# Presentation: 271266

## FDA Science BoardOffice of Cellular, Tissue, and Gene Therapies (OCTGT)Kathryn C. Zoon, PhDOctober 25,  2002

## Regulation of Biological ProductsBased on Sound Science, Law and Public Health Impact

- <date/time>

**Regulation of Biological Products****Based on Sound Science, Law and Public Health Impact**

**Review**

**Research**

**Surveillance**

**Policy**

**Compliance**

**100 years of Flexible Regulation**

## Why?

**Increase in regulatory activities in the areas of cellular and tissue-based products, gene therapies, and all forms of stem cell transplantation.**
**Consolidation of products into one office**
**Products getting more complex**
**New science advances**
**Need for seamless and transparent coordination and communication**

## Cell and Gene Therapy INDS Reviewed by CBER

**Cell and Gene Therapy INDS Reviewed by CBER**

## Mission

**Regulatory and review responsibilities:**
**Tissues**
**Cellular and Tissue-based products**
**Gene Therapies**
**Xenotransplantation**
**Unique assisted reproduction (ooplasm transfer)**
**Combination Products containing living cells/tissues**
**Assure the safety, identity, purity and potency         of novel products**

## Expertise

**Molecular and cell biology**
**Viral and nonviral gene therapy vectors**
**Nucleic acid chemistry **
**Genomics**
**Proteomics**
**Tissue and Organ Regeneration**
**Developmental and Reproductive Biology**
**Stem Cell Biology and Physiology**
**Medical**
**Pharmacology/Toxicology**

## Office of Cellular, Tissue, and Gene Therapies

- Dr. Phil Noguchi, Director

- Division of Clinical Evaluation &
-  Pharmacology/Toxicology
- (Vacant)

- Dr. Philip Noguchi, Office Director (Acting)
- Dr. Joyce Frey-Vasconcells,  Deputy Office Director(Acting)
- Regulatory Management Staff
- Acting Chief, Ms. Andrea Wright

- Division of Human Tissues
- Dr. Ruth Solomon, Division Director (Acting)

## Division of Cellular and Gene Therapies

- Dr. Eda Bloom, Chief

- Lab of Stem Cell Biology
- Dr. Stephen Bauer, Chief (Acting)

- Dr. Raj Puri, Director (Acting)

- Cell Therapy Branch
- Dr. Darin Weber, Chief (Acting)

- Lab of Molecular Tumor Biology
- Dr. Raj Puri, Chief

- Gene Therapy Branch
- Dr. Stephanie Simek,  Chief (Acting)

- Lab of Immunology and Developmental Biology
- Dr. Suzanne Epstein, Chief

## Human Tissue and Reproduction Branch

- Martha Wells, Branch Chief (Acting)

- Division of Human Tissues
- Dr. Ruth Solomon,  Division Director (Acting)

## Clinical Evaluation Branch

- Dr. Cynthia Rask, Chief (Acting)

- Division of Clinical Evaluation &
-  Pharmacology/Toxicology
- (Vacant)

- Pharmacology/Toxicology Branch
- (Vacant)

## Step-wise Approach to Application of Regulatory Requirements

**Good Manufacturing Practices **

- Full GMP
-  **21 CFR 210, 211**

**Product Characterization**

**Step-wise Approach to Application of Regulatory Requirements**

- Full characterization
-  **21 CFR 610**

**Phase III**

**Pre-clinical**

**Prior to Phase I : need product safety testing and basic characterization info **

**QA &QC, Clinical Monitoring Program**

## Ex Vivo Transduced CD34+ Cells Expressing HSV tk

**Growth factors**

**PBSC**

**CD34+**
**Selection**

**Retroviral Viral ****vector**

**Flt-3,         CSF, Fibronectin**

**CD34+ transduction**

**CD34+**** **
**expressing HSV tk**

**Anti-CD34+ **
**   ****MoAB**

## Biological – Medical Device Combination Products

**Biological **_**Products**__ _

**Combination**_**Products**_

**Medical**_**Devices**_

**+**

**Replace**
**Repair**
**Restore**
**Regenerate**

## General Principles

**Novelty of the drug**
**Extent previously studied**
**Known or suspected risks**
**Developmental phase **
**Building process**

