FDA Issues Draft Guidance for Complex Generic Drugs

In a move to facilitate the generic-drug review process and drug competition, the US Food and Drug Administration (FDA) has issued two draft guidance documents relating to the generic-drug review process for complex generics and has outlined future policy considerations for complex generic drugs.

The first draft guidance, ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin, is designed to assist applicants to determine when submission of abbreviated new drug applications (ANDA) for certain complex products, specifically peptides, would be appropriate. Peptides are compounds made up of 40 or fewer amino acids. The draft guidance is designed to assist potential applicants in determining when an application for a synthetic peptide drug product that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin should be submitted as an ANDA rather than as a new drug application (NDA). Specifically, this draft guidance covers the following peptide drug products: glucagon, liraglutide, nesiritide, teriparatide, and teduglutide.

In the draft guidance, the FDA notes that given the current state of technology for peptide synthesis and characterization, it believes it is now possible for an ANDA applicant to demonstrate that the active ingredient in a proposed generic synthetic peptide drug product is the “same” as the active ingredient in a previously approved peptide of rDNA origin. The agency notes that for a synthetic peptide that is intended to be a “duplicate” of a previously approved peptide of rDNA-origin, a determination of whether an application for the synthetic peptide should be submitted as an ANDA depends largely on its impurity profile as compared to the impurity profile for the peptide of rDNA origin. The agency noted in the draft guidance that differences in impurities, particularly peptide-related impurities, may affect the safety or effectiveness of a peptide drug product. The recommendations in the draft guidance are designed to help ensure that the risk of an immune response from the generic due to differences in impurities will not differ from that of the reference drug.

The second draft guidance, Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA, describes an enhanced pathway for discussions between the FDA and a prospective applicant preparing to submit or an applicant that has submitted an ANDA for a complex product to the FDA as defined in the guidance. Specifically, the guidance provides information on requesting and conducting product development meetings, pre-submission meetings, and mid-review-cycle meetings with the FDA.

Aside from the guidelines, the FDA outlined further plans the agency has to stimulate competition for complex drugs. “We’ll soon release other important policies aimed at spurring competition to complex drugs,” said FDA Commissioner Scott Gottlieb said, in an October 2, 2017 blog on FDA Voice, the agency’s blog. “But we know that better guidance isn’t the only answer. Some drugs lack generic competition because they cannot be measured through traditional in vivo bioequivalence methods and there’s no efficient and convincing bioequivalence test method available. In these instances, an applicant needs to conduct more extensive clinical endpoint testing to show bioequivalence of a generic drug to a brand-name drug. This can be burdensome and discourage generic product development. A further barrier to generic competition for certain complex drug products is the lack of established methods for showing the sameness of the active ingredient of a proposed generic drug to a brand-name drug for certain complex drugs.”

In his blog, Gottlieb said that over the next year, FDA’s generic drug regulatory science program will work to identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing, where feasible. To that end, the agency will hold a series of scientific workshops that will identify opportunities for complex generic drug development, discuss quantitative modeling approaches and principles and aid product-specific guidance development. “The workshops will also help in the development of new analytical tools that will help overcome the unique development and regulatory challenges for demonstrating active ingredient sameness in complex products,” he said. “We intend for these efforts to speed product development, reduce development costs, and improve access to these products.”

Source: FDA (ANDAs for synthetic peptide drug products), FDA (formal meetings), and FDA Voice (blog post)


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