How FDA decides to refuse a generic drug application

In fiscal 2025, FDA refused to receive 18 original generic drug applications, according to the agency's monthly activity report for that year¹. The agency's report for fiscal 2018⁸ counted 127. Over those seven years the number of applications arriving each year also fell, from 1,044 to 600, but refusals fell much faster.

A refuse-to-receive letter, which FDA staff shorten to RTR, is the earliest way a generic can fail. It comes before any scientist judges whether the copy works like the brand. It says only that the abbreviated new drug application, or ANDA, is too incomplete to review at all, and it sends the applicant back to the start of the line with only part of its fee returned.

The rules behind that decision sit in one federal regulation, one FDA guidance document from 2016 and two internal manuals. Together they explain why the count has dropped, and what still gets an application turned away at the door.

What "received" means in the regulation

For a brand-name drug, FDA "files" an application. For a generic it "receives" one. Under 21 CFR 314.101(b)⁹, receipt "means that FDA has made a threshold determination that the abbreviated application is substantially complete." If the application was complete on the day it arrived, FDA treats it as received as of that date.

Section 314.101 lists the grounds for refusal in two tiers. Paragraph (d) says FDA "may" refuse an ANDA that lacks a completed application form, is not in the required format, or "does not on its face contain information required" by the statute. In judging that last point, the regulation says, FDA "will consider the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies." Paragraph (e) lists cases where FDA "will" refuse, such as a product that must be licensed as a biologic.

After a refusal, the regulation gives the applicant three choices. It can withdraw the ANDA, correct the problems and resubmit, or do nothing, in which case "FDA may consider the ANDA withdrawn after 1 year."

Staff in the Division of Filing Review, part of FDA's Office of Generic Drugs, do the check. They work from a module-by-module checklist attached to MAPP 5200.14¹⁶, the office's internal manual on filing review, revised in October 2023. They look for a signed Form FDA 356h, a patent certification for every patent listed for the brand, the right reference product, comparative dissolution data, stability data and dozens of other items. Under the GDUFA III commitment letter¹², FDA "will strive to determine whether to receive ANDAs within 60 days." Its fiscal 2025 performance report to Congress¹³ puts the average time to a receipt decision at 38 days.

The nine-deficiency line

FDA's guidance, ANDA Submissions: Refuse-to-Receive Standards¹⁰ (Revision 2, December 2016), turns the regulation's "major or minor" language into a count. A major deficiency is one FDA judges "significant in nature," and a single one gets the application refused. A minor deficiency is "minor in nature and can be easily remedied."

If reviewers find nine or fewer minor problems, FDA notifies the applicant and allows seven calendar days to fix them. "Numerous minor deficiencies" also count as a major deficiency, the guidance says, and ten or more get the application refused. An internal manual, MAPP 5220.3¹⁷, tells filing staff to send those seven-day requests as information requests, by email in most cases. The GDUFA III letter adds a faster track, under which FDA will flag "minor technical deficiencies (e.g., document legibility)" within 10 days of submission, and if the applicant fixes one within 10 days it cannot be a basis for refusal.

A refused application that comes back is treated as a new submission, with a new receipt date and a new fee, the guidance says. The fee is large. FDA's fee notice for fiscal 2027¹⁴, which began Oct. 1, 2026, sets the ANDA fee at $375,684. The user fee statute, 21 U.S.C. 379j-42(a)(3)(D)¹⁵, requires FDA to refund 75 percent of the fee for an application it does not receive "for a cause other than failure to pay fees."

An application refused for unpaid user fees is handled differently. The guidance lists six fee situations that lead to refusal, from failing to pay the ANDA fee within 20 calendar days to citing a factory on FDA's facility arrears list. Once the money is paid, FDA issues a letter giving the application an adjusted receipt date. The money questions behind those rules are covered in GxRadar's explainer on GDUFA user fees.

What gets an application turned away

FDA's 2016 guidance names specific major deficiencies. It is not a complete list, the agency says, but it describes what reviewers have seen most often.

Each of those maps to a topic GxRadar has covered separately, from the Inactive Ingredient Database and Q1/Q2 sameness to tablet scoring and the 80-125 bioequivalence rule. FDA also published a separate guidance on refusals for unjustified impurity limits¹¹ in 2016.

A ranking of reasons from an earlier period appears in the same document. In fiscal 2015, it says, the five most frequent bases for refusal were "inadequate stability data; incomplete information request response; inadequate dissolution; drug product was not qualitatively and quantitatively the same (Q1/Q2 same) as the reference listed drug (RLD); and failure to respond to information request within the prescribed timeframe."

How the refusal count fell

From fiscal 2013 through 2015, the guidance reports, FDA refused 379 ANDAs for reasons other than unpaid fees, or 14 percent of original submissions in fiscal 2013, 10 percent in fiscal 2014 and 14 percent in fiscal 2015. Monthly activity reports since fiscal 2018 count refusals of original ANDAs on a consistent basis. GxRadar divided each year's refusals by the raw number of ANDAs submitted that year. A refusal letter can fall in a later fiscal year than the submission it answers, so the share is an approximation.

FDA's performance report to Congress uses a cohort method and gets smaller totals, but the same direction. It counts 37 refusals among 686 applications in fiscal 2023, 21 among 712 in fiscal 2024 and 17 among 468 in fiscal 2025. One slide in the Office of Generic Drugs' April 2026 presentation¹⁹ to a generic drugs forum is titled simply "Reduction in ANDA Refuse-to-Receive."

FDA's documents point to two changes. The 2016 revision reclassified some deficiencies from major to minor, which MAPP 5220.3 says satisfied a GDUFA II commitment to tell applicants about small problems they could fix within days. And the slide that follows the one on refusals in the April 2026 deck points applicants to an FDA resource page on improving the quality of ANDA submissions. Refusal is now a small share of what happens to a generic application. In fiscal 2025 the same monthly report counted 1,281 complete response letters, the rejection that comes after a full review.

Disputes, priority and a 2026 change

An applicant that disagrees with a refusal starts with the email address in the letter, the guidance says. If that fails, it can ask for a teleconference with a filing review team leader, and after that use FDA's formal dispute process above the division level.

Receipt also gates every later benefit. Under MAPP 5240.3¹⁸, decisions about priority review "will not be made until a submission is received for review as discussed in 21 CFR 314.101(b)." The review clock described in GxRadar's piece on ANDA goal dates starts from submission, but the priority decision explained in how FDA prioritizes generic applications waits for receipt. Problems found after receipt are handled through the major and minor amendment system in our explainer on ANDA deficiencies.

One of the old top reasons for refusal is changing. FDA's April 2026 slides say the Consolidated Appropriations Act enacted Feb. 3, 2026, requires the agency to identify the specific inactive ingredient behind a Q1/Q2 sameness failure and quantify the deviation, for ANDAs and related submissions pending on or after that date. Generic approvals that make it past receipt appear on GxRadar's approvals tracker.