# Presentation: 149798

## Biomarkers: Physiological & Laboratory Markers of Drug Effect

**Janet Woodcock, M.D.**
**Deputy Commissioner and Chief Medical Officer**
**Food and Drug Administration**
**February 1, 2007**

## Definitions

- Markers of drug effect or response (laboratory, physiological, or other) are a subset of the general class of biomarkers
- Other biomarkers may include diagnostic, prognostic or physiologic status information not linked to drug response

## 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 Pharmacogenomics Guidance further defines possible, probable and known valid biomarker categories depending on available scientific information on the marker

**BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.**

## Clinical Endpoint Definition

- “A characteristic or variable that reflects how a patient feels, functions or survives”
- (Note that, except for survival, assessing these involves some sort of intermediary measurement)
- Clinical endpoints are usually acceptable for evidence of efficacy for regulatory purposes
- In contrast, many types of biomarkers are used for safety assessment

## 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

## SURROGATE ENDPOINT

-   A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives.  Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.
- 					     Robert J. Temple**    **

## SURROGATE MARKER

- Use of this term is discouraged because it suggests that the substitution is for a marker rather than for a clinical endpoint

**BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.**

## Why Are Biomarkers Important?

- Diagnosis is the foundation of therapy
- Biomarkers are quantitative measures that allow us to diagnose and assess the disease process and monitor response to treatment
- Biomarkers are also crucial to efficient medical product development
- As a consequence of scientific, economic and regulatory factors, biomarker development has lagged significantly behind therapeutic development

## 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, e.g., toxicogenomics
- Evaluate human safety early in development

## 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

## Use of Surrogate Endpoints in Late Drug Development

- Efficacy:  Use to assess whether drug has clinically significant efficacy
- Surrogate endpoints may be used to support “accelerated approval” of a drug if the surrogate is deemed reasonably likely to predict a clinical endpoint of interest
- A few surrogate endpoints (e.g., blood pressure) are acceptable for full approval

## Use of Biomarkers in Clinical Practice

- Disease and disease subtype diagnosis
- Prognostic determination
- Selection of appropriate therapy
- Maximize efficacy
- Minimize toxicity
- Selection of correct dose
- Monitoring outcomes (good and bad)

## Biomarkers in Future Clinical Practice:The Ultimate in Personalized Medicine

**Imaging Marker**

-  Disease present?
-  Receptor subtype present?

-  Cell, protein, antibody, small MW chemical, physical measure
-  linked to endpoint outcome for efficacy or toxicity

-  2D6 cypP450 genotype

-  [Drug]plasma(free)
-   Inhibitory concentration 90%
-  e.g., antiviral protease inhibitors

-  PET, MRI,..
-  Physical direct evidence for change

**Or is this a regulatory & therapeutic nightmare?**

## Biomarker Development: More is 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 towards more targeted therapy will be limited and treatment will remain largely empirical (i.e, trial and error)
- It is imperative that biomarker development be accelerated along with therapeutics

## Problem:  Classic Thinking about Biomarkers Inhibits New Biomarker Development

- Development of biomarkers “confounded” with the surrogate endpoint issue
- Near impossibility of “validating” new surrogates has created a significant barrier
- I will present the classic view first (slides courtesy of Dr. Art Atkinson) and then a proposal for a new framework
- Note:  classic view not “wrong” as much as limiting

## Examples of Laboratory Markers

## Examples of Physiological Biomarkers

**  ****THERAPEUTIC      BIOMARKER/   **** ****   CLINICAL**
** **_**         **__**CLASS         **_**     **_** SURROGATE **_**      **_**OUTCOME**_
**  ****ANTIHYPERTENSIVE                   ********  B.P.                         ********  STROKE**
** **
**DRUGS FOR GLAUCOMA            ********  I.O.P.                   ********  LOSS OF VISION**
**OSTEOPOROSIS DRUGS      ********  BONE  DENSITY      ******** FRACTURE RATE**
**    ****ANTIARRHYTHMIC          ********  ARRHYTHMIAS           ********  SURVIVAL**

##     BLOOD LEVELS USED AS A SURROGATE FOR CLINICAL EFFICACY AND TOXICITY
   IN THE EVALUATION OF GENERIC DRUGS

**   ****IN THE EVALUATION OF GENERIC DRUGS**

- * **Comment by Carl Peck: CDDS WORKSHOP,  McLean, **
**   ****VA, May 13, 1998 **

- The Most Widely Used Surrogate Endpoint*

## HIERARCHY OF BIOMARKERS   (Classic view)

## HIERARCHY OF BIOMARKERS* (Classic view)

- _TYPE 0_:   NATURAL HISTORY MARKER             (Prognosis)
- _TYPE I_:   BIOLOGICAL ACTIVITY MARKER (Responds to therapy)
- _TYPE II_:  SINGLE OR MULTIPLE MARKER(S)
-                   OF THERAPEUTIC EFFICACY (Surrogate endpoint, accounts fully for clinical efficacy)

*** Mildvan D, et al.: Clin Infect Dis 1997;24:764-74. **

## Only Two Surrogate Endpoints for Cardiovascular Drugs*

-     **“****THE ONLY SURROGATE ENDPOINTS CURRENTLY USED AS A BASIS FOR APPROVAL OF CARDIOVASCULAR DRUGS ARE BLOOD PRESSURE AND SERUM CHOLESTEROL LEVEL”**

*** Temple R: Are surrogate markers adequate to assess**
** ****cardiovascular disease drugs? JAMA 1999;282:790-95.**

## “Validation” of Biomarkers (e.g., for use as Surrogate

_**BIOLOGICAL PLAUSIBILITY**_
-   **EPIDMIOLOGIC EVIDENCE THAT MARKER IS A RISK FACTOR**
**  ****MARKER  MUST BE CONSISTENT  WITH  PATHOPHYSIOLOGY**
-   **MARKER  MUST BE ON  CAUSAL  PATHWAY**
-   **CHANGES IN MARKER REFLECT CHANGES IN PROGNOSIS**

