2016 AAPS NBC CONFERENCE

MAY 17, 2016

Shashi Amur, Ph.D.Scientific Lead, Biomarker Qualification Program, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

BIOMARKER QUALIFICATION PROGRAM IN CDER, FDA

OVERVIEW

• Critical Path Initiative

• Drug Development Tool Qualification

• Biomarkers

• Biomarker Qualification (BQ)

• FDA Initiatives to Help Biomarker Development

• Summary

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CRITICAL PATH INITIATIVE AT FDA

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2006 20112004

FDA launched the Critical Path Initiative in 2004

• Recognized that drug development was not benefitting from many advances in

biomedical sciences and had become challenging and resource intensive

• Called for modernization of scientific and technical tools for drug development to

improve the evaluation and prediction of the safety, effectiveness, and

manufacturability of medical products

Clinical Outcome

Assessments

Animal Models

(Animal Rule)

Biomarkers

DDTs are methods, materials, or measures that aid drug development

DRUG DEVELOPMENT TOOLS (DDT) QUALIFICATION AT CDER

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Guidance for Industry and FDA Staff:

Qualification Process for Drug Development

Toolshttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/

Guidances/UCM230597.pdf

Drug Development Tools (DDT) Qualification

Programs Webpage on FDA.govhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualific

ationProgram/default.htm

DDT QUALIFICATION AT CDER

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BIOMARKERS

Definition: A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.*

Types: Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers.

Examples: Serum creatinine, HIV viral load, BRCA1 mutations, blood pressure, tumor volume by imaging

*Updated definition from the NIH-FDA Biomarker Working Group

http://www.ncbi.nlm.nih.gov/books/NBK326791/

BEST: BIOMARKERS, ENDPOINTS,

AND OTHER TOOLS RESOURCE

• A glossary of terminology and uses of biomarkers and endpoints in basic biomedical research, medical product development, and clinical care

• Created by the NIH-FDA Biomarker Working Group

• Publicly available at http://www.ncbi.nlm.nih.gov/books/NBK326791/

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WHY IS “BEST” NEEDED?

WHY IS “BEST” NEEDED?

• Language confusion can hinder medical product development, causing misinterpretation of evidence, misunderstanding of evidentiary requirements, and even failure in late-phase trials and potential harm to individuals.

• BEST harmonizes terms and definitions and addresses nuances of usage and interpretation among various stakeholders, including:

• Biomedical scientists

• Translational and clinical researchers

• Medical product developers

• Patient/disease advocacy groups

• Government officials

• Clinicians

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• Email biomarkers@ncbi.nlm.nih.gov.

“BEST” BIOMARKER CATEGORIES

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• Susceptibility/risk biomarker

• Diagnostic biomarker

• Prognostic biomarker

• Predictive biomarker

• Monitoring biomarker

• Pharmacodynamic/response biomarker

• Safety biomarker

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BIOMARKERS IN DRUG DEVELOPMENT

• Molecular pathways underpinning disease

• Mechanism of action of therapeutics

• Preclinical safety assessment

• Clinical trials

o Safety assessment

o Dose selection

o Stratification, Patient selection/enrichment , Surrogate endpoint

• Companion diagnostic

o Selection of right patients for increased efficacy/safety

PrototypeDesign orDiscovery

Clinical DevelopmentBasic Research

FDA Filing/Approval &Launch

PreclinicalDevelopment Phase I Phase II Phase III

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PATHWAYS TO INTEGRATE BIOMARKERS IN DRUG DEVELOPMENT AT CDER, FDA

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Amur et al, Clin. Pharm. Ther. 98 (1) 34-46, 2015

