For sponsors developing oncology therapeutics targeting solid tumors, the pre-IND Type B meeting represents a critical early checkpoint with FDA. The agency's feedback at this stage shapes foundational program decisions—ranging from nonclinical package adequacy and first-in-human dose selection to trial design, biomarker strategy, and CMC readiness—and misalignment with FDA expectations can result in clinical holds, protocol amendments, or significant delays before a single patient is enrolled.
The analysis below synthesizes recurring themes from FDA feedback documented across pre-IND and related Type B meeting interactions for solid tumor programs, drawn from publicly available FDA review narratives in Drugs@FDA. It covers ten core dimensions of typical pre-IND scope, including nonclinical toxicology, starting dose justification, CMC, dose optimization strategy, patient population and biomarker considerations, safety monitoring frameworks, clinical pharmacology, combination rationale, and PK/PD, providing regulatory and clinical teams with a structured reference for anticipating and preparing for FDA's most common areas of scrutiny.
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Common FDA feedback in pre-IND (Type B) meetings for solid tumor therapies
The overarching theme: bring a mature, complete package
The most consistent message across meeting minutes is a readiness principle. FDA treats these meetings as a forum to resolve specific remaining issues on an otherwise substantially complete package, not to substitute for missing development work. Reviewers reminded sponsors that major components should be in the original submission, with only minor components deferred and only when they would not materially affect review 154147. FDA also asked sponsors to notify the regulatory project manager (RPM) in advance of any major change to the development plan, meeting purpose, or questions, warning that FDA might not be prepared to reach agreement on changes introduced late 133. In one oncology program, FDA declined to hold a substantive meeting, citing insufficient data to support constructive discussion and recommending the meeting be delayed until the package matured, a readiness stance that applies equally at the pre-IND stage 145.
Recurring feedback by topic
1. Nonclinical / toxicology package
FDA rarely gives an unconditional endorsement of the nonclinical package at the meeting stage. In solid-tumor minutes, FDA characterized a package as only "possibly" sufficient and made final adequacy contingent on review of the complete study reports submitted to the IND 81. Specific items FDA required included complete GLP repeat-dose toxicology study reports (for example, 6-month rat and 3-month dog studies) and complete genetic toxicology study reports before later-phase studies could proceed 81. The practical takeaway: sponsors should expect FDA to reserve judgment until full GLP study reports are in hand, and should not treat a favorable meeting comment as a final adequacy determination.
2. First-in-human starting dose
FDA's feedback centers on a defensible, nonclinically-justified starting dose. In the cited solid-tumor first-in-human minutes, FDA accepted a starting dose derived by converting the NOAEL to a human equivalent dose (HED) using body-surface-area scaling and then applying a safety factor, concluding the proposed dose was "reasonably safe" and that the study could proceed 1. FDA also flagged program-specific risks (higher plasma concentrations associated with cardiovascular effects) and questioned whether the sponsor was targeting a plasma concentration or an MTD, without mandating a different method in that instance 1. Sponsors should be prepared to justify the method (NOAEL/HED versus MABEL) and the safety factor against the compound's specific toxicology signals.
3. CMC / manufacturing for the Phase 1 IND
CMC feedback at the IND stage is generally pragmatic. FDA stated it did not object to proposed drug substance or drug product specifications, while noting the drug substance specifications may need reevaluation as development progresses 50. On stability, FDA accepted that no stability data on the clinical batch would exist at IND submission, provided batch analyses were included and stability of the clinical batch was monitored concurrently during the clinical program 50. The recurring principle is that Phase 1 CMC expectations are calibrated to early development, but specifications are expected to tighten as the program advances.
4. Trial design, dose escalation, and dose optimization (Project Optimus)
The corpus did not surface language explicitly attributing Project Optimus recommendations to a pre-IND meeting, but FDA's dose-optimization expectations appear consistently across oncology meeting minutes and reviews, and sponsors should anticipate them from the earliest interactions. FDA's consistent message for solid tumors is to evaluate more than one dose and to justify the recommended dose rather than defaulting to the MTD:
- FDA told one sponsor that selecting a recommended dose from very limited safety data was "not optimal," that "further dose finding information is needed," and that there were insufficient data to conclude the proposed regimen was more tolerable and optimized than an alternative; it recommended "additional work be done for dose optimization" and additional safety data to justify the final regimen before Phase 3 257.
- In programs where no dose-response relationship for response rate was observed between dose levels, FDA concluded the optimized dosage was "inconclusive" 262261.
- FDA has aligned with sponsors on studying a lower dose specifically "for exploration of dose optimization purposes" to inform dose-response 263, and noted where dose-finding relied on a single dose that more exploration was needed 265.
