1. Chief, Gene Therapy Branch
The FDA Review Process
Dan Takefman, PhD
Chief, Gene Therapy Branch
DCGT/OCTGT/CBER/FDA
IOM Meeting 6/4/13 11

2. Overview IND Review Process Regulatory framework
Discipline review focus
FDA and RAC
Respective roles
How we interact 2 11

3. 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,
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

4. 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Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products, 2012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

5. 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

6. Yearly New GT IND Submissions (~ 370 Active INDs, 840 Total)6

7. Regulatory Timeline Preclinical Marketing Phase 1 Phase 2 Phase 3
File IND
EOP2 Meeting
Pre-BLA Meeting
Pre-IND
Pre-pre-IND
File BLA 7

8. 21 CFR
FDA’s primary objective in reviewing an IND are in all phases of the investigation, to assure the safety and rights of subjects…. 8

9. IND Submission: CMC Content
Safety of source materials, intermediates, and final product
Viral/microbial contaminants
Manufacturing process
Product testing for identity, purity, potency
As related to safety for early phase trials 9

10. 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

11. Pre-Clinical Proof-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

12. 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

13. 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

14. Patient Safety Monitoring
Systematic observations of patients should be performed
Clinical
Radiological
Laboratory
Defined timed intervals for observations 14

15. 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

16. 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

17. Overview IND Review Process Regulatory framework
Discipline review focus
FDA and RAC
Respective roles
How we interact 17 11

18. 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

19. 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

20. 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

21. 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

22. OCTGT Contact Information
Dan Takefman
Regulatory Questions
Contact the Regulatory Management Staff in OCTGT at or
or by calling (301)
References for the Regulatory Process for OCTGT
OCTGT Learn Webinar Series 22

23. Public access to CBER CBER website:
Phone: or
Consumer Affairs Branch (CAB)
Phone:
Manufacturers Assistance and Technical Training Branch (MATTB)
Phone:
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