the fda review process dan takefman, phd chief, gene therapy branch dcgt/octgt/cber/fda iom meeting...
TRANSCRIPT
The FDA Review Process
Dan Takefman, PhD
Chief, Gene Therapy Branch
DCGT/OCTGT/CBER/FDA
IOM Meeting 6/4/13
Overview
IND Review Process Regulatory framework Discipline review focus
FDA and RAC Respective roles How we interact
2
Basis for Review Decisions
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
Additional safeguards for children: (Subpart D) Guidance documents Internal and external science RAC recommendations FDA advisory committees 3
Relevant Guidances
Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products, 2012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 4
The IND Review Process
A Team Approach to IND Review: Regulatory Project Manager Chemistry, manufacturing, and controls (CMC)
reviewer Pharmacology/Toxicology reviewer Clinical reviewer Statistical reviewer
Within 30 days (in effect or hold) Outstanding hold and non-hold issues conveyed by
phone and detailed letter is issued. Must satisfactorily address hold issues prior to
beginning clinical trial 5
Yearly New GT IND Submissions(~ 370 Active INDs, 840 Total)
0
10
20
30
40
50
60
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
6
Regulatory Timeline
Phase 1 Phase 2 Phase 3Preclinical Marketing
Phase 4
File IND
File BLA
EOP2 Meeting
Pre-BLA Meeting
Pre-IND
Pre-pre-IND
7
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….
8
IND Submission: CMC Content
Safety of source materials, intermediates, Safety of source materials, intermediates, and final productand final product
Viral/microbial contaminants Manufacturing process Product testing for identity, purity, potency
As related to safety for early phase trials
9
Pre-Clinical Studies
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
10
Pre-ClinicalProof-of-Concept (POC)
POC in relevant animal models – bioactivity endpoints Extent of functional correction
Durability of effect Determine effective dose level range Optimize route of administration/dose
selection/dosing regimen Collect safety data in the animal models
11
Toxicology Studies
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
12
Clinical Studies: Early- Phase Considerations
Optimal dose and administration Starting dose level/dose-escalation
scheme Route of administration Dose schedule
Define appropriate patient population Staggering of dose escalation
13
Patient Safety Monitoring
Systematic observations of patients should be performed Clinical Radiological Laboratory
Defined timed intervals for observations
14
Clinical Trial Safety Monitoring
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
15
Key FDA Questions In An Early-Phase IND Review
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
subjects reasonable? 16
Overview
IND Review Process Regulatory framework Discipline review focus
FDA and RAC Respective roles How we interact
17
FDA and RAC
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.
18
FDA review
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.
19
RAC Review 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
20
FDA Interactions with RAC 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 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
21
OCTGT Contact Information
Dan Takefman [email protected]
Regulatory Questions Contact the Regulatory Management Staff in OCTGT
at [email protected] or [email protected] or by calling (301) 827-6536
References for the Regulatory Process for OCTGT http://www.fda.gov/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/ucm094338.htm
OCTGT Learn Webinar Series http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/
ucm232821.htm
22
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: [email protected] Phone: 301-827-3821
Manufacturers Assistance and Technical Training Branch (MATTB) Email: [email protected] Phone: 301-827-4081
Follow us on Twitter https://www.twitter.com/fdacber
23