## Risk based Approach to Regulation of Cells and Tissues

**Provide a unified regulatory framework**
**Provide greater flexibility and innovation in this field of medicine**
**Provide a tiered regulatory approach with the level of regulation proportional to the degree of risk**
**Risk determines level of regulation**
**Low Risk – tissues, Section 361, PHS **
**High Risk – Preapproval, Section 351, PHS or ****FD&C**

## The New U.S. FDA “Tissue Rules”

**Establishment Registration & Product Listing Rule****    ****(Final – 1/2001)**
**Notify FDA of location and tissue products prepared**
**Donor Eligibility Rule ****(Proposed)**
**Properly screen and test donors for communicable diseases**
**Good Tissue Practices (GTP) Rule ****(Proposed)**
**Proper handling, processing and storage of tissue **
**Record keeping and facility cleaning**

## Biosafety Testing for Cellular &Tissue-Based Products 

**Raw **
**materials**

- MasterCell Bank

- WorkingCell Bank

- MasterViral Bank

- In-process
- material

- Final
- Product

- Biosafety must be assessed at all stages of manufacturing

- Type and timing of testing depends on stage of    product manufacturing, source of material and    manipulation (e.g., genetic modification).
- Refer to ICH Guidance Documents for   additional information

## Regulatory Concerns Common to ALL Cellular Components

**Product Safety**
**Donor screening and testing**
**Product testing**
**Adventitious agents, tumorigenicity, pyrogenicity**
**Biocompatibility testing with device**
**Product Characterization**
**Identity, purity, potency, viability, stability**

## Regulatory Concerns Common to ALL Cellular Components

**Manufacturing Process – cGMPs**
**Control of product and process**
**Qualification of reagents**
**Segregation and tracking **
**different donors/different lots**
**Reproducibility/Consistency of Product Lots**
**Development of in-process and lot release specifications**
**Ensure efficacy**
**Not dependent on autologous, allogeneic, or cell lines**

## Clinical Efficacy Trial Design

**Size of Trial**
**Expected frequency and size of effect/benefit**
**Disease indication and stage of disease**
**Chronic disease vs. life-threatening**
**Patient Selection**
**Meaningful Endpoints**
**Potential Toxicity**
**Need to balance potential risk vs. potential benefits**
**Existing therapies**
**Safety database**
**Like products vs. novel****	**

## One Size does NOT! Fit ALL

**Flexibility Required**

## What are we doing?

**Continue to take an active role with other organizations – **Must Work Together!!
**FDA/NIH working group on Stem Cells**
**FDA representative on RAC for Gene Transfer Products**
**FDA industry working group to develop the Adenoviral Reference Material – just released**
**Establishing a working group for comparability for cellular products**
**Enhance our regulatory research to improve product safety for “new” product classes**

## What are we doing?Public Discussions

**BRMAC**
**Pancreatic Islets – March 2000**
**Human Stem Cells for Neurological Disorders – July 2000**
**Lentiviral Vectors – October 2001**
** ****Ooplasm Transfer in Assisted Reproduction – May 2002**
**Inadverent Germline Transmission – May 2002**
**Workshops**
**ICH Gene Therapy Workshop – Sept. 2002**
**Stem Cells and Regenerative Medicine:  Shaping the FDA Regulatory Approach, Natcher Aud. NIH, April 7-8, 2003 **

## What are we doing?

**Guidances – updates and new**
**Somatic Cell and Gene Therapy**
**Splitting into two documents – **
**Somatic Cell Therapy – specifics for cell types**
**Gene Therapy – specifics for vector types**
**Guidance for Reviewers – Reviewer Template**
**Cell Therapy Products**
**Gene Therapy Products**
**Post slides on CBER website**
**Try to take CBER booth to many conferences – have relavent guidances available, CD**