Pathways from Ideas or Lab to the Market: Regulation of Tissue Engineering and Regenerative Medicine

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Pathways from Ideas or Lab to the Market
Regulation of Tissue Engineering and Regenerative
Medicine Products

• Mark N. Melkerson, M.S.
• Director, Division of General, Restorative, and
  Neurological Devices,
• Office of Device Evaluation
• September 10, 2007

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Outline

• FDAs Role
• Definitions
• Introduction to FDA
• CDRH/Office of Device Evaluation
• Combination Products and Regenerative Medicine
• Internal Collaborative Efforts Review,
  regulations, guidance documents, and voluntary
  standards
• Critical Path Challenges
• Outreach Opportunites

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Total Product Life Cycle Vision
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FDAs role

• protect and promote public health
• apply appropriate level of regulation
• insure safety/effectiveness of medical products
• insure quality and consistency
• insure timely availability of new products
• create regulatory frameworks for new products aid
  manufacturers
• in submission preparation

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FDA regulates the marketingof finished products

• FDA does not regulate
• technologies
• materials
• processing techniques

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Definitions

• 5 product definitions exist
• Drug
• Biologic
• Device
• Banked human tissue
• Combination product

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Drug

• liquid, powder, tablet or other similar
  formulation that achieves its primary intended
  purpose through chemical action within or on the
  body or by being metabolized
• protein, peptide or carbohydrate produced from
  cell culture or in animal fluids be genetic
  alteration

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Biologic

• vaccines
• human blood or blood-derived products
• products containing intact cells, tissues or
  micro-organisms
• gene therapy

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Device

• apparatus, implant, in vitro reagent, including
  component or accessory, intended for diagnosis,
  mitigation, treatment or prevention of disease or
  to affect the structure/function of the body and
  its primary intended purposes are not achieved
  through chemical action within or on the body or
  being metabolized

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Banked human tissue

• intended for transplantation in another human to
  diagnose, cure, mitigate, treat or prevent
  disease
• recovery, processing, storage or distribution
  methods do not alter characteristics/function
• product not currently regulated as drug, biologic
  or device
• excludes vascularized organs, reproductive
  tissues, milk and bone marrow

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Combination product

• Drug biologic
• Drug device
• Device biologic
• Device drug biologic
• Specifically intended to exclude
• most concomitant use
• products containing 2 or more drugs, 2 or more
  biologics or 2 or more devices

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FDA Organization

• Office of the Commissioner
• Office of Combination Products
• CDRH (Center for Devices and Radiological
  Health) therapeutic devices, implants,
  diagnostic devices
• CBER (Center for Biologics Evaluation and
  Research) vaccines, blood and blood products,
  human tissue/tissue products for transplantation,
  cells, gene therapy, screening tests for blood
  safety
• CDER (Center for Drug Evaluation and Research)
  drugs, monoclonal antibodies, therapeutic
  proteins)
• CVM (Center for Veterinary Medicine)
• CFSAN (Center for Food Safety and Applied
  Nutrition)
• NCTR (National Center for Toxicological Research)

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Combination Products

• Premarket Review Lead Center
• Primary Mode of Action (PMOA)
• Final regulation published August 25, 2005 in the
  Federal Register http//www.fda.gov/OHRMS/DOCKETS/
  98fr/05-16527.htm
• Request for Designation
• Sponsor recommendation
• Guidance on how to write a request for
  designation (RFD) available at http//www.fda.gov/
  oc/combination/howtowrite.html

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Combination Products

• Combinations of different types of medical
  products
• Can be
• Physically or chemically combined
• Co-packaged in a kit
• Separate, cross-labeled products
• Early Development Considerations for Innovative
  Combination Products http//www.fda.gov/oc/combina
  tion/innovative.html

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Where is the Product Regulated?

• CDRH therapeutic devices, implants, diagnostic
  devices
• CBER vaccines, blood and blood products, human
  tissue/tissue products for transplantation,
  cells, gene therapy
• CDER drugs, monoclonal antibodies, cytokines

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CDRH/Office of Device Evaluation (ODE) Products

• Combination products
• Bone Void Fillers with growth factors,
  recombinant sequences, etc.
• Wound Dressings with antimicrobials, growth
  factors, and cells
• Drug eluting medical devices
• Tissue and tissue based products
• DBM and additives

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CBER/Office of Cellular, Tissue, and Gene
Therapies (OCTGT) Products

• Cellular therapies
• Tumor vaccines and immunotherapy
• Gene therapies
• Tissue and tissue based products
• Xenotransplantation products
• Combination products
• Devices used for cells/tissues

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Types of submissionsRequest to perform clinical
trial

• IDE investigational device exemptions
• CDRH/CBER
• IND investigational new drug
• CDER/CBER

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Types of submissionsMarketing/licensing
applications

• 510(k) premarket notification
• CDRH/CBER
• PMA premarket approval application
• CDRH/CBER
• BLA biologics licensing application
• CBER
• NDA new drug application
• CDER/CBER

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Types of submissionsOther marketing applications

