2016 aaps nbc conference may 17, 2016...2016 aaps nbc conference may 17, 2016 shashi amur, ph.d....
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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 [email protected].
“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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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
2
2
2
3
3
4
4
4
5
6
6
8
12
22
Number of Responses Obtained in Different Disease Areas
Survey Results
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Survey Results