precosegif.gifThe FDA’s Office of Generic Drugs posted a letter requesting comment on certain 180-day exclusivity forfeiture and Orange Book patent “delisting” issues.  This concerns an ANDA submitted to the FDA containing a paragraph IV patent certification requesting FDA approval for a generic version of Bayer Pharmaceuticals’ PRECOSE (acarbose) Tablets.

Before marketing a new branded drug, the manufacturer must file with the FDA a New Drug Application (NDA), including evidence the drug is safe and effective, and the identifying number and expiration date of any patent or patents covering the drug. When it approves the NDA, the FDA must publish the patent information, which it does in Approved Drug Products with Therapeutic Equivalence Evaluations (a/k/a the Orange Book).

Before marketing a generic drug, the manufacturer may submit an Abbreviated New Drug Application (ANDA). The ANDA must contain “a certification … with respect to each patent which claims [a drug or a method of using a drug listed in the Orange Book] for which the applicant is seeking approval under this subsection and for which information is required to be filed under subsection (b) or (c) of this section – (I) that such patent information has not been filed, (II) that such patent has expired, (III) [that] such patent will expire [on a specified date], or (IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted[.]”

The Act rewards the first manufacturer to file an approved ANDA containing the certification in paragraph IV by giving it a 180-day period of marketing exclusivity, which begins with the earlier of the applicant’s first commercial marketing of the generic drug or when the applicant prevails in a suit over infringement or the validity of the patents covering the branded drug.

Under changes made to the FDC Act by the 2003 Medicare Modernization Act (“MMA”), generic applicants that are “first applicants” are eligible for 180-day exclusivity, unless such eligibility is forfeited. 180-day exclusivity eligibility may be forfeited if, among other reasons, a “first applicant” “fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” (FDC Act § 505(j)(5)(D)(i)(IV)), or if such applicant fails to market the drug “30 months after the date of submission of the application” (FDC Act § 505(j)(5)(D)(i)(I)(aa)(BB)).

The U.S. Court of Appeals for the District of Columbia Circuit already took on the question as to whether the FDA may delist a patent upon the request of the NDA holder after a generic manufaturer has filed an ANDA containing a paragraph IV certification so that the effect of delisting is to deprive the applicant of a period of marketing exclusivity.

The D.C. Circuit held that the FDA’s requirement that a generic manufacturer’s patent challenge give rise to litigation as a condition of retaining exclusivity when a patent is delisted is inconsistent with the Hatch-Waxman Act, which provides that the first generic manufacturer to file an approved application is entitled to exclusivity when it either begins commercially to market its generic drug or is successful in patent litigation.

The reference listed drug (RLD) for Acarbose Tablets is Precose Tablets, the new drug application (NDA) held by Bayer Pharmaceuticals (Bayer). There is one patent listed for Acarbose Tablets, U.S. Patent No. 4,904,769, which expires on September 6, 2009. As you probably are aware, for it appears on the Paragraph IV list on FDA’s website, at least one ANDA for Acarbose Tablets containing a paragraph IV certification was received by the agency on March 22, 2005. By virtue of this filing, at least one applicant became eligible for 180-day generic drug exclusivity.

As you know, the FDA makes determinations regarding 180-day exclusivity only when it is in the position to either approve an application that may be eligible for 180-day exclusivity, or to act on a subsequent applicant’s ANDA as to which final approval may be delayed by another application’s eligibility for exclusivity.

As of the date of this letter, which is more than 30 months from March 22, 2005, no first applicant’s ANDA has been approved. Also, on April 16, 2007, Bayer requested that the ‘769 patent be “delisted” as to Precose, i.e., they withdrew the patent information. On September 26, 2007, FDA indicated in the Orange Book that the request to delist this patent had been submitted on April 16, 2007.

To determine whether any ANDA referencing Precose is eligible for final approval, the agency must consider how the 180-day generic drug exclusivity forfeiture provisions at section 505(j)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) apply to this set of facts. As part of the process for making such a determination, we are seeking your views regarding the applicability of sections 505(j)(5)(D)(i)(IV) — failure to obtain tentative approval within 30 months — and 505(j)(5)(D)(i)(I)(aa)(BB) — failure to market by 30 months. We also are interested in your views regarding the applicability of section 505(j)(5)(D)(i)(I)(bb)(CC) — relating to the delisting of a patent.

The FDA asks that you submit your comments by close of business on Wednesday, October 10, 2007. Please include the Reference Number OGD #07-1254. If you have any questions, please contact Cecelia M. Parise, Regulatory Policy Advisor to the Director, Office of Generic Drugs, at 240-276-9310.

More at the FDA Law Blog.

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