Acceptance through IND, NDA and BLA submissions (drug approval

process)Biomarker Qualification

Objective: Use the

biomarker in a single

drug development

program

Objective: Establish the

biomarker for use in

multiple development

programs

Biomarkers in Drug Development

Responsible Parties: One sponsor

contacts the review division

Process: Discuss; provide rationale

and data to the review division

Risk and Resource: Burden on one

sponsor

Biomarker Information: Embedded

in drug labels

Responsible Parties: Generally,

consortia contact the BQ Program

Process: Submit letter of intent;

follow the BQ process

Risk and Resource: Shared among

consortia members

Biomarker Information: Qualified

biomarkers announced as draft

guidance

BIOMARKER QUALIFICATION (BQ)

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Definition: A conclusion that, within a carefully and specifically

stated “context of use,” the biomarker has been demonstrated to

reliably support a specified manner of interpretation and application

in drug development

Context of Use (COU): A comprehensive statement that fully and

clearly describes the manner and purpose of use for the biomarker in

drug development

EFFORTS TOWARD DEVELOPING EVIDENTIARY STANDARDS

• PhRMA-FDA workshop, 2007

• Institute of Medicine “Workshop on Biomarker Qualification”, 2009

• FDA-cosponsored biomarkers workshop with HHMI, 2013

• FDA-cosponsored Brookings meeting, “Advancing the Use of Biomarkers and Pharmacogenomics”, 2014

• FDA-cosponsored workshop with M-CERSI and Critical Path Institute, “Evidentiary Considerations for Integration of Biomarkers in Drug Development” held August 2015

• Brookings Biomarker Meeting, October 2015

• FDA-FNIH Biomarker Consortium Workshop, April 2016

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CONSIDERATIONS FOR BIOMARKER QUALIFICATION

• Type and COU of the biomarker for use in drug development

• Characterizations of the various relationships among the biomarker, the clinical

outcomes, and the treatment (where applicable) required for the proposed COU

• Assay considerations (analytically validated method and understanding of potential sources of variability in the measurement)

• Biological rationale for use of the biomarker (if known)

• Type of data available to assess the strength of association of the biomarker with its proposed clinical outcome: retrospective or prospective, registry data, and/or randomized controlled trial (RCT) data

• Reproducibility of data (need for test dataset and confirmatory dataset)

• Use of appropriate, pre-specified statistical methods to demonstrate the hypothesized relationships for the COU

• Strength of evidence

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BIOMARKER QUALIFICATION PROCESS

Initiation Consultation and Advice

Review

Full qualification

package received,

reviewed by BQRT,

internal meetings

held, additional

information (if

needed) requested,

qualification

recommendations

Letter of Intent (LOI)

received, reviewed,

go/no go decision made,

Biomarker Qualification

Review Team (BQRT)

formed, internal meeting

held, briefing document

specifications sent to

submitter

Briefing document

received, reviewed,

internal meeting

held, pre-meeting

comments sent,

face-to-face meeting

held

Iterative process

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BIOMARKER QUALIFICATION PROCESS

LOI Consideration

BriefingDocumentEvaluation

Full QualificationPackage Evaluation

Drafting the Biomarker Guidance

Clearance of the Guidance and the

FR Notice

Public Comment and Finalization of

the Guidance

InitiationConsultation &

AdviceReview Clearance and Publication of the Guidance and FR Notice

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BIOMARKER QUALIFICATION AT FDA

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• Submitter can be a person, a group, organization (including the federal government) or consortium that takes responsibility for and initiates a BQ proposal using the procedures described in the DDT guidance

• No fees for submissions to the BQ program

• Once qualified for a specific context of use, a biomarker can be used by drug developers for other applications without re-review

• Incremental expansion of the qualified context of use over time may be undertaken

• Biomarkers considered for qualification are conceptually independent of the specific test or device performing the measurement

• Biomarker qualification is a tool for drug development, and not for approval/clearance of diagnostics or for companion diagnostics for use in clinical practice

LIST OF FDA-QUALIFIED BIOMARKERSGeneral Area Submitter(s)

Biomarker(s) Qualified for Specific

Contexts of Use

Issuance Date with Link

to Specific Guidance

Supporting

Information

Nonclinical

Predictive Safety and Testing

Consortium (PSTC),

Nephrotoxicity Working Group

(NWG)

