# Presentation: 282241

## 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@cber.fda.gov

## Pharmacology/Toxicology Staff in OCTGT/DCEPT

- Mercedes Serabian, M.S., DABT

- Branch Chief

- Cheauyun (Theresa) Chen, Ph.D.

- Chemist

- Ying Huang, Ph.D.

- Pharmacologist

- Richard McFarland, Ph.D., M.D.

- Medical Officer

- Yongjie Zhou, M.D., Ph.D.

- Biologist

## OCTGT IND/IDE Submissions:Gene Therapy & Somatic Cellular Therapies

*** as of 5/04**

*****

## Critical Path Development of Biotherapeutic Agents

**FDA Regulatory & Scientific Input**
**ICH documents**
**FDA guidances /PTCs/21 CFR **

**Basic Research**
**POC studies**
**Toxicology studies**

**Pre-PreIND discussions with FDA**
**PreIND discussions with FDA**

**Clinical Trials**

**Discovery Phase/Safety Assessment**

**IND submission**

**BLA License Application**

**Product License **
**Granted**

## 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)

## 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

## 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 studies...on 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.”

## OCTGT-Regulated Products:Application 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**** **

## 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

## 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)

## 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

## 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

## 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

## 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

## Early Communication with CBER...

- Sponsors should contact CBER/OCTGT at an early stage of preclinical development to discuss proposed study designs

## 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”

## 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

## CBER’s Web Page

- http://www.fda.gov/cber/publications.htm

## 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

## The CBER Connection...

- Pharmacology/Toxicology Branch
-                 [“Pharm/Tox”]
**OCTGT/DCEPT**
-  (301) 827-5102/6536 [phone]
-  (301) 827-9796 [fax]

## Slide 21