FDA Denies Citizen Petitions from Novo Nordisk, Allergan, and Amneal Pharmaceuticals

By Akia Thorpe -

January 12, 2018

The US Food and Drug Administration (FDA) has denied separate citizen petitions from Novo Nordisk, Amneal Pharmaceuticals, a Paterson, New Jersey-based generic-drug manufacturer, and Allergan that asked the agency to refrain from approving any abbreviated new drug applications (ANDAs) referencing certain blockbuster drug products.

The basis of the citizen petitions from Novo Nordisk and Amneal related to whether applications for a generic synthetic peptide that relies upon a peptide of rDNA origin should be submitted as an ANDA. The citizen petition of Allergan related to scientific validity of certain in vitro testing.

Novo Nordisk

The FDA denied Novo Nordisk’s citizen petition to refrain from approving generic versions of Novo’s blockbuster diabetes drug, Victoza (liraglutide [rDNA origin] injection), and two other products containing liraglutide, Saxenda (liraglutide [rDNA origin] injection), and Xultophy 100/3.6 (insulin degludec and liraglutide injection). The company also had asked the agency to refrain from approving any 505(b)(2) new drug application (NDA) that references any of Novo Nordisk's liraglutide-containing drugs unless clinical comparative studies are provided to establish safety and effectiveness. A 505 (b)(2) NDA is a pathway created by the Hatch-Waxman Amendments of 1984, with 505(b)(2) referring to a section of the Federal Food, Drug, and Cosmetic Act. It applies to various uses, including changes in dosage form, strength, route of administration, formulation, dosing regimen, or indication.

Novo Nordisk had also asked the agency to issue guidance for assessing whether a follow-on liraglutide product, whether synthetic or recombinant-derived, is sufficiently similar to Novo Nordisk's liraglutide to justify reliance on FDA's prior findings of safety and effectiveness. Novo Nordisk also asked the agency to consider developing guidance for and reviewing applications for follow-on versions of other polypeptide and complex polypeptide drugs.

Amneal Pharmaceuticals

Amneal Pharmaceuticals’ a citizen petition asking that the FDA refrain from approving any ANDA for teriparatide (rDNA origin) injection products for human use, which contain synthetically derived teriparatide active substance as generics to Forteo ([teriparatide (rDNA origin)] injection and only approve ANDAs for teriparatide injection products that contain recombinant human parathyroid hormone. Forteo is drug for treating osteoporosis by Eli Lilly and Company, which had 2016 sales of $1.5 billion. using a strain of Escherichia coli modified by recombinant DNA technology. In its petition, Amneal had argued that a synthetic peptide must not be accepted as a generic equivalent of a rDNA-derived peptide, and such submissions must be accepted only as 505(b )(2) applications.

FDA’s denial on petitions from Novo Nordisk and Amneal Pharmaceuticals

In the FDA’s denial letters to Amneal and Novo Nordisk, the agency referenced draft guidance,ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin. The draft guidance, if finalized as written, is intended to assist potential applicants in determining when an application for a synthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant DNA origin (peptide of rDNA origin) should be submitted as an ANDA or as a 505(b)(2) application. The draft guidance, if finalized as written, would cover five peptide drug products, including teriparatide and liraglutide.

The draft guidance proposes that submission of an ANDA for a synthetic peptide that references a peptide of rDNA origin would be generally appropriate if certain conditions are met. First is if applicant can show that, for each peptide-related impurity that is found in both the proposed generic synthetic peptide and the reference listed drug (RLD) that the level of such impurity in the proposed generic synthetic peptide is the same as or lower than that found in the RLD. The RLD s an approved drug product to which new generic versions are compared to show that they are bioequivalent. Other conditions are that applicant can: (1) show that the proposed generic synthetic peptide does not contain any new specified peptide-related impurity that is more than 0.5% of the drug substance; (2) characterize each new specified peptide-related impurity; and (3) justify for each new specified peptide-related impurity that is no more than 0.5% of the drug substance why such impurity does not affect the safety of the proposed generic synthetic peptide and does not affect its effectiveness.

The FDA said in its denial letters that it is continuing to consider the circumstances under which an application for a generic synthetic peptide that relies upon a peptide of rDNA origin should be submitted as an ANDA. It noted that the companies should submit comments to the FDA draft guidance and that it would be premature for the agency to comment further.

Allergan

In August 2017, Allergan filed a citizen petition concerning the agency's bioequivalence recommendations for Restasis (cyclosporine ophthalmic emulsion, 0.05%), a drug to treat dry eyes. In the petition, Allergan challenged the scientific validity of the in vitro testing option included in the agency’ October 2016 draft guidance on bioequivalence testing for cyclosporine (Draft Cyclosporine BE Guidance). The FDA said the petition reiterated many of the arguments and requests from Allergan's previous citizen petitions regarding BE recommendations for ANDAs for cyclosporine ophthalmic emulsion, 0.05% products. The petition was Allergan's third petition concerning the methods an ANDA applicant might use to demonstrate that a proposed generic drug is bioequivalent to Restasis.

In its denial letter to Allergan, the FDA explained that the Draft Cyclosporine BE Guidance's bioequivalence recommendations are being developed in accordance with the process outlined in the guidance for industry Bioequivalence Recommendations for Specific Products (Product-Specific BE Guidance).

Source: FDA (Amneal), FDA (Novo Nordisk), and FDA (Allergan)