1 development of biomarkers for decision-making in the development and regulatory evaluation of new...

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Development of Biomarkers for Decision-Making in the

Development and Regulatory Evaluation of New Drugs

John A. Wagner, MD, PhDStephen Williams, PhD

Chris Webster, BVM&S, PhDfor PhRMA Biomarker and Genomics Working Groups

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Overview

•Objectives and focus•Biomarker nomenclature•Fit-for-purpose qualification•Collaboration

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Objectives and Focus

• Landscape Intensified focus on biomarkers as aids to decision-

making in drug development and regulatory evaluation of new drugs

• Objectives Improved framework for regulatory adoption of new

biomarkers Refined nomenclature to enhance discussion Optimized business model for biomarker research

• Focus on a process To select suitable biomarkers for potential regulatory

purposes To define what research is needed for qualification and

regulatory use To execute the research in a cost-effective manner To review the results and agree whether the biomarker

meets specifications

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• FDA/NIH Consensus Conference 1999 laid groundwork for current biomarker science Biomarker

– A characteristic that is objectively measured and evaluated as an indicator of:

– Normal biologic processes;– Pathogenic processes; or– Pharmacologic response(s) to a therapeutic

intervention Surrogate Endpoint

– A biomarker that is intended to substitute for a clinical endpoint

– Expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence

Biomarker Nomenclature

Clinical Pharmacology & Therapeutics, 69:89-95, 2001

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•Biomarker vs Surrogate Endpoint distinction is not optimal for use of biomarkers in drug development Exposure-response guidance from FDA–Distinction based on evidentiary status of biomarkers

– Valid surrogates for clinical benefit – Candidate surrogates reflecting the pathologic

process – Measurement of drug action but of uncertain relation

to clinical outcome– Remote from the clinical benefit endpoint


FDA Guidance, Exposure-Response Relationships, 2003

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•Biomarker vs Surrogate Endpoint distinction is not optimal for use of biomarkers in drug development Draft guidance on Pharmacogenomic Data Submissions from FDA–Further distinction based on evidentiary status of biomarkers– Probable valid biomarker– Known valid biomarker


Draft FDA Guidance, Pharmacogenomic Data Submissions , 2003

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•Qualification (clinical validation/evaluation) Definition: The evidentiary process of linking a

biomarker with biology and clinical endpoints Purpose: Reliable biomarker data that is

scientifically and clinically meaningful Focus is on disease-related biomarkers

intended as indicators of clinical outcome Fit-for-purpose biomarker qualification is a

graded evidentiary process linking a biomarker with biology and clinical endpoints and dependent on the intended application

Fit-for-Purpose Qualification

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Biomarkers

Surrogate Endpoints

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Exploration

Demonstration

Characterization

Surrogacy

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Exploration Research and development tool

Demonstration Probable or emerging biomarker

Characterization Known or established biomarker

Surrogacy Biomarker can substitute for a clinical endpoint

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In vitro and/or preclinical evidence

No consistent information link with clinical outcomes in humans

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Adequate preclinical sensitivity and specificity

Linked with clinical outcomes

Not been reproducibly demonstrated in clinical studies

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Adequate preclinical sensitivity and specificity Reproducibly linked clinical outcomes

One or more adequately controlled prospective clinical study

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Association in treatment effects across studies

Association with times-to-events within studies

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Examples of Qualified Biomarkers

Exploration Numerous

Demonstration Adiponectin

Characterization HDL cholesterol

Surrogacy LDL cholesterol

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Regulatory Uses of Qualified Biomarkers

Exploration

Demonstration Supporting evidence with primary clinical evidence

Characterization Dose finding, secondary/tertiary claims

Surrogacy Registration

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Lifecycle of Qualified Biomarkers





Use for decision-making

Evidencedoes notsupport furtheruse

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Preclinical Exploratory PHASE 1 Promising directions identified

