Acknowledgments

1. C B E R FDA Draft Guidance:Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene TherapiesJohn Hyde, PhD, MDOCTGT / CBERCellular, Tissue and Gene Therapies ACFebruary 26, 2014

2. Rachael Anatol, PhD Kim Benton, PhD Peter Bross, MD Wilson Bryan, MD Kate Cook Bindu George, MD Changting Haudenschild, MD Ying Huang, PhD Ilan Irony, MD Ke Liu, MD, PhD Richard McFarland, MD, PhD Skip Nelson, MD, PhD Melissa Reisman, JD Laura Rich Michelle Roth-Cline, MD, PhD Bruce Schneider, MD Mercedes Serabian, MS Dan Takefman, PhD Celia Witten, PhD, MD Rachel Witten, MD Keith Wonnacott, PhD Lei Xu, MD, PhD Acknowledgments

3. Draft Guidance Comments • The draft guidance document is available through the FDA/CBER website: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM359073.pdf • The draft guidance document includes information on submitting comments to Docket FDA-2013-D-0576

4. Timeline • July 2, 2013: Draft guidance published for public comment • February 26, 2014: Advisory Committee discussion • May 9, 2014: End of comment period • Plan is to finalize guidance as soon as feasible thereafter

5. Motivation for Guidance • Cellular and gene therapy (CGT) products have distinctive features • Design of early-phase trials is often different than for other pharmaceuticals • Make IND sponsors aware of issues to consider in early-phase trials • Recommend ways to address the issues • Does not set forth new requirements

6. Intended Scope • Biological products for which OCTGT has regulatory authority • Not for: • Tissue-based products regulated solely under section 361 • Devices • Biologics regulated by Center for Drug Evaluation and Research (CDER)

7. Intended Scope • Focus in on clinical trial design • Separate OCTGT guidances address • Manufacturing issues • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074131.htm • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm072587.htm • Preclinical development • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm376136.htm

8. Guidance Outline I. Introduction II. Background III. Features of CGT Products IV. Clinical Trial Design V. Meetings with OCTGT VI. Guidance on Submitting an IND VII. References

9. Introduction and Background I. Introduction • Purpose and scope II. Background • Important early experiences with cellular and gene therapy products • Special features of CGT products

10. III. Features of CGT Products A. Product Characteristics • General: relative lack of clinical experience; may need invasive procedures • Cells: donors, differentiation, migration • Genes: expression control, genome alteration, shedding • Gene-modified cells: features of both cells and genes

11. III. Features of CGT Products B. Manufacturing Considerations • Complexity • May be limits on concentrations or doses • Logistics, possibly short “shelf life” • Might be subject-specific • Variability • May be a significant delay between enrollment and treatment

12. III. Features of CGT Products C. Preclinical Considerations • Conventional PK usually not feasible • Preclinical studies may be harder to extrapolate to humans • Species specificity • Immunogenicity

13. IV. Clinical Trial Design A. Objectives B. Choosing a Study Population C. Control Group and Blinding D. Dose Selection E. Treatment Plan F. Monitoring and Follow-up

14. IV. Clinical Trial Design A. Objectives • Safety • Dose exploration • Feasibility, logistics • Initial assessment of bioactivity

15. IV. Clinical Trial Design B. Choosing a Study Population • Will depend on product and disease • Considerations • Potential for product or effect to persist • Often significant uncertainly about risks • May need some potential for benefit in order to make risks acceptable • Healthy volunteers often not a suitable study population

16. IV. Clinical Trial Design B. Choosing a Study Population (cont.) • Disease stage or severity • Severe or advanced disease sometimes proposed as a way to make risk-benefit balance acceptable • But – these subjects might also be more vulnerable, less likely to benefit, or less informative • Such subjects should not be an automatic choice • Pediatric subjects • Specific regulations regarding pediatric research

17. IV. Clinical Trial Design C. Control Group and Blinding • Controls can be of value for safety and preliminary activity assessments • Blinding helpful but less critical in early phase than for late-phase trials • Invasive procedure in the control group might not be appropriate in early-phase trials

18. IV. Clinical Trial Design D. Dose Selection • Role of preclinical data • Allometric scaling for CGT products may be less precise than for small molecules • May be difficult to establish safe starting dose • Previous clinical experience with related products might be useful

