Earlier this year, the U.S. Food and Drug Administration (FDA) announced its Drug Competition Action Plan, which aims to bring more competition to the drug market and improve consumer access to drugs. As part of this effort, the Agency is focusing on ways to help bring complex generic drugs to market, providing competition to this subset of approved products. As defined in the Generic Drug User Fee Amendments for Fiscal Years (FYs) 2018-2022 (GDUFA II Commitment Letter), complex generic drug products are defined by the FDA as:

1. “Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of [active pharmaceutical ingredients], naturally sourced ingredients); complex formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels); or complex dosage forms (e.g., transdermals, metered dose  inhalers, extended-release injectables);
2. Complex drug-device combination products (e.g., auto-injectors, metered dose inhalers); and
3. Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement”.

Historically, complex generic drug products have been viewed as more difficult to “genericize” and therefore face less or no generic competition in the market, which the FDA is looking to change.

Discussion with the FDA on Complex Generic Drug Product Programs: Early and Often

As part of the push to increase efficiency and approval of more complex generic drug products, the Agency is encouraging Sponsors to contact and discuss complex generic products development programs with the FDA early in development. More frequent discussion with the Agency will allow for more efficient product development and approval. Demonstration of bioequivalence (BE) for complex generic drugs can be challenging; as discussed above some products are locally acting and cannot be measured systemically with traditional BE methods. Premier Consulting has extensive experience with locally acting drug products as well as pharmacokinetic modeling and analysis for 505(b)2 applications. The application of these tools can be critical for the development of some complex generic products. This in-depth experience can help Sponsors develop an efficient and cost-effective strategy for their complex generic product drug development program.

To facilitate early and frequent discussion with Sponsors of complex generic products, the FDA has recently released a new Draft Guidance entitled “Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA” (Center for Drug Evaluation and Research [CDER], Generics, October 2017). This Guidance provides information on how to request pre-ANDA meetings (product development meetings, pre-submission meetings, and mid-review cycle meetings) with the FDA and outlines proposed timelines for the FDA to meet performance goals for each type of meeting. Specifically, the Guidance outlines information which should be included in the meeting request, noting that if sufficient information is not provided, the request will not be considered submitted. Assessment of the provided information will allow the Office of Generic Drugs’ (OGD) Office of Research Standards (ORS) (within input from the Office of Pharmaceutical Quality) to determine whether a meeting should be granted; therefore submission of an adequate meeting request letter and package is critical. The Guidance also notes the importance of the meeting package in enabling the FDA to prepare for the meeting; the meeting package should be submitted concurrently with the meeting request.

In addition, the FDA has released an additional Draft Guidance specifically to help Sponsors developing a synthetic peptide drug product determine if an application which references a reference listed drug (RLD) of recombinant deoxyribonucleic acid (rDNA) origin should be submitted as an ANDA or an NDA (ANDAs for Certain Highly Purified Synthetic Peptide Drug Products that Refer to Listed Drugs or rDNA Origin Guidance for Industry, CDER, Generics, October 2017). Given changes in technology, the FDA now believes that it is possible to demonstrate that the active ingredient in a proposed synthetic generic peptide product is the “same” as the active ingredient in the RLD of rDNA origin. The Guidance notes that determination of ANDA versus NDA application largely depends on the impurity profile of the proposed generic peptide product in comparison to the impurity profile for the RLD peptide of rDNA origin. It is suggested that Sponsors developing a generic synthetic peptide product contact the OGD to determine whether an ANDA or NDA application is appropriate, either through a Controlled Correspondence or a pre-ANDA meeting.

Premier Consulting has extensive experience in interacting with the Agency (we have led more than 1100 Agency meetings and we routinely conducting 3-6 Pre-IND meetings a month) and can provide guidance in navigating discussions with the FDA. Our experience in preparing meeting request letters and meeting packages as well as in attendance at FDA meetings, will ensure that a complex generic product development meeting, pre-submission meeting, or mid-review cycle meeting is successful. Premier Consulting’s goal for these meetings is to achieve Agency buy-in on the proposed program and provide the sponsor with a clear path forward in their drug development program.

Strategic Development of Complex Generic Drug Products: Ongoing Changes

Commissioner Scott Gottlieb and the FDA have stated that efforts will continue to enable and promote competition of complex generic drugs over the coming year with the proposal and advancement of additional polices. Premier Consulting can help ensure that your proposed development program stays up to date in regard to changing regulatory policies as well as ensuring the most efficient strategy and program for your complex generic drug product.

A successful, efficient complex generic drug product program can provide a high-value opportunity for a drug development company. Contact Premier Consulting to see how we can support your complex generic drug product regulatory needs and help guide you through a successful ANDA, from early product development meetings to submission and approval.