Clinical Assay and Validation

PHASE 2 Clinical assay detects established disease

Retrospective Longitudinal PHASE 3

Biomarker detects preclinical disease and a “screen positive” rule defined

Prospective Screening PHASE 4

Extent and characteristics of disease detected by the test and the false referral rate are identified

Cancer Control PHASE 5

Impact of screening on reducing burden of disease on population is quantified

NCI Early Detection Research NetworkPhases of Discovery and Validation

Journal of the National Cancer Institute, 93:1054-1061, 2001

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Biomarker Issues

• Different systems of biomarker nomenclature• Different uses of biomarkers

Range from hypothesis generation to regulatory decisions

• Different technology platforms for biomarker assays Range from immunologic assays to expression

profiling to imaging • Potential role for multiplexed biomarkers• Different strategies for qualification (clinical

validation) and validation (assay or method validation)

• Role for collaboration in biomarker development

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Collaboration

•Options for collaboration Pharma, FDA, NIH or other academic/

governmental collaboration New independent entity (with FDA

collaboration) Pharma and FDA Pharma as consortium Status quo

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Collaboration

•How can members of PhRMA work with FDA, other government agencies and academia to develop and qualify biomarkers for use in regulatory decision-making?

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Two Broad Groups of Issues

• Group 1 Deciding which biomarkers to pursue, making a

development plan, executing the necessary studies Benefits from wide cross-collaboration by groups

within the interested community

• Group 2 Deciding what data would be necessary for

qualification of a biomarker (prospectively) or reviewing data on a biomarker and advising regulators on its acceptance

Should be independent of industry involvement

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Executive Consortium

• Industry Pharma/biotech, diagnostics, devices,

etc

•Government FDA NIH – NIBIB, NHGRI, etc CMS

•Academia

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Review and Acceptance Group

• FDA Relevant Review Division for each

biomarker (if applicable) New intercenter advisory group (cf. IPRG) Or designated FDA Advisory

Committee(s)–Recommend addition of co-opted members to

provide necessary expertise (e.g. in technical performance)

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Proposal – Form Follows Function

•Separate groups to deal with each group of issues “Executive consortium” deals with

issues in Group 1 “Review and acceptance group” deals

with issues in Group 2

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Role of the Executive Consortium

• Coordinates biomarker research Allows wide membership Ensures parties interested in specific

biomarkers are connected, brokers syndicates

Identifies “gaps” for qualification Provides a forum for sharing biomarker

science

• Acts as “expert interlocutor” with regulatory agencies

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Collaboration Issues

• Incentive Regulatory predictability and process

• Funding Research funded by interested syndicates Some research should be eligible for public

funding

• Intellectual Property• Anti-trust• Governance

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Acknowledgements

• PhRMA Biomarkers Working Group

David Kornhauser (BMS), chair John Wagner (Merck), co-chair Denise Bounous (BMS) Keith Chirgwin (Merck) Mark Corrigan (Sepracor) Wanju Dai (Aventis) James Devlin (Celera) Dennis Erb (Merck) Michael Garvin (PhRMA) Chetan Lathia (Bayer) Alison Lawton (Genzyme) Michael Luther (GSK) Stacy Lindborg (Lilly) Paul MacCarthy (Bayer) Robin Pitts-Wojcieszek (Lilly) Andy Plump (Merck) Stanley Roberts (Abbott) Mike Severino (Amgen) Paul Tarantino (Sepracor) Bill Trepicchio (Millenium) Steve Williams (Pfizer)

• PhRMA Genomics Working Group

Jamie Dananberg (Lilly) Ivone Takenaka (Abbott) Mike Bleavins (Pfizer) Jesse Berlin (J&J) Lewis Kinter (AZ)

• Others Paul Deutsch (Merck) Geoff Ginsburg (Millenium) Keith Gottesdiener (Merck) Richard Hargreaves (Merck) Ronenn Roubenoff (Millenium) Wes Tanaka (Merck) Bill Trepicchio (Millenium) Scott Zeger (Johns Hopkins)

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