1. FDA IND Review: Regulations and Challenges
Wilson W. Bryan, M.D.
FDA / CBER / OCTGT
Workshop on Cell and Gene Therapy Clinical Trials in Pediatric Populations
North Bethesda, Maryland
November 2, 2010

2. FDA / CBER / OCTGT Office of Cellular, Tissue and Gene Therapies
Celia M. Witten, Ph.D., M.D., Director
Stephanie Simek, Ph.D., Deputy Director
Richard McFarland, Ph.D., M.D., Associate Director for Policy
Suzanne Epstein, Ph.D., Associate Director for Research
Regulatory Project Management
Patrick Riggins, Ph.D., Director
Division of Cellular and Gene Therapies (DCGT)
Raj Puri, M.D., Ph.D., Director
Kimberly Benton, Ph.D., Deputy Director
Division of Human Tissue Products (DHT)
Ellen Lazarus, M.D., Director
Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT)
Mercedes A. Serabian, M.S., DABT, Pharmacology/Toxicology Branch Chief
Wilson W. Bryan, M.D., Clinical Evaluation Branch Chief

3. Pediatric Protocols in OCTGT
113 active pediatric trial protocols
19 “first-in-man” protocols
Increase in pediatric protocols submitted to OCTGT over the past several years

4. OCTGT Pediatric Trial Therapies and Indications
By Treatment Indication
Oncology – Medicine – 57
By Therapy
Cellular 60%
Gene 27%
Combination 4%
(Engineered Tissues)
Other 9%

5. FDA IND Review: Regulations and Challenges: Outline
Therapeutic Development
Objective
Process
Regulatory Process
IND Review
Clinical Hold
Pediatric Studies
CFR Subpart D
Regulatory Challenges

6. Therapeutic Development
Objective:
Provide evidence that drugs (including biologics, such as cell and gene therapies) are safe and effective for a specific indication.

7. Therapeutic Development
Process
Knowledge of the disease process
Drug discovery
Nonclinical (animal) study objectives:
Toxicity, biodistribution, carcinogenicity, proof-of-principle
Guide design (including dosing, population, and monitoring) of subsequent Phase 1 studies
Phase 1 objectives:
Safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, (and activity / efficacy, if feasible)
Guide dosing and monitoring of subsequent Phase 2 studies
Phase 2 objectives:
Determine dose, route, regimen, population, endpoints, and estimated magnitude of effect
Guide design of subsequent confirmatory (Phase 3) studies
Phase 3 objectives:
Evidence of efficacy and safety to support a marketing application (New Drug Application (NDA) or Biologics Licensing Application (BLA))

8. Regulatory Process Investigational New Drug application (IND)
Review Team
Project Manager
Chemistry, Manufacturing, and Controls (CMC)
Nonclinical Pharmacology / Toxicology
Clinical
Others (e.g., statistics, epidemiology, site inspectors, patient representative)
Objective: FDA’s primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects … (21 CFR (a))

9. Regulatory Process Investigational New Drug application (IND)
Clinical Hold:
A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation (21 CFR (a)).

10. Regulatory Process
Clinical Hold: FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that (21 CFR (b)):
Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;
(ii) The clinical investigators named in the IND are not qualified …;
(iii) The investigator brochure is misleading, erroneous, or materially incomplete;
(iv) The IND does not contain sufficient information … to assess the risks to subjects of the proposed studies.

11. Regulatory Process
Most common hold issues, particularly for Phase 1 (and Phase 2) studies:
Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury.
(iv) The IND does not contain sufficient information … to assess the risks to subjects of the proposed studies.

12. Regulatory Process
Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;
The assessment of whether a risk is reasonable includes consideration of available in vitro, animal, and clinical data, the study objectives, and the population (e.g., disease severity; prognosis; availability of alternative therapies) being studied.
For example, risks that are acceptable in a population with a late-stage malignancy might be unacceptable in a presymptomatic population with a genetic defect.

13. Regulatory Process: Phase 1 – Review Considerations
Study design
Proof-of-concept
Is there sufficient evidence of potential efficacy to justify the risks?
Population:
Do the potential benefits justify the risks for the study subjects in the experimental arm? and in the control arm (if any)?
Would a different study population have lower risk and still achieve the study objectives?
Stopping rules (and / or Data Safety Monitoring Board (DSMB))
Are appropriate controls in place to stop the study if adverse events suggest that there is an unreasonable risk?

