USFDA Draft Guidance: Early-Phase IND Protocol Recommendations for Solid Tumors
The U.S. Food and Drug Administration (FDA) has issued a draft guidance titled Early-Phase IND Protocol Recommendations for Solid Tumors, providing recommendations for sponsors and clinical investigators developing first-in-human (FIH) and other early-phase clinical trials involving investigational drugs and biological products for solid tumors.
Developed by the FDA’s Oncology Center of Excellence (OCE), in collaboration with CDER and CBER, the guidance focuses on improving clinical trial design, dose selection, patient eligibility and safety monitoring during early oncology drug development. It does not cover investigational products intended to treat hematologic malignancies.
Key Recommendations
1. Patient Eligibility Criteria
The FDA recommends avoiding unnecessarily restrictive eligibility criteria that could limit patient access and slow clinical trial recruitment. The guidance addresses prior therapies, age limits, brain metastases, HIV and hepatitis infections, washout periods, renal function and QT interval considerations. It also highlights appropriate inclusion of paediatric patients and patients with specific clinical conditions.
2. Dose Escalation and Trial Design
Sponsors should establish predefined dose-escalation methods using appropriate rule-based or model-based approaches. The protocol should explain dose increments, patient enrolment staggering, intra-patient dose escalation and dose delays, supported by adequate safety justification. Novel drug combinations should also consider how the contribution of each drug will be evaluated.
3. Dose-Limiting Toxicity (DLT) Assessment
The draft provides recommendations for defining DLT criteria, including haematological and non-haematological toxicities, treatment delays and other clinically significant events. The DLT observation period should reflect the product's characteristics, with longer monitoring where delayed toxicities are expected, particularly for certain cellular and immunotherapy products.
4. Dose Expansion and Assessment of Activity
Early-phase studies with dose expansion cohorts should include justified sample sizes and stopping rules for excessive toxicity or lack of activity. Sponsors should interpret efficacy findings from non-randomised studies cautiously, particularly for endpoints such as overall survival and progression-free survival.
5. Recommended Phase 2 Dose (RP2D) and Dose Optimization
The RP2D should not be determined solely by the maximum tolerated dose. Sponsors should evaluate the totality of pharmacokinetic, safety and efficacy information and explore multiple dose levels. Late-onset toxicities should also be considered when selecting the dose and treatment schedule for further development.
6. Patient Safety and Treatment Considerations
Protocols should define patient-level stopping rules, safety monitoring plans and criteria for continuing treatment beyond radiographic disease progression. Where treatment continues after progression, patients should be informed about available alternatives and potential risks through appropriate re-consent procedures.
7. Companion Diagnostics and Food Administration
Where biomarker-based patient selection is essential for safe and effective drug use, development and validation of an in vitro companion diagnostic may be required. Early consultation with FDA's Center for Devices and Radiological Health (CDRH) is recommended. The guidance also recommends a modified fasted administration approach in early-phase trials unless an alternative is scientifically justified.
8. Sampling and Analysis Plans
The draft recommends appropriate sampling and analysis plans for pharmacokinetics, ECG monitoring and immunogenicity. These plans should support dose selection, exposure-response assessments and safety evaluation. For biological products, immunogenicity monitoring should include assessment of anti-drug antibodies and their potential impact on safety, efficacy and pharmacokinetics.
Regulatory Significance
The draft guidance provides a structured framework for designing early-phase solid tumour trials, with emphasis on patient safety, scientifically justified eligibility criteria, appropriate dose escalation and dose optimization. It also encourages sponsors to consider product-specific risks and emerging clinical data when developing and amending protocols.
Consultation Period: FDA invites comments on the draft guidance. The FDA guidance webpage lists 11 January 2027 as the comment submission deadline. The document is non-binding and represents recommendations for public consultation; it is not intended for implementation in its draft form.
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