19. IV. Clinical Trial Design D. Dose Selection (cont.) • Describing dose • Challenging due to different attributes of product • Cellular product may be a mixture of cell types • Different subtypes may contribute differently • Gene transduction rates can be highly variable • Vector without gene might be relevant to safety

20. IV. Clinical Trial Design E. Treatment Plan • Dosing regimen is often single administration • Staggering administration • Cohort size • Operator training • Recording and evaluating procedures • Subject-specific product issues

21. IV. Clinical Trial Design F. Monitoring and Follow-up • General considerations • Primary objective should be safety • General safety monitoring • Bioactivity • May develop slowly or be delayed

22. IV. Clinical Trial Design F. Monitoring and Follow-up (cont.) • Special considerations for CGT products • Immunogenicity • Persistence of product or activity • Migration of cells • Shedding of microbial gene vector • Growth and development for pediatric subjects

23. IV. Clinical Trial Design F. Monitoring and Follow-up (cont.) • Duration of Follow-up • Should cover time during which product thought to present safety concerns • For most CGT products, >1 year is appropriate • There is a guidance document for certain gene therapy products

24. IV. Clinical Trial Design F. Monitoring and Follow-up (cont.) • Duration of Follow-up (cont.) • For cell harvest using pre-treatment – may need to follow donor after harvest even if product not given • Special considerations for pediatric subjects – effects on growth and development • Long-term follow-up may be less detailed than in main part of a study • Subsequent trials might proceed on interim data

25. IV. Clinical Trial Design F. Monitoring and Follow-up (cont.) • Stopping rules • Stipulate events that will lead to suspending treatment pending review • Uncertainty about nature, frequency, or severity of adverse reactions – rules limit number exposed to an unexpected safety problem • Events may call for change in enrollment, dosing, administration, or monitoring to mitigate risks • “Stopping” rule not a study termination rule

26. V. Meetings with OCTGT • Encourages prospective IND sponsors to meet with FDA staff • Suggests several clinical topics for discussion at a meeting

27. VI. Submitting an IND • Cites regulations and other guidances concerned with the information that should be provided in an IND submission • Brief general advice • Suggests formulating an overall development plan

28. Discussion Topicsfor the Advisory Committee

29. Discussion Topic 1:Choice of subject population Please discuss Sections IV.B.1 through IV.B.3 (pp. 7-9), which address the principles of choosing an appropriate subject population to study in early-phase clinical trials of CGT Products. Please identify any revisions or additions you recommend for this section.

30. Discussion Topic 2:Use of pediatric subjects Please discuss any revisions or additions that you recommend for Section IV.B.4 (pp. 9-10). In the discussion, please consider how data in adults could support the initiation of pediatric studies.

31. Discussion Topic 3:Choice of control group Please discuss section IV.C (pp. 10-11), which addresses choice of control groups. Please identify any revisions or additions you recommend for this section, particularly with regard to the need for and selection of an appropriate control in early-phase clinical trials if the CGT product requires an invasive procedure for administration.

32. Discussion Topic 4:Monitoring and follow-up Please discuss the principles that should be used to decide the duration and nature of safety follow-up for early-phase trials of cellular therapy products (IV.F, pp. 14-18).

33. Discussion Topic 5:Additional comments Please comment if you recommend modification in the draft guidance on any topic, if the draft guidance did not address a topic in sufficient detail, or if there are important topics that the draft guidance omitted. Please identify any revisions or additions you recommend for this draft guidance.

34. Conclusions • OCTGT has published this draft guidance in hopes of facilitating early-phase clinical development of cellular and gene therapy products • OCTGT is looking forward to receiving public comments in the docket and to discussions by this Advisory Committee in order to make the guidance as useful as possible

35. Comments on the GuidanceDocket FDA-2013-D-0576 (open until May 9) • Electronic comments: http://www.regulations.gov • Written comments:Division of Dockets Management (HFA-305)Food and Drug Administration5630 Fishers Lane, Rm. 1061Rockville, MD 20852 • Questions:Office of Communications, Outreach and Development:ocod@fda.hhs.gov, 1-800-835-4709, 301-827-1800, orhttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm