The FDA Review Recovery Playbook

Whether you have repetitive information requests, escalating deficiencies, gridlocked teleconferences, or have already received a clinical hold, complete response letter, or NSE determination — you need to move quickly and carefully.

FDA interactions rarely fail in a single moment. Instead, they drift away from the desired outcome through a series of small and seemingly inconsequential actions. But inevitably a company finds themselves in a situation they can’t ignore: the outstanding issues aren’t being resolved, and they are expecting or have already received a letter for a clinical hold, disapproval, or not-substantially-equivalent determination. You’re certainly not alone, and there is a path forward — but you need to be fast and deliberate.

Your mantra is “quickly and carefully.” The immediate concern is timing; the next concern is what to do next. This playbook covers how to recognize a deteriorating situation, what each formal decision letter actually means, and what your options are. It’s here to help you re-orient and make good decisions moving forward.

01 · THE BASELINE

The normal cadence of FDA reviews

Each submission has its own review team, logistics, timeline, decision-making sequence, and final outcome. However, there is a pattern to the reviews that you can see across submission types. Understanding the cadence of FDA’s review helps you understand what’s normal — and what’s not.

Action	Description	People involved
User fee	Selected submissions require a fee, typically for marketing of drugs (NDA, ANDA), biologics (BLA), and devices (513(g), 510(k), De Novo, PMA). If required, the fee must be paid before you may submit.	Each center and user-fee program has its own staff who handle inquiries.
Technical review	Ensures your submission meets technical requirements — such as eCTD, eSTAR, or eCopy — to be submitted to a specific portal such as the Electronic Submissions Gateway (ESG NextGen) or Document Control Centers (DCC).	Each center and submission portal has its own support staff who handle inquiries.
Administrative & filing reviews	Ensures there’s enough information to start the review; the specific information varies by submission type. This is a formal stage for many submissions, but still happens for those without a formal Refuse to Accept or Refuse to File.	Handled by core review-team personnel, but review is surface-level.
Substantive review	Review teams work through the submission. When information or rationale is missing, questions are sent by email, but some submissions can be paused until a formal response is submitted.	The full review team is involved, communicating via a Regulatory Project Manager or Lead Reviewer.
Final decision	Based on all information, FDA makes a final decision on the sponsor’s or applicant’s request — including allowing the product to be marketed in the US or allowing a US clinical study to proceed.	FDA leadership acts on the review team’s recommendation.

02 · EARLY SIGNALS

Read the warning signs before a decision

Deteriorating situations with FDA have a distinct feel, and you can usually sense something is off before anything formal happens. Each situation is unique, so that feeling of “something’s not right” can be a valuable guide. Here are the situations that can mean bad news.

Situation	What happens	Why FDA does this	When to be worried
Repeated requests	The review team sends repeated requests on the same topic, asking for the same thing.	Review teams are encouraged to give sponsors multiple opportunities before a negative decision, to show they’ve tried to resolve the issue.	Be worried when the request isn’t evolving.
Extensive references to prior feedback	Deficiencies or information requests make multiple references to prior FDA interactions or submissions.	Review teams are encouraged to show consistency in their feedback and decisions, demonstrated by the consistency of the request.	Be worried when multiple instances of prior feedback are referenced.
FDA ignores submitted information	FDA asks questions but appears to ignore information you submitted.	Review teams aren’t required to reference every submitted item, but ignoring it signals a major misalignment between company and team.	Be worried when FDA continuously ignores information you view as critical to a decision.
Jurisdiction	FDA is uncertain whether your product is in the right place (drug, biologic, device, or combination product).	The team must confirm the product is appropriate before proceeding, or determine whether a formal jurisdictional assessment is needed.	Be worried when FDA asks about what your product does or its mechanism of action very early in the review.

