GDUFA II: FDA Looks to Speed Up Generic Drug Approval Process

On 21 October, the US Food and Drug Administration (FDA) will meet to discuss plans for the second iteration of the Generic Drug User Fee Act (GDUFA II) under which FDA says it will begin offering eight-month and 10-month reviews of abbreviated new drug applications (ANDAs) between 2018 and 2022.

The speed at which FDA reviews and approves ANDAs has been a hot topic lately, particularly as at least 315 generics have doubled in price since 2010 and many of those seeing steep price increases do not have competition.

The discussion around generic drug reviews by FDA also has seen two congressional hearings in the last week – one of which was a grilling of Mylan CEO Heather Bresch over the rising price of EpiPens, which currently have no generic competition, and in another, Sen. Jerry Moran (R-KS) discussed generic approvals with FDA’s Janet Woodcock, specifically on the idea that the “median time it takes for the FDA to approve a generic is now 47 months or nearly four years” despite the addition of about 1,000 new FDA employees and new user fee funds.

Woodcock explained to Moran last week that that 47 months median time includes ANDAs that have been lingering since before the first GDUFA, noting that many generics do not get approved in the first cycle because many of the ANDAs do not meet FDA's standards.

Moran also highlighted the fact that more than 4,000 generic applications are awaiting FDA approval, but 1,575 of those applications are awaiting a response from industry, and only 369 ANDAs have yet to receive some kind of a review communication from FDA. 90% of backlogged ANDAs have received communication on their deficiencies, Woodcock told Moran.

The criticisms come as FDA has been making significant progress to reduce its ANDA backlog. More than 700 generic drugs were approved and tentatively approved in 2015, which was the highest figure ever.

The agency also said in March that it will speed up the review of so-called "sole-source" generic drugs, which could increase competition, help with drug shortages and may even drive down the cost of expensive generics that have no competition.

However, some in Congress want FDA to speed up the review and approval of new generics even more. New legislation unveiled last week would require FDA to expedite the review of generics and make a final decision within 150 days of receiving what Sen. Tom Cotton (R-AR) is calling “Priority Review Abbreviated New Drug Applications (ANDAs).”

GDUFA II and 8-Month Reviews

In terms of the next iteration of GDUFA, FDA acknowledges that enhancements to GDUFA I “did not meet industry's expectations and were reportedly commercially disruptive.”

For GDUFA II, FDA proposes two major changes to its submission review goals: First, the agency would simplify the system so all ANDAs and ANDA amendments would fall within a single, consolidated review goals scheme to streamline program administration, promote review efficiency and ensure that ‘‘no submission is left behind.’’
In addition, GDUFA II would create faster review goals for priority submissions. For an ANDA, standard review would be 10 months from submission and priority review would be eight months from submission.

FDA also says it will strive to “approve approvable ANDAs in the first review cycle; to approve potential first generics on the earliest lawful approval date, if known to FDA; and to tentatively approve first to file paragraph IV ANDAs so as to avoid forfeiture of 180-day exclusivity.

“GDUFA II’s ANDA review enhancements are substantially more specific and programmatic than corresponding elements of GDUFA I,” FDA says in the GDUFA public meeting announcement. “They would refine and enhance the efficiency of the ANDA review process from start to finish. The GDUFA II ANDA review program would start with submission of an ANDA. FDA would strive to determine whether to receive an ANDA within 60 days of the date of ANDA submission.”

Program Fee

Meanwhile, in order to provide a more predictable revenue base for FDA, GDUFA II will include an annualized ‘‘program fee’’ for ANDA holders.

“This annual fee will help offset the fluctuations in application fees from one year to another. An ANDA sponsor will pay a fee based on the total number of approved ANDAs that it and its affiliates own. ANDA sponsors will be split into three tiers based on ANDA ownership,” FDA says. “The proposed tier cutoffs were determined by industry and are meant to reflect a firm’s size, position in the market, and reliance on the program. With the introduction of the program fee, FDA has eliminated the fee for PASs.”

Under GDUFA II, no facility or ANDA sponsor would be charged an annual fee until an ANDA in which it is listed is approved.
In addition, the proposed new fee structure adds a facility category for contract manufacturing organizations (CMOs). CMOs will pay one-third the annual fee paid by firms that manufacture under ANDAs which they or their affiliates own, FDA says.

New Guidance

Building off product-specific bioequivalence guidance issued earlier in 2016, FDA says it will issue product-specific guidance identifying the methodology for developing drugs and generating evidence needed to support ANDA approval for 90% of new chemical entity new drug applications that are approved on or after 1 October 2017, at least two years prior to the earliest lawful approval date.

FDA also expects to issue a manual of policies and procedures (MAPP) setting forth a plan for reviewers on communication of minor technical deficiencies and on deficiencies potentially resolved with information in the ANDA at original submission, in order to provide applicants with an opportunity for resolution within seven calendar days. If such a deficiency is resolved within seven calendar days, FDA says that deficiency “would not be a basis for a refuse-to-receive decision.”

In addition, FDA is planning other changes that would result in more opportunities for ANDA applicants to address deficiencies within the current review cycle, instead of waiting to receive them in a complete response letter (CRL).

“Such ‘rolling review’ would promote a more efficient and effective review process and increase the overall rate of ANDA approval. During the review, to provide transparency concerning review status and the potential timing of FDA action, regulatory project managers would timely provide review status updates upon request of an applicant’s authorized representative, notify applicants of certain likely forthcoming major deficiencies, and notify applicants if FDA is likely to miss the goal date for a submission,” the agency adds.

FDA also would grant appropriate requests for teleconferences concerning first cycle major and subsequent CRLs. There is also a proposed GDUFA II pre-ANDA program for complex generics.

With respect to dispute resolution, the proposed Commitment Letter would provide that applicants may review requests for reconsideration at the Division level or original signatory authority, as needed, and there would be metric goals for FDA to respond to appeals above the Division level.

DMF Enhancements

GDUFA II also proposes enhancements of current drug master file (DMF) review procedures.

DMF review comments submitted to the DMF holder would be issued in parallel with review comments relating to the DMF for the ANDA, FDA says, noting the proposed Commitment Letter would also establish procedures and timelines for teleconferences to clarify DMF first-cycle review deficiencies.

“Once a DMF has undergone a full scientific review and has no open issues related to the review of the referencing ANDA, FDA would issue a First Adequate Letter. Once the DMF has undergone a complete review and the ANDA referencing it has been approved or tentatively approved, FDA would issue a No Further Comments Letter. By FY 2019, FDA would issue a guidance regarding post-approval changes to a Type II DMF and submission mechanisms for ANDA applicants who reference it,” the agency says.

As far as improvements for manufacturers, FDA says that in order to mitigate export-related challenges identified by US-based API manufacturers, FDA expects to issue guidance explaining the risk-based site selection model, undertake outreach to foreign regulators on the risk-based site selection model and to convey the current compliance status of US manufacturing facilities to foreign regulators.

For more information on GDUFA II, FDA posted minutes of its discussions with industry and other stakeholders.