Preclinical Evaluation of Cell and Gene Therapy Products

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Preclinical Evaluation of Cell and Gene Therapy
Products

• Mercedes A. Serabian, M.S., DABT
• FDA/CBER/OCTGT
• NIH/SBIR Workshop
• June 24, 2004
• Bethesda, MD
• serabian_at_cber.fda.gov

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Pharmacology/Toxicology Staff in OCTGT/DCEPT
Mercedes Serabian, M.S., DABT
Branch Chief
Cheauyun (Theresa) Chen, Ph.D.
Richard McFarland, Ph.D., M.D.
Chemist
Medical Officer
Ying Huang, Ph.D.
Yongjie Zhou, M.D., Ph.D.
Pharmacologist
Biologist
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OCTGT IND/IDE SubmissionsGene Therapy Somatic
Cellular Therapies

as of 5/04
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Critical Path Development of Biotherapeutic Agents

• FDA Regulatory Scientific Input
• ICH documents
• FDA guidances /PTCs/21 CFR

Clinical Trials

• IND submission

BLA License Application

• Basic Research
• POC studies
• Toxicology studies

Product License Granted

• Pre-PreIND discussions with FDA
• PreIND discussions with FDA

Discovery Phase/Safety Assessment
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The IND Review Process - Team Concept

• Regulatory project manager (RPM)
• Product reviewer (CMC)
• Preclinical reviewer (P/T)
• Clinical reviewer (C)
• Biostatistics reviewer (when applicable)
• Consult Reviewer (when applicable)

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Goals of Preclinical Safety Evaluation

• Preclinical considerations for Phase 1/2 trials
• Recommendation of initial safe dose dose
  escalation scheme in humans
• Identification of potential target organ(s) of
  toxicity/activity
• Identification of parameters to monitor
  clinically
• Identification of patient eligibility criteria
• Terminate potentially unsuccessful development
  programs

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How Are Animal Studies Integrated into the
Proposed Clinical Plan?

• 21 CFR, part 312.23 (a)(8)
• Pharmacologic Toxicologic Studies
• adequate information about the pharmacological
  toxicological studieson the basis of which the
  sponsor has concluded that it is reasonably safe
  to conduct the proposed clinical investigations.
  The kind, duration, scope of animal other
  tests required varies with the duration nature
  of the proposed clinical investigations.

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OCTGT-Regulated ProductsApplication of 21 CFR
312.23

• Somatic cell therapies/xenotransplantation
• Infused
• Surgically implanted
• Solid support (CBER CDRH)
• Encapsulated material (CBER CDRH)
• Aggregated form
• Gene therapies
• Direct administration
• Ex vivo transduced cells
• Hematopoietic stem cells
• Tumor vaccines
• May/may not require the use of an experimental
  device

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Preclinical Evaluation

• Traditional biologics vs. cellular gene
  therapy agents
• Similar general requirements for safety
• Pharmacologic profiles
• Proof-of-concept POC
• Dose-response relationship
• Toxicology profile

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Preclinical Evaluation Cellular Gene Therapy

• BUT the approach by which safety data are
  obtained will differ
• Gene Therapy .... Cell Therapy
• Animal models
• Biodistribution of vector Migratory
  potential
• Kinetics of gene expression Cellular
  differentiation
• Cell phenotype expressed
  Anatomic/functional integration
• into host physiology
• Post-transplant survival
• Long-term toxicity
• Reproductive toxicity
• Carcinogenicity/genotoxicity
  Tumorigenicity (proliferative
• Insertional mutagenesis
  potential)

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Gathering Information for Preclinical

• Animal experience with the intended product
• Previous human experience with the intended
  product
• Previous clinical experience of similar vector
  and/or transgene
• Availability of relevant animal species
• Availability of relevant animal model
• Availability of scientific literature

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Preclinical Data Before Phase 1 Clinical Trials...

• Pharmacology profile
• Feasibility/establishment of rationale
• In vitro bioactivity
• In vivo -Proof-of-concept POC
• Dose-response relationship
• Optimize ROA/dose regimen/species rationale
• Toxicology profile
• Identify, characterize, quantify the potential
  local and systemic toxicities in relevant animal
  species
• Identify target organs/sites for toxicity
• Reversibility (acute or chronic toxicities)
• Dose-response relationship

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Regulatory Expectations for Toxicology Studies

• 21 CFR 312.23 IND Content and Format
• Data should be adequate to support the proposed
  clinical trial
• Range of doses, schedule and/or duration of
  treatment, route of administration should mimic
  those planned for the clinic
• Sufficient safety data should be available to
  determine endpoints for monitoring in the clinic

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Submit Complete Study Reports

• Not just summarized statements
• Detailed description of the study performed
• Test article(s)/dose levels/dose regimen/study
  duration
• Study groups (controls, test article treatment
  groups, group sizes, etc)
• Detailed descriptive methodology
• Results for all parameters evaluated -
• Individual animal data for all parameters
  evaluated
• Summarized and tabulated results
• Textual results and interpretation

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Early Communication with CBER
Sponsors should contact CBER/OCTGT at an early
stage of preclinical development to discuss
proposed study designs
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Pre-pre-IND Process

• Non-binding, informal scientific discussions
  between FDA and sponsor
• Via telecons
• Via scientific meetings/workshops
• Via outreach presentations (i.e., this meeting)
• Often minimal pre-read materials submitted by
  sponsor
• Targeted discussion of specific issue of interest
• Allows for information exchange a two-way
  street

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Pre-IND Process

• Non-binding, but formal meeting between FDA and
  sponsor
• Pre-read materials must be submitted by sponsor
  at least 30 days prior to meeting
• Formal minutes generated by FDA - sent to sponsor
  within 30 days after meeting
• Meeting emphasis - summary data and sound
  scientific principles to support use of a
  specific product in a specific patient population

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For Additional Information..
CBERs Web Page http//www.fda.gov/cber/publicat
ions.htm
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Related Resources

• Guidance for Industry Providing Clinical
  Evidence of Effectiveness for Human Drug and
  Biological Products
• www.fda.gov/cder/guidance/1397fnl.pdf
• Guidance for Industry Guidance for Human Somatic
  Cell Therapy and Gene Therapy
• ICH S6 document Preclinical Safety Evaluation of
  Biotechnology Derived Pharmaceuticals
• ICH M3 document NonClinical Safety Studies for
  the Conduct of Human Clinical Trials for
  Pharmaceuticals
• www.fda.gov/cber/reading.htm

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The CBER Connection...
Pharmacology/Toxicology Branch
Pharm/Tox OCTGT/DCEPT [phone]/6536
phone [phone] fax
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