Key Points

• FDA Commissioner Scott Gottlieb has initiated multiple policy actions to simplify the approval pathway for generic drug products
• Commissioner Gottlieb hopes these efforts will improve access to medications and lower healthcare costs
• The FDA has placed special focus on “complex” generic drug products, which have traditionally been difficult to “genericize”
• New policies are meant to reduce the number of review cycles and lower right-to-refuse rates for complex generic drug applications
• The FDA has defined complex drug products, created expedited approval pathways, offered opportunities for feedback/advice, and published numerous guidances to benefit complex generic drug development

What Makes a Generic Drug Product “Complex”?

In recent years, the FDA has taken steps to clarify the approval process for complex generic drug products. According to FDA Commissioner Scott Gottlieb, complex drug products “generally have at least one feature that makes them harder to ‘genericize’ under our traditional approaches.” These features can arise from formulation, characterization, or manufacturing considerations, as we’ve addressed in a previous post.

When formulating a generic drug product, there are key sources of complexity that can be difficult to replicate:

• Active Ingredient: mixtures of APIs, polymeric compounds, peptides
• Formulation Technique: liposomes, suspensions, emulsions, gels
• Route of Delivery: locally-acting or targeted delivery
• Dosage Form: long-acting injectables and implantables, transdermals
• Drug-Device Combination: auto-injectors, nasal sprays, metered dose inhalers
• Bioequivalence Determination: certain drugs are not easily measured in the blood or act locally on a particular organ, making it difficult to prove bioequivalence

The FDA’s Efforts to Increase Complex Generic Approvals

In 2017, the FDA approved 1,027 new generic drugs, a record for the Agency. This increase in generic approvals is partially a result of the FDA’s Drug Competition Action Plan, which was designed to improve patient access to medicines and increase competition in the drug market. As the FDA Commissioner stated,

“Innovation in pharmaceutical development is essential because it creates new and sometimes life-saving therapies. But access to lower-cost alternatives, once patent and exclusivity periods lapse, also is critical to the nation’s health…Our goal is to broaden access to safe and effective generic drugs that can improve access to medicines and help consumers lower their health care costs. As in all of the things we do, we will steadfastly maintain FDA’s gold standard for rigorous, science-based regulation.”

As part of this effort, multiple policy announcements have addressed the regulatory pathway for complex generic drug products. According to Commissioner Gottlieb, these new policies are “aimed at ensuring that we provide as much scientific and regulatory clarity as possible with respect to complex generic drugs.”

Why Promote Complex Generic Drug Products?

The challenges that accompany complex generic drug product development lead to greater scientific and regulatory hurdles, such as higher right-to-refuse rates or additional ANDA review cycles. When companies are discouraged from pursuing generics, the lack of competition prevents patients from getting access to affordable medications. The FDA is committed to reducing the obstacles to complex generic drug product development and creating an efficient review process that results in high-quality ANDAs.

What Has the FDA Done?

The FDA has shown its commitment to improving the complex generic drug approval process through a series of actions in recent years. The following provides a list and summary of the steps taken so far to ensure growth in complex generic drug products.

1. Clearly Defined Complex Drug Products
2. Created an Expedited Review Process
3. Published Guidance for the Complex Generic Application Process
4. Published Guidance on Complex Peptide-Based Products
5. Provided Additional Information and Assistance to Complex Product Developers

Clearly Defined Complex Drug Products

In their commitment letter for the Generic Drug User Fee Act (GDUFA) II, the FDA clearly laid out a definition for complex drug products. The definition covers (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.”

Created an Expedited Review Process

In 2017, the FDA published a list of off-patent, off-exclusivity branded drugs without approved generics. While the Agency has introduced an expedited review process for generic drug applications with limited competition, many of these products haven’t been genericized due to complexity. With this expedited review pathway, the FDA hopes to encourage generic development for complex drug products.

Published Guidance for the Complex Generic Application Process

The FDA has released a draft guidance titled “Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA.” The document outlines processes for requesting meetings with the FDA to guide product development and submission. It also encourages communication between applicants and the Agency throughout the product development process, helping applicants address potential issues early in their programs. The guidance covers the following meeting types:

1. Product Development Meetings: Provide for discussion of specific scientific issues or questions. Gives applicants the opportunity to review their development plan and early stage data with the Agency
2. Pre-Submission Meetings: Provide an opportunity for prospective ANDA applicants to discuss and explain the format and content of the ANDA to be submitted. Allows the FDA to identify items or information that need further clarification before the submission takes place.
3. Mid-Review Cycle Meetings: Affords an opportunity for the FDA to discuss issues identified during review with the applicant.

Published Guidance on Complex Peptide-Based Products

“ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin” is a draft guidance that helps applicants determine when submission of ANDAs for peptide-based biologics is appropriate. Recommendations in the guidance address how evolving technology in synthetic peptide synthesis can be used to generate bioequivalent products—even when the innovator product is of rDNA origin. According to the FDA, “there are a number of branded medicines that are peptides, where exclusivity has lapsed, but these drugs face little or no competition.”

Provided Additional Information and Assistance to Complex Product Developers

In October of 2017, the FDA Office of Generic Drugs held three public meetings to discuss the development and characterization of complex generic drug products. The Agency addressed topics such as complex product characterization and novel techniques for demonstrating bioequivalence. In addition, the Office of Generic Drugs published 47 product-specific guidances focused on the development of complex generic drug products. These documents outline the FDA’s expectations on how to develop complex drug products and address the precise challenges that each product carries. The Agency’s regulatory science program is also working to fill scientific gaps and develop analytical tools that will address general issues in complex product development moving forward. According to an FDA statement, “We intend for these efforts to speed product development, reduce development costs, and improve access to these products.”

Conclusion

The FDA is improving the efficiency of the regulatory pathway for complex generic drug products. These efforts will help patients by enabling the development of complex generics and providing access to affordable medications.

Although the Agency continues to work on an easier regulatory pathway, this doesn’t change the fact that formulating, characterizing, and manufacturing complex generic drug products remains uniquely challenging. To successfully develop a complex generic, you need a partner who can navigate complex APIs, formulations, dosage forms, routes of administration, analytical challenges, and manufacturing processes to meet the FDA’s requirements.

Authors: Judy Cohen and Nick DiFranco