FDA’s refusal to make its new policy providing five years of market exclusivity for certain fixed-dose combination drugs retroactive could push firms left out of the new regime to sue the agency.

The agency issued final guidance on new chemical entity exclusivity determinations for certain fixed combinations on Oct. 10. The document is virtually identical to the draft guidance published in February.

The guidance revises the agency’s historical position that a fixed combination product was not eligible for five years of NCE exclusivity if it had a previously approved active moiety in the combination, even if the product also contained a new active moiety that had not previously been approved ([A#14140221006]).

The guidance states that from the date of the guidance’s publication, FDA will apply its new interpretation that a drug substance would be eligible for five-year NCE exclusivity, provided that it meets the definition of a new chemical entity, “regardless of whether that substance is approved in a single ingredient drug product, in a fixed combination with another drug substance that contains no other previously approved active moiety, or in a fixed combination with another drug substance that contains a previously approved active moiety.”

Gilead Wins And Loses

Two companies immediately won five-year exclusivity for their products under the new policy. FDA approved Gilead Sciences Inc.’s hepatitis C drug Harvoni (ledipasvir/sofosbuvir) and Eisai Inc.’s fixed combination Akynzeo (netupitant/palonosetron) for prevention of chemotherapy-associated nausea the day it issued the final guidance. Gilead confirmed that Harvoni was granted five years of exclusivity.

The first one-tablet oral hepatitis C treatment in the U.S., the drug has a price of $94,500 for a 12-week course of treatment ([A#14141010002]).

But Gilead, which along with Ferring Pharmaceuticals Inc. and Bayer HealthCare Pharmaceuticals AG convinced FDA to change its policy, will not get five years of exclusivity for its HIV quad treatment Stribild. The agency issued its draft guidance in response to citizen petitions filed last year on behalf of the three companies.

Gilead requested five years of exclusivity for two of the components in Stribild Also see "Gilead Compares Stribild To Prezista In Seeking Exclusivity For Fixed Dose Combinations" - Pink Sheet, 25 January, 2013.. Ferring requested the NCE exclusivity for Prepopik, a colon-cleansing drug used in preparation for colonoscopy Also see "NME Exclusivity Petitions Expand; Ferring Request For Colon-Cleansing Combo Has Urgency" - Pink Sheet, 4 February, 2013.. And Bayer sought five years of exclusivity for dienogest, the new active moiety in its fixed combination oral contraceptive Natazia.

Ferring’s attorney Theodore Sullivan, of Buchanan Ingersoll & Rooney, said he was still discussing with his client what action to take in response to the final guidance and that it was “too preliminary” to say if a suit was possible. The attorneys for the other firms could not be reached for comment.

FDA Refuses To Look At Recent Past

After FDA issued the draft guidance, Pfizer Inc. submitted a citizen petition in May asking FDA to apply its new interpretation of NCE exclusivity to its fixed combination Duavee (conjugated estrogens plus the previously unapproved bazedoxifene). The product was approved in October 2013 to treat moderate to severe vasomotor symptoms associated with menopause.

All four products were granted three years of exclusivity, which is awarded to products that contain a previously approved active moiety and for which clinical trials were essential to approval.

FDA received 10 comments in response to the draft guidance, all of which expressed support for the agency’s new policy. Most of the comments asked FDA to immediately implement the draft guidance (it took the agency eight months to do so) and many asked that the agency apply NCE exclusivity to recently approved applications.

The Pharmaceutical Research and Manufacturers of America did not directly address FDA’s intent to implement the policy prospectively. Instead, it encouraged FDA “to apply its policy change to all products subject to any application or applications that are new or currently pending before FDA.”

“FDA should also consider how to apply the new policy to approved applications in appropriate circumstances,” PhRMA added in a footnote. “This may be particularly appropriate where, for example, an application has been recently approved (especially after issuance of the draft guidance) and/or no ANDA or 505(b)(2) application has been submitted that references the application.”

The Biotechnology Industry Organization asserted that it is “entirely appropriate” for FDA to begin applying NCE exclusivity immediately – including to recently approved products for which no 505(b)(2) applications or ANDAs have been submitted.

Buchanan Ingersoll submitted comments on behalf of Ferring reiterating that FDA’s policy should apply to Prepopik. The firm said in a footnote that to the best of its knowledge neither Prepopik nor Stribild have been referenced by any generic application. It noted that Bayer settled ANDA litigation with Lupin Pharmaceuticals Inc. and that the extension of Natazia’s exclusivity term by two years would have no negative impact on Lupin’s proposed generic product.

The agency addressed this issue in an Oct. 10 letter to attorneys for Gilead and Ferring denying their petitions asking FDA to reconsider its denial of their original petitions. The agency said one factor for its decision not to grant Stribild and Prepopik five-year NCE exclusivity was the reliance by potential ANDA sponsors on the agency’s longstanding interpretation of exclusivity for fixed combination products.

“Regardless of whether ANDAs or 505(b)(2) applications have been submitted referencing these drugs, that would not conclusively establish that no sponsor has undertaken a development program with the expectation that the agency would continue to apply its historical interpretation,” the agency stated.

FDA also sent an Oct. 10 letter to Pfizer’s attorneys stating that Duavee was subject to the agency’s historical interpretation of relevant statutory and regulatory provisions at the time of approval and thus was not eligible for five-year NCE exclusivity.

All Over But The Lawsuits? NCE Exclusivity For Fixed-Dose Combos Remains Prospective

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