Despite promising biology and compelling animal data, approximately 1 in 10 INDs are placed on clinical hold by the FDA, and many more programs encounter avoidable delays; not due to poor science, but preventable strategic missteps in the final 6-18 months before submission. If you are approaching your IND filing, it is tempting to believe that the most difficult milestones are behind you. After all, the biology works as hypothesized, the mechanism is well-understood, and the animal data are convincing. However, at this juncture, each month of IND delay can cost $500K-2M in burn rate while eroding investor confidence and competitive positioning.

The issue is rarely poor science, but rather, it is a failure to convert the promising biology into a data package that addresses FDA’s key questions regarding the acceptability of first-in-human (FIH) exposure. According to the FDA, a Phase 1 study may be placed on clinical hold if subjects would face unreasonable and significant risk of illness or injury, if the IND lacks sufficient information to assess risk to subjects, among several other criteria.

In our experience, this is exactly where many promising programs slowly derail, which can eventually lead to significantly increased costs and delays in providing new medicines to patients. Unfortunately, the early signs of a derailment are not obvious. Programs can maintain momentum for many months before the consequences show up as:

  • Stalled momentum due to poor FDA meeting outcomes
  • Unexpected deficiencies during IND review
  • Late-stage unexpected and unbudgeted nonclinical studies
  • CMC setbacks that delay critical supply or tech transfer
  • Waning investor confidence in the program
  • Expensive rework because earlier work was not fit-for-purpose

The good news is that these issues almost always share a single root cause; a failure to integrate nonclinical, regulatory, CMC, and clinical strategies early enough. Without a  focused cross-functional effort, critical bottlenecks remain siloed until they are surfaced at critical inflection points.

The five patterns that derail pre-IND, and how to avoid them

1. Generating Data Without Addressing FDA’s Questions

Early stage teams are often very productive, running studies, generating massive datasets, and building a strong scientific narrative. However, without early strategic planning, these outputs rarely map to the specific questions regulators will scrutinize before clearing an IND.

Common Pitfalls:

  • Studies are scientifically interesting but do not inform key decision-making
  • Delaying FDA engagement (i.e., not taking advantage of INTERACT or pre-IND meetings)
  • Selecting test models that fail to support the intended clinical population, route of administration, etc.
  • Using endpoints with poor translatability to the clinical population
  • Failing to de-risk critical areas that will face the greatest regulatory scrutiny
  • Overlooking relevant guidances (e.g., ICH M3(R2) for nonclinical safety studies or specific disease-area guidances) and not tapping into deep expertise and experience of regulatory consultants

What do strong programs do differently? They define a fit-for-purpose minimum evidence package, engage the FDA early to align on high-risk areas, and build a cross-functional integrated development plan where all stakeholders are focused on supporting a favorable risk-benefit profile for the FIH study. INTERACT and pre-IND meetings are especially important as they enable early alignment with FDA on the development strategy, ensure necessary studies are appropriately designed to support regulatory decision making, minimize clinical hold risk, clarify endpoints and development goals, optimize resourcing and reduce costs. Thus, these meetings should be used to test specific assumptions, force clarity around risk areas, and confirm whether the planned evidence package is adequate to support the proposed FIH study.

2. Allowing Nonclinical, CMC, and Clinical Plans to Drift Out of Sync

A classic pre-IND failure mode is asynchronous development occurring across siloed functions. While each functional workstream might look reasonable on its own, together they fail to form a coherent IND narrative. Furthermore, the FDA evaluates your nonclinical, CMC, and clinical sections as an integrated package, and thus, it is critically important to ensure that you have consistent messaging across your entire IND application.

Common Pitfalls:

  • Allowing manufacturing timelines to evolve independently from nonclinical study needs
  • Running pivotal toxicology studies with material that does not represent the eventual clinical product
  • Designing a clinical protocol with assumptions (population, regimen, dose escalation) that outpace what the nonclinical data package can support
  • Introducing late process or formulation changes that raise comparability questions

What do strong programs do differently? They align bioanalytical, CMC, and toxicology milestones on a unified and integrated timeline. Every study and milestone exists for a reason; to systematically build a data package that will arm the FDA with the necessary information they need to clear your IND.

