Transition of Biomarkers to Surrogate Endpoints: A Critical Path Initiative

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

• Clinical Pharmacology Subcommittee of
  ACPSNovember 4, 2004Lawrence J. Lesko, Ph.D.,
  FCPDirector, Office of Clinical Pharmacology and
  BiopharmaceuticsCenter for Drug Evaluation and
  ResearchFood and Drug Administration

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

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

• .....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

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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/whitepape
r.html
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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.
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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.
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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

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Steps Taken and To-Be-taken -- Agency Side --
Many Hinted at in Critical Path

• Implemented EOP2A meeting (guidance in 2005)
• Investing in new pharmacometrics branch (IND)
• Developing drug/disease progression models
• 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
• Intend to establish a FDA WG on the topic
• Explore development of a potential guidance on
  biomarkers
• Initiated biomarker/surrogate discussion with the
  CPSC
• Expressed goal to develop new FDA-Industry-Academi
  c collaborations for critical path opportunities

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

• Non-profit, pre-competitive academic-industry-gove
  rnment consortium started in 1982
• Decline in semiconductor industry, geared
  towards, reliance on huge payoffs from individual
  success isolated research, reduction in RD
  funding, shift toward short-term RD, talent
  crisis, technology challenges,
• Lead industrys 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

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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
• Framing the issues (Dr. Woodcock)
• Industry perspective (Dr. Wagner)
• Academic perspective (Dr. Blaschke)
• Develop foundation for a national critical path
  opportunity
• Ambitious but optimistic
• Progress is dependent on funding, sustained
  commitment and dedicated staff