Implementing the Generic Drug User Fee Act: Struggles and Successes

Two years into the Generic Drug User Fee Act (GDUFA) program, enacted in July 2012, FDA officials are striving to meet goals and timelines for speeding new generic drugs to market. Agency reviewers have made some progress in eliminating the huge backlog in abbreviated new drug applications (ANDAs) pending in the Office of Generic Drugs (OGD), but not as quickly as manufacturers had anticipated. New guidance from FDA aims to help manufacturers meet standards and to streamline oversight. But a continual rise in submissions to the agency makes it hard for reviewers to get ahead, especially in the wake of a surge of 600 ANDAs filed in June to beat new stability testing requirements.

An efficient and comprehensive generic-drug review program is important for FDA to facilitate consumer access to high quality, low-cost generic drugs. Unfortunately, manufacturing problems with generics continue to precipitate recalls and shortages. FDA has blocked the import and sales of numerous generic products from leading manufacturers such as Wockhardt and Dr. Reddy’s Laboratories. And dissolution problems with beta blocker metoprolol have raised new concerns about the safety and efficacy of extended-release generic drugs.

Quality lapses make it difficult for the generic-drug industry to challenge policies linked to enhanced drug safety and prescribing. An FDA proposal to require label updates when new safety issues arise has generic-drug makers up in arms. Brand manufacturers support the FDA policy as a way to reduce their liability for quality and safety issues involving generics. But generic-drug firms fear that differing labels on brands and generics will confuse and alarm patients and prescribers. A recent survey sponsored by the Generic Pharmaceutical Association (GPhA) indicates that physicians and pharmacists would be less willing to prescribe and dispense generics if the rule is adopted, and many members of Congress have voiced concerns over the FDA proposal (1).

Similar issues regarding the “sameness” of generic and brand-name drugs have ignited battles over the labeling and distribution of future biosimilars. Brands are fighting generic-drug manufacturers over whether follow-on biologics can use the same name of the reference product, while also seeking curbs on automatic dispensing of biosimilars by pharmacists.

Promoting quality
FDA officials have long maintained that generic drugs that meet its rigorous standards for bioequivalence, stability, dissolution, and quality are just as safe and effective as the original brand. But ongoing problems with generic-drug quality have spurred new efforts by the Center for Drug Evaluation and Research (CDER) to ensure drug quality throughout the product life cycle.

CDER director Janet Woodcock’s strategy is to establish a new Office of Pharmaceutical Quality (OPQ) to implement a “one quality voice” approach. OPQ will feature review teams that assess the chemistry and controls aspects of a drug product from new drug application (NDA) through generic and over-the-counter versions. While seeking higher-level approval of the OPQ reorganization, CDER is piloting this approach, explained Woodcock at GPhA’s CMC workshop in June, noting that one team reviewing the reference drug and all later versions will avoid duplication.

OGD also looks to a risk-based approach to its chemistry review program to focus efforts on products that raise more crucial issues. OGD is implementing risk-based quality assessment for solid oral-dosage forms, based on a “failure mode, effects and criticality analysis” algorithm that assigns a risk score to each product. This approach is being tested now, explained Susan Rosencrance, OGD acting deputy director for chemistry, with the intent of expanding it to immediate release solid orals and other dosage forms.

OGD efforts to accelerate its review process have been hampered, though, by the steady rise in ANDAs and supplements. During GDUFA negotiations two years ago, industry and FDA estimated that approximately 700 new ANDAs would be filed each year, she noted. In fact, the volume exceeded 1000 last year and continues to climb, making it impossible for the agency to eliminate the backlog as fast as expected and creating concerns about how FDA will meet faster review goals that start to phase in next year.

The solution, from FDA’s perspective, is for manufacturers to submit more complete and high quality applications in the first place. This step would reduce review cycles and the need for multiple amendments that extend the review time frame. OGD acting director Kathleen Uhl emphasized the importance of high quality submissions at the GPhA workshop. Just filing more data does not necessarily make for a quality application, Uhl noted. OGD wants submissions to clearly demonstrate an understanding of the product and process and to avoid “superfluous data” that tries to cover up problems.

To this end, FDA issued draft guidance on ANDA content and format in June, identifying basic requirements for a complete, high-quality application (2). The guidance specifies the information to be provided in each section of an application, following the format of the Common Technical Document (CTD) developed under the International Conference on Harmonization (ICH). It also summarizes the statutory and regulatory requirements for ANDAs and provides references to other guidance documents.

The content and format guidance builds on an advisory issued last year on what ANDAs should include to avoid rejection under the agency’s Refuse to Receive (RTR) policy. FDA’s draft RTR guidance indicates what can trigger an RTR, including faulty listing of active and inactive ingredients, poor packaging information, lack of dissolution studies, and inadequate stability data (3). Last year, FDA issued multiple RTR letters to companies that failed to pay GDUFA facility user fees on time, but recently revised its policy to limit RTRs to applications clearly in arrears on fees or with serious shortcomings.

FDA also is updating and clarifying stability testing and assessment requirements for generic drugs as key to minimizing queries, reducing stability failures, and enhancing generic-drug quality overall. A final stability guidance for ANDAs was published in June 2013 (4), and FDA sought to clarify policy specifics in a Question & Answer guidance issued in May (5). Rosencrance acknowledged that the new policy represents “a huge change for industry,” and manufacturers raised multiple questions at the GPhA workshop about how FDA will implement the many specific requirements. But FDA is hopeful that the revision will be beneficial over the long run.

Despite these and other challenges, Uhl reported at the workshop that OGD has made progress in meeting key GDUFA goals. Some initial action has been taken on almost 50% of backlog applications, and she sees progress towards achieving parity in domestic and foreign plant inspections. OGD aims to finalize the RTR policy this year and to issue additional guidance on ANDA amendments and on manufacturing supplements. FDA is hiring more chemistry reviewers, as supported by GDUFA, and hopes to bring on board 140 new reviewers by fall. These efforts aim to help assure the high quality of generic medicines, which, said Uhl, is “imperative in assuring the American public that theproducts you make are of high quality.”

References
1. GPhA, Healthcare Professionals’ Perspectives (2014), www.gphaonline.org/media/cms/GPhA_Report_v2_4_FINAL_2_.pdf, accessed July 10, 2014.
2. FDA, Draft Guidance, Content and Format of Abbreviated New Drug Applications (June 2014).
3. FDA, Draft Guidance, ANDA Refuse-to-Receive Standards (October 2013).
4. FDA, Final Guidance, Stability Testing of Drug Substances and Products (June 2013).
5. FDA, Final guidance: Stability Testing of Drug Substances and Products, Questions and Answers (May 2014).