Don Henry is director of the Office of Program and Regulatory Operations in FDA’s Center for Drug Evaluation and Research’s Office of Pharmaceutical Quality.

Don Henry

In 1992, FDA’s Center for Drug Evaluation and Research (CDER) was struggling. Due to a lack of capacity and resources, new drug application reviews took longer than two years to complete, and more than 70% of medicines were first approved outside of the United States (1). Driven by the desire to better serve the US public, CDER made drastic changes to bolster its new drugs program. Within 10 years, CDER cut new drug approval timelines in half (2). Now, FDA approves the average new drug in well under one year and 75% of novel drugs before any other country (3). What fueled this dramatic turnaround?

Every five years, FDA and industry negotiate agreements on user fees to help fund FDA’s mission of protecting and promoting public health. FDA collects user fees from companies that produce certain products, including human drugs that require a marketing or licensing application, to generate funding for regulatory activities. These programs involve commitments made by FDA, such as predictable timelines to evaluate applications and release guidance on important topics to industry. FDA doesn’t operate on user fees alone; federal law authorizes FDA to collect user fees to supplement the annual funding Congress provides. User fees fund 65% of human drugs regulatory activities, which account for one-third of FDA’s total budget (4). Importantly, FDA decisions, such as whether to approve an application, do not depend on the ability to collect user fees. Since 1992, the mixture of public and user fee funding has enabled the timely availability of drugs for US patients without compromising scientific integrity or public health. In September 2022, President Biden reauthorized certain user fee programs through 2027 including the Prescription Drug User Fee Act (PDUFA VII), Generic Drug User Fee Amendments (GDUFA III), and Biosimilar User Fee Amendments (BsUFA III).

Over the years, user fees have delivered clear value to public health. Owing to the accomplishments under PDUFA I, the first user fee program authorized in 1992, the availability of new drugs increased. Thus, demand for more affordable generic drugs also rose. GDUFA I, enacted in 2012, enabled FDA to bring greater predictability to generic-drug reviews and promote timelier generic-drug availability for patients. At the start of GDUFA I in 2012, FDA was staring at a backlog of more than 4500 pending generic-drug submissions. FDA was able to take first action on greater than 90% of these backlog applications, while acting on more than 90% of new applications, before the end of GDUFA I (5). User fees have similarly expanded the availability of biosimilars. Before the enactment of BsUFA in 2012, there were approved biosimilars in Europe but none in the US. Now there are more than 40 approved biosimilar products for US patients. User fee programs have helped provide the resources and scientific expertise to improve the availability of high-quality drugs.

If one were to consider the FDA’s human drugs program as a business, because CDER does not make or sell a physical product, one might reasonably conclude that one of CDER’s core products is communication. Consider the myriad ways in which CDER communicates: industry meetings, application correspondence, public engagement, policy documents, scientific papers, public workshops, listening sessions, and conferences. A retrospective look at the now 13 authorizations of the above user fee programs supports this notion; many of the programs’ elements focused on high-quality communications. In examining the developments most relevant to manufacturing and pharmaceutical quality in the recent user fee authorizations, it is no surprise that many continue to focus on communication.

Overall, GDUFA III emphasizes the importance of high-quality communication to drive the submission of high-quality applications and the availability of high-quality drug products. One of the aims of GDUFA III is to enable generic-drug approvals in fewer review cycles. In part, this requires guidance from FDA on ways to maximize the efficiency and utility of the first assessment cycle. Within days of reauthorization, CDER released two quality-related draft guidance documents that were GDUFA III commitments. The first relates to facility readiness and goal date decisions and provides information to applicants on how FDA assigns goal dates based on a manufacturing facility’s readiness for inspection. Applications citing facilities that are not ready for inspection can slow an application’s approval, so CDER will now defer substantive application assessment if a facility is not ready for inspection at the time of submission. While most facilities are found to be compliant with current good manufacturing practice (CGMP) requirements, noncompliant facilities can impede the approval of otherwise worthy applications. Under GDUFA III, certain noncompliant facilities cited in generic-drug applications may be eligible to meet with FDA after receiving a Warning Letter to obtain preliminary feedback regarding corrective actions prior to a reinspection (6). Transparent communication regarding facilities will encourage effective steps toward enabling a drug approval.

Facilities are not the only element of an application that can slow or impede generic drug approvals. CDER also needs to find drug master files (DMFs) cited in drug product applications to be adequate in order to approve the application. CDER’s second draft guidance addresses the early assessment of DMFs, up to six months prior to the submission of certain abbreviated new drug applications (ANDAs) or supplements that will reference the DMF. Eligible ANDAs include, for example, drug products related to a drug shortage or a public health emergency (7). This earlier engagement on the assessment of DMFs can increase the likelihood that a DMF will be found adequate and thus that the associated ANDA will be found approvable. Of course, CDER will not find all ANDAs approvable. In these cases, GDUFA also expands the scope of controlled correspondence. After receipt of a complete response letter stating the reasons why a drug application was not approved, generic-drug manufacturers can now submit controlled correspondence to seek regulatory and scientific feedback and clarify deficiencies identified for the ANDA (8).

