Cellular Therapies for Cardiac Diseases

1
Cellular Therapies for Cardiac Diseases FDA
Preclinical Perspective

• Richard D. McFarland Ph.D., M.D.
• CBER/OCTGT/DCEPT
• BRMAC 37
• March 18-19, 2004

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Scope of Talk

• Framework for FDA Reviews
• Preclinical Models for Cardiac Diseases
• Introduction of Scientific Speakers

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FDA Review isProduct-based

• Parallels prudent product development
• Dependent on characteristics of specific product
• Preclinical studies designed to support use of
  specific products
• Clinical trial design supported by manufacturing,
  preclinical data
• Framed by regulations

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Investigational New Drug (IND)Regulations 21
CFR312.23 (8)

• Adequate information about pharmacological and
  toxicological studies of the drug involving
  laboratory animals or in vitro, on the basis of
  which the sponsor has concluded that it is
  reasonably safe to conduct the proposed clinical
  investigations. The kind, duration, and scope of
  animal and other tests required varies with the
  duration and nature of the proposed clinical
  investigations..

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IND Regulations 21CFR312.23 (8)(ii)(b)

• For each toxicology study that is intended
  primarily to support the safety of the proposed
  clinical investigation, a full tabulation of data
  suitable for detailed review..

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Goals of Preclinical Evaluation

• Provide rationale for proposed therapy
• Discern mechanism of action
• Identify at risk patient populations
• Recommend safe starting doses and escalation
  schemes for humans
• Preliminary risk/benefit assessment
• Identify parameters for clinical monitoring

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Use of Preclinical Models of Cellular Therapies

• Scientific rationale with the cellular product
  intended for clinical use
• Understanding of cell function, trafficking and
  differentiation
• Modelling of routes of administration

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Characteristics of Ideal Animal Model for Cardiac
Cell Therapies

• Similar pathophysiology to humans
• Improves predictability of human risks
• Similar anatomy to humans
• Allows modeling of catheter use with clinical
  catheter
• Allows for dose exploration
• Immune tolerance to human cells
• Allows use of clinical cellular product

9
Syngeneic Animal Models of Cardiac Diseases

• Can provide useful data for assessment of safety
• Analogous cell source from animals
• Potential processing, formulation, and storage
  differences
• Limited product characterization introduces
  uncertainty

10
Complexity due to Innovative Delivery Systems

• Intraoperative transepicardial injection (usually
  CABG)
• Catheter-mediated transendocardial injection
• Catheter-mediated via cardiac vein

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Small Animal Models in Published Literature

• Cryoinjury or coronary artery ligation primarily
  used to generate damaged myocardium
• Immunocompromised animals available (mouse and
  rat)
• Species used
• Mouse
• Rat
• Rabbit

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Large Animal Models in Published Literature

• Ameroid constrictor primarily used to generate
  ischemic area
• Amenable to catheter administration
• Amenable to clinical monitoring modalities
• Species used
• Dog
• Sheep
• Pig

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Potential Sources of Data to Support Initiation
of Clinical Trials

• Preclinical studies specifically designed to
  support a clinical trial
• Other potential sources
• Existing animal studies designed to answer other
  questions
• In vitro studies
• Clinical trials using the same product

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Using Published Animal or Human Studies as Sole
Support for Intiation 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
• Published reports must provide sufficient
  information for independent review

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Use of Published Studies (contd)

• Protocols must be sufficiently detailed
• Specifics of the route of administration
• Catheter specifics such as identity, flow rates
  and pressures
• Location of injection in relation to ischemic
  region
• Must contain details of routine monitoring and
  analytical plans

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Use of Published Studies (contd)

• Data must be presented in sufficient detail
• In-process and lot-release data (manufacturing)
• Complete study reports for animal and clinical
  studies

17
Use of Published Studies (contd)

• Cellular products used in published reports may
  not be comparable to the intended clinical
  product
• Insufficient data to allow comparability
  assessment
• Editorial constraints

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Regulatory Challenges

• 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 unreasonable and significant?

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Afternoon Speakers

• Focus on cells
• Doris Taylor, University of Minnesota
• Silviu Itescu, Columbia University
• Focus on devices
• D. Nick Jensen, FDA/CDRH
• Robert Lederman, NIH/NHLBI