The first iteration of the Generic Drug User Fee Act (GDUFA I) was introduced by the FDA in 2012 to provide a more predictable revenue stream with the goal of improving patient access to lower cost generic drugs by getting generic drugs to the market faster. GDUFA I also created a more consistent facility inspection structure to mitigate inspection delays in ANDA approvals. The Food and Drug Administration Safety and Innovation Act (FDASIA), for the first time, required user fees for original and prior approval supplement (PAS) generic applications and for generic manufacturers of active pharmaceutical ingredients (API), finished product and manufacturers performing certain unit operations; brand sponsors and manufacturers have been paying fees for years under the Prescription Drug User Fee Act (PDUFA). GDUFA I expired on September 30, 2017 and with that the second iteration of the Generic Drug User Fee Act (GDUFA II) came to fruition, effective October 1, 2017.

GDUFA II was carefully negotiated between FDA and industry for more than a year. The result of these negotiations produced several significant changes from GDUFA I such as streamlining the ANDA amendment structure by eliminating the tier designations and replacing it with “standard” or “priority” review, modifying the user fee structure by eliminating the PAS fee and introducing the ANDA program fee, enhancing the pre-ANDA programs, and establishing faster review time lines for priority submissions. The GDUFA II enhancements and commitments were designed to increase first cycle approvals, reduce overall review cycles, assist small business, and increase patient access to more affordable, quality generic drugs.

It has been over eight months since the President signed into law the Food and Drug Administration Reauthorization Act (FDARA) on August 18, 2017, and more than six months since GDUFA II became effective. Generic companies have certainly had sufficient time to consider the impact of GDUFA II on their business; initially most likely from the financial perspective as the ANDA Program Fee is new to GDUFA II, the PAS fee has been eliminated and facility fees are only incurred when the facility is referenced in an approved generic drug submission and the facility is engaged in manufacturing or processing of an API or finished dosage form (FDF). In addition, most Regulatory groups have now experienced the review enhancements, such as issuance of Information Requests (IRs) and/or Discipline Review Letters at mid-cycle, and on a rolling basis until the end of the review cycle, and notifications from the FDA Regulatory Project Manager (RPM) that a major deficiency is forthcoming.

However, it is worth asking whether generic companies are taking full advantage of provisions in GDUFA II which were added to improve generic access and promote competition, and whether generic companies have changed or adjusted their business and regulatory strategies accordingly. The business development units within generic drug companies usually data mine the Orange Book, IMS database, Clinicaltrials.gov, and other competitive intelligence sources to identify target brand products for generic development. Product selection is often, but not exclusively, based on margin, potential competition, RLD sales, whether high barrier to entry, and potential life cycle of a product. The product selection is company specific and depends on the company’s business plan and strategy which is usually designed to pursue a competitive advantage across its chosen market scope. 

Business development should take note that FDA is now required to publish a current list of all drug products for which all patents and periods of exclusivity have expired, and for which FDA has not approved an ANDA referencing the product. This information can be useful in identifying a potential area of opportunity for a generic company concerning a provision in Title VIII of FDARA (§ 801) which added 505(j) (11) to the FD&C Act. This provision created a new 8-month priority review pathway for ANDAs. FDA will consider an ANDA to be a priority review if it meets the criteria listed in either section 505(j) (11) (A) of the FD&C Act, or the Center for Drug Evaluation and Research’s (CDER’s) Manual of Policies and Procedures (MAPP) 5240.3, Prioritization of the Review of Original ANDAs, Amendments, and Supplements (Prioritization MAPP). In summary, an ANDA may qualify for priority review if the brand reference product has less than three approved generics with no blocking patents or exclusivities and/or the ANDA product is on the FDA’s drug shortage list.

