# Presentation: 266153

## A Framework for Biomarker and Surrogate Endpoint Use in Drug Development

**Janet Woodcock M.D.**
**Acting Deputy Commissioner**
**for Operations**
**November 4, 2004**

## Agenda

- Current Definitions
- Limitations of current conceptual and developmental framework
- Towards robust use of biomarkers in drug development
- Towards regulatory acceptance of surrogate endpoints

## Definitions

- NIH Definitions Working Group
**Development of terms and definitions**
**Overall conceptual model of biomarkers and surrogate EP**
**Offshoot of FDA/NIH Consensus conference on topic**
**Clin Pharm Thera 69:89, 2001**

## Biomarker Definition

**A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention**
**FDA draft Pharmacogenomics Guidance further defines possible, probable and known valid biomarker categories depending on available scientific information on the marker**

## Clinical Endpoint Definition

- A characteristic or variable that reflects how a patient feels, functions or survives
- (Note that, except for survival, all these involve some sort of intermediary measurement)

## Surrogate Endpoint Definition

- A biomarker intended to substitute for a clinical endpoint.  A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence

## Use of Biomarkers in Clinical Medicine

- Diagnosis
- Tool for staging disease
- Indicator of disease status
- Predict and/or monitor clinical response to an intervention

## More at Stake than Efficient Drug Development

- Biomarkers are the foundation of evidence based medicine-who should be treated, how and with what
- Absent new markers, advances in more targeted therapy will be limited and treatment will remain largely empirical
- It is imperative that biomarker development be accelerated along with therapeutics

## Examples of Biomarkers in Clinical Medicine

- Electrocardiogram
- PET brain image
- Serum chemistries
- Auto-antigens in blood
- Bone densitometric measurement
- Pulmonary function test
- Neonatal Apgar score

## Use of Biomarkers in Early Drug Development and Decision Making

- Evaluate activity in animal models
- Bridge animal and human pharmacology via proof-of-mechanism or other observations
- Evaluate safety in animal models
- Evaluate human safety early in development

## Examples of Biomarkers in Early Drug Development

**Serum chemistries**
**Cell surface protein expression**
**Drug pharmacokinetic measurements**
**Drug metabolizing isoenzyme phenotype**
**Serum transaminases**
**Genomic expression profile**
**Drug distribution or receptor occupancy via imaging**

## Use of Biomarkers in Later Drug Development and Decision Making

**Evaluate dose-response and optimal regimen for desired pharmacologic effect**
**Use safety markers to determine dose-response for toxicity**
**Determine role (if any) of differences in metabolism on above**
** ****Rolan.  Br J Phamacol 44: 219, 1997**

## Biomarkers in Later Clinical Development

- Psychometric testing
- Pain scales
- Imaging studies
- Culture status (antimicrobials)
- Pulmonary function tests
- Serum chemistries
- Electrocardiogram

## Use of Surrogate Endpoints in Later Drug Development

**Efficacy:  Use to asses whether drug has clinically significant efficacy **
**Safety:  Use to predict the safety profile when used in the “real world”**

## Surrogate Endpoints in Drug Development

**Blood pressure**
**Intraocular pressure (glaucoma)**
**HgB A1c**
**Psychometric testing**
**Tumor shrinkage (cancer)**
**ACR criteria (rheumatoid arthritis)**
**Pain scales (pain)**

## Limitations of Current Conceptual and Developmental Framework

- Biomarkers represent bridge between mechanistic understanding of preclinical development and empirical clinical evaluation
- Regulatory system has been focused on empirical testing:  skewing overall clinical evaluation towards “all empirical”
- Early mechanistic clinical evaluation often lacking

## Limitations of Current Conceptual and Developmental Framework

**Business model for biomarker development is lacking**
**Consequence:  no rigorous pursuit  of evidence to “Qualify” marker or to assemble data for regulatory approval**
**Exploration of clinical relevance is generally ad hoc**

## Urgent Need to Overcome Current Obstacles

- New opportunities to link biomarker development to the drug development process
- Requires clear regulatory framework for the technical evaluation that is required
- Need to spur new business models

## Limitation of Current Conceptual Framework for Development of Surrogate Endpoints

**Current model for surrogacy based largely on cardiovascular and HIV experiences in the 1990’s**
**CAST outcome:**
**Surrogate:  suppression of VBP’s**
**Mortality increased in treatment arms**
**Temple.  “A regulatory authority’s opinion about surrogate endpoints”.  Clinical Measurement in Drug Evaluation.  Wiley and Sons.  1995**

