Levothyroxine NDAs May Be Refused Filing After First Product Approval - FDA

Levothyroxine NDAs may be refused filing following approval of the first levothyroxine product, FDA said in a draft guidance issued August 18.

The draft guidance, presented in question and answer format, details the agency's proposed implementation for its new policy requiring NDA approval for all oral levothyroxine sodium products as of Aug. 14, 2000.

Any levothyroxine product on the market after Aug. 14, 2000 without an approved NDA, including drugs with NDAs pending, will be subject to enforcement action as an unapproved new drug, FDA said.

FDA will review all NDAs for levothyroxine products that are filed before the first NDA for the drug is approved, the agency explained in the draft guidance. This leaves the possibility that there could be multiple approved levothyroxine NDAs.

After the first levothyroxine NDA is approved, however, "FDA may refuse to file any 505(b)(2) application for a drug product that is a duplicate of the product approved in the first NDA," the draft guidance states. This includes applications that have been submitted but not yet filed.

Levothyroxine products were introduced before FDA's 1962 NDA requirement for safety and efficacy evaluation. FDA is requiring that manufacturers of the thyroid hormone replacement product obtain NDA approval because "no currently marketed orally administered levothyroxine sodium product has been shown to demonstrate consistent potency and stability," FDA said in its 1997 announcement of the new policy (¹ (Also see "LEVOTHYROXINE MANUFACTURERS HAVE THREE YEARS TO OBTAIN NDA APPROVAL UNDER FDA POLICY; AGENCY CITES POTENCY AND STABILITY PROBLEMS WITH THYROID PRODUCTS" - Pink Sheet, 18 Aug, 1997.)).

FDA indicates that five-year exclusivity, usually provided for drugs that contain no previously approved active moiety, would not be available to levothyroxine products, since levothyroxine has already been approved as an active ingredient in two NDAs, Forest's Thyrolar and Warner-Lambert's Euthroid.

Three-year exclusivity, however, would be available for applications containing "reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant."

FDA is not requiring levothyroxine manufacturers to conduct new clinical investigations. The agency has indicated, rather, that NDAs may rely upon investigations the applicant has neither sponsored nor obtained right of reference to, such as literature reviews.

Because new clinical information is not required, it is likely that no company will qualify for the three-year eligibility period, eliminating the potential problem of multiple exclusivity periods for multiple NDAs.

If an application is refused for filing because the first levothyroxine NDA has already been approved, it may be resubmitted as an ANDA, provided the application has the required data, FDA suggested.

FDA will not select a reference drug until a complete ANDA is submitted. If only one levothyroxine NDA has been approved at the time the first ANDA is submitted, that product will become the reference drug.

However, if more than one levothyroxine NDA has been approved before FDA receives a request to submit an ANDA, "the market leader among the approved products will be designated as the reference listed drug," FDA said. The agency noted that it is possible that there will be more than one reference listed drug for levothyroxine.

Knoll's Synthroid has been the market leader for levothyroxine. The company has requested that FDA revise its schedule for submitting levothyroxine NDAs to allow companies more time, particularly in light of the agency's recent draft guidance on bioavailability studies for levothyroxine (² (Also see "FDA Okays Levothyroxine Test It Objected To In Synthroid Promos - Knoll" - Pink Sheet, 23 Aug, 1999.)).

A user fee will be assessed for each levothyroxine NDA, FDA said, since levothyroxine has not been approved for any indication as a single agent.

Under FDA's December 1997 pediatric final rule, levothyroxine applications will be required to include pediatric information unless the requirement is waived or deferred. The agency indicated that levothyroxine applicants should discuss this issue with the division, as "it is possible that adequate data to support safety and effectiveness for pediatric use may be available in the scientific literature."