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Development of Products for Prevention and Treatment of Acute and Chronic Graft-Versus-Host Disease (DRAFT)

This guidance assists sponsors in developing drugs, biological products, therapeutic devices, and cell processing devices for preventing or treating acute graft-versus-host disease (aGVHD) or chronic graft-vs-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). It covers clinical development programs and critical design elements for early and late phase trials.

This is a draft guidance. Not for implementation.

  1. Conduct thorough non-clinical testing following relevant guidances before clinical trials
  2. Design dose-escalation studies carefully considering:
    • Patient population selection
    • Duration of DLT observation
    • Dose optimization strategy
  3. For pivotal trials:
    • Use randomized controlled design where possible
    • Include appropriate control arms
    • Stratify for key prognostic factors
    • Collect comprehensive efficacy and safety data
  4. Develop standardized approaches for:
    • Response assessment
    • Adverse event monitoring
    • Concomitant medication management
    • Data collection and analysis
  5. Consider early FDA consultation on:
    • Novel endpoints
    • Biomarker development
    • Companion diagnostics
    • PRO measures
  6. Plan for adequate follow-up duration and data collection to support marketing applications
  7. Implement rigorous safety monitoring considering the immunocompromised population

Key Considerations

Clinical testing

  • First-in-human trials should identify recommended phase 2 dose based on PK/PD data, clinical activity, safety and tolerability
  • Pivotal trials should be randomized controlled trials for prevention and first-line treatment
  • Single-arm trials may be acceptable for refractory disease with no available therapies
  • Minimum 180 days follow-up for aGVHD and 1 year for cGVHD trials
  • Response endpoints accepted for traditional approval

Non-clinical testing

  • Follow guidance for anticancer pharmaceuticals and severely debilitating/life-threatening disorders
  • Special considerations for cellular/gene therapy products

Labelling

  • Protocol should specify standardized instructions for immunosuppression tapering
  • Raw data supporting efficacy assessments should be collected to allow independent adjudication

Safety

  • Monitor early nonrelapse mortality
  • Detailed analysis of infections required
  • Collect adverse events through at least 5 half-lives or 28 days from last dose
  • Special attention to graft failure, relapse, post-transplant lymphoproliferative disease, bleeding

Other considerations

  • E9: Statistical Principles for Clinical Trials
  • E10: Choice of Control Group and Related Issues in Clinical Trials
  • E11 (R1): Clinical Investigation of Medicinal Products in the Pediatric Population

Original guidance

  • Development of Products for Prevention and Treatment of Acute and Chronic Graft-Versus-Host Disease
  • HTML / PDF
  • Issue date: 2023-09-28
  • Last changed date: 2023-09-28
  • Status: DRAFT
  • Official FDA topics: Medical Devices, Drugs, Biologics
  • ReguVirta summary file ID: 08b7d3de8ac81ce73dad1313685a24f5
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