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  1. From Our Perspective

Generic Drugs in the 21st Century: FDA’s Actions Create Transparency and Value for Complex Generic Product Development

By Robert Lionberger, PhD, Director of the Office of Research and Standards in CDER’s Office of Generic Drugs

Robert Lionberger
Robert Lionberger

Advancing complex generic drug development is an important part of FDA’s goal to help make sure patients have access to a broad range of potentially cost-saving medicines.

Complex generic products earned their name because many have complex active ingredients, dosage forms, routes of administration, or drug-device combinations. Examples of complex products include inhalers, topical products, and extended release injectables. Generics of complex brand name drugs or reference listed drugs can be more difficult to develop. As such, a complex drug product is less likely to have an available generic.

Many complex drug products did not exist when the Drug Price Competition and Patent Term Restoration Act of 1984, informally known as the Hatch-Waxman Amendments, established the modern system of generic drug regulation under which applicants can submit an abbreviated new drug application (ANDA) to FDA for assessment and approval. 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. 

GDUFA’s Role in Spurring Development of Complex Generics

FDA has taken a multifaceted approach to encourage development of complex generics through the Generic Drug User Fee Amendments (GDUFA) program. Since the enactment of GDUFA I in 2012, the agency has steadily improved the scientific foundations for complex generics. GDUFA I formalized funding for a regulatory science program that addresses scientific challenges that delay access to complex generics. Through one facet of this program, FDA publishes guidances that describe the agency’s thinking on scientific expectations for specific generic drug products, including complex generics. These product-specific guidances (PSGs), nearly 1,900 to date, provide recommendations for industry to help streamline the development and assessment process so that more generics can be developed, approved, and made available for patients.

The reauthorization of GDUFA in 2017 (GDUFA II)called for earlier and enhanced communication between FDA and industry and included special provisions for complex generics. These provisions, known as the pre-ANDA program, provide product development assistance to complex generic drug developers. Through written communications and meetings before ANDA submission and throughout the application process, FDA clarifies regulatory and scientific expectations. To date, FDA has granted more than 200 pre-ANDA meetings.

Negotiations are underway for GDUFA III. While the agency cannot comment on the negotiations, the agency views the collaborative discussions with industry as a chance to build on the successes of GDUFA I and GDUFA II to invest in FDA initiatives to support complex generic development and assessment.

FDA’s Actions to Create Transparency and Value for Complex Generics

In addition to GDUFA, FDA has undertaken initiatives to help advance complex generic development and approval through increased interaction with industry, improved assessment efficiency, and enhanced regulatory and scientific clarity.

  • Maximal use of generic drug pathways: As mentioned, many complex drugs did not exist when the Hatch-Waxman Amendments established the ANDA regulatory pathway for generics in 1984. Through guidances, scientific workshops, and other targeted efforts, FDA is increasing scientific and regulatory clarity to maximize use of its generic drug approval pathway for complex generics. When drug developers use the ANDA pathway, the public gains the benefit of a proven system for pharmacy-level substitution of generics. Because of this system, the U.S. leads the world in the extent and speed of use of approved generics, and complex generics can leverage this great success of the Hatch-Waxman Amendments even further.
  • Center for Research on Complex Generics: In 2020, FDA awarded a five-year grant jointly to the University of Maryland and the University of Michigan to establish the Center for Research on Complex Generics. FDA’s goal in establishing the center is to increase access to safe and effective complex generic drugs through collaborative research, training, and exchange. The center will facilitate communication and information sharing among FDA, academia, and generic drug companies. It also will make complex analytical assays and pharmaceutical development expertise accessible to the generic industry to support more efficient development of high-quality complex generics. The first co-sponsored workshops with the center will take place later this year.     
  • Increased transparency: FDA created a webpage with information on PSGs for complex generic drugs that the agency plans to issue or revise in the coming year. PSG revisions provide updated recommendations based on new scientific information, which ultimately help streamline generic drug development. This added clarity is intended to help drug firms better plan their generic drug development programs.
  • Increased innovation and efficiency: Generic drug applications include evidence establishing “bioequivalence” to the brand that, in simple terms, means there is not a significant difference from the brand name drug in the availability of the active ingredient at the site of drug action. New or revised PSGs for complex generics often recommend innovative in vitro (outside of a living organism) bioequivalence approaches. These new approaches are more efficient and economical than comparative clinical endpoint bioequivalence studies because such clinical studies generally require recruitment of large numbers of patients over a long time. In fiscal year 2020 alone, 32 new or revised PSGs introduced an in vitro option to demonstrate bioequivalence.  
  • FDA’s Drug Competition Action Plan (DCAP): Established in 2017, DCAP encourages robust and timely market competition for generic drugs and helps bring greater efficiency and transparency to the generic drug assessment process without sacrificing scientific rigor. DCAP helps remove barriers to generic drug development and market entry to spur competition so consumers can access the medicines at more affordable prices. DCAP includes a targeted initiative to maximize scientific and regulatory clarity for complex generics. The program’s efforts should foster complex generic drug development and approval to an even greater extent through future innovative policies.

Successes So Far and More on the Horizon

FDA, industry, and other stakeholders are beginning to see the agency’s efforts produce results for patients and consumers. We have approved more than 100 complex generics each year since 2018. Each month, new complex generic options become available to patients in need.  
Some important recent approvals include:  

  • In December 2020, we approved the first complex generic of glucagon to treat severe hypoglycemia (very low blood sugar) in patients with diabetes. This approval of a synthetic peptide was possible because of FDA research on analytical methods for peptides and immunogenicity testing for peptides.  
  • In January 2021, we approved the first complex generic for a parenteral (non-oral) iron product that treats iron deficiency anemia. Our scientific investment in characterization and advanced bioequivalence study designs was essential to this approval.  
  • In February 2021, we approved a complex generic for loteprednol etabonate ophthalmic (eye-related) suspension to treat eye inflammation using a new in vitro bioequivalence approach. Without the new approach, applicants would have had to recruit hundreds of cataract surgery patients to demonstrate bioequivalence. Investments in particle size characterization and eye models supported this more efficient bioequivalence method.  

In addition, this May FDA is hosting a webinar, “FDA Product-Specific Guidances: Lighting the Development Pathway for Generic Drugs,” which will give an overview of PSGs and their role in facilitating generic drug development and generic drug application assessment. FDA will also continue to give constructive feedback to applicants early in product development.  
Ensuring transparency and clarity during the assessment process, publishing guidance documents based on the latest science, and conducting and publishing scientific research help drive complex generic product approval that meet our high scientific standards. We know the promise and potential of complex generics, and we intend to focus our regulatory and scientific initiatives to expand and strengthen this important area of our nation’s public health system.  

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