Urinary biomarkers: Albumin, β2-

Microglobulin, Clusterin, Cystatin C,

KIM-1, Total Protein, and Trefoil

Factor-3

4/14/2008: Drug-Induced Nephrotoxicity

Biomarkers Reviews

Nonclinical

International Life Sciences

Institute (ILSI)/Health and

Environmental Sciences Institute

(HESI), Nephrotoxicity Working

Group

Urinary biomarkers: Clusterin, Renal

Papillary Antigen (RPA-1)

9/22/2010: Drug-Induced Nephrotoxicity

BiomarkersReviews

NonclinicalPJ O’Brien, WJ Reagan, MJ

York, and MC Jacobsen

Serum/plasma biomarkers: Cardiac

Troponins T (cTnT) and I (cTnI)

2/23/2012: Drug-Induced Cardiotoxicity

BiomarkersReviews

Clinical Mycoses Study GroupSerum/bronchoalveolar lavage fluid

biomarker: Galactomannan

10/24/2014: Patient Selection Biomarker for

Enrollment in Invasive Aspergillosis (IA)

Clinical Trials

Reviews

Clinical

Chronic Obstructive Pulmonary

Disease (COPD) Biomarker

Qualification Consortium

(CBQC)

Plasma biomarker: Fibrinogen

7/6/2015; Prognostic Biomarker for

Enrichment of Clinical Trials in

Chronic Obstruction Pulmonary Disease

(COPD)

Reviews

ClinicalPolycystic Kidney Disease

Outcomes Consortium

Imaging biomarker: Total Kidney

Volume (TKV)

8/17/2015: Prognostic Biomarker for

Enrichment of Clinical Trials in Autosomal

Dominant Polycystic Kidney Disease

Reviews

www.fda.gov/biomarkerqualificationprogram

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BIOMARKER QUALIFICATION (BQ) SUBMISSIONS

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Biomarker Qualification Program Metrics

Number in Initiation Stage 7

Number in Consultation and

Advice Stage18

Number in Review Stage 2

Total Number of Active

Projects27

Number Qualified 6

From the Drug Development Tool (DDT) Qualification Projects at CDER, FDA:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualification

Program/ucm409960.htm

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TYPES OF SUBMISSIONS WE ARE SEEING FOR BIOMARKER QUALIFICATION

19% Patient Selection*

26% Preclinical Safety

30% Response

22% Clinical Safety

4% Monitoring

N=27

* Diagnostic, prognostic and predictive biomarkers used for patient selection

Qualification of Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease

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QUALIFICATION OF TOTAL KIDNEY VOLUME (TKV) IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Joint FDA-EMA submission from Polycystic Kidney Disease Outcomes Consortium (PKDOC)

PKDOC

approach

TKV BQ SUBMISSION

• Objective: Clinical trial enrichment in Autosomal Dominant Polycystic

Kidney Disease (ADPKD)

• Stage of Drug Development for Use: All clinical stages of ADPKD

drug development, including proof of concept, dose-ranging, and

confirmatory clinical trials.

• Proposed Context of Use: Baseline TKV can be applied as a

prognostic biomarker that, in combination with patient age, can be

used to help identify those ADPKD patients who are at the greatest

risk of advancing in the course of their disease to a point where there

is substantial decline in renal function as measured by clinically

meaningful outcomes (30% worsening of eGFR , 57% worsening of

eGFR (equivalent to doubling of serum creatinine), and ESRD).

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eGFR: Estimated Glomerular Filtration rate; ESRD: End Stage Renal Disease

QUALIFICATION OF TKV IN ADPKD

FDA analysis and conclusions

• Biomarker Qualification Review Team (BQRT) conducted additional analyses and performed model development and cross validation

o FDA analyses were limited to patients with an eGFR ≥25 and at least 12 years of age, which represent the population likely to be enrolled in clinical trials

o Some subjects had imaging performed with more than one modality. FDA reviewers selected magnetic resonance imaging (MRI) data as the first preference, computer tomography (CT) data as the second preference and ultrasound (US) data as the last preference

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QUALIFICATION OF TKV IN ADPKD

• Inclusion of TKV in addition to patient age and eGFR (addition of eGFR as a covariate suggested by FDA and EMA ) in the best fit model, provided a modest improvement in predicting the risk of a confirmed 30% decline in eGFR. This finding was confirmed using cross-validation and in a separate internal dataset (external validation)

• There were too few ESRD and 57% decline in eGFR events over the time frame of a feasible clinical trial to perform meaningful analyses.

