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GDUFA I and II: Considerations for Complex Generics Innovators

The increasing complexity of brand-name drugs has made development of generic alternatives more challenging as well. As complex generic drug products can provide a high-value opportunity for drug development companies, they are similar to 505(b)(2) products in that they may require early and flexible interaction with the FDA. The same expertise Premier Consulting holds in developing new, creative strategies to gain regulatory agreement on a less-defined development path through the 505(b)(2) pathway positions us to develop and guide successful, efficient complex generic drug programs.


Before the Generic Drug User Fee Act (GDUFA) was enacted in 2012 as part of the Food and Drug Administration’s Safety and Innovation Act (FDASIA), the FDA did not have the appropriate resources to address not only the complexity, but the volume of ANDA applications received. GDUFA requires reauthorization every five years, with GDUFA II currently in place through September 2022.

It is important to continue to bring generic drugs into the market, as their approval fosters competition and may drive prices down. This makes important drugs more readily available to a broader range of patients who require these drugs to stay healthy. The FDA and industry representatives worked together to negotiate guidelines to increase the FDA’s capacity to safely and effectively move these generic drugs through the approval process. ANDA applications benefit from the shorter approval goal dates and predictable timelines for ANDA actions and communication during the review period.

In GDUFA I there was a tiered submission process, with different cohorts and tiers receiving different goals. Not only was this challenging for the FDA to administer and operationalize, but this process resulted in significant gaps between commitments and expectations. GDUFA II eliminated this tiered system and consolidated review goals, which can now be measured against commitment letters from the FDA.

GDUFA Changes: What to Know

Major changes from GDUFA I to GDUFA II, focusing on changes in fee structures:

GDUFA I outlined user fees totaling $300 MM per year, while GDUFA II user fees are up to $493.6 MM per year – this increase was implemented to maintain the productivity of the FDA, to provide the proper resources for thorough scientific review of the high volume of ANDAs received. Necessary fees established in 2012 with GDUFA I were based on an estimation of 750 ANDAs reviewed annually. However, reports over the first 4 years of the program show the FDA averaged receipt of over 1,000 ANDAs annually.

The FDA has reaffirmed their commitment to investing in ANDA programs by eliminating Supplement Fees associated with Prior Approval Supplements (PAS) in GDUFA II. Abolishing these fees not only reduces the need for some administrative resources but also creates a greater degree of predictability within the GDUFA II budget, as the number of PAS submissions can be highly variable.

Small Business Considerations

An exciting change in GDUFA II is a modification to the User Fee structure, put in place to encourage ANDA submissions. The change introduces Small Business Considerations by shifting the basis for User Fees away from application volume and toward annual program fees. This system avoids biasing the system away from small businesses, and consists of three major changes:

  1. A facility listed in an ANDA is no longer required to pay annual fees on pending applications – these User Fees now only come into play once the ANDA on which the facility is listed has been approved (this differs from the one-time backlog fee, which is maintained with GDUFA II).
  2. Annual fees are no longer calculated on a per-ANDA basis. The new system is set up to have ANDA holders pay yearly fees based on the total number of ANDAs they have, structuring these fees to effectively differentiate between a business owning hundreds of approved ANDAs and a business that may only have a single approved ANDA.
  3. Contract manufacturing organizations, or CMOs, hired by ANDA sponsors to manufacture generic drugs will now pay only 1/3 of the annual fee paid by an ANDA sponsor that manufactures their own drugs. A Domestic Finished Dosage Form (FDF) facility pays a fee of $211,305, while a Domestic CMO will pay only $70,435. A facility fee of $44,226 applies for a Domestic Active Pharmaceutical Ingredient (API) facility. These fees also apply to foreign FDF, CMO, and API facilities, and are assessed at $226,305, $85,435, and $59,226, respectively. These fees are adjusted annually for inflation, with the listed fees effective on October 1, 2018, for fiscal year 2019.

Other GDUFA Improvements

An improvement under GDUFA II comes in the form of a partial application fee refund offered for withdrawal of an ANDA application prior to being received. Under GDUFA I, Sponsors had no incentive to withdraw and correct an application, even if they become aware of a fatal flaw in the application. The flawed ANDA would be reviewed for completeness, requiring FDA time, resources, and man-power – only for the Sponsor to receive a Refuse-to-Receive, or RTR. With GDUFA II, if for any reason a Sponsor decides to withdrawal an ANDA application before it has been received for filing by the Office of Generic Drugs, they are entitled to a 75% refund of the application fee for the fiscal year in which the application was submitted.

Additional fees that have been amended under GDUFA II? Fees paid by State or Federal Government entities that sponsor or manufacture drugs, but do not distribute them commercially, have been eliminated. As mentioned above, a facility that qualifies as both an API and FDF facility is no longer required to pay both fees, but only the FDF fee. Certainty has also been introduced to the Foreign Fee differential. Under GDUFA I, it was possible for the fee to vary between $15,000 and $30,000 annually. Under GDUFA II, this fee has been set at $15,000.

While GUDFA II outlines a consolidated pathway to reduce the time and number of review cycles necessary to obtain ANDA approval of complex generic products, it is up to the Sponsor to ensure each application is submitted correctly and in entirety, including each completed form and all necessary verification statements.

Complex Generics and 505(b)(2)

The major challenge with the development of complex generics is avoiding multiple cycles of review. Any major or more than nine minor deficiencies in an ANDA application will garner an RTR letter and require significant re-work for both applicants and the FDA. In a market where generic product timing is essential, as we have blogged about previously, this can be fatal for the future of the generic product.

ANDA applications for complex generics, like 505(b)(2) applications, require creativity and an innovative approach to obtaining a successful path to approval. The multidisciplinary teams at Premier Consulting have over 15 years’ experience evaluating, strategically positioning, and justifying the similarities of complex products to reference products for both NDA and ANDA applications. The similarities in pre-NDA and pre-ANDA meetings make Premier Consulting ideal for guiding complex drug products through ANDA approval (Complex Generic Products service).

Premier Consulting will be meeting with companies like yours at CPhI in Madrid, Spain, October 9 – 11, 2018. To request a meeting or learn more about ways we can help with strategy development and submission for complex generics and innovative medicines for generics, FDF, and API companies, contact us.


William Stoltman, JD
Senior Director of Quality Assurance / Compliance