Transition of Biomarkers to Transition of Biomarkers to Surrogate Endpoints: A Critical Path Surrogate Endpoints: A Critical Path Initiative…..Initiative…..…..Introduction…..Introduction

Clinical Pharmacology Subcommittee of ACPSClinical Pharmacology Subcommittee of ACPSNovember 4, 2004November 4, 2004

Lawrence J. Lesko, Ph.D., FCPLawrence J. Lesko, Ph.D., FCPDirector, Office of Clinical Pharmacology and Director, Office of Clinical Pharmacology and BiopharmaceuticsBiopharmaceuticsCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchFood and Drug AdministrationFood and Drug Administration

Biomarkers: The Fear FactorBiomarkers: The Fear Factor

Biologisk markor Biomarqueur

Biologische merker Marcatore biologico

Biologischer marker Marcador biologico

Biological marker

DefinitionsDefinitions

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.

The Problem: Pace of Biomarker The Problem: Pace of Biomarker Discovery Keeps Increasing Without Discovery Keeps Increasing Without Measurable Improvements in Predicting Measurable Improvements in Predicting SuccessSuccess

Past focus and overemphasis on biomarkers as Past focus and overemphasis on biomarkers as surrogates has yielded only few successessurrogates has yielded only few successes– Numerous workshops, symposia and publicationsNumerous workshops, symposia and publications– Conditions favoring/against surrogate statusConditions favoring/against surrogate status– Exposure-response guidance Exposure-response guidance – Only general validation specifications linked to useOnly general validation specifications linked to use– Resistance stemming from past failuresResistance stemming from past failures– Paralysis related to statistical rigorParalysis related to statistical rigor– Fragmented into therapeutic area specificFragmented into therapeutic area specific– Unrealistic expectationsUnrealistic expectations

Surrogates aside, begin enhancing the Surrogates aside, begin enhancing the integration and use of biomarkers over the integration and use of biomarkers over the entire course of drug developmententire course of drug development

Biomarkers: A Lot Has Happened Biomarkers: A Lot Has Happened But How Can Things be Improved?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

Critical Path Initiative: A Call Critical Path Initiative: A Call to Action 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

The Biomarker VisionThe 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.

The Biomarker ChallengeThe 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.

New Construct….Breaking Pattern, Going New Construct….Breaking Pattern, Going Down a Different Path…..With Two Down a Different Path…..With Two ObjectivesObjectives

(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

Steps Taken and To-Be-taken -- Steps Taken and To-Be-taken -- Agency Side -- Many Hinted at in Agency Side -- Many Hinted at in Critical PathCritical 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 modelsDeveloping drug/disease progression models Have articulated a step-wise framework for model-based Have articulated a step-wise framework for model-based

(quantitative) drug development(quantitative) drug development Will conduct an inventory of surrogate markers Will conduct an inventory of surrogate markers

epidemiologic, pathophysiologic, therapeutic or other epidemiologic, pathophysiologic, therapeutic or other supporting evidencesupporting evidence

Intend to establish a FDA WG on the topicIntend to establish a FDA WG on the topic Explore development of a potential guidance on biomarkersExplore development of a potential guidance on biomarkers Initiated biomarker/surrogate discussion with the CPSCInitiated biomarker/surrogate discussion with the CPSC Expressed goal to develop new FDA-Industry-Academic Expressed goal to develop new FDA-Industry-Academic

collaborations for critical path opportunitiescollaborations for critical path opportunities

Steps Taken and To-Be-Taken – Steps Taken and To-Be-Taken – Industry Side -- Semiconductor Industry Side -- Semiconductor Research CorporationResearch Corporation

Non-profit, pre-competitive academic-industry-Non-profit, pre-competitive academic-industry-government consortium started in 1982government consortium started in 1982– Decline in semiconductor industry, geared towards, Decline in semiconductor industry, geared towards,

reliance on huge payoffs from individual success reliance on huge payoffs from individual success isolated research, reduction in R&D funding, shift isolated research, reduction in R&D funding, shift toward short-term R&D, talent crisis, technology toward short-term R&D, talent crisis, technology challenges, challenges,

– Lead industry’s long-term research effortsLead industry’s long-term research efforts– Advance problem-solving technologyAdvance problem-solving technology– Integrated university research capabilityIntegrated university research capability– Hub of a large global network of collaborative sitesHub of a large global network of collaborative sites– Developed a central vision and implemented action Developed a central vision and implemented action

planplan

Goals for the Committee: Goals for the Committee: Strategies to Move ForwardStrategies to Move Forward

Input (science, data, opportunities, obstacles, Input (science, data, opportunities, obstacles, culture, process, impediments, culture, process, impediments, collaborations) to help define a new path collaborations) to help define a new path forward for biomarkers and surrogatesforward for biomarkers and surrogates– Framing the issues (Dr. Woodcock)Framing the issues (Dr. Woodcock)– Industry perspective (Dr. Wagner)Industry perspective (Dr. Wagner)– Academic perspective (Dr. Blaschke)Academic perspective (Dr. Blaschke)

Develop foundation for a national critical Develop foundation for a national critical path opportunitypath opportunity– Ambitious but optimisticAmbitious but optimistic– Progress is dependent on funding, sustained Progress is dependent on funding, sustained

commitment and dedicated staffcommitment and dedicated staff