How should the US Food and Drug Administration (FDA) define the term "first-to-file" when it comes to approving new generic drug products? While the question seems small, at stake is nothing less than potentially billions in savings for consumers and the US government.
In 2012, Congress pushed through a major piece of legislation to overhaul various aspects of how FDA regulates products. The law, the Food and Drug Administration Safety and Innovation Act (FDASIA) contained dozens of provisions, including the Generic Drug User Fee Act (GDUFA).
GDUFA was modeled off of similar user fee programs for innovative pharmaceuticals and medical devices, and was intended to levy a fee on all generic manufacturers and generic drug applications to help fund FDA's operations. In theory, the additional money would be used to increase FDA's oversight over the industry, and also allow it to hire additional staff to review generic drug applications more quickly and eventually eliminate the number of backlogged applications.
In return for the additional funding, FDA agreed to meet specific goals for the review of generic drug products. For example, by the end of the fifth year of the GDUFA program, FDA is expected to review and act upon 90% of abbreviated new drug applications (ANDAs) within 10 months of the date of submission.
The Importance of 30 Months
Overall approval metrics weren't the only commitment FDA made to the generic drug industry, however.
Section XI of the "GDUFA Program Performance Goals and Procedures" letter explains FDA will:
"strive to review and act on all ANDAs that are submitted on the first day that any valid Paragraph IV application for the drug in question is submitted within 30 months of submission to avoid causing first applicants to inadvertently forfeit 180-day exclusivity eligibility under 21 U.S.C. § 355(j)(5)(D)(i)(IV)."
This jumble of regulatory jargon is actually quite important.
Under existing regulatory provisions established by the Hatch Waxman Act, generic drug companies are given a powerful incentive to challenge patents held by branded pharmaceutical companies. If a generic drug manufacturer is the "first to file" a successful challenge against a product's patented exclusivity (also known as Paragraph IV certification), FDA will grant that product 180 days of exclusivity during which time no other generic equivalent of that drug is allowed to be sold.
However, that exclusivity is contingent upon the product first being approved by regulators—something that doesn't always happen within the customary 30-month stay of approval or by the successful conclusion of litigation in the generic company's favor.
In plain terms: If FDA isn't able to finish reviewing an application by the time a drug could be allowed on the market, consumers don't have access to lower-cost generic equivalents. That can raise patients’ insurance premiums, out-of-pocket expenses and even their taxes as governments are forced to pick up the tab for higher-cost medications.
Policy Attempts to Clarify Prioritization Status
In an attempt to implement the terms of Section XI of the GDUFA commitment letter, FDA released a new Manual of Policies and Procedures (MAPP 5240.3 Rev. 1) in August 2014 establishing how its Office of Generic Drugs will prioritize the review of ANDAs that are "first to file."
The policy overturned FDA's former policy of first-in first-out drug reviews in favor of an approach that calls for important applications to be pushed to the front of the review line. "Potential first generic products for which there are no blocking patents or exclusivities on the reference listed drug may receive expedited review," FDA wrote.
But this explanation has been met with substantial confusion within the industry, FDA explained in a new posting in the Federal Register.
"[S]takeholders have characterized a ‘first generic’ as the first ANDA submitted, the first ANDA approved, the first ANDA marketed, all first-to-file ANDAs, and a company’s 'top priority' ANDA," FDA wrote. "Without clear criteria for this category, there is the potential for confusion and inconsistent review prioritization."
New ‘First Generic’ Definition
To clarify this confusion, FDA has now proposed a common definition of the term "first generic" in a Federal Register filing:
A first generic application is any received ANDA:
(1) That is a first-to-file ANDA eligible for 180-day exclusivity, or for which there are no blocking patents or exclusivities; and
(2) for which there is no previously-approved ANDA for the drug product.
FDA said it hoped the newly proposed criteria would "appropriately focus FDA’s resources on approving as quickly as possible, new safe and effective generic drug products for patient use." Implied in that statement is that other criteria—the priority review of a company's "top priority" ANDA, for example—might be substantially more burdensome to implement.
The new policy also reflects "industry intent," FDA stated in its Federal Register notice.
Now it's up to industry to confirm with FDA if that definition was, in fact, its intent. FDA has established a public docket it says will help it to collect comments on the policy and, if necessary, make adjustments to the "first generic application" definition.
One area FDA says it could stand to receive feedback on is how the "first generic" status should respond to changes in status. For example, patent litigation might defeat one applicant, but spare another. FDA notes that an ANDA submission "that originally met the criteria for a 'first generic' submission may no longer meet those criteria at some point." How, then, should FDA accommodate changes in "first generic" status?
For industry, this is a chance to weigh in on a small but exceedingly important regulatory definition.
Comments on the policy will be accepted by FDA through 19 December 2014.
Federal Register Notice
FDA GDUFA Commitment Letter
MAPP 5240.3 Rev. 1