President Obama recently signed into law The Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA will reauthorize for another five years the Prescription Drug User Fee Act (PDUFA V) and the various related user fee agreements between the drug and device industries and FDA. FDASIA includes provisions related to drugs, devices, generic drugs, and biosimilar biological products.
Below is a summary of certain key provisions pertaining to innovator and, where specified, generic drugs and biosimilar biological products.
Review timeline changes: Title I, “Fees Related to Drugs,” contains the biggest changes sponsors will see in review timelines for New Drug Applications (NDAs) for New Molecular Entities (NMEs) and original Biologic License Applications (BLAs). FDA will get an additional 60 days for the review of these applications, whether the application is a priority application (six month review clock starting 60 days after receipt of the application) or a standard application (10 month review clock starting 60 days after receipt of the application). However, while the review cycle will be longer for these applicants, they will have additional opportunities to interact with FDA throughout the development and review process. The goal for the additional review time and increase in communications is to reduce the number of review cycles necessary to get to approval. Whether this will be of real benefit to the industry will unfold in the coming years, but the proof will be a reduction in total time from the first submission of the application to approval. Keep a close eye on a rise in the number of first cycle approvals to see if this bargain is showing benefits to the industry.
Generic drug user fees: Title III, the “Generic Drug User Fee Amendments of 2012” (GDUFA), establishes filing fees for Abbreviated New Drug Applications (ANDAs) and ANDA prior approval supplements, as well as: a one-time backlog fee for ANDAs pending on October 1, 2012 that have not received tentative approval; a one-time fee on owners of certain drug master files; and annual fees for facilities that manufacture generic drugs and active pharmaceutical ingredients (API) for generic drugs. The goal of the fee is to generate a total of US$299 million annually to be dedicated to human generic drug activities. Failure to pay the fees will subject the violators to various penalties, including some penalties that could affect third parties. For example, if the owner of a facility that makes even just one generic drug fails to pay the annual fee, all drugs and API manufactured in that facility, or containing an ingredient manufactured in that facility, shall be deemed misbranded. That penalty appears to apply to branded pharmaceuticals as well as all generics manufactured there. The law sunsets on October 1, 2017.
Biosimilar user fees: Title IV, the “Biosimilar User Fee Act of 2012” (BUFA), adopts the format and structure for prescription drug user fees to a large extent. Like PDUFA, it includes application, establishment, and product fees; virtually identical exclusions from the definition of biosimilar biological product application (such as in vitro biological products); and a waiver from the application fee for small businesses’ first application. A significant difference is that it also includes development program fees that apply to investigational biosimilars. The fees include an initial fee that is due either five days after the Secretary grants a request for a biosimilar development meeting or upon submission of an investigational new drug application (IND), whichever is earlier. In addition, an annual fee will be assessed for each year following the initial fee. Although there are generally no refunds, waivers, exemptions, or reductions for the development program fees, a sponsor who pays those fees prior to October 1, 2017 but submits a biosimilar biological product application for the product after that date is entitled to reduce its biosimilar biological product application fees by the cumulative amount of the development program fees it paid. These BUFA provisions sunset on October 1, 2017.
Pediatric drugs and devices: Title V, “Pediatric Drugs and Devices,” makes permanent the Best Pharmaceutical for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). BPCA provides an additional six months of patent exclusivity as an incentive for manufacturers to test on-patent drugs for pediatric use. PREA grants FDA authority to require studies in children concerning certain medical products and under other specific circumstances. Until now, BPCA and PREA have been subject to reauthorization every five years as part of the PDUFA process.
Drug supply chain: Title VII, “Drug Supply Chain,” pertains to the drug supply chain and expands information and registration requirements around the manufacture, preparation, compounding, inspection, and importation of drugs from facilities. The drug supply chain provisions do not cover the concepts supported by some in Congress and several industries involved in the supply chain process. Those provisions were intended to create a uniform national standard to govern product traceability and pre-empt state law requirements. We understand that work on this issue continues, but prospects for the passage of drug supply chain provisions during this Congress remain unclear.
Antibiotic incentives: Title VIII, “Generating Antibiotic Incentives Now,” provides a battery of incentives to encourage companies to develop new antibacterial and antifungal drugs intended to treat serious and life-threatening infections, such as methicillin-resistant Staphylococcus aureus (MRSA). The incentives include: five-year extensions of exclusivity otherwise available to new drugs under the Hatch-Waxman and Orphan Drug Acts; Priority Review; Fast Track status; and the ability to request and receive written recommendations from FDA on the nonclinical and clinical investigations necessary for approval. The Secretary must adopt final regulations implementing Title VIII within two years, but in the interim must grant designations to drugs that qualify. Stakeholders should take advantage of the opportunity to comment on rulemaking to seek clarification of certain possible ambiguities. These include: whether a qualified infectious disease product may receive five-year extensions for more than one category of exclusivity; how FDA should interpret the exclusion of a “subsequent application filed with respect to a product” (including whether combination products containing a previously approved drug are excluded); and whether drugs intended to prevent, detect or identify qualifying pathogens qualify for the incentives, or whether only those that treat infections qualify.
Breakthrough therapies: Title IX, “Drug Approval and Patient Access,” provides for facilitated development and review of drugs designated as “breakthrough therapies.” The sponsor of a drug may request a breakthrough therapy designation from Secretary of HHS at the time of the submission of an application for the investigation of the drug under section 505(i) or section 351(a)(3) of the Public Health Service Act. To achieve the designation, a drug must be intended to treat a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that it may demonstrate substantial improvement over existing therapies. Drugs with breakthrough therapy designations are eligible for additional FDA interaction and guidance throughout the development process. Title IX also creates a demonstration project that provides priority review vouchers to companies that develop a drug for a pediatric rare disease. The voucher can be redeemed by the company for a subsequent application or transferred to another company.
Drug shortages: Title X, “Drug Shortages,” provides for the collection and reporting of information related to drug shortages. It does not include other provisions that were discussed in connection with drug shortages such as penalties or changes in Medicare drug reimbursement in response to shortage situations. Congress will almost certainly continue to consider and debate this issue post-FDASIA.
Hydrocodone: During floor debate of FDASIA, the Senate approved an amendment offered by Senator Manchin (D-WV) that would change the classification of hydrocodone-containing pain relief products from Schedule III to the more-restrictive Schedule II under the Controlled Substances Act. The provision was removed from FDASIA during conference. Title XI, “Other Provisions,” requires FDA to hold a public meeting on the scheduling of hydrocodone.
REMS: While the change to the FDA’s authority over Risk Evaluation and Mitigation Strategies (REMS) in Title XI, “Other Provisions,” makes no real substantive changes to the agency’s authority to require a REMS, it does allow FDA to designate certain minor modifications to a REMS that can be made through a less burdensome administrative process.