## Surrogate Endpoint Development

**HIV epidemic in 1990’s spurred evaluation of the use of surrogate endpoints**
**Rigorous statistical criteria for assessing correlation of candidate surrogate with clinical outcome***
**No surrogate EP has met these criteria**
***Prentice.  Stat in Med 8: 431, 1989**

## Surrogate Endpoint Development

**HIV RNA copy number is now used as early drug development tool, surrogate endpoint in trials, and for clinical monitoring of antiviral therapy**
**Lack of complete correlation with clinical outcomes has not compromised utility**
**Successful development of antiretrovirals and control of HIV infection**

## More Fundamental Problems with the Current Framework for Surrogate Endpoints

**There is no “gold standard” clinical outcome measurement**
**Survival:  data show that desirability of longer survival dependent on quality of life, in many individuals’ estimation**
**Generalizability of any single outcome measure can be limited by trial parameters**

## More Fundamental Problems with Current Framework for Surrogate Endpoint Development

**Many clinical outcomes are multidimensional—a single outcome measure may miss domains of interest**
**Very difficult to capture both benefit and harm within a single measure—very unlikely for a biomarker.  The concept of “ultimate clinical outcome” includes parameters such as duration of observation that are important dimensions.**
**However, knowledge about these dimensions could be acquired outside of the biomarker measurement**

## Problems with Surrogate Endpoint Framework

**Per-patient view of outcomes very different from population mean view of outcomes.  **
**Newer (and older, e.g., metabolizing enzymes) biomarkers provide information at the individual level **

## Problems with Surrogate Endpoint Framework

**For above reasons, should view drug development as “progressive reduction of uncertainty” about effects—or “increasing level of confidence” about outcomes**
**Multidimensional NOT binary information set**

## Problems with Surrogate Endpoint Framework

**No single measurement contributes all knowledge**
**Population mean findings may not be valid for any given individual**

## Future of Surrogate Endpoint Development

- Composite outcome measurements
- Responder rather than population mean analyses
- Individualized therapy

## Future of Surrogate Endpoint Development

- With these evaluations, also will require larger treatment effects to provide face validity
- Basic problem is that drugs don’t work very well on a population basis right now

## Towards Robust Use  of Biomarkers in Drug Development

- Biomarkers must be USED to be accepted
- Add-on costs in clinical trials have been a significant barrier
- Requires government-academic-industry collaboration and focus

## Towards Robust Use  of Biomarkers in Drug Development

- Diagnostic and imaging industry sector needs to be fully engaged
- FDA must provide regulatory framework

## Development of New Biomarkers

- New biomarkers can revolutionize both development and use of therapeutics and preventatives
- Requires commercial development of the particular biomarker technology
- Regulatory pathways for efficient development of therapeutic/biomarker pair also needed

## Towards the Regulatory Acceptance of Surrogate Endpoints

**Further exploration of conceptual framework needed: re-assessment of the idea of “validation”; perhaps adoption of new nomenclature**
**More emphasis on multidimensional approach to efficacy**
**Greater emphasis on safety biomarkers**

## Towards the Regulatory Acceptance of Surrogate Endpoints

**Replace idea of “validation” with understanding of degree of certainty in various dimensions**
**Usefulness of any surrogate will be disease-, context-, and to some extent intervention-specific.**
**Develop framework for understanding usefulness of surrogate as evidence of effectiveness (or safety)  in a context-specific manner**

## Summary

- Important public health need for development of additional biomarkers to target and monitor therapy
- This requires use in clinical trials during drug development
- Business model/regulatory path for such markers is not clear to industry
- Clarification and stimulus required

## Summary

- Definitions for biomarkers, clinical outcomes and surrogate endpoints have been developed
- Further development of the model needed in order to increase use and utility of markers in drug development
- Single measurements will rarely capture all dimensions of clinical outcomes

## Summary

**A multidimensional and continuous model needs to replace the current single dimension, binary model of clinical effect**
**Outcomes happen to people, not populations.  In order to target therapy, individual outcomes, (e.g. responder analyses, individual AEs etc.) will need to be correlated with biomarker status**

## Summary

- FDA is considering development of these concepts as part of its “Critical Path” Initiative.
- Development would include process for refining general framework as well as individual projects on biomarker and surrogate endpoint development