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Complex Generics Getting Too Complicated for the Generic Approval Pathway? GDUFA II and the Pre-ANDA Program to the Rescue

Finally there is hope for Sponsors of complex generics with the new Pre-ANDA program outlined in GDUFA II. More good news: the 505(b)(2) experts have got you covered for the development of complex generics.

Until now, Sponsors of complex generic products either submitted an NDA via the 505(b)(2) pathway if their product met the criteria for this pathway, or were compelled to follow the traditional generic approval pathway (505(j)). The chances of getting a generic application (ANDA) successfully filed, and approved after the first round of review are surprisingly low, and probably even lower for complex generics. The resulting delays in product approval can be devastating for the marketing success of a generic product. The resulting lack of generic competition for complex products drives up the cost of these medicines and can limit access for patients in need.

The reauthorization of the Generic Drug User Fee Amendments (GDUFA) for FY2018–2022 (referred to as GDUFA II), signed into law on 18 August 2017, aims to improve the process for getting complex generics approved. After consultation between the FDA and industry and with input from public stakeholders, the GDUFA II commitment letter recognized that unlike traditional generic products, complex products require consultation with the FDA to gain agreement on novel development strategies. These strategies require innovative approaches and mechanisms for leveraging existing knowledge. These are the same tenets that make the 505(b)(2) such an innovative and adaptive pathway for product approval. More on the similarities later.

When Is a Generic Drug Product a Complex Generic?

The FDA defines complex generics as (i) products with complex active ingredients, formulations, routes of delivery, dosage forms, (ii) complex drug-device combination products, and (iii) “other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.”

The FDA provides examples of complex products in the draft Guidance (Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA) including peptides, polymeric compounds, complex mixtures, naturally sourced ingredients, liposomes, colloids, locally acting drugs such as dermatological products, and complex ophthalmological products, otic dosage forms that are formulated as suspensions, emulsions, or gels, transdermals, metered dose inhalers, extended-release injectables.

This list is very familiar to the 505(b)(2) experts at Premier Consulting because these complex products are often approved via the 505(b)(2) pathway for new drugs. In fact, Premier Consulting has worked on every one of the product types in the provided examples.

What Have We Learned from GDUFA I?

Last week at the Association for Accessible Medicines Technical Conference, the FDA provided an update on GDUFA I (FY2012–2017) and explained the expectations for GDUFA II (FY2018–2022) regarding complex generic drug products. During GDUFA I, the FDA received an average of 1000 ANDAs per year, exceeding projections. Seven hundred eighty‑eight (788) product‑specific guidances were released, 493 (37%) of which were for complex drug products.

Under GDUFA I, 127 pre‑ANDA meeting packages were reviewed, almost all for complex drug products. The number of applications, controlled correspondence, and ANDA applicants are continuing to rise, and the complexity of the applications and correspondence is increasingly more complex. Despite this, the FDA met or exceeded every formally negotiated GDUFA goal and  continues to raise the bar in GUDFA II.

The outstanding challenge for generic products, and especially for the complex ones, is multiple review cycles. As mentioned above, multiple review cycles are inefficient and lead to a substantial amount of re‑work for both the Agency and the applicants, demonstrated by the low percentage of ANDAs approved in the first cycle (12.8% in FY2017). Approximately 21% of ANDAs are returned with a Refuse-To-Receive (RTR) action (10.5% in FY2017), mainly due to quality issues such as inadequate stability and dissolution data. Incomplete English translations of documents in the application is also a significant factor. A RTR can be an indicator of further problems with the application, as only 3.8% of these will receive first cycle approval once received (or tentative approval) compared to 11.5% that were accepted for filing without a RTR action. This is especially true if the application is resubmitted too quickly without thoroughly addressing the deficiencies.

For ANDAs and Prior Approval Supplements that were received in GDUFA I, approximately 50% resulted in a complete response action, meaning that the applications were not approvable in the first cycle. Similar to the RTR, the majority of deficiencies in complete response letters were related to dissolution, stability, excipients, and facilities.

An approval delay from a RTR or a complete response letter is always undesirable but can be catastrophic for a generic product in which timing is everything, as we have previously blogged.

Enter GDUFA II and the Pre-ANDA Program

The FDA has taken a number of steps to help applicants circumvent the high number of RTRs. Specifically, the Agency released two draft guidances describing changes to generic drug programs: one describing pre‑ANDA meetings (Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA) and another regarding synthetic peptide drug products with rDNA reference listed drugs (ANDAs for Certain Highly Purified Synthetic Peptide Drug Products that Refer to Listed Drugs or rDNA Origin Guidance for Industry). Both are summarized in our recent blog post on complex generic drug products.

GDUFA II will introduce new meetings to accelerate access to generics of complex products, including product development, pre‑submission, and mid‑review‑cycle meetings. The goal of the Pre‑ANDA Program in GDUFA II is to reduce the number of review cycles necessary to obtain ANDA approval of complex generics products.

Pre‑ANDA submission meetings are an important opportunity to discuss the strategy and format of the planned application, and provide an opportunity for the FDA to give advice that will enable efficient review and improve the chance of first cycle approval. In addition, these meetings will allow the FDA to share information with the internal ANDA review team in order to prepare for unique review issues.

Getting It Right, Early

Complex products require innovation, creativity, and a multiple disciplinary approach in obtaining a successful path to approval. As we have blogged on multiple occasions, the need for getting early FDA feedback for unique and complex products is critical. But especially important is the need to get feedback on all the relevant issues prior to submitting an application.

Premier Consulting’s multidisciplinary team includes in-house regulatory experts, and PhD pharmacokinetic, CMC, and research scientists who assist you with pre-ANDA meetings and the submission of a high-quality, approvable application. We have 14 years of experience in evaluating, strategically positioning, and justifying the similarities of complex products to reference products for both NDA and ANDA applications. As part of this process, we represent Sponsors in FDA meetings multiple times per month.

Contact Premier Consulting to find out more about how we can guide your complex drug product through ANDA approval.


Angela Drew, PhD
Product Ideation Consultant

Ruth Stevens, PhD
Strategic Advisor