# Presentation: 218531

## Development of Biomarkers for Decision-Making in the Development and Regulatory Evaluation of New DrugsJohn A. Wagner, MD, PhDStephen Williams, PhDChris Webster, BVM&S, PhDfor PhRMA Biomarker and Genomics Working Groups

## Overview

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

## 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

## 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
- 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

## 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 

- 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

- Biomarker Nomenclature

- FDA Guidance, Exposure-Response Relationships, 2003

## 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 guidance on Pharmacogenomic Data Submissions from FDA
- Further distinction based on evidentiary status of biomarkers
- Probable valid biomarker
- Known valid biomarker

- Biomarker Nomenclature

- Draft FDA Guidance, Pharmacogenomic Data Submissions , 2003

## 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

- 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

##  Fit-for-Purpose Qualification

|  |
| --- |
| Biomarkers |
|  |
| Surrogate Endpoints |

## Fit-for-Purpose Qualification

| Exploration |
| --- |
| Demonstration |
| Characterization |
| Surrogacy |

## Fit-for-Purpose Qualification

| Exploration | Research and development tool |
| --- | --- |
| Demonstration | Probable or emerging biomarker |
| Characterization | Known or established biomarker |
| Surrogacy | Biomarker can substitute for a clinical endpoint |

## Fit-for-Purpose Qualification

| Exploration | Research and development tool |
| --- | --- |
|  | In vitro and/or preclinical evidence |
|  | No consistent information link with clinical outcomes in humans  |
|  |  |

## Fit-for-Purpose Qualification

| Demonstration
 | Probable or emerging biomarker |
| --- | --- |
|  | Adequate preclinical sensitivity and specificity  |
|  | Linked with clinical outcomes |
|  | Not been reproducibly demonstrated in clinical studies |

## Fit-for-Purpose Qualification

| Characterization | Known or established biomarker |
| --- | --- |
|  | Adequate preclinical sensitivity and specificity  |
|  | Reproducibly linked clinical outcomes  |
|  | One or more adequately controlled prospective clinical study  |

## Fit-for-Purpose Qualification

| Surrogacy
 | Biomarker can substitute for a clinical endpoint |
| --- | --- |
|  | Association in treatment effects across studies |
|  | Association with times-to-events within studies |
|  |  |

## Examples of Qualified Biomarkers

| Exploration | Numerous |
| --- | --- |
| Demonstration | Adiponectin |
| Characterization | HDL cholesterol |
| Surrogacy | LDL cholesterol |

## Regulatory Uses of Qualified Biomarkers

| Exploration |  |
| --- | --- |
| Demonstration | Supporting evidence with primary clinical evidence |
| Characterization | Dose finding, secondary/tertiary claims |
| Surrogacy | Registration |

## Lifecycle of Qualified Biomarkers

| Exploration | Research and development tool |
| --- | --- |
| Demonstration | Probable or emerging biomarker |
| Characterization | Known or established biomarker |
| Surrogacy | Biomarker can substitute for a clinical endpoint |

- Use for decision-making

- Evidence
- does not
- support
- further
- use

## NCI Early Detection Research NetworkPhases of Discovery and Validation

- NCI Early Detection Research NetworkPhases of Discovery and Validation

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

## 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

## 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

## 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?

## 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

## Executive Consortium

- Industry
- Pharma/biotech, diagnostics, devices, etc
- Government
- FDA
- NIH – NIBIB, NHGRI, etc
- CMS
- Academia

## 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)

## 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

## 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

## 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

## 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)