• PDP product development protocol
• CDRH
• HDE humanitarian device exemptions
• CDRH
• Orphan drug/biologic application
• CDER/CBER

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Examples of Combination Products with CDRH Lead

• Demineralized Human Bone Matrix (DBM) with
  Carrier
• Spinal Fusion Device
• Recombinant Growth Factor (rhBMP-2)
• Human Cultured Skin Products
• Skin cells on collagen, gauze, plastic
• Human Collagen with Lidocaine not tissue per
  CFR 1271.3

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Demineralized Bone Matrix (DBM)

• Is a Human Cellular and Tissue-based Products
  (HCT/P)
• Unless combined with articles (additives not for
  storage, preservation or sterilization) such as
  glycerol, sodium hyaluronate, calcium sulfate,
  gelatin, or collagen

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Demineralized Bone Matrix (DBM)

• Are Devices when DBM products include additives
• Orthopedic Class II
• Periodontal Class II
• Are Combination Products with Device Lead when
  DBM products include growth factors, Class III

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Demineralized Bone Matrix (DBM)

• Gem 21S Dental Bone Graft with Growth Factor
• GEM 21S is a dental bone filling device with a
  biological component that is used to treat
  patients who have bone defects due to periodontal
  disease.
• Regulated as a Device (PMA)

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Spinal Fusion Device

• Infuse Bone Graft
• A genetically-engineered human protein (rhBMP-2)
  and an absorbable collagen sponge made from cow
  (bovine) collagen used along with internal
  stabilization (an IM nail) to help heal a fresh,
  open fracture of the tibia.
• Regulated as a Device (PMA)

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Human Cultured Skin Products

• Dermal (skin) Substitute
• Made from living human cells placed on a
  dissolvable mesh material
• Over time, the cells grow and form a skin
  substitute and the mesh is absorbed
• Scaffold
• Bovine Collagen or Synthetic
• Cells fibroblasts/keratinocytes
• Autologous or Allogeneic (neonatal foreskins)
• Examples
• Apligraf, TransCyte, Dermagraft, OrCel

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Human Cultured Skin Products

• Reviewed under Medical Device
• Authorities
• Class III (PMA or HDE)
• Primary Mode of Action
• Primary mode of action is physical - e.g., wound
  closure by cultured skin
• Secondary Action
• Secondary mode of action to deliver a biologic
  (cells) or drugs (cytokines) to the wound
• Product labeling reflects this mechanism of action

Dermagraft
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Product Development Process

• Inspiration
• Design
• Bench/Toxicology/Animal Testing
• Clinical Testing (Feasibility/Pilot/Pivotal)
• Premarket Revew and Product Approval
• Commercial Use (Post-market studies)
• Refinement (New Indications)
• Obsolescence 

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Starting Clinical Studies

• Identify FDA organizational unit and regulatory
  pathway early
• Early interactions with FDA are critical
• Know your guidance documents
• Consider early in development the questions that
  will be asked at the clinical study phase
• Think about some of the early commercialization
  issues and opportunities

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Example BMP device submission

• descriptions of products/components
• descriptions of manufacturing processes
• Quality Systems Regulations (QSR)
• current Good Manufacturing Processes (cGMP)
• reports of laboratory studies
• reports of animal studies
• reports of prior clinical experience

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Example BMP device submission

• Good Laboratory Practices (GLP)
• Good Tissue Practices (GTP)
• clinical trial design
• investigator selection and institutional review
  boards
• informed consent
• data reporting, maintenance and monitoring
• adverse event reporting

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Example BMP device submission

• recombinant human growth factor
  carrier/scaffold intended for lumbar spinal
  fusion
• RFD determined PMOA to be device function
• ? lead jurisdiction to CDRH with support from CDER

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Example BMP device submission

• multiple components and component combinations
• ? multiple non-clinical characterizations prior
  to clinical exposure
• BMP
• carrier/scaffold
• BMP carrier/scaffold
• other components (excipients)
• complete combination device

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Example BMP device submission

• non-clinical evaluations
• laboratory characterizations
• physical
• chemical
• biological
• mechanical
• animal models
• multiple species, locations and doses
• single species, specific location, doses

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Example BMP device submission

• clinical evaluation
• complete combination device
• multiple phases
• feasibility (I), pilot (II), pivotal (III)
• specific anatomical location
• dosing
• effectiveness
• safety
• immunology
• adverse events

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Example BMP device submission

• inspections
• complete combination device
• mixture of device and drug regs
• QSRs for device components
• cGMPs for drug components
• ability to choose appropriate regs for specific
  components or processes
• clinical data
• Verified by device bioresearch monitoring (BIMO)

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Summary of Example BMP device submission

• identification of appropriate regulations may be
  complex
• correct amount of regulation may not be obvious
• early contact/collaboration recommended to reduce
  development time and expenses

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FDA Collaborative Efforts

• CDRH and CBER -- Draft Guidance for Industry --
  Preparation of IDEs and INDs for Products
  Intended to Repair or Replace Knee Cartilage
  http//www.fda.gov/cber/gdlns/kneecart.htm
• CDRH and CBER -- Participation in ASTM Committee
  F04 - Division IV - Tissue Engineering

