FDA IND Review: Regulations and Challenges

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

2. FDA / CBER / OCTGTOffice 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 – 56 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 312.22(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 312.42 (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 312.42(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 § 50.54. However, OCTGT does not refer the study for consideration under § 50.54.

17. Pediatric Studies: CFR Subpart D • The agency encourages IRBs considering referring a clinical investigation under § 50.54 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 50.54 of clinical investigations regulated by FDA to FDA's Office of Pediatric Therapeutics, which will coordinate the review. • FDA’s guidance on § 50.54 referrals may be located at http://www.fda.gov/RegulatoryInformation/Guidances/ucm127541.htm

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 Informationwilson.bryan@fda.hhs.gov OCTGT Regulatory Issues Patrick Riggins, Ph.D. Regulatory Management Branch Chief Patrick.riggins@fda.hhs.gov 301-827-5366

23. 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 FDA / CBER / OCTGT / DCEPT Clinical Review Teams

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