EMA: European Medicines Agency

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DRAFT GUIDANCE FOR TKV IN ADPKD

Use Statement:

TKV, measured at baseline, is qualified as a prognostic enrichment biomarker to select patients with ADPKD at high risk for a progressive decline in renal function (defined as a confirmed 30% decline in the patient’s eGFR) for inclusion in interventional clinical trials. This biomarker may be used in combination with the patient’s age and baseline eGFR as an enrichment factor in these trials.

Conditions for qualified use:

1. Quantitative Imaging Biomarker

2. TKV-based selection in clinical trials:

- Patient population

- Patient selection

- Measurement applicability

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458483.pdf

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FDA INITIATIVES TO HELP BIOMARKER DEVELOPMENT

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FDA INITIATIVES TO HELP

BIOMARKER DEVELOPMENT

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JOINT FDA-EMA LOI

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm422888.htm

LIMITED CONTEXT OF USE –BIOMARKER QUALIFICATION

CDER provides an avenue to qualify a biomarker for a

“limited” context of use in order to expedite the

integration of the biomarker in drug development and

to possibly generate additional data that can help in

qualifying the biomarker for the “expanded” context of

use.

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A CONTINUUM, NOT A DICHOTOMY…

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Source: Slide Set from Dr. Martha Brumfield, President and CEO of Critical Path Institute

8 letters issued to date

http://www.fda.gov/Drugs/DevelopmentApprovalP

rocess/ucm434382.htm

LETTERS OF SUPPORT

This is a letter issued to a

submitter that briefly

describes CDER’s thoughts

on the potential value of a

biomarker and encourages

further evaluation.

This letter does not

connote qualification of a

biomarker. It is meant to

enhance the visibility of the

biomarker, encourage data

sharing, and stimulate

additional studies.

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• Discussion of the science, medicine, and regulatory aspects of innovation in drug development

• Nonbinding meeting

• Not a meeting about a specific approval pathway

• Scope includes early biomarkers and clinical outcome assessments, natural history studies, technologies (not manufacturing), and clinical trial designs and methods

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformion/Guidances/UCM417627.pdf

CPIM (CRITICAL PATH INNOVATION MEETING)

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TIMELINE FOR SALIENT BQ-RELATED EFFORTS

PhRMA-

FDA

Workshop

Brookings

Meeting

BMQ

Guidances and MAPPs

FDA-EMA collaboration

CPIM

Meeting/workshop

OND survey

LOS

LOS

(7)

FR notice - survey Plasma

fibrinogen in

COPD

Total Kidney

Volume in

ADPKD

2008 2009 2010 2011 2013 2014 2015

CPIM

introduced

IOM

meeting

2nd

nephrotox

BMs

Cardiac

toxicity BMs

Guidance DDT

Qualification (final)

Invasive

Aspergillosis BM

CDER DDT

Qualification

MAPP

HHMI Level

of Evidence

Meeting

LOS

Brookings

Meeting

LOI Harmonization

FR notice -

BQ survey

OND

survey

1st nephrotox BMsGuidance DDT

Qualification (draft)

CPIM

Guidance

and MAPP

Histopath

Guidance

(draft)

Quarterly

EMA-FDA

teleconferences

2007 2012 2016

M-CERSI

Meeting

FDA-FNIH

Workshop

SUMMARY

• Biomarkers can be integrated into drug development through either of two pathways:

