The FDA Review Process
Dan Takefman, PhD
Chief, Gene Therapy Branch
DCGT/OCTGT/CBER/FDA
IOM Meeting 6/4/13
Overview
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IND Review Process
 Regulatory framework
 Discipline review focus
FDA and RAC
 Respective roles
 How we interact
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Basis for Review Decisions
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Regulatory requirements are based on the following:
 Public Health Service Act (PHS Act)
 Food Drug & Cosmetic Act (FDC Act)
 Regulations described in 21 CFR
 IND regulations: 21 CFR 312
 Biological product regulations: 21 CFR 610,
210-211
 Protection of human subjects: 21 CFR 50
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Additional safeguards for children: (Subpart D)
Guidance documents
Internal and external science
RAC recommendations
FDA advisory committees
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Relevant Guidances
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Draft Guidance for Industry: Preclinical Assessment
of Investigational Cellular and Gene Therapy
Products, 2012
Guidance for Industry: Clinical Considerations for
Therapeutic Cancer Vaccines, 2011
Guidance for FDA Review Staff and Sponsors:
Content and Review of Chemistry, Manufacturing,
and Control (CMC) Information for Human Gene
Therapy Investigational New Drug Applications
(INDs), 2008
Guidance for Industry: Gene Therapy Clinical Trials Observing Subjects for Delayed Adverse Events,
2006
ICH Guidances
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The IND Review Process
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A Team Approach to IND Review:
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Regulatory Project Manager
Chemistry, manufacturing, and controls (CMC)
reviewer
Pharmacology/Toxicology reviewer
Clinical reviewer
Statistical reviewer
Within 30 days (in effect or hold)
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Outstanding hold and non-hold issues conveyed by
phone and detailed letter is issued.
Must satisfactorily address hold issues prior to
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beginning clinical trial
Yearly New GT IND Submissions
(~ 370 Active INDs, 840 Total)
60
50
40
30
20
10
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
0
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Regulatory Timeline
Preclinical
Phase 1 Phase 2 Phase 3
Marketing
Phase 4
File IND
Pre-IND
Pre-pre-IND
EOP2 Pre-BLA
Meeting Meeting
File BLA
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21 CFR 312.22
FDA’s primary objective in reviewing
an IND are in all phases of the
investigation, to assure the safety
and rights of subjects….
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IND Submission: CMC Content
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Safety of source materials, intermediates,
and final product
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Viral/microbial contaminants
Manufacturing process
Product testing for identity, purity, potency
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As related to safety for early phase trials
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Pre-Clinical Studies
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Scientific basis for conducting clinical trial
Recommend initial safe dose & dose-escalation
scheme in humans
 Identification of potential target tissue(s) of
toxicity/ activity
 Identification of parameters to monitor clinically
 Identification of patient eligibility criteria
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Pre-Clinical
Proof-of-Concept (POC)
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POC in relevant animal models –
bioactivity endpoints
 Extent of functional correction
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Durability of effect
Determine effective dose level range
 Optimize route of administration/dose
selection/dosing regimen
Collect safety data in the animal models
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Toxicology Studies
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Identify, characterize, quantify the potential
local and systemic toxicities in relevant
animal species
 Identify target organs/sites for toxicity
 Reversibility (acute or chronic toxicities)
 Dose response relationship
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Clinical Studies: EarlyPhase Considerations
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Optimal dose and administration
 Starting dose level/dose-escalation
scheme
 Route of administration
 Dose schedule
Define appropriate patient population
Staggering of dose escalation
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Patient Safety Monitoring
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Systematic observations of patients
should be performed
 Clinical
 Radiological
 Laboratory
Defined timed intervals for observations
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Clinical Trial Safety Monitoring
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Safety monitoring should be guided by:
 Findings from Preclinical studies
 Features of the underlying disease
 Anticipated disease-product interactions
 Long term follow-up for applicable products
Safety reporting requirements described in 21
CFR 312
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Key FDA Questions In An
Early-Phase IND Review
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Does the submission contain sufficient information to
assess risks to the subjects in the proposed trial?
 Are source materials, manufacturing process, and final
product sufficiently characterized to provide adequate
assurance of safety?
 Were adequate preclinical studies performed?
 Were data submitted in sufficient detail to conduct an
independent FDA review?
 Does the design of the clinical trial contain adequate
safeguards for subject safety?
 Is the design of the clinical trial adequate to achieve
stated aim?
If sufficient data are present, are the risks to human
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subjects reasonable?
Overview
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IND Review Process
 Regulatory framework
 Discipline review focus
FDA and RAC
 Respective roles
 How we interact
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FDA and RAC
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Distinct and complementary roles in the
review of clinical trials involving gene transfer.
NIH RAC provides an invaluable service by
allowing open public discussion of
applications to initiate gene therapy trials that
present novel ethical or scientific
considerations.
Only FDA may authorize, at a Federal level,
clinical trials using unapproved products.
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FDA review
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Emphasis in early clinical phases is on review of data
and clinical study design to support safety.
Review is in the context of a regulatory framework.
Reviewer and sponsor interaction occurs throughout
product lifecycle.
 Pre-pre INDs to post marketing
Science based decision making.
Confidentiality restrictions limit what FDA can discuss
in public.
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RAC Review
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Focus on scientific and ethical issues
 Scientific perspectives
 Can include ad hoc experts from around the world
Public forum
Recommendations to improve knowledge gained in
pre-clinical studies and early-phase clinical trials
 Activity endpoints
 Understanding mechanism of action
Less detailed material to review
Minimal role in manufacturing review, but may
provide recommendations to improve product/product
design
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FDA Interactions with RAC
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Non-voting representative
 Other FDA staff typically attend or watch videocast
Participates in Gene Therapy Safety Advisory Board
(GTSAB) discussions
FDA can advise and clarify policies/regulations during
RAC meetings
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FDA does not comment on review decisions at meetings
FDA benefits from:
 Public discussion of potential risks and ethical
considerations
 Scientific review and discussion
FDA use of the GeMCRIS database
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OCTGT Contact Information
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Dan Takefman
 Daniel.Takefman@fda.hhs.gov
Regulatory Questions
 Contact the Regulatory Management Staff in OCTGT
at CBEROCTGTRMS@fda.hhs.gov
 or Lori.Tull@fda.hhs.gov
 or by calling (301) 827-6536
References for the Regulatory Process for OCTGT
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http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianc
eRegulatoryInformation/OtherRecommendationsforManufacturer
s/ucm094338.htm
OCTGT Learn Webinar Series
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http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm23
2821.htm
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Public access to CBER
 CBER website:
 http://www.fda.gov/BiologicsBloodVaccines/default.htm
 Phone: 1-800-835-4709 or 301-827-1800
 Consumer Affairs Branch (CAB)
 Email: ocod@fda.hhs.gov
 Phone: 301-827-3821
 Manufacturers Assistance and Technical Training Branch (MATTB)
 Email: industry.biologics@fda.gov
 Phone: 301-827-4081
 Follow us on Twitter
 https://www.twitter.com/fdacber
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