opportunity on the Critical Path to New Medical Products” (2004), p. 23.

9. New Construct….Breaking Pattern, Going Down a Different Path…..With Two Objectives (1) General, conceptual framework to continuously reduce uncertainty associated with biomarkers over the course of the entire drug development process Process/methods applicable to many therapeutic areas Increase disease progression knowledge Systematically aggregate knowledge using M/S Establish predictive nature of biomarkers Standards for biomarker performance (2) Better articulate the standards or specifications to validate and accept biomarkers for intended use including surrogates for registration, and any extensions of their application, e.g., additional drug classes

10. Steps Taken and To-Be-taken -- Agency Side -- Many Hinted at in Critical Path Implemented EOP2A meeting (guidance in 2005) Implemented EOP2A meeting (guidance in 2005) Investing in new pharmacometrics branch (IND) Investing in new pharmacometrics branch (IND) Developing drug/disease progression models Developing drug/disease progression models Have articulated a step-wise framework for model-based (quantitative) drug development Have articulated a step-wise framework for model-based (quantitative) drug development Will conduct an inventory of surrogate markers epidemiologic, pathophysiologic, therapeutic or other supporting evidence Will conduct an inventory of surrogate markers epidemiologic, pathophysiologic, therapeutic or other supporting evidence Intend to establish a FDA WG on the topic Intend to establish a FDA WG on the topic Explore development of a potential guidance on biomarkers Explore development of a potential guidance on biomarkers Initiated biomarker/surrogate discussion with the CPSC Initiated biomarker/surrogate discussion with the CPSC Expressed goal to develop new FDA-Industry-Academic collaborations for critical path opportunities Expressed goal to develop new FDA-Industry-Academic collaborations for critical path opportunities

11. Steps Taken and To-Be-Taken – Industry Side -- Semiconductor Research Corporation Non-profit, pre-competitive academic-industry- government consortium started in 1982 Non-profit, pre-competitive academic-industry- government consortium started in 1982 –Decline in semiconductor industry, geared towards, reliance on huge payoffs from individual success isolated research, reduction in R&D funding, shift toward short- term R&D, talent crisis, technology challenges, –Lead industry’s long-term research efforts –Advance problem-solving technology –Integrated university research capability –Hub of a large global network of collaborative sites –Developed a central vision and implemented action plan

12. Goals for the Committee: Strategies to Move Forward Input (science, data, opportunities, obstacles, culture, process, impediments, collaborations) to help define a new path forward for biomarkers and surrogates Input (science, data, opportunities, obstacles, culture, process, impediments, collaborations) to help define a new path forward for biomarkers and surrogates –Framing the issues (Dr. Woodcock) –Industry perspective (Dr. Wagner) –Academic perspective (Dr. Blaschke) Develop foundation for a national critical path opportunity Develop foundation for a national critical path opportunity –Ambitious but optimistic –Progress is dependent on funding, sustained commitment and dedicated staff