At a recent Congressional hearing, representatives from the FDA and the Association for Accessible Medicines (formerly the Generic Pharmaceutical Association) called on Congress to pass re-authorization of the Generic Drug User Fee Amendments (GDUFA), which is slated to expire later this year.

Five years after the enactment of Generic Drug User Fee Amendments of 2012 (GDUFA), which set user fees for the generic drug industry to supplement the costs by the the US Food and Drug Administration (FDA) for reviewing abbreviated new drug applications (ANDAs) and for inspecting drug-manufacturing facilities, the legislation is up for renewal in the US Congress. So what are regulatory agencies and the generic drug industry asking for Congress to do? DCAT Value Chain Insights examines the latest. 

The regulatory perspective

Under GDUFA, the industry is required to pay user fees to supplement the costs of reviewing generic drug applications and inspecting facilities as well as require the FDA to meet performance goals in the review of ANDAs. These additional resources were intended to support the FDA’s efforts to reduce a backlog of pending applications, cut the average time required to review generic drug applications for safety, and increase risk-based inspections. GDUFA is also designed to enhance global supply-chain safety by requiring that generic drug facilities and sites around the world self-identify. The current legislative authority for GDUFA expires at the end of September 2017. At that time, new legislation will be required for the FDA to continue to collect generic drug user fees for future fiscal years. In August 2016, the FDA and the generic drug industry agreed on the terms of a GDUFA reauthorization package, referred to as GDUFA II, ahead of the September 2017 expiration date of  the original legislation. Companion legislation, the Biosimilar User Fee Act of 2012 (BsUFA), which authorizes the FDA to assess and collect fees for biosimilar biological products from October 2012 through September 2017, is also up for legislative renewal.

A hearing of the Subcommittee on Health of the US House of Representatives’ Energy and Commerce Committee on March 2, 2017 brought together stakeholders from regulatory agencies and the generic drug industry to gain their feedback on the reauthorization of GDUFA, also known as GDUFA II, which would set another five years of related measures.The committee heard testimony from Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the US Food and Drug Administration, David Gaugh, senior vice president for sciences and regulatory affairs at the Association for Accessible Medicines (AAM) (formerly, the Generic Pharmaceutical Association), Kay Holcombe, senior vice president of science policy at Biotechnology Innovation Organization, Juliana Reed, immediate past president of the Biosimilars Forum, an organization composed of biosimilar developers, and Bruce Leicher, board chair of the Biosimilars Council, a division of the AAM.

Key aspects of GDUFA for the generic drug industry are applying the additional resources gained through user fees to reduce the backlog of ANDA applications under the FDA’s review; improving communication and transparency with the FDA; enhancements to the FDA’s inactive ingredient database; relief for small businesses under GDUFA; and FDA’s reporting on resource management, planning, and its performance in meeting set goals.

In her testimony before the subcommittee, Dr. Woodcock commented on the progress of the GDUFA program, pointing to recent high approval rates for generic drugs over the time since GDUFA was put into place, citing that approximately 25% of all generic drugs that the FDA has ever approved were approved in the past four years. She added that reauthorization of GDUFA would allow the FDA to make further improvements. These include: granting priority review to qualified ANDA submissions and expediting the review process for priority ANDAs to eight months instead of the 10 months for standard ANDAs, and program enhancements, such as establishing a pre-ANDA program to reduce the number of cycles to drug approval for complex generics. GDUFA II would also increase transparency and accountability and would expand program reporting on a monthly, quarterly, and annual basis, enabling Congress, industry, and other stakeholders to gauge the performance of generic drug programs.

In her testimony, Dr. Woodcock highlighted certain performance goals met by the FDA under GDUFA as outlined below. 

