FDA Regulation of Human Cell and TissueBased Products

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FDA Regulation of Human Cell and Tissue-Based
Products

• Jill B. DealInternational Regulatory Practice

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Proposed Approach to Regulation of Cellular and
Tissue Based Products Reinventing the
Regulation of Human Tissue
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WHY?

• Regulation highly fragmented
• No clearly defined criteria for product
  characterization industry confusion
• Need for unified approach for old and new
  products
• Need to permit flexibility and innovation

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Tiered Risk-Based ApproachGoals

• Prevent unwitting use of contaminated tissues
  with potential for transmitting infectious
  diseases, e.g., AIDS, hepatitis
• Prevent improper handling or processing that
  might contaminate/damage tissues
• Ensure clinical safety and effectiveness is
  demonstrated where highly processed tissues, used
  for other than their normal function, are
  combined with non-tissue components or used for
  metabolic purposes

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Included

• Products containing human cells or tissues or any
  component which is intended to be implanted,
  transplanted, infused or transferred into a human
  recipient
• Musculoskeletal
• Ocular
• Cellular
• hemapoietic stem cells
• reproductive tissue
• heart valves
• dura mater

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Not Included

• Vascularized organs
• Minimally manipulated bone marrow (both regulated
  by HRSA)
• Transfusable blood products (already regulated by
  FDA)
• Ancillary tissue-related products used in
  propogation, storage or processing or secreted
  from cells or tissues e.g., milk, collagen,
  urokinase, cytokines (already regulated by FDA)
• Xenograft transplantation (regulated separately
  by FDA)

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Concerns Direct Transmission of Communicable
Disease

• Autologous v. allogeneic use?
• Banked, shipped or processed in a facility
  handling cells or tissues from multiple donors?
• Viable or non-viable tissue?
• Obtained from a sexually intimate partner?
  (reproductive cells/tissues)

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Concerns Processing

• More than minimally manipulated? (Structural
  processing does not alter original
  characteristics of tissue or relevant biologic
  characteristics of cells or tissues)
• Used for normal (homologous) function?
• Combined with non-cell/non-tissue components?
• Used for metabolic function?

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Concerns Clinical Safety and Effectiveness

• Same factors as processing concerns
• May differ depending whether use is local,
  structural, reproductive or metabolic purpose
• Stem cells subject to product, class specific
  controls and standards to be certified to See 63
  FR 2985 (Jan. 20, 1998)

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Concerns Promotion and Labeling

• cross cut all cells and tissue products

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Proposed Approach Implemented by Tissue Action
Plan (March 1998)

• Proposed Rule Establishment and Listing for
  Manufacturers of Cellular and Tissue-Based
  Products, 63 FR 26744 (May 14, 1998) (finalized
  Jan. 19, 2001)
• Proposed Rule Suitability Determination for
  Donors of Human Cellular and Tissue-Based
  Products, 64 FR 52696 (September 30, 1999)
• Proposed Rule Current Good Tissue Based
  Practices Inspection and Enforcement, 66 FR 1507
  (Jan. 8, 001)

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Establishment Registration

• 361 of PHS Act-prevent communication of
  transmissible disease
• accrue and maintain basic knowledge of industry
• permit communication with industry
• register facilities, list products, keep
  information updated
• all covered establishments

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Included

• Owners and operators of establishments or persons
  engaged in the recovery, screening, testing,
  processing or storage or distribution of human
  cellular or tissue based products

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Exempted

• scientific and educational purposes (solely)
• autologous transferors
• Carriers
• facilities which receive or store solely for
  pending scheduled implantation, infusion or
  transfer within the same facility

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Suitability Determination

• 361 of PHS Act
• all establishments covered by registration rule
• 361 productsminimally manipulated means not
  promoted for any use other than homologous, not
  combined/modified with drug or device, no
  systemic effect and is for autologous use,
  family-related allogeneic use or reproductive use
• 351 products-biologics, medical devices

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Exempted from Testing Requirements

• banked cells and tissue for autologous use
• reproductive cells donated by a sexually intimate
  partner for reproductive use

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GTP Rule

• 361 of PHS
• 361 products
• 351 products (GTP requirements plus GMP and QS
  requirements)
• proper handling, processing, storage, labeling,
  recordkeeping and establishment of a quality
  program

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Goal of GTP Rule

• No communicable disease agents
• Not contaminated during manufacturing
• Function and integrity of cells or tissues not
  compromised

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Manufacture

• Any or all steps in the recovery, processing,
  storage, labeling, packaging or distribution of
  any human cell or tissue product and the
  screening and testing of a cell or tissue donor

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Responsibility under GTP Rule

• Establishment responsible for making the product
  available for distribution
• Considered and rejected assigning responsibility
  to each entity providing services

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Range of Risks Establishes Degree of Regulation

• No Regulation 361 Products
• Autologous Transfer
• Minimally manipulated products

• 351 Products
• BLA/PMA
• More than minimally manipulated, non-homologous
  combination, metabolic

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Other Activities To Implement TAP

• Formation of Tissue Reference Group (TRG)
• Purpose
• Consider questions and make recommendations
  regarding jurisdiction, policy and regulations
• Promote consistency in implementation of TAP
• Request for Designation can be made to TRG or to
  FDA Ombudsman

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Other Activities to Implement TAP

• Workshops, FDA and FDA/NIH
• Gene therapy letter (July 6, 2001), Cell Therapy
  Letter (coming soon)
• Approval of FDA Form 3356 for registration/listing
  
• TAP and web pages
• Compliance Program on Inspection of Tissue
  Establishments
• Guidance Program on Inspection of Tissue
• Guidance for Industry on Availability of Licensed
  Donor Screening Tests Labeled for Use with
  Cadaveric Blood Specimens

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Where are we now?

• Suitability and GTP rules finalized by end of
  2002
• Most gene therapy trials restarted
• Development of a standard for adenoviruses
  (Williamsburg Bioprocessing Foundation)
• Special office within CBER for human cell,
  tissue, gene therapy (October 2002)
• FDA to issue guidance or regulations for stem
  cell products

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Importance to Clients Developing Human
Cell/Tissue Products

• Use of TRG to draft a meaningful regulatory
  strategy and, therefore, a meaningful business
  plan
• Use flexibility of New Approach to obtain a lower
  degree of regulation by FDA (costs/time to
  market)

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