FDA will reconsider whether approval of new salt formulations under the Sec. 505(b)(2) process is appropriate, but any changes will not prevent approval of a pending competitor to Pfizer's antihypertensive Norvasc .

FDA reaffirmed its interpretation of the 505(b)(2) in an Oct. 14 response to citizen petitions filed by Pfizer, Apotex and the Biotechnology Industry Organization. ¹ FDA's response makes clear that it does not intend to change its position that Dr. Reddy's pending NDA for amlodipine maleate could be approved under the 505(b)(2) regulation.

FDA "declines to alter its current interpretation of Sec. 505(b)(2)," the agency told Pfizer. However, FDA said it would rethink "future" use of the regulatory pathway when it is used solely for a change in a drug's active ingredient.

Any change in policy would have to occur through rulemaking and public comment and would be instituted prospectively.

The Dr. Reddy's NDA, which seeks approval of a different salt form of Norvasc (amlodipine besylate), has been "approvable" at FDA since October 2002 pending resolution of chemistry, manufacturing & controls and labeling issues. Reddy's has said it expects approval by year-end (² Also see "Dr. Reddy’s Seeks Partner For Norvasc Salt, Says Pfizer Will Not Delay Launch" - Pink Sheet, 9 June, 2003., p. 7).

Although FDA's response removes one potential regulatory obstacle for Dr. Reddy's, the agency notes that it has not yet resolved "scientific" questions raised by Pfizer about the application.

FDA's answer to BIO's petition, which focused on the potential use of 505(b)(2) for follow-on biologics, similarly resolved the regulatory issue while leaving open "scientific" questions (see ³ Also see "Generic Biologics: 505(b)(2) Route Still Open, But Scientific Issues Unresolved" - Pink Sheet, 20 October, 2003.).

Apotex' petition advanced many of the same arguments made by Pfizer in seeking the withdrawal of Synthon's paroxetine mesylate, which was approved under the 505(b)(2) process in July (⁴ Also see "Early Paxil Competitor? FDA Approves Synthon’s Paroxetine 505(b)(2)" - Pink Sheet, 14 July, 2003., p. 21).

Apotex has the only approved ANDA for a generic equivalent of GlaxoSmithKline's Paxil (paroxetine hydrochloride) (see ⁵ Also see "Paxil Generics Grab 65% Of New Scripts; Apotex May Sue Over Par/GSK Deal" - Pink Sheet, 20 October, 2003.).

Apotex told the agency to expect to be sued if it did not respond to the petition quickly. FDA agreed to address issues raised in all three petitions by mid-October (⁶ [A#00650390013], p. 16).

The agency expected litigation no matter what it decided. The Oct. 14 response defends the legal basis for the agency's past actions under 505(b)(2).

In particular, FDA dismissed arguments that 505(b)(2) merely codifies the agency's "paper NDA" policy. Pfizer maintained that 505(b)(2) applications could only be approved based on studies in the published literature.

"The statute does not limit the sources of the studies on which 505(b)(2) applicants may rely to published literature or other publicly available studies - even though Congress could easily have added such a limitation," FDA said.

The petitioners "should have been well aware that the agency would permit a 505(b)(2) applicant to rely on the findings of safety and effectiveness for an approved NDA, based not only on the broad statutory language first enacted" in the 1984 Waxman/Hatch amendments, "but also on the agency's subsequent publicly announced interpretation and application of Sec. 505(b)(2)," FDA said.

"Since 1984, 505(b)(2) applications have been used by a wide range of sponsors in the pharmaceutical industry (including petitioner Pfizer and members of petitioner BIO) to obtain approval of more than 80 drug products," FDA noted.

"Over 30 additional 505(b)(2) applications are currently under review by the agency. Most of these applications have not been solely literature-based 505(b)(2) applications."

The agency, however, agreed with Pfizer on one important point: FDA may not assign an "A" therapeutic equivalence rating to a drug product that contains a different salt from the reference drug.

The statement reflects the agency's current practice: Synthon's paroxetine mesylate, approved in July, is not "AB" rated with Paxil. Dr. Reddy's has said it does not expect a bioequivalence rating for its amlodipine maleate.

FDA's decision to reconsider the use of the pathway in the future is also a symbolic concession to Pfizer. The company objected to past statements by agency officials that the 505(b)(2) process could serve the public health by making cheaper drugs available more quickly.

In its response to Pfizer, FDA acknowledged that use of the 505(b)(2) process to allow approval of new salt formulations "may have undesirable policy and public health consequences."

Approval of active ingredient changes under 505(b)(2) "has been very limited," the agency noted. "FDA believes that its decisions to date on these applications have been justified by the language of the statute, the legislative history, and the purposes of the Hatch-Waxman Amendments."

However, "this use of Sec. 505(b)(2) does not result in the approval of an innovative drug product that offers a new therapeutic benefit or alternative, such as a new indication, novel dosage form or improving administration for a new patient population," FDA said. "Nor do such changes in the active ingredient generally represent an improvement in terms of safety or effectiveness."

"It may undermine current incentives for development of promising new active moieties that Congress included in the Hatch-Waxman Amendments," FDA said. "It may lead to proliferation of pharmaceutical alternative drug products, with resulting confusion in the marketplace."

"It may divert resources, otherwise available for innovative drug research, to the development and patenting of alternative active ingredients, where such patents are used solely either to establish a barrier to competition or to preempt the holder of the listed drug from establishing such a barrier."

Therefore, the agency "may wish to consider further whether there is some narrow subset of applications that should be exempted from the scope of Sec. 505(b)(2) in the future."

"FDA is particularly interested in examining the use of 505(b)(2) applications to obtain approval of drug products for which the only difference from the listed drug is in the form of the active ingredient, such as a change in salt." The agency is "considering whether to begin a public process to seek input from interested parties, including the pharmaceutical and health care industries, as well as consumer groups" on this issue.

Pfizer continues to pursue another avenue to block the Reddy's application. A federal appeals court heard arguments in July on whether Pfizer's patent term extension for Norvasc encompasses the maleate form of amlodipine or is limited to the besylate salt (⁷ Also see "Pfizer Norvasc Patent: Will Court Limit Extension To “Approved” Product?" - Pink Sheet, 14 July, 2003., p. 22).

FDA 505(b)(2) Policy Affirmed; Any Changes Will Be Too Late For Norvasc

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