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Regulatory Focus™ > News Articles > 2020 > 9 > Generic drugmakers get guidance on tentative approvals, CRLs

Generic drugmakers get guidance on tentative approvals, CRLs

Posted 28 September 2020 | By Kari Oakes 

Generic drugmakers get guidance on tentative approvals, CRLs

Generic drug makers received a final and a draft guidance from the US Food and Drug Administration (FDA) on 28 September that address components of the submission process for an abbreviated new drug application (ANDA).
The draft guidance for generic drugmakers seeks to address problems created when a sponsor fails to respond to an ANDA complete response letter (CRL) within the timeframe stipulated by federal regulations.
The three choices an ANDA sponsor has on receipt of a CRL are to resubmit the ANDA with material that address the identified deficiencies; withdraw the ANDA; or ask for a hearing. “If an applicant fails to take one of these three actions within one year after issuance of a CRL, FDA may consider this failure to be a request to withdraw the ANDA unless the applicant has requested an extension of time to address all deficiencies identified in the CRL,” said FDA in announcing the availability of the guidance.
Under the Generic Drug User Fee Amendments (GDUFA), FDA has been seeing “a steady increase” of ANDAs that have been sitting in pending status for more than a year after CRL issuance, said the agency in the background section of the new draft guidance. The lengthy response times and multiple extensions that FDA has historically granted generics sponsors are “disruptive” to the ANDA assessment process, especially when the pending status stretches to several years, said the agency. During such long lag times, changes to the US Pharmacopeia requirements and reference drug labeling can make some of the original ANDA content obsolete; staff turnover during the lag also results in inefficiencies when new FDA staff must take up the assessment.
To address the problem of so many ANDAs sitting in limbo after CRLs, FDA clarifies in the guidance that for an applicant who has not submitted all materials necessary to correct deficiencies within 1 year of issuance of a CRL, “FDA may consider this failure to be a request by the applicant to withdraw the ANDA.”
After written notification, the applicant will have 30 days to respond in writing by explaining why the ANDA should not be withdrawn and to request an extension. The guidance details items the sponsor should include in requesting an extension, including why the response was late in the first place, what work remains to be done and evidence of progress toward responding to the CRL, and how much additional time is being requested.  
In evaluating requests for CRL response extensions, the guidance says it will consider whether previous extensions have been granted, what deficiencies were identified in the CRL, and any extenuating factors, such as logistical difficulties, the sponsor may have encountered. Public health considerations will also factor into the agency’s decision about a CRL response extension.
The guidance also details notification requirements when a CRL extension is denied, and timeframes for the sponsor and FDA to communicate after the notification.
In the Federal Register announcement of the guidance, FDA noted particular questions it is seeking answers to during the 60-day public consultation period. These include whether particular types of deficiencies are difficult to address within the 1-year window for CRL response, and why applicants may need more than a year to respond to a CRL.  
FDA finalizes guidance on amendments after ANDA tentative approval
The final guidance, entitled “ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs,” follows a January 2019 draft version. Aside from some technical clarifications the final guidance mirrors the draft, which provides recommendations to sponsors who need to submit amendments to ANDAs for generic drugs that have received tentative approval. The scope of the guidance includes amendments seeking final approval. (RELATED: FDA drafts guidance on tentatively approved ANDAs, Regulatory Focus 16 January 2019)
The final guidance provides background on the ANDA submission process and when tentative approvals are issued.
The guidance carries forward provisions for antiretroviral medications for HIV/AIDS that received a carveout in the draft: “FDA will not delay assessment of amendments to ANDAs submitted and tentatively approved under the President’s Emergency Plan for AIDS Relief (PEPFAR). Under PEPFAR, certain antiretroviral products that have been granted a TA may be distributed for use outside of the United States, even when there is still patent and/or exclusivity protection in the United States. For such products, FDA will set a goal date for assessing amendments to PEPFAR ANDAs consistent with the criteria outlined in the Amendments Guidance,” according to the guidance.
The guidance also addresses how requests for final approvals will be handled, with FDA action depending on whether the requests contain “substantive changes to an ANDA.”
Various situations for ANDA applications with tentative approval status and requests for major or minor modifications are addressed in the guidance; also addressed are such updates as Orange Book and exclusivity changes, and changes to labeling or product quality.
“This guidance also provides recommendations on the timing and content of amendments to tentatively approved ANDAs to facilitate submission in a timely fashion that can result in final approval on the earliest lawful approval date,” said FDA in announcing the availability of the final guidance.  
The guidances are offered as part of FDA’s Drug Competition Action Plan, a program intended to “encourage innovation in drug development and accelerate the public availability of safe, high quality, lower-cost medications,” according to FDA; both guidances are designed to boost the number of affordable generics on the market by helping applicants avoid delays on the path to final approval. The guidance addressing CRL responses, said the agency, should help streamline the ANDA process and help FDA meet its GDUFA requirements and “promote efforts to address deficiencies faster,” said FDA.
Draft guidance
Final guidance


Tags: FDA, generics, US

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