The process for requesting priority review requires the ANDA applicant to provide FDA with “complete, accurate information regarding facilities involved in manufacturing processes and testing of the drug that is the subject of the application, including facilities in corresponding Type II active pharmaceutical ingredients drug master files referenced in an application and sites or organizations involved in bioequivalence and clinical studies used to support the application”1 not later than 60 and not earlier than 90 days prior to ANDA submission. FDA has exercised broad discretion in interpreting this requirement which is outlined in the draft November 2017 “Guidance for Industry: ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence).” The guidance notes that the pre-submitted facility information “must be unchanged relative to the date of the ANDA submission to maintain eligibility for a priority review goal. However, applicants may exclude a facility that was not used to generate data to meet any of the application requirements for the submission and that is not the only facility intended to conduct one or more unit operations in commercial production.”

The guidance requests information from modules 1, 2, 3 (drug substance, drug product and Product Development Report) as well as module 5 including the specific sections of the comparative bioavailability and bioequivalence study reports such as: study report (ICH E3, Section 1, Section 3 to 15), protocol and amendments (ICH E3 16.1.1), list and description of investigators (ICH E3 16.1.4), randomization schemes (ICH E3 16.1.7), discontinued subjects (ICH E3 16.2.1), protocol deviations (ICH E3 16.2.2), subjects excluded from the statistical analysis and adverse effects and serious adverse effects) (ICH E3 16.2.3).

The pre-submission facility information described in the above-referenced guidance can pose a daunting task for Regulatory staff as well as the related functional areas within a generic organization when a company is pursuing the priority review pathway. For generics, it is typical for the supporting business units such as R&D and Quality to provide Regulatory with documents and required information very late in the ANDA compilation process. It is not unusual for Regulatory to receive the final Product Development Report, stability, final finished product specifications and/or Certificates of Analysis the day before or day of ANDA filing. 

Companies should carefully consider how they manage their internal processes if they want to take advantage of the 8-month priority review. Planning must occur early in the development process and include Regulatory and Project Management. It is critical that timelines be established early to ensure timely filing of the pre-submission information including close coordination with the CRO. For many generic companies, this represents a paradigm shift and will require engagement of Senior Management to ensure accountability in meeting established timelines. Lack of disciplined internal processes can result in lost opportunity which are increasingly fewer in the generic space.

Another potential area of opportunity for generic companies is the “Competitive Generic Therapies” as outlined in Section 506H of the FD&C Act, as amended by FDARA (§ 803). Per section 506H, FDA is authorized to designate a drug as a “competitive generic therapy” upon request by the applicant. To qualify as a competitive generic, there must exist “inadequate generic competition” which is defined as no more than one approved ANDA for the corresponding reference product (RLD). In addition, for a drug to be considered a “competitive generic therapy” there must be no unexpired patents or exclusivities as listed in the current edition of the Orange Book at the time of ANDA submission. This does not include products listed in the discontinued section of the Orange Book. Generic firms should be aware that a request for a competitive generic therapy designation must be made prior to or concurrent with the ANDA submission.

A 180-day exclusivity period is available only to the “first approved applicant” of an ANDA designated as a “competitive generic therapy.” The competitive generic 180-day exclusivity works similarly to the conventional Hatch-Waxman 180-day exclusivity as it prevents FDA from approving another ANDA for the same product until day 181 from the date of the first commercial marketing of the competitive generic therapy. It is important to note that certain aspects of the forfeiture provisions enacted under the Medicare Modernization Act (MMA) apply to the competitive generic therapy exclusivity. The ‘first approved applicant” can forfeit their 180-day exclusivity if it “fails to market the competitive generic therapy within 75 days after the date on which the approval of the first approved applicant’s application for the competitive generic therapy is made effective.”²

Generic firms should take note that FDARA § 804 which amended the FD&C Act to add Section 506I  requires NDA and ANDA holders to report in writing to FDA “180 days prior to withdrawing [an] approved drug from sale, or if 180 days is not practicable as soon as practicable but not later than the date of withdrawal.”³ In addition, sponsors must notify FDA in writing “within 180 calendar days of the date of approval of the drug if the drug will not be available for sale within 180 calendar days of such date of approval.”³

Considering the benefits afforded to a generic firm that obtains a competitive generic therapy designation such as enhanced communication with FDA and a 180-day exclusivity period, Business Development and/or Product Selection Committees should take note and adjust their selection process and criteria accordingly.