In general, improved communication improves generic-drug development. CDER’s Pre-ANDA program, first introduced in GDUFA II, assists applicants and prospective applicants developing complex generic products (9). Although GDUFA II set standards for communication through the Pre-ANDA program, GDUFA III enhances the dialogue between CDER and potential ANDA applicants (10). A critical element of the Pre-ANDA program is the release of Product-Specific Guidances (PSGs) that provide the agency’s current thinking and expectations on how to develop drug products that are therapeutically equivalent to reference listed drugs. This transparency can be especially beneficial for stakeholders eyeing complex generic drugs that are difficult to develop. GDUFA III establishes goal timelines for releasing PSGs for complex innovator drug products to speed generic-drug development. For example, a GDUFA III goal is to issue PSGs for 75% of complex products within three years of the innovator product approval date. Under GDUFA III, when a new or revised PSG is published, a potential applicant may now request a teleconference to obtain CDER feedback on the potential impact of the PSG on its development program (11). These additional Pre-ANDA communications promote a more efficient ANDA review process for complex generic-drug products, and aim to reduce the number of review cycles and facilitate approvals.

User fees continue to play an important role in expediting the development and approval of new drugs. With the PDUFA reauthorization, industry now has additional tools to overcome chemistry, manufacturing, and controls (CMC) challenges in product development. Improved communication is also a hallmark of PDUFA VII, which establishes two new types of meetings to expand communication and feedback during drug development. In addition to the traditional development meetings (Type A, B, and C), there is now a Type D meeting for quick discussion on a narrow set of issues. Another new meeting option is Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) to facilitate successful investigational new drug applications. Early input from FDA to a sponsor, regarding novel and unique challenges in the development phase, might prevent delayed entry into the clinic (12).

In October 2022, FDA announced a CMC Development and Readiness Pilot program to further expedite the development of products that address unmet medical needs. Products with accelerated clinical development timelines often face CMC development and CGMP compliance challenges. Under the pilot, FDA can provide product-specific CMC advice during product development by including an option for two additional CMC-focused meetings (Type B) and additional CMC-focused discussions based on readiness and defined CMC milestones. For those sponsors who request to participate in the pilot, FDA will evaluate the anticipated clinical benefits of facilitating earlier access, the novelty of the product, the complexity of the manufacturing process, the sponsor’s overall manufacturing experience, and the sponsor’s experience with the product.

PDUFA VII also aims to advance the implementation of innovative manufacturing technologies. Over the course of PDUFA VII, FDA will conduct a workshop that includes industry and public feedback and publish a draft strategy document for public comment on innovative manufacturing technologies. This document will outline the strategy to facilitate the implementation of innovative manufacturing technologies, including addressing barriers to their adoption (13). These engagement opportunities will help FDA encourage the submission of products made using innovative manufacturing technologies to assure process and product quality.

Over the past decade, BsUFA has enabled the approval of the first biosimilars in the US, including four interchangeable biosimilars that can be more easily substituted for innovator products. Biosimilars provide more treatment options for patients and improve the availability of biological products. As science often drives biosimilar product development, in addition to sharing several goals with PDUFA VII, BsUFA III establishes a regulatory science pilot program to improve the efficiency of developing biosimilar and interchangeable products. Five projects have already been funded to help advance these goals (14). Three projects focus on improving biosimilar product development by addressing aspects of the similarity assessment. These assessments might be aided by advanced or standardized analytical methods and improved understanding of the impact of the product formulation and container. The two other projects advance the development of interchangeable products by using 

 methods, rather than switching studies, to predict immunogenicity risks that can arise when a patient switches products. The overall objective of the BsUFA regulatory science pilot program is to improve the availability of biological treatment options for patients.

It turned out that the reauthorizations of GDUFA, PDUFA, and BsUFA were just a start. Many other provisions were later included as reforms in the Consolidated Appropriations Act 2023 under the Food and Drug Omnibus Reform Act of 2022 (FDORA). Many of these provisions also relate to communication including, for example, issuing guidance and holding a public meeting related to the designation of advanced manufacturing technologies (15). A theme seems clear: high-quality communication is an enabler of CDER’s approval of high-quality drug products. This is why FDA strives to engage with applicants and manufacturers developing products and technologies, provide clear expectations and feedback, and minimize deficiencies in the application assessment process. User fees provide the resources and engagement opportunities to do so and expand the availability of high-quality medicines to patients. Although the implementation of the recently reauthorized user fee commitments and FDORA provisions is still in progress, they build on a foundation of successful progenitor programs. User fee programs have been a significant asset to US healthcare and have undoubtedly increased the availability of safe, effective, and high-quality medicines for the American public.

Food and Drug Administration: Effect of User Fees on Drug Approval Times, Withdrawals, and Other Agency Activities

https://phrma.org/policy-issues/Research-and-Development/PDUFA

5. FDA. Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA). (2016) (testimony of Janet Woodcock). 

6. FDA. GDUFA III Changes for Facilities, 

7. FDA. FDA Revises Generic Drug Application Prioritization Policy to Ensure Fairness to Applicants, Efficiently Allocate Limited Agency Resources, and Protect the Public Health. 

Guidance for Industry, Post-Complete Response Letter Clarification

Teleconferences Between FDA and ANDA Applicants Under GDUFA

GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 

 Product-Specific Guidances for Generic Drug Development 

SOPP 8101.1: Regulatory Meetings with Sponsors and Applicants for

Drugs and Biological Products, Version 11 

PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2023 through 2027 

14. FDA. BsUFA Regulatory Research Pilot Program New Research Awards, 

15. H.R.2617 - 117th Congress (2021-2022): Consolidated Appropriations Ac

When referring to this article, please cite it as Henry, D. High-Quality Communication Enables High-Quality Drug Products. 

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