FDA Perspectives on Clinical Trial Development of Gene Therapy

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FDA Perspectives on Clinical Trial Development of
Gene Therapy

• Changting C Haudenschild, M.D
• changting.haudenschild_at_fda.hhs.gov
• OCTGT/CBER/FDA
• ASGT 12th Annual Meeting
• May 27-30, 2009

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FDA Organization

• CBER - Center for Biologics Evaluation and
  Research
• Office of Cellular, Tissue, and Gene Therapy
• Office of Vaccines Research and Review
• Office of Blood Research and Review
• CDER - Center for Drug Evaluation and Research
• CDRH - Center for Devices and Radiological Health
• CFSAN Center for Food Safety and Applied
  Nutrition
• CVM Center for Veterinary Medicine
• NCTR National Center for Toxicological research

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Diversity of Products in OCTGT

• Gene products
• Replacement therapy for monogenic disease
• Modification of physiological homeostasis
• Cellular products
• Autologous selected, cultured, or modified
• Allogeneic selected, cultured, or modified
• Genetically modified somatic cells
• Tissue and tissue based products
• Xeno-transplantation products
• Combination products

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Gene Therapy Products

• Definition
• All products that mediate their effects by
  transcription
• and/or translation of transferred genetic
  material and/or by
• integrating into the host genome and that are
  administered
• as nucleic acids, viruses, or genetically
  engineered
• microorganisms. The products may be used to
  modify cells
• in vivo or transferred to cells ex vivo prior to
  administration
• to the recipient.
• Gene transfer via vectors
• Cells modified by gene transfer vectors

2006 Guidance for Industry - Gene therapy
Clinical Trials- Observing Subjects for Delayed
Adverse Events
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Information Needed to Start an Early- Phase
Clinical Study

• Product manufacture, characterization, and safety
  testings
• http//www.fda.gov/cber/gdlns/gtindcmc.htm
• Safety information to show that the proposed
  treatment is reasonably safe to administer in
  human, based on
• Pre-clinical studies conducted in appropriate
  animal species/models
• Data from previous or ongoing clinical studies
• Published scientific data

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Information Needed to Start an Early Phase
Clinical Trial

• Starting dose or dose range
• Rationale of route of administration
• Delivery device
• Biological activity data
• Gene expression in target tissues
• Measurable transgene product in target tissues

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Clinical Study Design

• Patient selection
• Dose selection
• Product administration
• Safety monitoring
• Collection of activity/efficacy data
• Study endpoints

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Patient Population

• Define the disease indication
• Specify eligibility criteria
• Diagnostic/staging criteria
• All patient should be on optimal medical therapy
• Special consideration for treating pediatric
  patients
• Treat adult patients first to collect safety data
• Scientific justification of treating pediatric
  patients

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Dosing Selection

• Starting dose should be consistent with
  biological activity and below the dose at which
  adverse effects were seen in pre-clinical studies
• Staggered patient enrollment
• Conservative dose escalation
• MTD may not be definable

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Product Administration

• Rationale for the procedure selection
• Detailed procedural information with supporting
  data
• Dose/volume/injection times
• Delivery devices are subject to review
• Safety monitoring plan for invasive procedures
• Training plan may be needed for the use of the
  delivery device

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Safety Monitoring

• Based on
• Animal and in vitro studies
• Understanding of mechanism of action of the
  products
• Published information
• Continuous improvement of safety monitoring plan

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Safety Monitoring Plan

• Examples
• Inflammatory response to
• Product (virus vectors)
• Mechanical injury due to the procedure
• Immunological response to
• Virus vectors
• Transgene product
• Modified autologous cells
• Long-term follow-up for gene therapies
• Guidance for Industry 2006 Gene therapy
  clinical trials observing subjects for delayed
  adverse events

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Collecting Data Biologic Activity and Efficacy

• In vivo biological activity
• Duration and level of gene expression
• Duration and level of transgene proteins
• Clinical evaluation

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Study Endpoints for an Early Phase Study

• Evaluate specified safety
• Product related
• Procedure related
• Select optimal dose that will be used for the
  late phase studies
• Identify evidence of biological drug activity
• Gain early evidence on effectiveness

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Efficacy Endpoints for a Late Phase Study

• Regular approval
• Clinical benefits
• Increased survival
• Symptomatic improvement
• Accelerated Approval
• Established surrogate endpoints that are
  reasonably likely to predict clinical benefit
• Postmarketing studies are required to demonstrate
  clinical benefits

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Information Needed to Start a Late-Phase Study

• Product characterization and consistency
• A well-controlled, scientific valid Phase 2 study
  is valuable and may be critical in decisions
  regarding dose, endpoints, time of evaluation,
  etc
• Preliminary safety profile should be established
• Biological activity, and preliminary
  effectiveness should be demonstrated
• Pivotal study design should be supported by the
  data from the early phase studies

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Meeting with FDA to Discuss a Late-Phase Study
Design

• Background data to support statistical design and
  power of the study to achieve objectives
• Specific target population
• Optimal dose and regimen
• Proposed control arm and randomization plan
• Safety motoring plans (short term and long-term)
• Efficacy endpoint(s)
• Statistical Analysis Plan

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Challenges in Small Trial Design

• Special design methods may be indicated for small
  trials
• Blinding may be not feasible, or patients may be
  unwilling to enter a randomized trial
• Double blind and placebo-control features may be
  not feasible
• Historical control is considered
• If natural history of the disease is well
  characterized and is relatively stable over time
• If no treatment available or standard treatment
  is highly ineffective

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Requirements for NDA/BLA Approval (CFR 601.25)

• Safe for the use described in labeling
• Demonstration of substantial evidence of
  effectiveness for the use described in labeling.
  Effectiveness is established by adequate and
  well-controlled studies (CFR 314.126)
• Not misbranded

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Early Communication with FDA

• Non-binding, informal scientific discussion
  between FDA and sponsor
• Via telecons
• Via scientific meetings/workshops
• Via outreach presentations
• Discuss specific issue(s) of interest
• Contact information
• Patrick Riggins Ph.D
• patrick.riggins_at_fda.hhs.gov
• Branch Chief
• Regulatory Management Staff

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THANK YOU