3. Misinterpreting FDA Feedback

A surprisingly common issue is assuming alignment with the FDA when in fact there is none. Because the FDA typically provides narrow responses to the questions asked, and rarely commit to a position when data are premature, responses may not adequately paint the full picture of the Agency’s position.

The quickest way to invite a clinical hold is to mistake a cautious or narrow FDA response for an endorsement. Any regulatory expert will tell you that the true strategic insights lie in reading between the lines:

  • What did the FDA not explicitly endorse?
  • Where did they request additional justification?
  • Where was their wording conditional or cautious?
  • Which specific topics drew disproportionate attention?

What do strong programs do differently? They ensure cross-functional stakeholders and regulatory experts review and challenge critical areas of the briefing book before submission, craft clear questions that force actionable feedback, and translate FDA input into risk flags with formal mitigation plans. Regulatory experts with deep experience in reading FDA feedback language, tone, and nuance are essential to interpret what FDA is truly signaling and turn that guidance into clear, executable next steps.

4. Inadequate FIH Study Justification

Development teams often underestimate the level of scrutiny applied to the details of FIH studies, which is especially true for investigational products with no precedent, novel modalities, long-duration therapies, and targeted delivery technologies.

Common Pitfalls:

  • Relying on a FIH dose justification that lacks a solid empirical basis
  • Failing to construct a clear translational bridge from nonclinical findings to human expectations
  • Proposing a patient population that does not align with the investigational product’s mechanism, or safety profile
  • Listing potential toxicities without a concrete plan to detect, manage, and act on them

A successful IND clearance relies on an integrated, evidence-based narrative that justifies your target patient population, starting dose, escalation plan, and safety rules. Attempting to fill gaps in this narrative late in the pre-IND stage, often under tight timelines and tight budgets, is a recipe for a clinical hold.

What do strong programs do differently?

  • Draft the FIH rationale and protocol synopsis early to guide data generation efforts
  • Tie every major nonclinical study to a specific element of the eventual clinical program (target population, dose, schedule, route, escalation)

Outline exactly how inflection points that would cause the study to pause, stop, or change course will be managed in the protocol, rather than just acknowledging their possibilities with no action plan.

5. Treating Regulatory Strategy as a Documentation Exercise Rather than Risk Reduction

Teams often narrowly view regulatory as a downstream administrative function that involves writing briefing books, scheduling FDA meetings, compiling modules, and formatting submissions. While certainly important, these activities are execution, and not strategy.

Successful IND planning is fundamentally an exercise in risk-reduction. A winning strategy is focused on predicting as best possible the concerns regulators will have about your proposed program, and then addressing those risks before they can stall progress.

Common Pitfalls:

  • Treating regulatory involvement as something that begins once the data package is nearly complete
  • Assuming that each functional workstream can manage its own risks independently
  • Not testing assumptions early with seasoned experts and FDA
  • Failing to maintain a cross-functional risk register that includes nonclinical, CMC, clinical, and regulatory risks
  • Failing to convert FDA feedback into specific risk-mitigation actions and decision points

What do strong programs do differently? They treat regulatory strategy as an active, cross-functional risk-management process. They identify the issues most likely to be raised by FDA, assign ownership for each major risk, define mitigation plans, and revisit those risks as the program evolves. Strong teams also test assumptions early with seasoned experts and use FDA engagement strategically to obtain a gauge on the development plan before major capital is committed.

Is your pre-IND strategy FDA-ready? Our regulatory experts have guided 100+ programs through successful IND clearance. Schedule a 30-minute strategy session to identify potential blind spots in your development plan.


Email us at contact@lumanity.com to start the conversation today.


Many promising programs slowly derail, which can lead to significantly increased costs and delays in providing new medicines to patients.