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FDA Collaborative Efforts

• Public Workshop -- Processing Methods for
  Orthopedic, Cardiovascular, and Skin Allografts
• October 11 and 12, 2007
• Location Masur Auditorium, National Institutes
  of Health, Bethesda, MD
• Public Workshop -- In Vitro Analyses of
  Cell/Scaffold Products
• December 6 and 7, 2007
• Location National Transportation and Safety
  Board (NTSB) 490 LEnfant Plaza East, SW
  Washington, DC

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FDA Collaborative Efforts

• CDRH, CBER, and CDER are developing and/or
  leveraging existing guidances to support specific
  areas of regenerative medicine products and
  tissue engineered medical products
• CMC guidances for cellular products
• General (CT and GT) preclinical guidances
• Guidances for devices may be applicable to
  scaffolds
• Many clinical guidances cross-cut product areas
  (current efforts underway in bone graft
  substitutes)

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FDA Critical Path Initiative

• Critical Path Opportunities Report
• http//www.fda.gov/oc/initiatives/criticalpath/
• Critical Path Opportunities List
• http//www.fda.gov/oc/initiatives/criticalpath/re
  ports/opp_list.pdf

• Development of biomarkers
• Clinical trial designs
• Bioinformatics
• Manufacturing
• Public health needs
• Pediatrics

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Identifying and Validating Biomarkers and Assays

• Products with biological components that
  polymerize in situ
• Standard biocompatibility assessments (e.g.,
  extracts, animal testing) may not provide the
  most meaningful information
• When should such tests be used and how
• might they be used to provide more
• meaningful insight?

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Identifying and Validating Biomarkers and Assays

• Biomarkers What types of studies are needed to
  learn
• What cell signals accurately predict patients
  that might
• derive the most (or least) benefit?
• Can these biomarkers impact the size of clinical
  studies and permit
• more patient specific therapies?
• What cell signals accurately predict future
  clinical outcomes? Could
• these biomarkers reduce the length of clinical
  studies?

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Assembling and Maintaining Complex Tissue

• Products with a major contributing component that
  changes over time
• E.g., a cell/scaffold heart valve which initially
  functions through a bioresorbable scaffold, but
  later cell growth forms tissue
• (Short term) (Long term)
• (devicelike)
  (biologiclike)
• What are the best approaches for assessing
  Product
• performance during the transition from
  device-driven
• to biologic driven components?

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Assembling and Maintaining Complex Tissue

• Physiological tissues are complex in structure
  and contain multiple interacting cell types  
• Biological components are sensitive to their
  environment
• What composition and scaffold geometries lead to
  the
• optimal clinical result?

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Outreach/ External Collaborations

• Government organizations
• MATES
• NHI
• NCI
• CDC
• NIST
• Liaison meetings
• ISCT
• TERMC
• Standards organizations
• ASTM F04
• AAMI
• ISO TC 150, TC 106, TC 194

• Research collaborations
• NCTR
• NIST
• NIH
• CDC
• Academic Institutions
• Workshops
• International activities
• WHO
• ICH
• GHTF

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Outreach / External Collaborations

• Multi-Agency Tissue Engineering Science (MATES) -
  Interagency Working Group
• GOALS (per current 5-year plan)
• Facilitate communication across
  departments/agencies by regular information
  exchanges and a common web site.
• Enhance cooperation through co-sponsorship of
  scientific meetings and workshops, and
  facilitation of the development of standards.
• Monitor technology by undertaking cooperative
  assessments of the status of the field.
• Provide for support of tissue engineering
  research through interagency funding opportunity
  announcements.

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Strategic Priorities for Federal Agencies

• Understanding the Cellular Machinery
• Identifying and Validating Biomarkers and Assays
• Advancing Imaging Technologies
• Defining Cell/Environment Interactions
• Establishing Computational Modeling Systems
• Assembling and Maintaining Complex Tissue
• Improving Tissue Preservation and Storage
• Facilitating Effective Applications, Development,
  and Commercialization

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Final Comments

• As products become more complex FDA looks towards
  working with academic, industry, and clinical
  experts to understand the composition and
  functioning of this challenging medical therapies
• Working together we can ensure that safe and
  effective innovative technologies reach patients
  in the most rapid manner

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Opportunities

• Public Workshops
• Guidance documents
• http//www.fda.gov/cdrh/guidance.html
• Standards
• http//www.fda.gov/cdrh/stdsprog.html
• Medical Device Fellowship Program
• http//www.fda.gov/cdrh/mdfp/
• FDA Advisory Committees
• http//www.fda.gov/cdrh/panel/

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Contact Information

• Mark N. Melkerson, M.S.
• Division Director, DGRND
• ODE/CDRH/FDA
• 9200 Corporate Boulevard (HFZ-410)
• Rockville, MD 20850
• 240-276-3737
• mark.melkerson_at_fda.hhs.gov