Submitting a New Drug Application (NDA) is one of the most resource intensive steps in drug development. For small life science companies, success depends on more than simply reaching the submission milestone. The true measure of success is FDA approval.
Why Perform an NDA Gap Analysis?
An NDA gap analysis conducted well in advance of filing helps identify and resolve issues that can slow reviews, trigger information requests, or delay approval by months or even years. By surfacing deficiencies early, Sponsors reduce the risk of refuse-to-file outcome, extended review cycles, and costly long-term delays. A structured NDA gap analysis gives companies the best chance to move through review smoothly and reach approval more efficiently.
Facet has prepared and submitted two to four marketing applications each year for the past decade. Collectively, our regulatory experts have supported more than fifty NDAs and BLAs. That experience highlights a consistent lesson: The fastest path to approval is identifying and addressing moderate- and high-risk gaps before submission. An independent NDA gap analysis from a third party can confirm which gaps are real, which require mitigation, and which solutions will best reduce approval risk.
Meeting FDA Expectations: Where NDA Submissions Often Fall Short
An NDA must present a clear and consistent story across nonclinical, clinical, and chemistry, manufacturing, and controls (CMC). Reviewers expect:
- Study reports and datasets that demonstrate safety and efficacy
- CMC data showing validated, reproducible manufacturing and adequate stability
- Documentation that reflects the full development history, including IND content and prior FDA interactions
- Labeling proposals that align with evidence and intended use
When these elements are incomplete or inconsistent, even strong science can be undermined. Facet regularly sees Sponsors encounter submission gaps such as:
- Missing or incomplete nonclinical or clinical datasets
- Toxicology studies that do not support the proposed dose or duration
- Manufacturing changes without sufficient comparability data or scientific justification
- Mismatches between IND and NDA content
- FDA feedback that was received but not fully addressed
These common issues delay reviews and create unnecessary regulatory risk. An NDA gap analysis gives Sponsors the opportunity to identify and fix them before filing, improving the chances of a smoother review and timely approval.
Methodology for NDA Gap Analysis
As a Sponsor, identifying gaps in your development program and in your NDA should be an iterative process. Facet recommends a three-step plan your cross-functional team can cycle through as new data emerge.
Step 1: Make a List of All Perceived Gaps
Bring together your development team and brainstorm areas of weakness or limitations in the development program and in the application. Ensure the team understands the key messaging and claims for the product before making the list. Ask for candid input. Team members should not worry about judgments or about proposing solutions at this stage. Anything related to the product or application that keeps them up at night should be listed, no matter how trivial. Spreadsheets and collaboration tools are useful for organizing and maintaining a running list.
Step 2: Assess the Risks, Risk Level, and Potential Mitigations
For each gap identified in the first step, determine the possible outcomes, the potential impact on FDA review, the probability that FDA will flag the gap as an impediment to approval, and one or more potential mitigations. This work requires experience interacting with FDA, scientific expertise, creativity, and sound judgment. It is rarely possible or practical to mitigate every risk. Timelines and budgets matter. Some risks have low impact on review yet require significant time and resources to address, which can offset the benefit of filling the gap.
Step 3: Develop and Implement a Plan to Mitigate Gaps With Unacceptable Risk
Rank the list you created in the first step, based on the risk factors identified in the second step to estimate the likelihood that FDA would not approve the NDA because of a gap. Prioritization is not always easy for these four reasons.
- Every company and team must establish their risk tolerance.
- The likelihood of FDA not approving the application in the face of a given gap is an educated estimate.
- The estimated approval probability must be weighed against timelines, costs, and the risks associated with filling the gap.
- A company’s risk tolerance levels and the estimated FDA probabilities can change over time.
Facet has seen companies succeed with either a team consensus approach or a subject matter expert-weighted vote to finalize priorities, select mitigations, and assign owners with tasks and completion dates.
Cross-Functional Coordination
NDA readiness depends on alignment across regulatory, clinical, nonclinical, CMC, biostatistics, and quality. The NDA gap analysis process pulls these functions into one conversation so the scientific narrative, data, and documents all tell the same story. External reviewers add objectivity and often surface risks that internal teams have normalized or overlooked.
Prioritizing and Addressing Deficiencies
Use a simple risk matrix that scores impact on approval and probability of occurrence. Focus first on high impact items with moderate or high probability. Examples include: missing bridging data after a change in manufacturing site, unvalidated analytical methods tied to critical quality attributes, or a toxicology package that does not support the proposed clinical dose and duration. For medium impact gaps, select pragmatic mitigations that fit your timeline and budget. For low impact gaps with high mitigation cost, document the rationale for deferral and be ready to respond during review.
Use a simple risk matrix that scores both the impact on approval and the probability of occurrence. Focus first on high impact items with moderate or high probability. Examples include:
- Missing bridging data after a manufacturing site change,
- Unvalidated analytical methods tied to critical quality attributes,
- Toxicology packages that do not support the proposed clinical dose or duration.
For medium impact gaps, select pragmatic mitigations that fit your timeline and budget. For low impact gaps with high mitigation cost, document the rationale for deferral and be ready to respond during review.
Best Practices for NDA Readiness
- Start Early: Run an NDA gap analysis well before your planned submission window so the team has time to execute mitigations.
- Keep it Iterative: Reassess after major data reads, protocol amendments, and manufacturing changes.
- Document Decisions: Record gap definitions, risk ratings, chosen mitigations, and rationale. Clear documentation helps reviewers follow your logic.
- Use an Independent Reviewer: A third party NDA gap analysis provides a second set of eyes that can assess your package the way FDA will.
An Independent NDA Gap Analysis Adds Value
Even with a solid internal process, you may still have gaps that cause concern. An experienced independent consulting company, such as Facet Life Sciences, can perform an NDA gap analysis and provide an objective opinion. This service gives you a second set of eyes on the application. Experts review the content from the FDA’s perspective. The result can be identification of gaps your team may have missed or a better understanding that a perceived issue is not likely to affect FDA approval.
How Facet Supports Sponsors
Facet’s core strengths include FDA meeting guidance, regulatory strategy, and gap analysis services. Our team provides objective evaluations of NDA readiness, identifying gaps across development, medical, regulatory, and asset valuation areas. We recommend practical risk mitigations with clear timelines and estimated costs. For small life science companies with limited resources, this clarity keeps programs aligned with business goals and accelerates progress toward approval.
Prepare Your NDA for Approval, Not Just Submission
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