Over the past few years, we have seen some changes in the regulatory environment with a new Drug Competition Action Plan and FDA guidances focused on introducing more competition into the drug market with the goal of increasing access to drugs that consumers need.  These guidance documents are meant to provide information on abbreviated approval pathways and provide clarity on the regulatory pathway for complex generic drugs in order to speed approval allowing for more competition in the market place, which may impact pricing.

While it is important to understand how to navigate the complex generic drug approval pathway, it is first necessary to determine whether your drug product should be submitted as an abbreviated new drug application (ANDA) for approval as a generic or if it requires submission of a 505(b)(2) new drug application.  This particular issue is addressed in a guidance, finalized May 2019, “Determining Whether to Submit an ANDA or a 505(b)(2) Application.”  The guidance defines an ANDA as an application for a duplicate of a previously approved drug product that is the same with respect to the active ingredient[s], conditions of use, route of administration, dosage form, , strength, conditions of use, and labeling [with certain permissible differences]) of a previously approved drug product that relies on FDA’s findings that the previously approved drug product, the reference listed drug, is safe and effective.  Some examples of permissible labeling differences may include changes to certain inactive ingredients, exclusion of certain conditions of use, and changes due to the generic drug product and reference listed drug being produced or distributed by different manufacturers.  An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product.  A 505(b)(2) application contains or references full reports of safety and effectiveness and one or more of the investigations relied upon by the applicant for approval were not conducted by the applicant and for which the applicant has not obtained a right of reference or use from the company by or for whom the investigations were originally conducted [Guidance for Industry:  Applications Covered by Section 505(b)(2)].

The guidance outlines regulatory considerations for ANDA and 505(b)(2) applications as described below.  FDA will generally refuse to file a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval via an ANDA.  An applicant may submit a suitability petition (21 CFR 314.93) to the FDA requesting permission to submit an ANDA, known as a petitioned ANDA, for a generic drug product that differs from the RLD in its dosage form, route of administration, strength or active ingredient (in a product with more than one active ingredient).  The FDA will not approve a suitability petition if determined that safety and effectiveness of the proposed changes from the reference listed drug cannot be adequately evaluated without data from investigations that exceed what may be required for an ANDA or the petition is for a drug product for which a pharmaceutical equivalent has been approved in an NDA.  The FDA will not accept an ANDA for filing for a product that differs from the reference listed drug until the suitability petition has been approved.

In some circumstances, an applicant may seek approval for multiple drug products containing the same active ingredient(s), known as bundling, when some of the products would qualify for approval under the 505(b)(2) pathway and some of the products would qualify for approval under the ANDA pathway.  The FDA allows the applicant to submit one 505(b)(2) application for all such multiple drug products that are permitted to be bundled.  An example referenced in the draft guidance where bundling into one 505(b)(2) submission would be allowed includes an applicant seeking approval of multiple strengths of a product where only some of which are listed in the Orange Book, as reference listed drugs.

There is potential market exclusivity with an ANDA or 505(b)(2); however, the length of exclusivity depends on the specific scenario and the type of application.  An approved ANDA may result in 180 days of market exclusivity or none; only the first submitted and approved ANDA for a generic of a reference listed drug is eligible for 180 days market exclusivity.  A 505(b)(2) may be granted 3 years market exclusivity if one or more of the clinical investigations, other than bioavailability/bioequivalence studies, was essential to approval of the application.  A 505(b)(2) application may be granted 5 years market exclusivity if it is for a new clinical entity or 7 years market exclusivity if it is for an orphan drug product [Guidance for Industry:  Applications Covered by Section 505(b)(2)].

Over the past few years, FDA has released guidance documents and manuals of policies and procedures (MAPPs) and held workshops focused on their initiatives to increase scientific and regulatory clarity with respect to complex generic drug products.  A draft guidance titled “Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA” was issued in October 2017 to provide ANDA applicants information on preparing and submitting meeting requests and meeting materials for complex generic drug products.  Complex products are defined as 1)  complex active ingredients (peptides, polymeric compounds, mixtures of active pharmaceutical ingredients, naturally sourced ingredients,) complex formulations (liposomes, colloids), complex routes of delivery (locally acting drugs such as dermatological products and complex ophthalmological products and otic dose forms that are formulated as suspensions, emulsions, or gels), complex dosage forms (transdermals, metered dose inhalers, extended-release injectables), 2)  complex drug-device combination products (auto-injectors, metered dose inhalers), or 3) other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.  The guidance describes 3 types of meetings for complex products that may be submitted as an ANDA:  product development meetings, pre-submission meetings, and mid-review-cycle meetings. The draft guidance includes details for how it is determined if meetings are granted and the review timeframe goals for FY2018 through FY2022. In addition, FDA released the MAPP:  Evaluating Request for and Conducting Product Development and Pre-Submission Pre-ANDA Meetings in September 2019.  In April 2019, FDA also launched a website dedicated to providing information on upcoming product-specific guidances for complex generic drug product development.  A list of past workshops, guidances, and MAPPs focused on complex generic drug products can be found at the FDA website featuring news and information about the Drug Competition Action Plan.

Additionally, a draft guidance released on 03 January 2018 “Good ANDA Submission Practices,” addresses common, recurring deficiencies seen in ANDAs that may lead to delay in approval.  Common deficiencies include not correctly addressing patent and exclusivity information for the RLD, not providing adequate and properly prepared clinical summary data tables for bioequivalence studies, and not submitting draft container and carton labels with an accurate representation of the formatting that will be used for the final printed labels.  In a statement from Dr. Gottlieb, FDA commissioner at the time, “it currently takes on average about 4 cycles for an ANDA to reach approval – not necessarily because the product will not meet our standards, but sometimes because the application is missing the information necessary to demonstrate that it does” (Press Release 03 January 2018).  This guidance as well as a manual of policies and procedures (MAPP:  Good Abbreviated New Drug Application Assessment Procedures) aim to help reduce the number of review cycles ANDAs undergo prior to approval.  In June 2019, FDA finalized a guidance, ANDA Submissions – Content and Format, meant to assist applicants in preparing a complete; high-quality ANDA for submission.  This guidance describes information that should be included in an ANDA and identifies additional guidance documents that would help applicants during preparation of their submission.

These guidance documents provide clarity on abbreviated approval pathways and highlight priorities of the FDA to increase competition in the marketplace with a focus on speeding generic approvals, including complex generic drug products.