FDA often flags PMAs for missing sections, poor data organization, weak justifications, or inadequate clinical and manufacturing info. Learn the top reasons applications face delays or denials and proven strategies to ensure a complete, high-quality submission.
Premarket Approval applications undergo intense scrutiny, and it’s normal for FDA to ask questions or request additional information. However, certain recurring pitfalls can lead to significant delays, “refuse-to-file” decisions, or even PMA denials if uncorrected. FDA has observed that PMAs which are incomplete, inconsistent, or poorly organized tend to face more review cycles and longer approval times. As a sponsor, understanding these common deficiencies – essentially the reasons FDA might say “This application is not sufficient because…” – helps you proactively address them before submission. Below we identify frequent PMA shortcomings and provide guidance to avoid each, ensuring your application passes FDA’s acceptance tests and substantive review with flying colors.
One of the most basic yet common errors is omitting an item required by regulation or FDA’s PMA checklist. For example, failing to include an appropriate financial disclosure for clinical investigators, or missing a section like the device environmental assessment (even if it’s a simple exclusion claim). FDA will Refuse to File a PMA if it does not contain all the items listed in Section 515(c)(1)(A-G) of the FD&C Act and 21 CFR 814.20, unless a valid justification for omission is provided. If you leave out something like the bibliography of known adverse information, or the statement regarding compliance with ClinicalTrials.gov requirements, that’s a red flag.
Use FDA’s published guidance and checklists when preparing your PMA. FDA often provides an “administrative checklist” for PMA acceptance. Go through 21 CFR 814.20 line by line and ensure each required element is either included or justified. For instance, if an item is not applicable (e.g., your device has no explant so patient ID cards aren’t needed), explicitly state that and why. Have a fresh set of eyes internally or via a consultant do a pre-submission quality audit of the PMA content. That quality control audit should verify that all required forms (like Form FDA 3674 for trial registry compliance) and sections are present. By being meticulous, you prevent a refuse-to-file scenario that can cost you 45+ days.
PMAs that are disorganized, confusing, or contain inconsistencies frustrate reviewers and invite more questions. Examples include contradictory statements in different sections (e.g., the device description in one place doesn’t match the description in the labeling), unlabeled or hard-to-follow data (tables with no clear units or definitions), or simply thousands of pages of raw data with no summary. FDA reviewers have limited time; if they cannot easily locate information or decipher results, they may issue deficiencies asking you to clarify or reformat. In extreme cases, if the application is so unclear that FDA cannot proceed with review, they might refuse to file it. One specific recurring issue: inconsistent data – say your clinical study section reports 2 deaths, but your summary or labeling says 3 deaths. Such discrepancies erode FDA’s confidence.
Tell a clear story with your PMA. Use a logical structure, and adhere to FDA’s guidance on format (e.g., if using the eSTAR template, it guides you through organizing content). Include a detailed table of contents and even sub-TOCs for appendices if needed. Cross-check every section for consistency: device details in the engineering report should align with those in the IFU. Summarize key findings in the narrative before presenting large datasets. For example, precede a 100-page biocompatibility report with a one-page summary of results and conclusions. Use tables and figures effectively, and ensure all are labeled and referenced in the text. Perform an internal consistency check: have one team member read the entire PMA to spot any conflicting info or unclear parts. Also, maintain version control – sometimes, last-minute changes to one document (like labeling) aren’t propagated to others. A thorough review near finalization will catch these. Remember, a well-organized PMA not only avoids deficiencies, it also fosters goodwill – reviewers are more likely to trust and favorably review an application that appears high-quality and coherent.
FDA often finds that PMAs lack adequate justification for certain approaches or omissions. For instance, if you chose an unusual trial design or endpoint, did you justify why? If you didn’t test something that guidance recommends (like a particular biocompatibility test or a stress test), did you explain why not? A common deficiency is when sponsors fail to justify omitting certain manufacturing information or not conducting a recommended test. FDA might say: “Provide a rationale for why X was not evaluated” or “Justify how the device meets Y requirement in absence of direct testing.” Another example is not explaining deviations in clinical protocols or not providing context for outlier results. Lack of justification can make FDA think you overlooked something, rather than consciously determined it was unnecessary.
