A PMA not approvable letter pauses FDA review of a device without ending it. What it means, the 180 day response clock and the options that follow.
Last updated: November 10, 2026
A not approvable letter tells a medical device company that the FDA does not believe its premarket approval application can be approved because of significant deficiencies. It is not a final denial. The review clock stops, and the company can amend, seek review or withdraw, usually within 180 days.
Scope: how FDA decides on original PMAs under the current MDUFA V goals, what each decision letter means, the response clock, and how a not approvable letter differs from a denial order. Novocure’s November 9, 2026 letter for Optune Mya is the worked example.
What is a PMA not approvable letter?
A not approvable letter is the FDA’s notice that it has completed its review of a premarket approval (PMA) application and does not believe the device can be approved because of significant deficiencies. The application stays open, the device cannot be marketed, and the company decides what to do next.
PMA is the pathway for most Class III devices, the highest risk category, where the sponsor has to show reasonable assurance of safety and effectiveness, usually with clinical data. FDA’s PMA review page says the letter will describe the deficiencies, including each applicable ground for denial under section 515(d)(2) of the Food, Drug, and Cosmetic Act, and that “when practical, FDA will identify what is necessary to make the PMA approvable.” The grounds run from inadequate evidence of safety or effectiveness to manufacturing that does not meet quality system requirements and labeling problems.
According to FDA’s guidance on review clocks, the agency generally sends a major deficiency letter first, and moves to a not approvable letter when the applicant’s response does not resolve the issues or interactive review cannot fix them.
What decisions can the FDA make on a PMA?
FDA’s PMA review page lists four actions on a filed application: an approval order, an approvable letter, a not approvable letter, or an order denying approval. A major deficiency letter can come earlier, but FDA’s guidance says it is the one letter that does not count as a MDUFA decision.
| FDA action | What it means | Effect on the clock | Counts as a MDUFA decision? |
|---|---|---|---|
| Major deficiency letter | FDA needs significant additional information | Review stops; resumes at the remaining FDA days on a complete response | No |
| Approval order | Device may be marketed under the approved conditions and labeling | Review ends | Yes |
| Approvable letter | Application substantially meets requirements; specific information or conditions, such as a manufacturing inspection, still needed | Review on hold; new response timeframe on a complete reply | Yes |
| Not approvable letter | FDA does not believe the application can be approved because of significant deficiencies | Review on hold; new response timeframe on a complete reply | Yes |
| Denial order | Final action ending FDA’s review | Review ends | Yes |
Sources: FDA PMA Review Process page; FDA guidance “FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Goals,” October 3, 2022.
How long does the FDA take to review a PMA?
Under MDUFA V, which covers fiscal years 2023 through 2027, FDA’s goal is a MDUFA decision within 180 FDA days for 90% of original PMAs that do not need an advisory committee, and within 320 FDA days for 90% of those that do. FDA days exclude the time a sponsor spends answering questions.
The calendar reality is longer. The MDUFA V commitment letter sets a shared FDA and industry goal for average total time to decision, which includes sponsor response time, of 290 calendar days for fiscal 2023 and 2024 submissions and 285 calendar days for fiscal 2025 through 2027.
| Step | Timing | Source |
|---|---|---|
| Acceptance review | Within 15 calendar days of receipt | FDA guidance, MDUFA V letter |
| Filing decision | Within 45 days of receipt; the 180 day review period starts at filing | FDA PMA review page |
| Day 100 meeting request | Request by day 70 of the review | FDA PMA review page |
| Substantive interaction | Within 90 days of filing for 95% of submissions | MDUFA V letter |
| MDUFA decision, no panel | 180 FDA days for 90% | MDUFA V letter |
| MDUFA decision, with advisory committee | 320 FDA days for 90% | MDUFA V letter |
| After an advisory committee | Decision within 60 days of the recommendation, as resources permit | MDUFA V letter |
| Average total time to decision | 285 calendar days, FY2025 to FY2027 submissions | MDUFA V letter, FDA guidance |
What happens to the review clock after a not approvable letter?
The clock stops. FDA’s guidance says that when it issues a not approvable letter, it stops the review clock and places the application on hold. When it receives a complete response, it resumes the clock with a new response timeframe rather than picking up the old one.
