Overview of FDA Regulatory Issues

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Overview of FDA Regulatory Issues

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

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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

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How We Got Here Timeline
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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.

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Roles of Federal Agencies

• Health Resource Services Agency (HRSA)
• Organ procurement allocation

• Food and Drug Administration (FDA)
• Regulatory oversight of clinical uses of
  pancreatic islets

• National Institutes of Health (NIH)
• Funding of basic research and clinical research
  uses of pancreatic islets

• Centers for Medicare and Medicaid (CMS)
• Reimbursement issues

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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

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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.

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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?

Pancreas
Dissociate
Lot Release Testing
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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.

Pancreas
Dissociate
Lot Release Testing
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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.

Pancreas
Dissociate
Lot Release Testing
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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

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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

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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

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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
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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

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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

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Day 2 Speakers (Clinical)

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

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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