_**STATISTICAL CRITERIA**_
-    **CHANGES  IN MARKER  MUST  BE  CORRELATED  WITH**
**     ****CLINICAL OUTCOME**   (but correlation does not equal causation)
- (Not confounded by adverse drug effects)

## ADDITIONAL SUPPORT FOR BIOMARKER as SURROGATE*

_**SUCCESS IN CLINICAL TRIALS**_
-   **EFFECT ON SURROGATE HAS PREDICTED OUTCOME WITH**
**     ****OTHER DRUGS OF SAME PHARMACOLOGIC CLASS**
-   **EFFECT ON SURROGATE HAS PREDICTED OUTCOME FOR **
**     ****DRUGS IN SEVERAL PHARMACOLOGIC CLASSES**
_**OTHER BENEFIT/RISK CONSIDERATIONS**_
-   **SERIOUS OR LIFE-THREATENING ILLNESS WITH NO**
**     ****ALTERNATIVE THERAPY**
-   **LARGE SAFETY DATA BASE**
**•****   ****SHORT-TERM USE**
**• ****  ****DIFFICULTY IN STUDYING CLINICAL ENDPOINT**

*** Temple R: JAMA 1999;282:790-5.**

## Problems with Current Biomarker Conceptual Framework 

- Overemphasis on “surrogacy” as single objective of biomarker development
- Difficulty in achieving surrogate “validation” frustrates progress
- New science and technology will contribute numerous candidate biomarkers—require path forward

## Fate of Most Candidate Biomarkers

- Discovered in academic laboratory
- Clinical series results published
- Further small academic series published
- Some uptake in academic centers in clinical care
- Assay may be commercialized as laboratory service

## Fate of Most CandidateBiomarkers

- Small number may be developed into commercially available laboratory tests
- Fewer may become integrated into clinical care
- Evidence base for use often remains slim/controversial
- Not adopted for regulatory use because of absence of needed evidence

## Limitations of Current Conceptual and Developmental Framework

- Practical business and conceptual models for biomarker development are lacking
- Consequence:  no rigorous pursuit  of evidence to develop 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 to spur assessment of new markers
- Requires clear regulatory framework for the technical evaluation that is required
- Need to identify new business models

## Future of Drug Development and Biomarker Development Tightly Linked

- 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”
- Mechanistic clinical evaluation lacking

## Pursuit of Surrogacy

- Surrogate EP supposed to “completely correlate with the clinical endpoint”
- This is not possible and has led to serious (but I would argue, misplaced) disillusionment with the use of biomarkers
- Flemming TR, DeMets DL: Surrogate endpoints in clinical trials: are we being misled?
-                  Ann Intern Med 1996;125:605-13

## 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 spurred the use of new surrogate endpoints for antiretroviral therapy
- Rigorous statistical criteria for assessing correlation of candidate surrogate with clinical outcome were published*
- No surrogate EP has ever 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

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

- There is no “gold standard” clinical outcome measurement – concept of “ultimate” clinical outcome is flawed
- Survival:  data show that desirability of longer survival dependent on quality of life, in many individuals’ estimation.
- Generalizability of any single outcome measure (e.g., mortality) can be limited by trial parameters (e.g., who was entered)
- Confusion between desirability of prolonged observation (for safety and long term outcomes) and use of surrogate

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

- Patient outcomes are multidimensional—a single outcome measure (whether clinical or surrogate endpoint) can 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

## Additional Problems with Surrogate Endpoint Framework

- Per-patient view of outcomes very different from population mean view of outcomes.
- For example, “ultimate” benefit in survival of 8% over placebo not meaningful to you if you are not in the 8% who actually respond
- Newer (and older, e.g., metabolizing enzymes) biomarkers provide information at the individual level

## Towards the Robust Use of Biomarkers in Drug Development

- Implement new biomarker use throughout preclinical and clinical development
- “Qualify” biomarker for intended use: less focus on surrogacy
- Goal is understanding mechanistic bases for individual response to therapy to increase *informativeness *of development process
- Achieve more predictable drug development and therapeutic outcomes

## Towards Robust Use of Biomarkers in Drug Development

- Biomarkers must be studied in order to be “qualified” for an intended use
- Add-on costs in clinical trials have been a significant barrier, as have trial organization issues
- Requires government-academic-industry collaboration and focus

## Towards the Robust Use of Biomarkers in Drug Development

- FDA’s Critical Path Initiative:  proposal to use consortia to qualify biomarkers through resource sharing
- Currently such consortia are being set up in areas such as animal safety testing and overall biomarker development
- Clinical safety biomarkers of great interest

## Promising Safety Biomarkers

- Drug Metabolizing enzyme status
- GMP (TPMT)
- “Strattera”
- Irinotecan (UGT1A1)
- Warfarin
- Genetic Basis of AE’s
- Abacavir

## Biomarker Development Consortia

- Predictive Safety Consortium
- C-Path Institute
- Animal safety biomarkers
- “The Biomarker Consortium”
- FNIH-NIH-FDA-PhRMA
- Genetic basis of adverse events
- Industrial consortium
- ECG Warehouse-cardiac biomarker
- FDA-Duke University

## Towards Greater Regulatory Acceptance of Surrogate Endpoints

**Further exploration of conceptual framework needed: re-assessment of the idea of “validation”; perhaps adoption of new nomenclature, i.e., “qualification for use”**
**More emphasis on multidimensional approach to efficacy**
**More emphasis on incremental rather than binary approach using composite endpoints**

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