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FDA Perspective on the Development of Cellular Therapies for Repair and Regeneration of Joint Surfaces - Preclinical Perspective. Richard D. McFarland Ph.D., M.D. Medical Officer CBER/OCTGT/DCEPT/PTB mcfarlandr@cber.fda.gov CTGTAC # 38 March 3, 2005. Scope of Talk.

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FDA Perspective on the Development of Cellular Therapies for Repair and Regeneration of Joint Surfaces - Preclinical Perspective

Richard D. McFarland Ph.D., M.D.

Medical Officer

CBER/OCTGT/DCEPT/PTB

mcfarlandr@cber.fda.gov

CTGTAC # 38

March 3, 2005

scope of talk
Scope of Talk
  • CBER-CDRH Collaboration on Joint Surface Repair Products
  • Framework for FDA Preclinical Review Of Cellular Products for Joint Surface Repair
    • General- Preclinical Study Design and Review
    • Specifics- Cellular Products for Joint Surface Repair
  • Introduction to Preclinical Discussion Questions
cber cdrh collaboration on cartilage repair products
CBER-CDRH Collaboration on Cartilage Repair Products
  • FDA Critical Path Initiative
    • http://www.fda.gov/oc/initiatives/criticalpath/
    • CBER Stakeholder meeting, Fall 2004
  • CBER-CDRH Joint Team- Fall 2004
  • CTGTAC Meeting #38- March 2005
cber cdrh joint team
CBER-CDRH Joint Team
  • Monthly Collaborative Meetings
  • Shared Educational Activities
    • Internal
    • Outreach
  • Composite Review Teams
    • Pre-IND, pre-IDE meetings
    • IND, IDE
    • BLA, PMA, 510K
fda review framework for joint repair products
FDA Review Framework for Joint Repair Products
  • Parallels prudent product development
  • Dependent on characteristics of specific product
    • Cellular
    • Device
    • Combination
  • Preclinical studies designed to support use of specific products
  • Framed by regulations
    • IND (21CFR 312), BLA (21 CFR 601)
    • IDE (21CFR 812), PMA (21 CFR 814)
goals of preclinical evaluation
Goals of Preclinical Evaluation
  • Provide rationale for proposed therapy
  • Preliminary risk/benefit assessment
  • Recommend safe starting doses and escalation schemes for humans
  • Identify “at risk” patient populations
  • Identify parameters for clinical monitoring
  • Discern mechanism of action
  • Characterize product and compare to normal tissues
  • Qualification of analytical tests used during manufacturing and lot release
routine preclinical questions
Routine Preclinical Questions
  • Does the submission contain sufficient information to assess risks to the subjects in the proposed trial?
    • Were adequate preclinical studies performed?
    • Were data submitted in sufficient detail to conduct an independent review?
  • If sufficient data are present, are the risks to human subjects from product administration reasonable?
potential sources of data to support initiation of clinical trials
Potential Sources of Data to Support Initiation of Clinical Trials
  • Safety Assessment in Animal Model
    • GLP-compliant toxicology studies
    • Well-controlled studies conducted “in house”
  • Cross reference to data on identical/similar product previously submitted to FDA
  • In vitro studies
  • Previous human experience
  • Published data in peer-reviewed journals
perils of using published animal or human studies as sole support for initiation of clinical trials
Perils of Using Published Animal or Human Studies as Sole Support for Initiation of Clinical Trials
  • Often they were not designed to answer a toxicologic question, and therefore, adequate toxicology endpoints may not have been incorporated into the design
  • Often do not contain sufficient detail of study design, toxicities, study dropouts, etc., to allow for independent review
potential animal study designs
Potential Animal Study Designs
  • Pharmacology or “proof of concept” studies in animal model of disease
  • Toxicology studies in healthy animals
  • Hybrid pharmacology-toxicology study design
    • Animal model of disease
    • Toxicology endpoints
toxicology study design
Toxicology Study Design
  • Appropriate controls
  • Mimicking clinical treatment as closely as possible
    • Product, ROA, formulation, device, dose regimen, etc…
  • Reasonable group size
  • Endpoints
    • Mortality, clinical observation, hematology, serum chemistry, gross pathology, histopathology, body weights, food consumption etc…
potential characteristics of ideal animal model for cellular therapies for joint surface repair
Potential Characteristics of “Ideal” Animal Model for Cellular Therapies for Joint Surface Repair
  • Similar characteristics to humans
    • Anatomy
    • Biomechanics
    • Pathophysiology
    • Cell biology
  • Immune tolerance to human cells
    • Allows use of clinical cellular product
ideal animal model for cellular therapies for joint surface repair
“Ideal” Animal Model for Cellular Therapies for Joint Surface Repair
  • Unfortunately an “ideal” model does not exist.
  • Therefore, we (FDA and sponsors) must understand the capabilities and limitations of the available models
established animal models for joint surface repair products
Established Animal Models for Joint Surface Repair Products
  • Numerous species have been reported in scientific literature introducing inherent interspecies variation including:
    • Body and Joint Size
    • Anatomic Features
      • Gross
      • Microscopic
    • Cell Biologic Features
    • Physiologic Features
  • Applicability for regulatory use therefore also varies
established animal models for joint surface repair products1
Established Animal Models for Joint Surface Repair Products
  • Analogous cellular products from animal source can provide data for assessment of safety
    • Potential processing, formulation, and storage differences between animal and human products
    • Limited characterization of the animal cellular product introduces uncertaintyin the extrapolation to human studies
preclinical issues for committee discussion
Preclinical Issues for Committee Discussion
  • Committee is asked to provide FDA insights with respect to the following specific issues through their discussion this afternoon
  • Discussion will help guide FDA in future decisions in this product area
animal models for prediction of safety and clinical activity
Animal Models for Prediction of Safety and Clinical Activity
  • Exploration of dose and allometric scaling
  • Significance of interspecies differences for use analogous animal cells to model human chondrocytes
    • Anatomy
    • Cell physiology
  • Methods for evaluation of intraarticular toxicity and /or cartilage formation
    • Non-invasive imaging modalities
    • Biomechanical tests
    • Arthroscopic biopsy
  • Need for tumorigenicity studies of cultured chondrocyte cellular products
pivotal toxicology study design
Pivotal Toxicology Study Design
  • Support for exploratory clinical trials
    • Animal model(s)
    • Study duration
  • Support for licensing application
    • Animal model(s)
    • Study duration
  • Appropriateness of measures of systemic toxicity such as clinical pathology tests and histopathology
    • Cellular products
    • Modified cellular products that may secrete molecules capable of producing systemic toxicities
allogeneic cellular products
Allogeneic Cellular Products
  • Potential additional safety concerns beyond those posed by an autologous product should be addressed