Title: Transition of Biomarkers to Surrogate Endpoints: A Critical Path Initiative
1Transition 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
2Biomarkers The Fear Factor
Biologisk markor Biomarqueur Biologische
merker Marcatore biologico Biologischer marker
Marcador biologico Biological marker
3Definitions
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.
4The 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
5Biomarkers 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
6Critical 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
7The 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.
8The 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.
9New 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
10Steps 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
11Steps 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
12Goals 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