• The FDA met or exceeded all GDUFA review goals to date, including goals for original ANDAs, ANDA amendments, prior approval supplements, known as PAS, and controlled correspondence.
• In 2016, the FDA approved or tentatively approved 835 ANDAs. This was the most approvals in one year. The agency’s previous high was 619.
• The FDA expanded consumer access to generic medicines, with approximately 25% of all currently approved generic drugs approved over the past four years, as noted previously.
• The FDA was able to expedite the review of potential “first generic” ANDAs as a means to open the market to generic competition for the first time. Most “first generic” ANDAs cannot lawfully be filed until a specific date, either four or five years after the innovator drug, was approved. On this date, the FDA often receives a bolus of ANDAs, from many different applicants. Beginning October 2014, in accordance with GDUFA I, these ANDAs received goal dates. For example, in 2016 the FDA had timely approvals of nine generic versions of AstraZeneca’s Crestor (rosuvastatin calcium), a cholesterol drug with approximately $5 billion in annual sales.
• Prior to GDUFA, ANDAs were approved in one review cycle less than 1% of the time. Now, approximately 9% of ANDAs are approved in the first review cycle.
• The FDA expanded communications to facilitate generic drug approval. In 2016 the agency sent product developers approximately 1,800 communications and ANDA applicants approximately 6,600 communications. The FDA also issued 158 product-specific guidances, identifying methodologies for developing drugs and generating evidence needed to support generic approval. These guidances are designd to help companies develop ANDAs that will meet FDA’s regulatory expectations. Over 1,500 product-specific guidances are currently available as resources for prospective applicants.
• Before the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, the law required the FDA to inspect domestic facilities at a two-year interval but frequency of inspections was not specified for foreign facilities, regardless of their relative risk. Since 2012, the FDASIA directed the FDA to target inspections globally on the basis of risk. Many ANDAs rely on third-party facilities to manufacture active pharmaceutical ingredients or perform other roles in product development, and many of these facilities are located outside of the US. Under GDUFA, the FDA has achieved the goal of risk-based inspection parity for foreign and domestic facilities.

Dr. Woodcock said that the FDA achieved these results by building a modern generic drug program to comply with GDUFA I, which involved major reorganizations, including elevating the status of the Office of Generic Drugs to “Super-Office” status, on par with the Office of New Drugs. The FDA also established a new Office of Pharmaceutical Quality to integrate the quality components of ANDA review. FDA’s Office of Regulatory Affairs also made inspection program enhancements. In addition, the agency re-engineered its business processes, developed an integrated informatics platform to support the review process, and hired and trained over 1,000 new employees.

Dr. Woodcock summarized her support for GDUFA II by saying that “the FDA and the regulated industry, in consultation with other stakeholders, spent nearly a year developing the proposed GDUFA II agreement. It contains numerous, major reforms to address the main challenge facing the generic drug review program—namely, multiple review cycles. It is very inefficient for FDA and applicants alike to cycle through an ANDA over and over again. GDUFA II’s pre-ANDA program, ANDA review program enhancements, and priority review program will increase the odds of first-cycle approval, reduce the number of cycles to approval, and expand consumer access to quality, less expensive generic medicines. While we have made significant progress in our generic drug review, GDUFA II will support the agency in improving consumers’ timely access to generic medicines.”

Industry weighs in
David Gaugh, senior vice president for sciences and regulatory afairs at the Association for Accessible Medicines (AAM) (formerly the Generic Pharmaceutical Association [GPhA]), gave his testimony in support of passing GDUFA II. Mr. Gaugh noted that the FDA remains underfunded, which has prompted the generic drug industry to step up and aid in providing the FDA with additional user fee resources to address the ongoing challenges caused by the challenges of an increasingly global drug supply chain.

“Generic manufacturers make complex and highly confidential analysis when selecting which products to pursue. This analysis can include assessing the complexity in reverse engineering, the state of the intellectual property, the size of the market, the likely number of competitors, the product development and manufacturing capabilities and costs. Because of these complexities, AAM believes that the best way to control drug costs generally, is through policies that incentivize competition and Generic Drug User Fee Amendments (GDUFA II) does just that,” Mr. Gaugh stated in his testimony.

The priority of the generic drug industry in the GDUFA II negotiations was to achieve a more effective and transparent generic drug review program, Mr. Gaugh said. “We believe that accomplishing this goal will improve the rate of first-cycle approvals on the earliest legally eligible date through greater transparency and communication during the review process. Greater communication and cooperation between FDA and generic drug sponsors benefits both parties by sharing knowledge and experiences throughout the review process. Our industry’s goal was not merely a faster FDA review timeline, but a more effective review process – that enables more approvals during the first-review cycle. Similar to the goals of the branded drug user fee program, PDUFA [Prescription Drug User Fee Act], reducing multiple FDA review cycles is a critical component of increasing access to affordable generic alternatives. The fewer review cycles required to get to approval, the sooner patients and payors can experience the benefits of generic drug competition. We strongly believe GDUFA II is well positioned to achieve this goal,” he stated.