1. Regulatory submissions for drug approval in the context of an individual drug development program

2. Biomarker qualification

• Biomarker qualification is a voluntary process intended for biomarkers that will be used in multiple drug development programs

• No fees are charged for evaluating Biomarker Qualification Submissions

• Once qualified, the biomarker can be used for the specific context of use in regulatory submissions without having to reconsider and reconfirm its suitability

• Early engagement with FDA on biomarker qualification is encouraged

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ACKNOWLEDGEMENTS

Janet Woodcock

ShaAvhrée Buckman-Garner

Suzie McCune

Chris Leptak

Marianne Noone

Sarmistha Sanyal

Kylie Haskins

Ru Chen

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Questions?

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Email: Shashi.amur@fda.hhs.gov

WHAT DO WE SEE AS OBSTACLES TO BIOMARKER QUALIFICATION?

• Lack of a clear Context of Use

• Insufficient supportive data

• Insufficient resources to support biomarker development and qualification

• Challenges in the aggregation of requisite data

• Issues with sample storage

• Assay validity/reproducibility

• Lack of clear evidentiary standards

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WHAT DO WE HEAR?

• Terminologies are confusing

• The BQ process takes too long

• These are multi-million dollar efforts pulled together with

tentative resources and we cannot afford to waste time…

• We want clearer timelines and deliverables

• The evidentiary bar for BQ is very high

• We are hearing conflicting views from the Review Divisions in

CDER about whether qualification is even needed

• Why should we choose qualification when the biomarkers can

be accepted through the IND/NDA/BLA submissions?

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SO, WHAT ARE WE DOING ABOUT IT?

• BEST Glossary from FDA-NIH Biomarker Working Group

• Limited COU BQ, Letters of Support (LOS)

• Streamlining steps in the process for BQ

• Increased focus on communication with submitters

• Increased focus on communication with CDER staff

• Surveys to understand where biomarker development is needed

• Front loading Context of Use discussions

• Convening workshops towards development of evidentiary standards

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COMMUNICATION

• Enhanced interaction with submitters

• Enhanced interactions with consortia, NCATS, and NIH

• International interactions (EMA/IMI)

• Presentations

• Publications

• FDA webpage- Information for submitters

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FDA WEBPAGEINFORMATION FOR THE SUBMITTERS

• Contact Information and Submission Procedures

• Submission Information

o Cover letter template

o LOI template

o FDA-EMA Joint LOI template

o Briefing Document template

o Biomarker Qualification Submissions Checklist

o Context of Use explanation

o COU example for a hypothetical biomarker

o FAQs

• Additional Information

o BQ Presentation (recorded)

o Relevant BQ-related Publications

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OPPORTUNITIES FOR COLLABORATION

• Prioritize specific diseases and respective biomarkers whose development

and qualification would advance drug development and satisfy unmet

medical needs

• Develop analytical standards for biomarker measurement

tools…Reproducibility initiatives…

• Coordinate existing partnerships and consortia so that they effectively

direct their efforts toward development and qualification of priority

biomarkers

• Train investigators on regulatory considerations for biomarker

development

• Encourage and fund biomedical research that is necessary as the basis for

development of new biomarkers

• Develop evidentiary standards for context-of-use-specific biomarker

qualification

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Survey to identify biomarkers needed

in drug development

FR NOTICE- SURVEY

• Goal: Identifying Potential Biomarkers for Qualification and Describing Contexts of Use to Address Areas Important to Drug Development

• Logistics: Published on February 13, 2015 with a deadline of April 14, 2015. Extended to May 15, 2015

• Two options given for providing responses

- Docket (35 responses received)

- Survey Monkey (38 responses received)

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Traumatic Brain Injury

Pancreatic

Infectious

Metabolic

Protein Misfolding

Cardiovascular

Renal

Pulmonary

Miscellaneous

Musculoskeletal

Hepatic

Autoimmune

Oncology

Neurology

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2

2

3

3

4

4

4

5

6

6

8

12

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Number of Responses Obtained in Different Disease Areas

Survey Results

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Survey Results