Generic Drug User Fees Mark a Step in the Right Direction

The recent development of a proposed Generic Drug User Fee Act (GDUFA) is designed to improve FDA's oversight authority and resources to expedite the review process and better regulate the increasingly global drug-manufacturing industry.

For several years, the production of drugs has been shifting away from US manufacturing facilities. The impact of this manufacturing shift is not inconsequential and has led to concerns about the safety of these drug products.

With more than 80% of APIs coming into the United States from foreign facilities, concerns about the safety of these drugs has become paramount. Chief among these supply concerns is effective regulatory oversight. Such oversight includes adequate review of drug applications and regular inspection of all manufacturing facilities to ensure that GMPs are in place and being followed. Inadequate resources and programs within FDA to perform these activities is a threat to patient safety and to the competitiveness of compliant manufacturers. This is where GDUFA can start to make a difference.

Background

The Bulk Pharmaceuticals Task Force (BPTF), an affiliate of the Society of Chemical Manufacturers and Affiliates (SOCMA), and the European Fine Chemicals Group (EFCG), a sector group of the European Chemical Industry Council (CEFIC), have publicly expressed concerns over the risk to public health associated with drugs produced at substandard foreign facilities. For years, these industry groups have supported registration and foreign-inspection fees as a means for increasing revenues to FDA to support more foreign inspections. More recently, a 2008 US Government Accountability Office (GAO) report pointed out that in 2007, FDA inspected less than 8% of foreign establishments and estimated that, at that rate, it would take 13 years to inspect all such establishments. Further, GAO noted that FDA lacked complete and accurate information on foreign drug-manufacturing establishments; such information crucial to understanding the drug supply chain.

In 2011, FDA engaged BPTF, EFCG, and the Generic Pharmaceutical Association (GPhA) to negotiate a comprehensive Generic Drug User Fee program. The end result of the negotiations was GDUFA, which is waiting for action by the US Congress in the current legislative session.

A primary reason for proposing GDUFA was to improve approval times for abbreviated new drug applications (ANDAs), eliminate the backlog of thousands of amendments and approvals, and ensure drugs (specifically, finished-dose and active ingredient) were being manufactured according to cGMPs. In 2011, the average ANDA approval time had slipped to more than 30 months with a backlog of more than 2000 applications; the backlog is increasing daily. Adequate FDA resources to provide effective reviews, as well as holdups due to inadequate or nonexistent inspections of production sites, contributed to these delays. BPTF, along with EFCG and GPhA, worked with FDA through a series of meetings to define performance goals, procedures, and funding to ensure a sustainable, effective program for generic drugs.

Key goals

As stated in the FDA letter published on the FDA website on Jan. 5, 2012, titled "Proposed Human Generic Drug Performance Goals and Procedures Fiscal Years 2013 through 2017," there are three primary aims of the GDUFA program: safety, access, and transparency.

Safety will be enhanced by ensuring that industry participants, foreign or domestic, who participate in the US generic-drug system are held to consistent high-quality standards and are inspected biennially, using a risk-based approach, with foreign and domestic parity.

Access will be enhanced by expediting the availability of low-cost, high-quality generic drugs by bringing greater predictability to the review times for abbreviated new drug applications, amendments and supplements, increasing predictability and timeliness in the review process.

Transparency will be enhanced by increasing FDA's ability to protect Americans in the complex global supply environment by requiring the identification of facilities involved in the manufacture of generic drugs and associated API as well as improving the FDA's communication and feedback with industry to expedite product access.

The improvements to safety and transparency are exactly what BPTF and EFCG have been advocating. All parties to the GDUFA negotiations indicated that they were willing to pay fees for inspections and filings to provide the necessary resources to ensure the FDA could meet the performance goals defined in GDUFA.

Challenges ahead

Although the negotiated goals will go a long way in improving the safety of drugs in the supply chain, there were some disappointing aspects of the final plan. Industry associations hoped for faster implementation timelines than were identified in the FDA Performance Goals letter. For example, it is expected that inspection parity will increase confidence that drugs produced in foreign facilities are safe, but that goal is not expected to be met until 2017.

BPTF and EFCG also hoped for issuance of GMP certificates similar to those issued by European Union inspectorates. However, rather than issue these certificates, FDA will use an online database to indicate the inspection status of a facility. This database went online before approval or implementation of the GDUFA program and displays a site's status, if inspected in the calendar years 2009 and 2010. However, it is the BPTF's opinion that although the database is useful, providing that it is updated by the FDA in a timely manner (which is not currently the case), it will not be as useful to industry as a GMP certificate. In addition, it is unknown whether other regulatory agencies or drug-ingredient customers will accept this database status as an alternate to a formal GMP certificate.

The industry associations recognize the difficulty that FDA faces in bringing on personnel, appropriately training them, and getting systems in place to carry out GDUFA. Although not perfect, the Act is a big step forward in improving review timelines and parity of facility inspection.

The aims of GDUFA are important to American consumers, who can expect a safer and more efficient drug supply, and to the industry, which can expect a more level playing field. However, until the program is written into law, little progress will be made. While FDA indicates it will implement some review and inspection efficiencies immediately, many of the negotiated goals of GDUFA are several years away. BPTF and other organizations intend to work with Congressional representatives and their staff members to emphasize the importance of this initiative and encourage rapid evaluation and implementation.

This work should build on previous interactions with Congress, including the Sept. 14, 2011, testimony before the US Senate Committee on Health, Education, Labor and Pensions (HELP) carried out by Deborah Autor, deputy commissioner for Global Regulatory Operations and Policy at FDA, and other leading industry representatives.

GDUFA is limited to generic drugs. Similar oversight of manufacturing sites making branded drugs and over-the-counter drugs is also needed, especially for those sites making APIs. It is hoped that the increased inspectional resources focused on foreign manufacturers under GDUFA will increase the inspection frequency and oversight of all foreign facilities. BPTF and EFCG encourage FDA to further collaborate with other countries with mature regulatory systems to recognize each other's inspections. Manufacturing sites often receive multiple inspections from different regulatory agencies focused on the same products and facilities. These duplicative efforts may be better spent inspecting sites with less mature regulatory agency oversight that may not have ever experienced a thorough regulatory audit.

In the near term, BPTF is pleased with the recent GDUFA initiatives and fully supports its promotion into law by Congress. Patient safety will be increased through increased application reviews, more frequent inspection of foreign facilities, and speedier access to safe and effective generic medicines.