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FDA Reissues CRL Guidance for Generic Drugs After Five Months

The FDA has reissued a July 2022 guidance for complete response letters (CRLs) for generic drug applications after only five months, although the December 2022 version was made necessary by the newest version of the generic drug user fee agreement. Perhaps the most important feature of the revised guidance is that it allows the FDA to reclassify a minor amendment to a generic drug application as a major amendment when the manufacturer submits that amendment more than a year after receiving a CRL.

The guidance stated that the FDA has seen a steady increase in the delays of abbreviated new drug applications since passage of the first Generic Drug User Fee Agreement (GDUFA I) in 2012. The FDA has often granted multiple extensions to manufacturers that receive a CRL for their application, but this can result in a response to deficiencies that arrives multiple years after the CRL. Among the problems that have emerged in connection with these delays are that the manufacturing facility evaluation may become outdated, turnover among the FDA’s review team for that application, and changes to requirements under the U.S. Pharmacopeia may render obsolete some of the information in the application.

GDUFA III provided several enhancements to the generic drug program that are intended to reduce the average number of cycles an ANDA application goes through before approval. The target performance goals for GDUFA III include action on 90 percent of standard original ANDAs within 10 months of the date of the submission. Another objective is for the FDA to act on 90 percent of standard major amendments within the applicable assessment goal.

Many of the standard deadlines found in the July 2022 version of the guidance remain unchanged, but the December 2022 version highlights the change in handling of minor amendments to the application. There are exceptions to the policy of converting a minor amendment to a major amendment after a year has passed since the date of the CRL, such as when the pharmaceutical is on the FDA drug shortage list. Another possible exception is when the pharmaceutical is part of a response to a public health emergency or may be included in the response at a later date.

The applicant has a year to either fully address all deficiencies identified in a CRL or file an amendment that includes a request for an extension. Failure to do so will result in an FDA notice of a presumed withdrawal of the application, but the applicant has 30 days to respond to this notice. That response must include an explanation of why the ANDA application should not be withdrawn and a formal request for an extension. The request for an extension should include an explanation as to why the manufacturer could not address the deficiency in the application within the time given.

Among the factors the FDA will contemplate when considering a request for an extension are the number, length and reasons for any previously granted extensions and the number and types of deficiencies identified in the CRL. There may be extenuating circumstances beyond the control of the applicant, such as an inability to obtain a sample of the reference listed drug, or the reference standard for that pharmaceutical if it is no longer being marketed.

The appendix in the guidance recites several additional factors that may influence the FDA’s consideration of whether to grant an extension in addition to those already discussed. One example is when the applicant is transferring production of its drug products to a new facility, and when the manufacturer is unable to obtain the active pharmaceutical ingredient (API) from the API manufacturer.


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