New Era for Generic Drugs

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Pharmaceutical Technology, Pharmaceutical Technology-10-02-2012, Volume 36, Issue 10

The promise of the Generic Drug User Fee Amendments of 2012 is to end multiyear reviews of new generic drugs and the ever-growing queue of pending applications.

The promise of the Generic Drug User Fee Amendments of 2012 (GDUFA) is to end multiyear reviews of new generic drugs and the ever-growing queue of pending applications. After years of resistance, generic-drug makers agreed last year to provide funds to FDA to support speedier approval of abbreviated new drug applications (ANDAs) and prior approval supplements (PASs), as well as timely inspection of domestic and foreign manufacturers and suppliers of APIs.

Jill Wechsler

To launch the new fee program on Oct. 1, 2012, FDA issued a wave of Federal Register notices and guidance documents in August 2012 that officially inform manufacturers of relevant procedures and obligations. The various fees authorized by GDUFA will provide $299 million in funding for FDA in fiscal year 2013 and $1.5 billion over five years. Application fees of approximately $50,000 will add up to almost $100 million, primarily from payments on an expected 750 to 900 ANDAs each year, plus some 750 supplements. Approximately $15 million will be levied on newly referenced (type II) drug master files (DMFs) on a one-time basis according to a fairly complex process; an FDA Q&A guidance spells out specifics on this and other issues and how fees will be calculated (1).

Identifying facilities

Approximately $175 million in fees will be levied annually on facilities operated by manufacturers of both finished dosage forms (FDFs) and API producers, the majority (approximately $140 million) collected for FDFs. The payments will be $15,000-$30,000 higher for foreign facilities to reflect added inspection costs, and plants that produce both finished drugs and APIs will pay both fees. One tricky issue is how to account for facilities with several buildings at one site. Such complexes may owe only one fee if FDA determines that the site can be inspected at one time, based on activities and ownership structure. But one company with several distinct facilities most likely will pay fees for each location.

This manufacturer "self identification" program expects to collect information from 3000 or so organizations, facilities, and sites utilizing existing electronic data submission processes and familiar file formats to reduce the data collection burden on the agency and industry (2). Manufacturers will provide Data Universal Numbering System numbers and Facility Establishment Identifiers plus physical addresses and contact details. Various producers have to register with FDA, but do not have to pay fees, including repackagers, manufacturers of positron emission tomography drugs, and sites conducting bioequivalence or bioavailability studies and other analytical testing.

In addition to determining who has to ante up, FDA expects the facility identification program will provide important information to promote global supply chain transparency. The data will go into new generic-drug facility databases, which will provide information to help FDA address global supply chain issues. Among other stated goals, FDA will conduct biennial GMP surveillance inspections of generic API producers and product manufacturers, with the aim to achieve parity in inspection frequency between foreign and domestic firms in 2017.


Cutting the backlog

FDA's Office of Generic Drugs (OGD) also will collect a one-time ANDA backlog fee this year on pending ANDAs, which will generate an expected $50 million to support the processing of almost 3000 ANDAs currently in the application queue. Many of these applications are categorized as "incomplete" or were hit with "not approvable" or "complete response" letters years ago, but were not withdrawn by the manufacturer. The initiative aims to clear out 90% of the ANDAs and amendments in the backlog by 2017.

Hot-Topic Roundup

FDA would like to whittle down the backlog before launching the GDUFA backlog program and announced in June that it plans to cancel backlogged applications that have not involved any communication with the sponsor since 1991. An August Federal Register notice further encourages manufacturers to withdraw backlogged applications that they no longer wish to pursue (3). The agency calculated that if 2000 applications remain in the backlog (of the 3000 pending in August), the backlog fee would be $25,000 per application.

FDA also promises to meet a range of GDUFA performance goals outlined in a commitment letter to manufacturers that is structured similarly to programs that have been in place for brand drugs for 20 years (4). Under a phased-in approach, FDA will "review and act on" 60% of ANDA submissions within 15 months by the third year of the program; the timeframe tightens in year five to review of 90% of submissions within 10 months. ANDA evaluation will take longer if a manufacturer files major amendments during the review process, and OGD won't accept an ANDA until the application fee is paid, a situation that could be important in determining which generic firm is "first to file."

OGD will strive to clarify review decisions by issuing complete response letters and DMF "completeness assessments," instituting rolling reviews, and holding first cycle deficiency meetings with sponsors. If minor problems crop up during a review, OGD staff will try to inform sponsors of "easily correctable deficiencies" that can be remedied quickly. OGD reviewers expect that issues raised in complete response letters will be addressed initially through teleconferences with the agency; eventually GDUFA will provide time and resources for sponsors to meet with OGD reviewers in person to discuss specific complete response letter issues.

Sponsors still may file applications on paper, but FDA does not have to meet user-fee performance goals unless the ANDA is filed electronically, a process that FDA expects will become universal in the near future. FDA would like to see continued improvement in the quality of applications to reduce the frequent back-and-forth questioning that routinely delays approvals. OGD has been encouraging generic-drug makers to adopt quality-by-design (QbD) approaches by issuing sample pharmaceutical development reports with QbD principles for both immediate-release and modified-release solid oral dosage forms. The agency recently updated its Question-Based Review system to incorporate QbD models and has tightened initial criteria for filing ANDAs to discourage incomplete submissions. OGD has established a central system to track the progress and status of each application as it moves through the review process, and a broader OGD quality management system aims to clearly document procedures to provide more consistency across review divisions. Some of the GDUFA revenues also will support development of further guidance and research to facilitate development of more complex generic products, such as anti-epileptic drugs and inhaled products.

FDA held a public meeting in September to review with manufacturers these and other program implementation issues. GDUFA policies also were a prime topic at the PDA/FDA Joint Regulatory Conference on September 11, 2012 in Baltimore and at the fall technical conference on Oct. 2-3 sponsored by the Generic Pharmaceutical Association.

Implementing GDUFA will involve a significant expansion in OGD staff on all levels, along with extensive training for new hires and expanded IT systems. To provide the broader management structure needed to oversee this more complex generic drug program, CDER director Janet Woodcock recently announced plans to elevate OGD to a "super office" with other offices reporting to it. Instead of being part of CDER's Office of Pharmaceutical Science (OPS), OGD will be a parallel umbrella organization, similar to CDER's Office of New Drugs and Office of Compliance. New OGD director Greg Geba will head the super OGD, reporting directly to Woodcock and better positioned to work with CDER's Office of Executive Programs on GDUFA implementation.

The larger plan is to replace OPS with a new Office of Pharmaceutical Quality (OPQ), which will be responsible for overseeing drug quality throughout the product lifecycle. The new OPQ will absorb certain OPS functions as well as some activities performed by the Office of Manufacturing and Product Quality in the Office of Compliance. And, when we went to press, there was considerable anxiety that Congress would fail to enact an FDA appropriations bill by Oct. 1, which is needed for the agency to collect any 2013 user fees. Hopefully, that impass will be remedied by the time you read this report.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, Read Jill's blogs at


1. FDA, Guidance for Industry: Generic Drug User Fee Amendments of 2012, Questions & Answers (FDA, Rockville, MD, August 2012).

2. FDA, Guidance for Industry: Self-Identification of Generic Drug Facilities, Sites and Organizations (FDA, Rockville, MD, August 2012).

3. Federal Register Vol. 77, No. 166 (August 27, 2012).

4. FDA, Human Generic Drug Performance Goals and Procedures, Fiscal Years 2013 through 2017, posted at (July 17, 2012).