1. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development IND Case Studies Deborah Lavoie, J.D., RAC Branch Chief, Regulatory Management Staff Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research FDA

2. Working with FDA: Biological Products and Clinical Development Deborah Lavoie The Good IND  Sponsor had a pre-IND telecon prior to submitting IND. Sponsor asked specific questions. Information package contained detailed CMC, preclinical, and clinical information/proposals. Sponsor included information about drugs/device used with biological product. Sponsor obtained valid cross-references as needed.

3. Working with FDA: Biological Products and Clinical Development Deborah Lavoie The Good IND cont…  Because of Pre-IND meeting, potential hold issues were such that the review team could contact the Sponsor to resolve before the 30 day date.  Sponsor responds promptly to potential hold concerns allowing FDA enough time to review the new information.  Result: IND allowed to proceed.

4. Working with FDA: Biological Products and Clinical Development Deborah Lavoie The Good IND Grows Up  Sponsor submits annual reports within 60 days of anniversary date that IND went into effect.  Sponsor correctly submits adverse event reports, in triplicate, to IND. 21 CFR Subpart D – Responsibilities of Sponsors and Investigators  Sponsor contacts FDA before making a significant change.

5. Working with FDA: Biological Products and Clinical Development Deborah Lavoie The Bad IND  No Pre-IND meeting.  Sponsor submitted 1 copy of IND, to the wrong address.  IND submission bound incorrectly, pages not numbered, no table of contents, submission not tabbed, information is scattered. SOPP 8007 – DCC Binding Procedures for Regulatory Documents available at http://www.fda.gov/cber/regsopp/8007.htm  IND missing a CMC section.  Sponsor submitted IND, then went on 2 week vacation, with no additional contact person provided.  Result: Initial processing of IND delayed. FDA unable to communicate potential hold concerns. IND placed on Hold.

6. Working with FDA: Biological Products and Clinical Development Deborah Lavoie The Bad IND cont…  Sponsor responds to hold Doesn’t label submission correctly –Please identify submission as “CLINICAL HOLD COMPLETE RESPONSE” Doesn’t respond to all hold issues detailed in hold letter  Result: response is incomplete.  Sponsor resubmits response Response is complete, but inadequate Result: Sponsor is issued a continued hold letter

7. Working with FDA: Biological Products and Clinical Development Deborah Lavoie The Bad IND Turns Good  Sponsor discusses unresolved issues with reviewers.  Submits a correctly labeled and bound response to hold, in triplicate, to IND.  Result: hold is removed.

8. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: Communication  Request and schedule a Pre-IND mtg. prior to submitting an IND. Pre-IND meetings usually take place ~60 days after receipt of your meeting request.  Know who your main FDA contact is for specific products/indications.  Before requesting informal feedback, find out reviewer preferences (i.e., phone discussion, fax, email, what information you should provide)  Ensure Sponsor’s official contact is reachable and knowledgeable regarding the IND. Can have additional contacts. Inform Investigators of appropriate communications with FDA.

9. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: Submissions  All IND original submissions and amendments, must be submitted in triplicate and should include a Form FDA 1571. Be sure to reference your IND/IDE number.  Make sure your submission is bound correctly and you have the correct address. For CBER see: “SOPP 8007-DCC Binding Procedures for Regulatory Documents” found at http://www.fda.gov/cber/regsopp/8007.htm If done improperly, review of submission will be delayed.  We encourage electronic submissions, for more information see http://www.fda.gov/cber/esub/esub.htm

10. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: During IND Review  Reviewers may attempt to resolve potential hold issues with the Sponsor that can be addressed during the 30 day initial review clock. This may not happen if: –Issues are such that could not be adequately responded to & reviewed in less than 30 days. For example: additional preclinical studies needed. –Large number of cross-disciplinary issues, such that resolving and reviewing all issues by deadline will be difficult. –Sponsor unreachable.

11. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: Product Highlights to Address at Pre-IND Stage  Describe the product. If the product is a gene therapy, a description of the vector and vector derivation. If the product is a cellular therapy, a description of the cell source, donor testing, and whether source is autologous or allogeneic.  Describe manufacturing and processing steps, including any in-process testing and critical reagents (source & grade).  Describe product storage, release testing (safety and characterization), and how administered.

12. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: Preclinical Highlights to Address at Pre-IND Stage  Provide a comprehensive summary of all preclinical (in vitro and in vivo) studies and results obtained.  Provide a discussion based on preclinical studies addressing rationale for proposed therapy, dosing, toxicity, monitoring, eligibility criteria.  Provide a detailed outline of all proposed preclinical study designs with the intent of submitting resultant data in the IND submission.

13. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: Preclinical Highlights to Address at Pre-IND Stage, Cont.  Can you provide the following: What is the ability of your product to induce the desired pharmacologic/biologic effect. The dose/activity and the dose/toxicity relationship? The relationship of route of administration and the dosing regimen to activity and toxicity of your product? The risks for toxicity? How do the adverse findings observed compare to other disease-induced findings? What is the incidence of the toxicity findings in normal animals?

14. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Lessons Learned: Clinical Highlights to Address at Pre-IND Stage  Name and CV of investigator(s), and name and address of institutional review board. Investigator information should be provided, by each investigator, using a Form FDA 1572 “Statement of Investigator”  Title & objective (purpose of the study, can be primary and secondary)  Background: general investigational plan, rationale, previous clinical & preclinical experience, choice of dose and route of administration including rationale.  Protocol should address sample size, key inclusion and exclusion criteria, concomitant medications, dosage & administration, study schedule, safety monitoring, termination criteria.  Any outcome measures or analysis plan.

15. Working with FDA: Biological Products and Clinical Development Deborah Lavoie Thank You  Questions? Contact me: Deborah Lavoie, J.D., RAC Branch Chief, Regulatory Management Staff Office of Cellular, Tissue, and Gene Therapies Center for Biologics Research and Review/CBER EMAIL: deborah.lavoie@fda.hhs.gov Information about OCTGT found at http://www.fda.gov/cber/genadmin/octgtprocess.htm