SILENCE FROM FDA IS NOT APPROVAL

FDA’s position on claims may feel unpredictable, and lengthy review times create a considerable lag between a problem and any action. But that lag doesn’t mean the review is healthy. Trust the signal when the requests stop evolving and start looking backward.

03 · THE LETTERS

Different outcomes, different language

Each submission has its own set of decisions with FDA-specific language. IDEs are approved or disapproved, but this language does not apply to INDs — the effect may be the same, but INDs are put on clinical holds or allowed to proceed, not approved or disapproved. Understanding the specific language helps you recognize what’s happening.

Action	Submission type	What it means
Clinical hold	Investigational New Drug (IND)	An order that prevents the initiation of a clinical study for a new investigational drug or biologic, typically because of a safety question. Must be resolved by a formal response before the study may begin.
Disapproval	Investigational Device Exemption (IDE)	An order that prevents the initiation of a clinical study for a new investigational device due to safety concerns. Must be resolved by a formal response before the study may begin.
Complete response letter (CRL)	Biologics License Application (BLA) or New Drug Application (NDA)	The drug or biologic may not be marketed in the US. The applicant must address each item in the complete response in a formal response.
Not substantially equivalent (NSE)	510(k) review	The device may not be marketed in the US. There are multiple reasons for NSE; the sponsor may need to submit a new 510(k) with new data, or submit a De Novo or PMA.
Denied / disapproved	De Novo / Premarket Approval (PMA)	The device may not be marketed in the US. The sponsor must address each item in the letter in a new submission (De Novo) or response (PMA).
Jurisdiction decisions	All submission types	The review team is uncertain about, or disagrees with, a product’s jurisdiction — often a combination product in the wrong center, or a product mis-identified as a device that may be better regulated as a drug or biologic. Typically resolved with the Office of Combination Products (OCP) via a Pre-Request for Designation (Pre-RFD).
Refuse to Accept (RTA) / Refuse to File (RTF)	Marketing submissions (NDA, BLA, 510(k), De Novo, PMA)	The application is too incomplete to review. The applicant must provide the missing information in response to the RTA/RTF.

04 · YOUR MOVES

How to move quickly and carefully

FDA is always on a clock, whether you have a submission under review or have already received a decision. FDA has congressionally mandated reporting for PDUFA and MDUFA review times, and those clocks keep ticking after the decision. This means FDA typically cannot pause an ongoing review or give you extra time to think. Each day counts at every stage — if you think you’re headed in the wrong direction, you need to move.

If your submission is still under review, the biggest decision is whether to continue or withdraw:

• Continue to a final decision. This can help you understand which outstanding items must be resolved for the decision versus a “nice to have” the team has requested. FDA reviewers are prevented from recommending that you withdraw, but withdrawal is always an option before a final decision — and can be the right one.
• Withdraw the submission. Withdrawing removes your option to appeal, but may be more palatable to investors by avoiding a final, written statement from FDA that your product isn’t safe or effective.

Either way, talk to an expert. You shouldn’t make this decision alone, and moving carefully is just as important as speed. Get input as soon as possible on whether there’s any chance of success this cycle or whether it’s better to withdraw and regroup.

If FDA has already made a decision, your time-critical decision is what comes next:

• Appeals. Post-decision options include appeals to different levels (Office Director, Center Director, or Commissioner) and least-burdensome requests for certain device submissions. These must be submitted in a timely manner, usually 30 to 60 days after the letter. Appeals can result in the decision being upheld, overturned, or returned to the team to reconsider — highly dependent on your specifics. Casually pursuing an appeal without a clear strategy risks alienating the review team and draining resources, so proceed with caution.
• Post-decision feedback. Mechanisms include a Type A meeting (drugs and biologics) or a Submission Issue Request (SIR; devices). Like appeals, these must be received in a timely manner, usually within about 60 days. They’re less contentious and carry less risk of alienation, but require additional resources and time — and they don’t revisit the decision itself, only how to move forward.
• Responding and resubmitting. Sometimes it’s appropriate to simply address the outstanding item and resubmit or respond. This works best when the request is clear and uncomplicated.
• Talk to an expert. Whatever you think is right, you need input specifically from an expert to understand the best option for your situation before you proceed.

