IND

1
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
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
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
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
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/reg
  sopp/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
The Bad IND cont

• Sponsor responds to hold
• Doesnt label submission correctly
• Please identify submission as CLINICAL HOLD
  COMPLETE RESPONSE
• Doesnt 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
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
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 Sponsors official contact is reachable
  and knowledgeable regarding the IND.
• Can have additional contacts.
• Inform Investigators of appropriate
  communications with FDA.

9
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
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
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
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
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
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
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_at_fda.hhs.gov
• Information about OCTGT found at
  http//www.fda.gov/cber/genadmin/octgtprocess.htm