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This is a draft guidance. Not for implementation.
Recommended Actions
- Conduct thorough non-clinical testing following relevant guidances before clinical trials
- Design dose-escalation studies carefully considering:
- Patient population selection
- Duration of DLT observation
- Dose optimization strategy
- For pivotal trials:
- Use randomized controlled design where possible
- Include appropriate control arms
- Stratify for key prognostic factors
- Collect comprehensive efficacy and safety data
- Develop standardized approaches for:
- Response assessment
- Adverse event monitoring
- Concomitant medication management
- Data collection and analysis
- Consider early FDA consultation on:
- Novel endpoints
- Biomarker development
- Companion diagnostics
- PRO measures
- Plan for adequate follow-up duration and data collection to support marketing applications
- 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
- Consider patient and transplant-related factors impacting outcomes
- Biomarker development and companion diagnostics may be needed
- Drug-drug interactions should be evaluated early
- PRO endpoints may support efficacy claims for cGVHD
Relevant Guidances
- Ethical Considerations for Clinical Investigations of Medical Products in Children (Draft)
- Clinical Investigator Disqualification Procedures and Administrative Actions
- Investigator Responsibilities - Protecting Human Subjects and Ensuring Data Integrity in Clinical Research
- Patient-Reported Outcome Measures: Development, Implementation and Evaluation in Clinical Trials
- Statistical Guidance for Reporting Diagnostic Test Results with Qualitative Outcomes
- Benefit-Risk Factors in IDE Applications for Medical Device Clinical Investigations
- Design Considerations for Medical Device Pivotal Clinical Studies
Related references and norms
- 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
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