05 · THE RIGHT HELP

Get the right help

You’re ready to move quickly. Regardless of submission type or where you are in the review, you need to talk to the right expert to confirm your options and the best course of action for your specific situation. The person you need is not your average former FDA reviewer or standard regulatory-affairs consultant. There’s a big difference between responding to deficiencies on a submission that was always going to succeed and interacting with FDA on a submission that has been at serious risk of an adverse outcome from the beginning.

You need someone with extensive experience with submissions on the edge, who understands how FDA’s leadership makes those decisions. There’s no substitute for experience actually making decisions at FDA. Experience with appeals and adverse decisions from inside the Agency cannot be gained anywhere else, and it’s critical for navigating these situations. You’re looking for a select group of people with higher-level experience inside the Agency who have been in these situations.

MOVE QUICKLY AND CAREFULLY. TALK TO SOMEONE. NOW.

Now you know what your options look like and who to talk to. Remember your mantra — quickly and carefully — and don’t wait for the clock to make the decision for you.

FDA sources & references

• 21 CFR 312.42 — Clinical holds and requests for modification: Grounds for a clinical hold and the 30-day complete-response timeline. fda.gov ↗
• 21 CFR 312.48 — Dispute resolution (IND): Reconsideration and escalation of disputes during the IND process. fda.gov ↗
• 21 CFR 314.110 — Complete response letter to the applicant: What a CRL is and the applicant’s three options after receiving one. fda.gov ↗
• 21 CFR 314.103 — Dispute resolution (NDA/ANDA): Division-level and higher review of application disputes. fda.gov ↗
• 21 CFR 10.75 — Internal agency review of decisions: The agency-wide mechanism behind formal dispute resolution. fda.gov ↗
• 21 CFR Part 807, Subpart E — Premarket notification (510(k)): Substantial-equivalence requirements and the basis for an NSE determination. fda.gov ↗
• Guidance for Industry: Submitting and Reviewing Complete Responses to Clinical Holds: FDA procedures for responding to and lifting a clinical hold. fda.gov ↗
• Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products: Type A, B, and C meetings, including post-action meetings after a CRL. fda.gov ↗
• Guidance for Industry and Review Staff: Formal Dispute Resolution — Sponsor Appeals Above the Division Level: How to appeal a scientific or medical decision above the review division. fda.gov ↗
• Guidance: The 510(k) Program — Evaluating Substantial Equivalence in Premarket Notifications [510(k)]: FDA’s decision framework and the reasons a device is found NSE. fda.gov ↗
• Guidance: De Novo Classification Process (Evaluation of Automatic Class III Designation): Route to Class I or II marketing authorization after an NSE for a novel device. fda.gov ↗
• Guidance: CDRH Appeals Processes: Appealing significant device decisions under section 517A and 21 CFR 10.75. fda.gov ↗

Is your FDA review heading the wrong way?

Deffai’s former FDA reviewers and directors have participated in appeals, including commissioner-level appeals. We understand how FDA makes decisions because we’ve been in those leadership roles. If your FDA review feels like it’s drifting off-track, get perspective from our team today.

Johnny Lam, PhD — Head of Regulatory Strategy · Laura Rose, PhD — Cofounder & Chief Regulatory Officer

This document is general educational information about FDA review setbacks — such as clinical holds, complete response letters, and not-substantially-equivalent determinations — and about the options available to sponsors and applicants. It is not legal or regulatory advice and does not create an attorney–client or consulting relationship, nor does it substitute for FDA’s guidance documents or the applicable regulations. Regulatory strategy is highly product- and indication-specific, and FDA’s views are informal and non-binding. Confirm current FDA procedures and consider professional review of your specific program before acting.