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This is a draft guidance. Not for implementation.
What You Need to Know? 👇
What are the key efficacy endpoints FDA accepts for GVHD prevention trials?
GVHD-free survival (GFS) is the primary clinical endpoint representing clinical benefit for traditional approval. GFS measures time from HSCT to onset of GVHD or death. Overall survival may also be used but should be supported by GFS analysis.
How does FDA define steroid-refractory acute GVHD for clinical trials?
FDA accepts criteria including: progression after 3 days of >2 mg/kg methylprednisolone equivalents, no improvement after 7 days of >2 mg/kg, progression to new organ after >1 mg/kg treatment, or recurrence during steroid taper.
What response criteria does FDA accept for chronic GVHD treatment studies?
Complete Response requires no clinically active disease in all organs without new therapy. Partial Response requires organ-level improvement in one or more organs without progression elsewhere and no new therapy. Assessments occur through 6 months.
Are single-arm trials acceptable for GVHD drug approval?
Single-arm trials may support approval when intended population has refractory disease with no available therapies. However, randomized controlled trials are preferred, especially for first-line treatments and when effective standard-of-care exists.
What special considerations apply to pediatric GVHD clinical trials?
Pediatric patients have lower GVHD risk than adults and may have different response profiles. Clinical trials including both populations should stratify randomization by age group. Age-appropriate PRO tools are required for pediatric studies.
How should drug-drug interactions be evaluated in GVHD drug development?
Sponsors should conduct in vitro metabolism studies for CYP3A and transporter interactions before first clinical trials. GVHD patients commonly use concomitant medications like antifungals that may interact, requiring dose modification strategies in trials.
What You Need to Do 👇
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