There are potential unknown opportunities for a generic firm, especially when considering fluctuations in the market place. Firms, both brand and generic, constantly discontinue/remove product from the market due to their specific business objectives and needs. A lost product for one company could be a new opportunity for another.

GDUFA II also established for the first time a unified approach for formal meetings between FDA and ANDA applicants; again, NDA applicants have benefited from this type of program for years. The program is designed to assist ANDA sponsors of complex products before submission of an ANDA. The intent of the pre-ANDA program is for FDA to clarify for applicants the regulatory expectations early in the product development process and assist applicants with developing more complete submissions. The primary objective of this enhanced interaction with FDA is to promote a more effective and efficient ANDA review process and reduce the number of review cycles needed for ANDA approval.

The GDUFA II Commitment Letter defines complex products as:

1. Products with complex active ingredients; complex formulations); or complex dosage forms
2. Complex drug-device combination products (e.g., auto-injectors, metered dose inhalers); and
3. Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.⁴

The pre-ANDA program offers two options for prospective sponsors/applicants: product development meeting and/or pre-submission meeting. The purpose of the product development meeting is to discuss specific scientific issues or questions for which FDA will provide focused advice regarding certain aspects of an ongoing ANDA development program. The pre-submissions meeting provides a prospective applicant with an opportunity to confer directly with FDA on the content and format of the ANDA prior to submission. It is important to remember that FDA expects an applicant to request no more than one product development meeting for the specific complex product per year; although more than one product development meeting for a specific complex product can be requested.

The pre-ANDA program is a significant improvement over past practices for development of complex generic products. Previously, sponsors either had to rely on Controlled Correspondence for FDA feedback, the services of a consultant or simply “flying blind”. This enhancement affords an opportunity to discuss and confer directly with FDA on specific scientific issues relating to complex generic product development and ideally should decrease the number of review cycles and improve overall approval time lines for these products. Generic developers of complex products should ensure that a comprehensive and well-defined development strategy is in place prior to any meeting requests. Understanding and identifying the critical topics and assuring meeting objectives and goals are well-defined are key components for success.

Generic companies continue to face multiple challenges in an ever-increasing competitive market place; price erosion, lack of blockbuster brand drugs coming off patent and/or exclusivity, recent court decisions involving pay-for-delay patent settlements, evolving regulatory and scientific requirements to name a few. The enhancements and provisions in GDUFA II can afford generic companies with new opportunities to gain a competitive advantage in the marketplace provided a company has the vision and a well-defined strategy for leveraging these changes and enhancements to maximize value for their company.  The question is, do you have a strategy? 

References

1. Hyman, Phelps and McNamara, P.C. – Food and Drug Administration Act of 2017, September 7, 2017.
2. FDA Draft Guidance for Industry – ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence (November 2017, Pharmaceutical Quality/CMC).
3. FDA Draft Guidance for Industry – Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA (October 2017, Generics).
4. GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022 (GDUFA II Commitment Letter 5/12/16).
5. Food Drug Administration Reauthorization Act, Pub. L. No. 115-52, 115th Congress, H.R. 2430 – August 18, 2017.

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Janis A. Picurro
Lachman Consultants

Janis A. Picurro is a Principal Consultant in the regulatory practice at Lachman Consultants. Ms. Picurro is a senior level regulatory professional with over 24 years’ experience in the pharmaceutical industry. She has a broad working knowledge of regulatory requirements for generic drugs from development to approval and has extensive experience in ANDA, IND, NDA (505 (b)(2)) and DMFs. She is experienced in solid dosage forms, including OTC.