Mr. Gaugh noted that key areas of focus in GDUFA II include: a 10-month review period for ANDAs and an eight-month review period for priority ANDAs, including the inspection components of the review process; providing official GDUFA II goal dates for all pending GDUFA I applications; creating a pre-ANDA submission pathway for complex generic drug applications; increased transparency and communication between the FDA and ANDA applications throughout the review process to reduce the number of review cycles; increased FDA financial and performance reporting to maximize transparency to Congress, industry, and the public; and support for small businesses by exempting them from a facility fee until the first ANDA in that facility is improved.

The AAM supports the GDUFA II package as negotiated and agreed to with the FDA. By designing GDUFA II to spread the fees across multiple stakeholders and sources to keep individual costs as low as possible, generic drug programs are expected to help continue to provide cost savings to patients, Mr. Gaugh said.

“[T]he GDUFA II user fee proposal is a culmination of months of negotiations between FDA and industry, and the final product as transmitted to Congress represents a careful balance among all the stakeholders involved. We respectfully urge the Committee to approve GDUFA II as negotiated and agreed by FDA and generic drug manufacturers, without any changes to the agreement. It is also vital that the agreement be approved in a timely manner so that patients, the FDA, and generic manufacturers can begin to see the many benefits. Nothing is more important to our industry than ensuring patients have access to the lifesaving generic medications they require, and GDUFA II provides a critical step toward accomplishing this goal,” Mr. Gaugh concluded.

On the biosimilars side
The Biosimilar User Fee Act (BsUFA), also known as BsUFA I, was also enacted in 2012 for a period of five years, as part of the FDA Safety and Innovation Act. The first BsUFA allowed the FDA to build a new infrastructure for biosimilar drug approval and to support the abbreviated development process for such drugs. One of the first steps in the development and review process for a biosimilar is for an applicant to join the FDA’s Biosimilar Product Development (BPD) Program, created as a part of BsUFA I, to provide a mechanism and structure for applicants to engage with the FDA during the development of a biosimilar. Like GDUFA, BsUFA will expire in September 2017.

“As of February 2017, 64 programs were enrolled in the BPD Program and CDER has received meeting requests to discuss the development of biosimilars for 23 different reference products,” Dr. Woodcock stated in her testimony to the Subcommittee on Health.

“While we have made significant progress in creating and implementing this fairly new program, there is more work to do and, as with any new initiative, there are challenges that we need to address. These challenges in BSUFA I provide context for the discussions we had with industry during the BSUFA II negotiations. The ability to hire the right staff is critical to ensure the timely review of new biosimilars. While it’s true that FDA has been somewhat limited in its capacity to recruit and retain the critical scientific, technical, and professional talent needed to address the complex and often novel scientific and legal issues involved in biosimilar review, we are committed to making meaningful and measurable progress,” she also stated.

The lack of additional staffing to handle the increased workload for biosimilar review has also impacted review performance, with the FDA meeting only 50% of its initial advisory meetings within its 90 day meeting goal in 2015. While the agency’s performance improved in 2016, the FDA still faced challenges that year and was unable to meet some of the applicable performance goals.

BsUFA II incorporates lessons learned from implementation of BsUFA I and provides a roadmap to overcome some of the unexpected challenges encountered with BsUFA I. The key provisions in BsUFA II include: the establishment of an independent fee structure based on BsUFA program costs to generate a total of $45 million in revenue for fiscal year 2018; establishing a new application review model similar to that under the Prescription Drug User Fee Act V for new molecular entity new drug applications and original biologics license applications to minimize the number of review cycles necessary for biosimilar approval; and the issuance of six guidances by the FDA for reviewing or taking action on a biosimilar applications.

In testimony before the Subcommittee on Health in the March 2 hearing, Bruce Leicher, board chair of the Biosimilars Council, a division of AAM, stated: “We took a hard look at the first five years [of BsUFA I]. Not only are new FDA resources needed, more efficient regulatory approaches that use funding more wisely are necessary to accelerate FDA review. Together we included innovations from BsUFA I and PDUFA to enhance the review process and to ensure regulatory clarity. The BsUFA II user fees are now tied to the level of resources needed and adjust with resource demand.”

He added:“BsUFA II is the culmination of months of hard work and negotiations between FDA and industry. It represents a careful balance among the stakeholders. We respectfully urge the Committee to approve a clean draft of BsUFA II, without any changes to the underlying agreement,” Mr. Leicher said.