FDA and EMA re-launch parallel advice pilot for complex generics

Quick background: complex and hybrid products

• Complex generics are defined by FDA as products with a complex active ingredient, formulation, delivery route, dosage form or method of administration. Some examples include polymers or large molecules like peptides, liposome formulations, and drug-device combination products. The inherent complexity of these products can make the product development process significantly more difficult. For example, an inhalation product (such as an orally inhaled or nasal drug product) requiring a metered-dose inhaler (MDI) may also be required to administer a specific amount of a product in a specific particle size to ensure proper absorption of the product. Alternately, an extremely small product (such as a nanomedicine) may be difficult to characterize, making it challenging to demonstrate sameness.
• Hybrid medicines are defined by the EMA as drug products that depend both on comparisons to a reference product and on new data from clinical trials. In these cases, additional original data is warranted due to a different strength, different route of administration or different indication from the reference. These are sometimes referred to as the EMA’s version of complex generics.
• Getting a complex generic or hybrid medicine to market is challenging. The generic drug pathway was not set up with complex products in mind. As the FDA has previously acknowledged: “Many complex drug products did not exist” when the Hatch-Waxman Amendments were first passed into law. “As drugs have increased in complexity in recent years, the scientific and regulatory roadmaps for drug development and approval may not be as well-established for more complex generics.”
• The FDA has taken some actions to make the path to market easier for these products. The generic drug user fee program (GDUFA) has focused on complex generics, making significant revamps in its first reauthorization (GDUFA II) like the pre-ANDA program for complex generics. This program allows these developers of complex generics to work with FDA through the regulatory process and reduce the number of review cycles needed to obtain approval. FDA also develops product-specific guidances detailing expectations for bioequivalence (BE) studies, but many complex generics do not yet have this roadmap. Most recently, GDUFA III included enhancements like promoting the development of more product specific guidances (PSGs) to foster development of complex products. AgencyIQ has compiled a list of all the Commitments under GDUFA III and when the FDA is expected to meet them, which you can read here.
• Lack of international harmonization is a challenge for generic products. As compared to novel drugs, where almost every country has a roughly comparable system to allow for the approval of a new drug, not every country has a similar legal process in place to support the approval of generic drugs or their substitution on the market. The International Council for Harmonization (ICH) has developed limited standards for generic drugs, such as the M13 guideline on bioequivalence for immediate-release solid oral dosage forms [ Read AgencyIQ’s detailed analysis of that document here here.]

FDA and EMA first kick-started the Parallel Scientific Advice (PSA) Pilot Program for Complex Generic/Hybrid Products in September 2021

• As AgencyIQ discussed at the time, the program set out to provide a forum for sponsors to concurrently seek out scientific advice from the FDA and EMA related to Abbreviated New Drug Applications (ANDAs) and Marketing Authorization Applications (MAAs). The two agencies already operate a parallel scientific advice program for drugs and biologics; this pilot is an expansion of that program. The program officially launched on September 15, 2021.
• The PSA program consists of three stages. First, the requestor submits scientific questions related to development to both FDA and EMA. Both agencies must grant the meeting request to move forward. Second, the submitters provide a full meeting package with detailed information on the development history and context, available data, and questions. FDA and EMA will review the package and meet to discuss the package before having a meeting with both agencies and the submitter to provide direct insight. Finally, both regulators will provide written responses related to the questions posed. Importantly, the meeting will not impact either agency’s regulatory decisions after the fact. [ For more detail, see AgencyIQ analysis here.].

Today, an FDA blog post “launched” the program again, providing a status update and urging participation.

• FDA published a “From Our Perspective” blog post on February 7, 2024 titled, “FDA and EMA Launch Parallel Scientific Advice Pilot Program for Complex Generics.” The piece was authored by SARAH IBRAHIM, the Associate Director of Stakeholder and Global Engagement in CDER’s Office of Generic Drugs (OGD).
• In short, the piece reports that the program has had light uptake thus far, with just two applicants completing the PSA process in almost two-and-a-half years. Still, Ibrahim claims in the post that the experience thus far has benefitted both applicants and regulators. The agency also intends to implement recommendations received from the previous participants to improve the program via procedural and timeline clarifications.
• The post acknowledges – and attempts to counter – hesitancy to participate stemming from “misperceptions that conflicting advice from both agencies could require additional testing, a lack of binding or enforceable commitments from the agencies could limit the value and impact of the PSA advice, and sharing confidential information may potentially compromise competitive advantages.” To combat this, the program utilizes confidentiality agreements and redaction to protect sensitive information.
• FDA outlines three examples of “good candidates” for participation. The first two relate to BE studies, either to propose one BE study to satisfy both agencies when recommendations differ, or to discuss the use of a common comparator in BE studies. The third example is more general, involving “proposals to use modeling and simulation to improve efficiency of the development program.”

Analysis

• The “launch” of the PSA pilot program aims to address hesitancy and encourage more industry participation. The agency even emphasizes that a single justification letter request can be sent to both EMA and FDA. Based on the examples of candidate provided, the pilot appears to be most useful in early stages of development, prior to the initiation of BE studies.
• The PSA pilot brings an international angle to the meeting repertoire available to complex generic/hybrid product developers. In addition to the pre-ANDA program, PSA meeting content could have some potential overlap with another pilot program, the Model-integrated Evidence (MIE) Industry Meeting Pilot Program launched in September 2023. As explained at a recent “deep dive” meeting on the MIE Pilot Program, this latter program aims to provide a channel for early communication on innovative approaches to establishing bioequivalence, such as quantitative methods and modeling (QMM). The MIE Pilot is open to complex and non-complex products, and its goals are reminiscent of the third example of a “good candidate” for the PSA Pilot. FDA has been clear that applicants should not pursue the pre-ANDA and PSA program simultaneously, but has not advised on whether PSA and MIE Pilot participation can be concurrent. Still, complex generic developers may want to take advantage of multiple early interaction programs as they navigate this challenging development process.
• What’s next? The pilot program does not have a hard stop and will accept requests “until the agencies determine the number of completed PSA meetings is sufficient to assess the pilot program.”

Featuring previous research by Lily Rosenfield.
To contact the author of this item, please email Amanda Conti ( [email protected]).
To contact the editor of this item, please email Kari Oakes ( [email protected]).

Key Documents and Dates

• From Our Perspective: FDA and EMA Launch Parallel Scientific Advice Pilot Program for Complex Generics