Transcript What is the “Critical Path”?

Welcome to Durham!
FDA Critical Path
&
Clinical Trials Transformation Initiative
Dr. Rachel Behrman
Director, Office of Critical Path Programs
U.S. Food & Drug Administration
Dr. Robert Califf
Vice-Chancellor, Clinical Research, Duke University
Moderated by:
Mark Uehling, Editor, ClinPage
CPI Partnerships
Rachel E. Behrman, M.D., M.P.H.
Director, Office of Critical Path Programs
Office of the Commissioner, FDA
March 16, 2008
Topics for Discussion
• Why the Critical Path Initiative?
• Why Partnerships?
• Why Duke?
• Why CTTI?
Why CPI?
• The old system was not working well
– Too many questions crucial to the development
and use of medical products cannot be answered
by a brut force approach grounded in antiquated
science and executed in isolation
– We are perceived as a fragmented industry,
divorced from the reality of these pressing
problems
• No entity can afford not to capitalize on
expertise and resources of others
• FDA was willing, and able, to take a
leadership role in fostering innovation
Precedents for a New Paradigm
• Anti-retroviral drug development
– Prompt response by all stakeholders to public
health emergency facilitated rapid development of
therapies
– Collaboration (including sharing data) among
companies established a database sufficient to
allow FDA to consider plasma viremia and
adequate surrogate for traditional approval
• Anti CMV drug development
– Required one company to continue development
of a life and sight saving product in the face of a
shrinking market
– Required the agency to rethink the evidentiary
basis needed for approval
What is the “Critical Path”?
• There is a “critical path” of medical product
development stretching from candidate identification
to commercial production
• Involves serial evaluation of product performance
through preclinical testing, clinical evaluation, and
manufacturing
• FDA’s Critical Path Initiative focuses on the sciences
used to do these evaluations
– Medical Product Development Tools
– Technical Standards
– Regulatory Policy and Scientific Standards
Guiding Principles of CPI
• Facilitate infrastructure and “toolkit” development
– Not focus on development of specific products
• Encourage collaborative efforts among
government, academia, industry, and patient
groups
• Develop relevant standards (regulatory and data)
• Build support for academic science bases in
relevant disciplines
• Create opportunities to share existing knowledge
and databases
Wide Spectrum of Collaborations
•
International efforts
– Data standards
– Global alliance for TB drug development
– WHO and antimalarial drug development
•
With Fellow Feds
– Developing internet portal for submission of adverse event information
(MedWatchPlus)
– Piloting single repository of investigatory information (Firebird)
– Public repository of all prescription drug labeling (DailyMed)
•
Sentinel
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Public-private consortia
– Data standards (HL-7, CDISC, CDASH)
– CPath Institute
• Predictive safety testing consortia
• Genetic basis of AE
– DCRI
• Cardiac safety (ECG warehouse, DES/DAP study)
• CTTI
Clinical Trials Transformation
Initiative
• Established out of shared vision
– Current problem (clinical trials enterprise is being
strangled and, therefore, cannot answer the pressing
questions facing society)
– Path forward (focus on the enterprise as a quality
system, e.g., ‘product’ must be fit for use)
– Mutual need (no one entity can fix this alone and
certainly not in a timely manner)
• MOU between Duke and FDA announced in FR
11/2007
– Duke and FDA share an interest in HSP and
modernizing the clinical trials enterprise
– Duke to convene a PPP with FDA and Duke as
founding partners that will include a broad coalition of
stakeholders
Numerous and Diverse
Stakeholders
CPI
Centers
CDER
CDRH
CBER
CFSAN
CVM
OC
Partners
Industry
Academics
Non-profits
Professional societies
Sister agencies (NIH CDC, DOD VA)
Forces
Congress
DHHS
Patients
Consumers
Potential Constraints
IT
Legal
Funding
Conflicting priorities
Update on Selected Projects
•
Modernizing bioinformatics
– BIB and BRBs process functioning well
– Developing portal for AE reports (MedWatchplus)
– Heading towards eliminating paper submissions
• Public knowledge that we will develop an omnibus regulation
• Data standards efforts well established
• Increased collaboration with CDISC, CDASH and others
•
BIMO/HSP
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Clarify AE reporting (to IRBs, investigators)
Delineate who is an investigator and what are their responsibilities
Consider guidance on what constitutes appropriate monitoring
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Follow-on biologics
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Biomarkers
–
Qualification
• CDER survey in progress
• Framework document in draft
– Increasing use in risk management (e.g., genomic markers for toxicity)
Current Challenges Include
•
Monitoring
– §312.23(a)(1)(vi) – [The sponsor shall submit…] The name and title of the
person responsible for monitoring the clinical investigation
– §312.50 – Sponsors are responsible for …ensuring proper monitoring of
the investigation(s)…
– §312.56(a) – The sponsor shall monitor the progress of all clinical
investigations being conducted under its IND.
