# Presentation: 372842

##  Overview of FDA Regulatory Issues 

- Darin J. Weber, Ph.D.
- Office of Cellular, Tissue and Gene Therapies

## Topics

- How We Got Here – A Timeline
- Goals of This Meeting
- Roles of Federal Agencies
- Introduction to FDA Questions for Discussion
- Speakers to Set the Stage for Discussion of FDA Questions

## How We Got Here – Timeline

## Goals of This Meeting 

- To discuss FDA expectations for manufacturing data and clinical evidence to be provided in a BLA for approval of allogeneic islets as a treatment for Type 1 Diabetes Mellitus.
- To obtain advice and perspectives from members of the BRMAC about data to be provided in a BLA for allogeneic pancreatic islets
- To provide a public forum to obtain input from stakeholders interested in this therapy.

## Roles of Federal Agencies

- _Health Resource Services Agency_ (HRSA)
- Organ procurement & allocation

- _National Institutes of Health_ (NIH)
- Funding of basic research and clinical research uses of pancreatic islets

- _Food and Drug Administration_ (FDA)
- Regulatory oversight of clinical uses of pancreatic islets

- _Centers for Medicare and Medicaid_ (CMS)
- Reimbursement issues

## Islets as a Licensed Product Intro. to Manufacturing Considerations

- Must have a well established islet preparation process & documented record of product manufacturing consistency
- Islets prepared in manufacturing facility meeting cGMP requirements
- Comply with lot release testing requirements under 21 CFR 610 “General Biological Products Standards”

## FDA CMC Question #1

- Please discuss the use of  manufacturing experience data as a basis for developing pre-defined acceptance criteria for source organs used to prepare islets.

## FDA CMC Question #2

- Balancing the need for well controlled manufacturing process with need for manufacturing flexibility:
- Is it reasonable to expect that criteria or algorithms can be developed, based on data collected during IND studies, to predetermine under what conditions the use of a specific reagent, reagent concentration, or processing method is appropriate?

- Dissociate

- Lot Release Testing

## FDA CMC Question #3

- Assessment of islet potency:
- Please discuss any assay or assays that are currently, or could be, performed on the final islet product before patient administration, which may be predictive of the ability of the islets to perform as expected after patient administration.

- Dissociate

- Lot Release Testing

## FDA CMC Question #4

- Comparability of islets prepared with different manufacturing processes:
- What should be key measures for demonstrating allogeneic islet product comparability?
- Please discuss appropriate analytical assays, bioassays, preclinical studies, and clinical studies that may be required.

- Dissociate

- Lot Release Testing

## Islets as a Licensed Product Introduction to Clinical Considerations

- Approval will be based upon data from domestic (IND) or foreign studies that are:
- Well designed, well conducted
- Performed by qualified investigators
- Conducted in accordance with ethical principles
- Data must demonstrate safety & efficacy

## FDA Clinical Question #1

- Clinical outcome measures
- Importance & limitations of:
- Insulin Independence
- Hemoglobin A1c, serum c-peptide, mean amplitude of glycemic excursions
- Acute diabetic complications (hypoglycemic unawareness, hospitalizations, death)
- Long term diabetic sequelae (nephropathy, neuropathy, etc.)
- Others

## FDA Clinical Question #2

- Clinical development and risk-benefit assessment
- Safety data
- Nature and extent of “long-term” clinical data.
- Use of historical control data
- Use of clinical data from small subsets of subjects with type 1 DM
- Baseline criteria to consider
- Age, extent and nature of diabetic complications, etc

## Format for this Meeting

| Day 1: Thursday October 9th
CMC Issues |
| --- |
| HRSA and FDA Presentations |
| Guest Presentations |
| Open Public Hearing |
| Discussion of CMC Questions |

| Day 2: Friday October 10th
Clinical Issues |
| --- |
| HRSA and FDA Presentations |
| Guest Presentations |
| Open Public Hearing |
| Discussion of Clinical Questions |

| Thursday October 9th
Update on Research Programs |
| --- |
| FDA Presentations |
| Closed Session |

## Day 1: Speakers (CMC)

- Overview of Organ Procurement in the U.S. - Dr. James Burdick, HRSA
- _Moving from Investigational to Licensed Islet Products_
- Expectations for Facilities & cGMPs
- Dr. Nicholas Obiri, FDA
- Islet Processing and Product Quality Issues  - Dr. Keith Wonnacott, FDA

## Day 1: Speakers (CMC)

- Islet Processing: Evolution and Current Standards
- Dr. Camillo Ricordi, University of Miami
- Current Status of Islet Characterization and Quality
- Dr. Bernhard Hering, University of Minnesota

## Day 2: Speakers (Clinical)

- Update on Clinical Islet Transplantation
- Dr. James Shapiro, University of Alberta
- Pancreas Allocation Issues
- Dr. Jim Burdick, HRSA

## Day 2: Speakers (Clinical)

- Ethical Considerations in Allogeneic Islet Transplantation
- Dr. James Childress, University of Virginia
- Clinical Development of Islet Products
- Dr. Dwaine Rieves, FDA