There is no formal performance goal for that second look. The guidance says only that, “although not a performance goal, FDA intends to review a complete response to a not approvable letter within 180 calendar days.” Compare that with an approvable letter, where FDA aims to decide within 60 days of the sponsor’s response, as resources permit. In practice, a not approvable letter can add six months of FDA time on top of however long the company needs to build its answer.
What can a company do after a not approvable letter?
FDA’s PMA review page gives the applicant three options: amend the application as the letter requests, treat the letter as a denial and seek administrative review, or withdraw the PMA.
- Amend. The amendment is treated as a major amendment under 21 CFR 814.37(c)(1). If it carries significant new data, the page says the review period can be extended by up to 180 days.
- Treat it as a denial and seek review. The company can consider the letter a denial under 21 CFR 814.45 and request administrative review by filing a petition for reconsideration under 21 CFR 10.33.
- Withdraw. The company can withdraw the PMA, often to redesign a study or resubmit later as a new application.
A fourth route sits before any of these: meeting with the review team to understand exactly what evidence would close the gap. That is the step Novocure said it is taking.
How long does a company have to respond?
FDA considers a PMA voluntarily withdrawn if the applicant does not respond to a not approvable letter within 180 calendar days, citing 21 CFR 814.44(g). The same rule covers approvable, major deficiency and not filing letters.
The guidance adds a detail the public PMA page leaves out: FDA will automatically grant one 180 day extension, for a total of 360 calendar days. After that, an amendment is treated as a resubmission with a new PMA number and a new user fee. For a company weighing whether it needs a new trial, that 360 day ceiling is the real planning horizon.
How is a not approvable letter different from a denial order?
A not approvable letter keeps the file open; a denial order closes it. FDA’s guidance calls a denial “a final action” that marks the end of review and says it will normally be preceded by another FDA action, such as a not approvable letter, though no statute requires that.
| Question | Not approvable letter | Denial order |
|---|---|---|
| Is review over? | No, the application is on hold | Yes, final action |
| Can the device be marketed? | No | No |
| Can the company respond with data? | Yes, by amendment | Only through review rights or a new submission |
| What triggers it? | Significant deficiencies after FDA review | A deficient amendment, a refusal to amend, or a request for review after a letter |
| Public notice? | Not required by the sources we reviewed | FDA publishes a Federal Register notice, per its PMA page |
| Review rights | Can be treated as a denial to seek review | Order includes notice of the opportunity to request review under the FD&C Act |
Per the PMA page, FDA issues a denial order after an approvable or not approvable letter when the amendment still leaves a ground for denial, when the applicant says in writing it will not amend, or when it petitions for review.
Is a not approvable letter the same as a complete response letter?
No. A complete response letter is what drug and biologic sponsors receive when the FDA will not approve a marketing application. A not approvable letter is a device action under the PMA rules in 21 CFR Part 814, with its own clock, response window and review rights. Coverage often uses the terms loosely, but the timelines that follow are different, so investors and partners should read device letters on device rules.
When does a PMA go to an advisory panel?
FDA’s PMA page says the agency may refer an application to an outside panel and that, in general, all PMAs for a first of a kind device go before the appropriate panel. Later applications for that device type usually do not, unless they raise an issue a panel can best address. The meeting is public, and FDA considers the transcript and recommendation before deciding whether it agrees.
A panel changes the schedule as well as the evidence debate: the MDUFA goal moves from 180 to 320 FDA days.
What did Novocure’s not approvable letter say?
Novocure said on November 9, 2026 that the FDA issued a not approvable letter for its PMA for Optune Mya, a Tumor Treating Fields device, in adults with brain metastases from non small cell lung cancer following stereotactic radiation. The company said the FDA determined that “uncertainty around the degree of clinical benefit” prevented approval and did not raise safety concerns.
Novocure said it is evaluating the feedback and plans to meet with the FDA to see whether any options would support approval without additional clinical studies, adding that there can be no assurance of an approval. MedTech Dive reports the application followed the Phase 3 METIS trial, which delayed brain metastasis progression against best supportive care but showed no difference on secondary endpoints including neurocognitive failure and overall survival. The release does not state the date of the letter, so the exact end of the response window is not public.