Anticipate questions and address them proactively in your PMA. Put yourself in the reviewer’s shoes: what aspects of your device or data are unusual or might raise concern? Provide rationales in the appropriate section. For instance, if you did not perform a particular test because a similar one covers it, say so: “Device did not undergo ISO XYZ test because the ABC test was performed, which is a more stringent evaluation of the same characteristic.” If you have limitations in your clinical data (maybe no sham control due to ethical reasons), clearly justify and, if possible, provide supporting literature that backs your approach. Where applicable, reference FDA guidance documents or standards to show alignment, and if you diverge from them, justify that divergence. By being transparent about your decision-making and the sufficiency of your evidence, you preempt FDA’s need to ask “why?” in a deficiency letter.
Perhaps the most critical deficiencies relate to clinical data. FDA might conclude that the clinical evidence is not sufficient to establish effectiveness or safety. Examples: too few patients, missing long-term follow-up, high lost-to-follow-up rates not analyzed, lack of a control or bias in trial conduct. If your pivotal study doesn’t meet its endpoint or if there were protocol deviations, expect deficiencies probing those. Common questions: “Provide additional analysis of X subgroup” or “Clarify the clinical significance of Y result” or “The study did not include Z population – how will this affect labeling?” In worst cases, FDA might say “The submitted data do not provide reasonable assurance of effectiveness for [the device]” – essentially a not-approvable finding. Clinical deficiencies are serious; they often require substantial efforts to address (like collecting new data or analyses).
Ensure your clinical development plan aligns with FDA expectations from the start. Engaging FDA early (Pre-Subs, IDE discussions) can iron out what dataset will be needed. By PMA submission time, ideally you have a clean, robust dataset that meets the pre-defined success criteria. Still, when writing the PMA, be candid about limitations and how you mitigate them. For example, if 10% of patients were lost to follow-up, perform a worst-case analysis showing it doesn’t overturn conclusions, and include that analysis proactively. If your study had any safety signals, address them: perhaps certain adverse events occurred, but you modified the device or have a mitigation, explain that clearly. Also include any supporting data (even if outside the main trial) that bolster your case: e.g., “Additionally, 50 patients in an OUS registry showed similar outcomes, supporting the pivotal trial results.” In other words, make the strongest possible case with the data you have. Provide FDA with a detailed benefit-risk discussion, acknowledging risks but emphasizing the benefits and how risks are mitigated, which may stave off a deficiency where FDA says “justify why benefits outweigh risks.” If you find your data truly has holes (perhaps you didn’t meet the primary endpoint), it’s often better to address it head-on (propose a plan or modified indication) rather than hoping FDA won’t notice – they will. Being forthright can turn a potential showstopper into a solvable issue, e.g., narrowing the indication or planning a post-approval study.
FDA frequently identifies gaps in the Quality System / manufacturing section of PMAs. For example: insufficient detail on sterilization validation, missing process validation results for a critical manufacturing step, or lack of description of how the manufacturing meets QSR requirements. FDA might ask for “additional information regarding the methods, facilities, and controls used in manufacturing” if what you provided doesn’t instill confidence. If you requested to omit some manufacturing info (as allowed under certain circumstances) without strong justification, FDA could refuse to file or issue a deficiency. Also, if there’s a change in manufacturing site not reported, or if they find out (via inspection) that your quality system has issues, those are deficiencies to address before approval (often resulting in an approvable letter until fixed).