14. Regulatory Process: Phase 1 – Review Considerations
Dose
Starting dose
Maximum dose
Are the proposed starting dose and the proposed maximum dose justified by the available nonclinical and/or clinical data?
Rate of dose escalation
Is the rate of dose escalation acceptable, considering the available nonclinical and/or clinical data?
Regimen
Is the regimen appropriate for the stage of drug development?

15. Regulatory Process: Phase 1 – Review Considerations
Monitoring
Intervals (both intra-cohort and inter-cohort)
TGN 1412 experience
Are these intervals justified by the available nonclinical and clinical data?
What are the appropriate intervals when there is concern about long-term toxicity?
Procedures
Are monitoring procedures sufficiently sensitive and frequent?
Do the monitoring procedures have unacceptable risks?
Duration of follow-up
What duration of follow-up is necessary when primary toxicity may be long-term, as in some cell and gene therapy studies?
Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events

16. Pediatric Studies: CFR Subpart D
Subpart D § 50.52: Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.
OCTGT believes that most cell and gene therapy trials have more than a minor increase over minimal risk.
To provide evidence of the prospect of direct benefit, OCTGT often asks IND sponsors to provide proof-of-concept data from nonclinical and / or previous human studies.
If a cell or gene therapy study is not approvable under §50.52, the study might be approvable under § However, OCTGT does not refer the study for consideration under §

17. Pediatric Studies: CFR Subpart D
The agency encourages IRBs considering referring a clinical investigation under § first to discuss with the sponsor whether there are appropriate modifications to the protocol that would allow the clinical investigation to be approved under another provision of Subpart D.
IRBs should send referrals under 21 CFR of clinical investigations regulated by FDA to FDA's Office of Pediatric Therapeutics, which will coordinate the review.
FDA’s guidance on § referrals may be located at

18. Regulatory Challenges in Pediatric Clinical Trials: For the sponsor
Minimize risks while maintaining prospect of direct benefit and acceptable risk-benefit ratio
What constitutes sufficient evidence of a prospect of direct benefit (i.e., proof-of-concept (POC) data)? Should nonclinical POC studies be replicated by independent groups?
What is the appropriate study population? Is there an adult population that would be sufficiently informative, with an acceptable risk-benefit ratio?
What study procedures (e.g., MRI, lumbar puncture) are acceptable?
Consider the risk of the procedure, the benefit (if any) of the procedure to the subject, and the value of the resulting data (benefit of generalizable knowledge).

19. Regulatory Challenges in Pediatric Clinical Trials: For the sponsor
For pediatric studies, OCTGT asks the
sponsor to describe the following:
how the study meets the requirements of Subpart D
why the study of children is scientifically necessary

20. Regulatory Challenges in Pediatric Clinical Trials: For the FDA
Can study risks be sufficiently minimized so that it would be appropriate for a pediatric study to be a first-in-man study for a new experimental cell or gene therapy?
When adults are studied before proceeding with a study in children, review considerations include:
The number of adults
The duration of monitoring of adult subjects before proceeding in children
The data necessary to provide sufficient evidence of safety and/or proof-of-concept in adults before proceeding in children

21. Regulatory Challenges in Pediatric Clinical Trials: For the IRB
Do some IRBs defer assessment of the scientific and/or ethical/human subject protection issues to other entities (e.g., FDA; NIH Recombinant DNA Advisory Committee (RAC))?
How do IRBs determine whether early stage gene or cell transfer studies have a prospect of direct benefit?

22. Contact Information
OCTGT Regulatory Issues
Patrick Riggins, Ph.D.
Regulatory Management Branch Chief

23. FDA / CBER / OCTGT / DCEPT Clinical Review Teams
Oncology
Peter Bross (TL)
Bindu George (TL)
Chaohong Fan
Sadhana Kaul
Robert Quan Le
Lydia Martynec
David Maybee
Olumide Olajide (fellow)
Donna Przepiorka
Kevin Shannon
TL = Team Leader
General Internal Medicine
Changting Haudenschild (TL)
Bruce Schneider (TL)
Mark Borigini
John Hyde
Agnes Lim
Steven Winitsky
Rachel Witten
Lei Xu
Michael Yao
Yao-Yao Zhu

24. FDA IND Review: Regulations and Challenges
Wilson W. Bryan, M.D.
FDA / CBER / OCTGT
Workshop on Cell and Gene Therapy Clinical Trials in Pediatric Populations
North Bethesda, Maryland
November 2, 2010