The case is a clean example of the category: no safety issue, an effect on the primary endpoint, and a reviewer unconvinced the size of that effect means enough for patients. Those are the letters where the company’s first question is whether existing data, reanalyzed or supplemented, can close the gap, or whether the honest answer is a new trial.
Our framework: a 30 day plan after a not approvable letter
- Map every deficiency to a ground. List each cited ground under section 515(d)(2) and classify it as evidence, manufacturing, labeling or process.
- Separate fixable from fatal. Labeling and manufacturing gaps can often be closed by amendment. A benefit question usually needs new analysis or new data.
- Request the meeting early. Ask the review team which specific analyses or data would make the application approvable.
- Set the clock. Calendar day 180 and day 360 from the letter date, and plan backward from the earlier one.
- Price the options. Compare a major amendment, administrative review and withdrawal with resubmission on cost, time and probability.
- Write the disclosure carefully. Say what the FDA cited, whether safety was raised and what the next step is, and avoid implying a timeline the agency has not agreed to.
What to watch next
- Novocure’s update after its FDA meeting and whether it pursues an amendment without a new study
- FDA’s MDUFA V performance reports on PMA decision times
- Negotiations on the next device user fee agreement, since MDUFA V runs through fiscal 2027
- Any FDA moves on breakthrough device and first of a kind panel policy
Frequently asked questions
What does a not approvable letter mean for a medical device?
It means the FDA has finished reviewing a PMA and does not believe the device can be approved because of significant deficiencies. The device cannot be marketed, but the application is not closed.
Is a not approvable letter a rejection?
It is a negative decision, but not a final one. Only a denial order ends FDA’s review.
How long does a company have to respond to a not approvable letter?
180 calendar days, after which the PMA is considered withdrawn. FDA guidance says one 180 day extension is granted automatically, for 360 days in total.
What happens after 360 days without a response?
Per FDA guidance, a later amendment is treated as a resubmission with a new PMA number and a new user fee.
How long does the FDA take to review a response to a not approvable letter?
FDA says it intends to review a complete response within 180 calendar days, but this is not a formal performance goal.
What is the FDA’s review goal for a PMA?
Under MDUFA V, a decision within 180 FDA days for 90% of original PMAs without an advisory committee, and 320 FDA days with one.
What is the difference between an approvable and a not approvable letter?
An approvable letter means the application substantially meets requirements and needs specific additional information or conditions. A not approvable letter means significant deficiencies stand in the way of approval.
Can a company appeal a not approvable letter?
It can treat the letter as a denial and request administrative review by filing a petition for reconsideration under 21 CFR 10.33, according to FDA’s PMA page.
What is a major deficiency letter?
A request for significant additional information during review. It stops the clock but is not a MDUFA decision, and review resumes at the remaining FDA days once a complete response arrives.
Does a not approvable letter mean the device is unsafe?
Not necessarily. Deficiencies can involve effectiveness, manufacturing or labeling. Novocure, for example, said the FDA raised no safety concerns about Optune Mya.
Is a not approvable letter public?
FDA does not publish a notice for it in the sources we reviewed; companies usually disclose material letters themselves. Denial orders are noticed in the Federal Register.
Sources
Primary
- U.S. Food and Drug Administration, “PMA Review Process,” content current as of May 27, 2025
- U.S. Food and Drug Administration, “FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Goals,” guidance, October 3, 2022
- U.S. Food and Drug Administration, “MDUFA Performance Goals and Procedures, Fiscal Years 2023 Through 2027” (MDUFA V commitment letter)
- U.S. Food and Drug Administration, CDRH Learn, “Introduction to the Premarket Approval Application (PMA) Program”
- Novocure, “Novocure Provides Regulatory Update on US FDA Premarket Approval,” November 9, 2026
Attributed
- MedTech Dive, “Novocure denied FDA approval for metastatic cancer treatment,” November 9, 2026 (METIS trial context)
Related coverage
- 510(k) vs PMA: how medical devices get cleared
- What is a Class I, II or III medical device?
- FDA approval process explained for drugs
- November 10 briefing, including Novocure’s Optune Mya letter
- Siemens Healthineers carves out diagnostics as Olyrian
- BioMed Nexus company directory
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