# Presentation: 873979

## 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

## 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.

## 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.

## 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.

## 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.

## 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

## 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.

## 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.

## 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_

## 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.

## 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.

## 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.

## 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?

## 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.

## 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_