Treat the manufacturing section with the same seriousness as the clinical section. Include a comprehensive description of manufacturing and quality control. Follow the guidance “Quality System Information for PMAs” – often FDA expects a summary of your design controls process, your critical suppliers and how you qualify them, etc. If you have not finalized something (say final packaging is being validated), proactively state the timeline and maybe commit to a condition of approval if necessary. One strategy is to have a third-party mock audit of your manufacturing and include a brief report or statement of readiness in the PMA. Provide results of any relevant process validations (e.g., if your device is sterilized, provide bioburden, sterilization validation info, etc.). Show that you have implemented Good Manufacturing Practices – mention if you have ISO 13485 certification or similar, as that can give FDA confidence (though they will verify via inspection). The goal is to convince the FDA reviewer (and the field inspector) that by the time of approval, the device can be made reliably and consistently. Also, address Quality System Regulation (QSR) compliance upfront: e.g., “The company’s quality system is compliant with 21 CFR Part 820; last FDA inspection (if any) outcomes; design history file summary can be made available on request.” That way, you potentially preempt the deficiency of “provide documentation that your manufacturing is under control.”
Labeling may seem straightforward, but FDA often finds issues such as inadequate instructions, missing warnings, or promotional claims not supported by data. A common deficiency: “Revise labeling to include [specific warning/precaution].” Or “Clarify the intended use – labeling indicates a broader use than studied.” If your labeling suggests a use beyond what your data support, FDA will flag that. If you didn’t include necessary caution statements (e.g., MRI safety status for an implant, if applicable), they’ll ask. Poor patient labeling (for patient-used devices) is another area – FDA may say provide a better patient guide or simplify language.
Develop labeling carefully, referencing FDA’s labeling guidances and device-specific requirements. Ensure the Indications for Use in labeling exactly matches the studied indication. Include all known contraindications, warnings, and precautions gleaned from your trials and similar devices. If your device type has known risks, proactively put them in warnings. Cross-check labeling claims against your PMA data; remove or soften any claim not directly supported. Use clear language, especially in patient labeling – consider user testing for clarity if needed. If applicable, include statements required by regulation (like the prescription device caution, sterilization method, single-use only, etc.). Also, consider that the advisory panel or FDA might request additions – think ahead: for example, if your trial excluded certain patient groups, add a precaution about untested populations. By delivering robust labeling initially, you reduce back-and-forth with FDA on that front.
If FDA or an advisory panel (or prior interactions) raised specific concerns and you didn’t address them in the PMA, expect a deficiency. For example, an advisory committee might have in a prior meeting (for a similar device) recommended certain testing or analysis – FDA might ask why you didn’t do likewise. Or if FDA’s guidance on your device type says “we recommend testing A, B, C” and you only did A and B, they’ll likely ask about C.
Do your homework on FDA expectations. Review any relevant FDA guidance documents, standards recognition, and even advisory panel transcripts for similar devices. Address those points either by performing the recommended tests or explaining why not needed. Document in your PMA pre-submission meetings outcomes: “FDA agreed in Pre-Sub that test C could be deferred to postmarket” – then FDA reviewers see that rationale. Essentially, show FDA you were aware of and considered their known concerns. This level of preparedness can prevent a deficiency letter essentially rehashing known guidance.
Think of your PMA as if you were writing the FDA’s review memo for them – make it easy for them to find everything and to say “yes.” Perform a mock review: have regulatory experts (like ADBC CRO team members not involved in writing) review your near-final PMA as if they were FDA, to spot any weak areas or likely questions. It’s better you find and fix an issue than FDA finding it. Utilize checklists such as FDA’s “refuse to file” criteria and premarket report guidance.
Finally, even the best PMA may still get some FDA questions – that’s normal. The key is to minimize major deficiencies and avoid easily preventable mistakes. This keeps the review focused on substantive scientific issues rather than paperwork issues. By avoiding common pitfalls – missing pieces, sloppy data presentation, unsupported claims – you expedite your path to approval. ADBC CRO’s deep experience with PMAs can help audit and polish your submission so that when FDA opens that binder (or eSTAR file), they nod in approval at the completeness and quality, rather than jotting down a laundry list of deficiencies.