•
Safety Reporting
– §312.32(c)(1)(i)(A) – [The sponsor shall notify FDA and all participating
investigators …of] Any adverse experience associated with [note –
‘reasonable possibility/possible’ standard] the use of the drug that is both
serious and unexpected…
– §312.53(c)(1)(vii) - …the investigator will promptly report to the IRB…all
unanticipated problems involving risk to human subjects…
– §312.64(b) – An investigator shall promptly report to the sponsor any
adverse effect that may reasonably be regarded as caused by, or probably
caused by, the drug. If the adverse effect is alarming, the investigator
shall report the adverse effect immediately
– §312.66 – The investigator shall also assure the he or she will promptly
report to the IRB….all unanticipated problems involving risk to human
subjects…
FDA Perspective on CTTI
• As policy, how would you prioritize resources
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Clinical monitoring
Safety reporting
Expanded access and charging for investigational therapies
Registration and Listing
Labeling
• Examples of what a broad partnership could
contribute
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Expertise
Outside perspectives
Data
Novel approaches
Comprehensive discussion
CPI in Action (2/08)
• What is the appropriate course of action in a patient with a DES
who has tolerated DAP therapy for a year?
• Traditional approach – 5 trials conducted by 5 individual
companies conducted over many years and costing hundreds of
millions of dollars
• CPI approach - collaboration
– Convener: DCRI (under MOU with FDA)
– Facilitator: FDA (OCPP, CDRH, CDER)
– Participants: Academia, industry, professional societies, feds, to
include patient groups
– Outcome:
• Large simple trial involving 5 device manufacturers and 2 drug
manufacturers
• Plan is to enroll first patient by 8/31/08
• Cost: approximately 24M
• Duration: 2-3 years
• Bonus – data warehouse
Looking Forward
• Unique regulatory opportunity
– Title VI of FDAA mandates CPI
• RU must take into consideration CP reports and priorities when
identifying unmet needs related to FDA regulated products
• The Secretary may enter into CP-PPPs to implement the CPI of
the FDA by developing innovative, collaborative projects
– 13M in this year’s budget
• Without a robust clinical trial enterprise, we will not be
able to bring life saving and sustaining therapies to
patients
• CTTI offers us an unparalleled opportunity
– Direct attention
– Focus resources
– Make progress
Office of Critical Path
Programs
Provides central for Agency CP efforts
• Receives and vets external and internal cross-cutting CP proposals
• Coordinates the agency CP steering committee
– Includes all centers
– Established as a venue for information exchange
– Helps to coordinate allocation of resources
• Develops and executes collaborative projects with other public and
private organizations
• Assists Centers, and their CP organizations, with developing and
executing projects
• Conducts continuing outreach and education (internal and external)
• Disseminates CP findings
• Directs and facilitates translation of CP results to FDA regulatory
policy and scientific standards
Critical Path Initiative - History
•
Innovation/Stagnation: Challenge and Opportunity
on the Critical Path to New Medical Products
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Released March 2004
http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf
Evaluated the slowdown, instead of the expected
acceleration, in innovative medical therapies reaching
patients.
Innovation/Stagnation: Critical Path Opportunities
List and Report
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Released March 2006
http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_rep
ort.pdf
http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_list.
pdf
Describes specific areas of opportunity for improvement
Vision for Postmarket
Safety Surveillance (Sentinel)
• We (collectively, collaboratively) must build postmarket
evaluation system; provisions in section 905 of FDA
Amendments Act mandate this activity
• Model likely will be a combination of distributed and
federated date sources, including
• Network will be an amalgamation of national databases
– Need to exploit vast quantities of claims data
– Must learn to capture emerging EHR ‘market’
– Multiple pilots underway or being planned, hosted by PPPs, that will
expedite access to diverse databases and evaluate methods for
adverse event surveillance and signal generation are being explored
Welcome to Durham!
EXTRA SLIDES
March 16-18, 2008
Washington Duke Inn, Durham NC
My organization has made strategic
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