5. Patient population, eligibility, and biomarker/CDx strategy
FDA feedback on population is oriented to matching the enrolled patients to the study's purpose. Reviewers supported enrolling patients with locally advanced or metastatic solid tumors who had received appropriate standard-of-care therapy, or who were unlikely to tolerate or benefit from standard therapy 108110129. FDA emphasized disease-specific, protocol-defined eligibility (measurable/evaluable disease, adequate organ function, required prior therapy) and clarified cohort requirements where needed 117. On biomarkers and companion diagnostics, FDA supported biomarker-defined enrollment and, where applicable, endorsed a defined diagnostic algorithm (for example, multiplex IHC screening followed by NGS confirmation to determine eligibility), advised early consultation with CDRH on CDx development, and recommended collecting detailed local-test information and banking specimens to support a future CDx bridging study 109116.
6. Safety monitoring, DLT definitions, and stopping rules
The corpus contained limited pre-IND-specific language on Phase 1 safety architecture. The closest concrete example, from the lorlatinib review, shows FDA-driven protocol changes adding LVEF assessment to strengthen safety monitoring and modifying the DLT definition for dose modifications in the setting of toxicity 168. Sponsors should still expect FDA to scrutinize DLT definitions, cohort review procedures, and stopping rules, but this analysis could not document a representative pre-IND example, and that is a gap worth probing further.
7. Clinical pharmacology, QT/cardiac safety, and drug-drug interactions
FDA typically calls a proposed clinical pharmacology plan "conceptually acceptable" while conditioning final adequacy on the data submitted later, and requests specific studies before Phase 3, such as a food-effect study with the final formulation, meal-timing documentation in CRFs, and full DDI protocols for review 195. On cardiac safety, FDA has expected dedicated monitoring (ECGs, 24-hour Holter, echocardiograms) where warranted 189, and has accepted concentration-QTc analysis when the upper confidence interval stayed below the threshold of regulatory concern 186. For DDI, FDA has accepted PBPK-modeling-based strategies to assess the drug as both victim and perpetrator, while still asking for definitive study protocols 195197.
8. Combination therapy rationale and contribution of components
For solid-tumor combinations, FDA consistently expects the program to demonstrate that each component contributes to the effect and that the combination outperforms the individual components, generally through monotherapy comparator arms or equivalent evidence 250251245. On nonclinical rationale, FDA has warned that a mechanistic rationale "may be plausible but [is] speculative" when no nonclinical combination studies are provided 175. On contribution of components, FDA has flagged undersized monotherapy cohorts as potentially inadequate to assess contribution and asked for justification or larger cohorts 175, and has stated that contribution will remain a review issue where a monotherapy arm is appropriate 237. On safety, FDA has stressed the difficulty of attributing adverse events to individual agents absent a suitable comparator, and has looked for monotherapy safety data to support the combination 239240241244.
9. PK sampling, pharmacodynamic biomarkers, and immunogenicity
FDA has favored intensive PK sampling to adequately characterize exposure (particularly absorption and early exposure), cautioning that sparse sampling can be too limited for some questions 214225. FDA has viewed mechanistically relevant target-engagement/PD biomarkers and biomarker-based PK/PD modeling as reasonable and potentially useful to support dose selection 216. The corpus did not contain a solid-tumor-specific FDA immunogenicity recommendation from a meeting minute; the explicit immunogenicity examples came from non-solid-tumor products 209211, so this remains an area to confirm program by program.
What this means for a pre-IND package
Read together, the minutes point to a predictable set of FDA priorities at the pre-IND stage for solid tumor therapies: (1) come to the meeting with a substantially complete package and specific, answerable questions 154147133; (2) present complete GLP toxicology and genotoxicity reports rather than summaries, and expect adequacy to be confirmed only on review 81; (3) justify the first-in-human starting dose against the compound's toxicology, typically via NOAEL/HED plus a safety factor, and be ready to defend the method 1; (4) build dose optimization into the plan early and do not rely on the MTD alone to define the recommended dose 257262263; (5) align the population, eligibility, and any biomarker/CDx strategy to the study purpose, engaging CDRH early where a companion diagnostic is contemplated 108117109116; and (6) for combinations, come with a nonclinical rationale and a design that can establish each component's contribution 175237250.
Limitations
Pre-IND meeting minutes are not public standalone documents, so this synthesis relies on FDA review narratives that reference meeting outcomes; some concrete examples derive from later Type B meetings rather than the pre-IND meeting itself. Keyword retrieval over the review corpus can surface later-stage or non-solid-tumor material, which was excluded from the findings above where identifiable. Two areas, Phase 1 safety architecture (DLT/stopping rules) and immunogenicity, produced limited solid-tumor pre-IND evidence and warrant program-specific follow-up.