Generic Drug User Fee Act II: The positive features for generic drug industry

Introduction

The Generic Drug User Fee Act (GDUFA) was authorized as part of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA). On 9 July 2012, GDUFA was signed into law by the President. GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and improve upon the predictability of the review process. The Generic Drug User Fee Act of 2012 (GDUFA I) authorizes the Food and Drug Administration (FDA) to collect user fees for the review of certain generic human drug applications and associated Type II active pharmaceutical ingredient (API) drug master files (DMFs), and to conduct associated inspections. Authority for the GDUFA program expires on 30 September 2017.

Outcome of GDUFA I commitments found positive; GDUFA I metric goals have improved the speed and predictability of abbreviated new drug application (ANDA) review and improved access to quality, affordable generic medicines. Approximately 835 combined tentative and final approved in FY16 (greatly exceeds old record of 619 approvals in FY12). FDA has met or exceeded all of its negotiated GDUFA I commitments till date. To maintain and grow consumer access to generics medicines, timely reauthorization of GDUFA II is required.

The performance goals and program enhancements for the Generic Drug User Fee Act (GDUFA) reauthorization for fiscal years (FYs) 2018–2022 are known as GDUFA II. It is commonly referred to as the “goals letter” or “commitment letter”.

In preparation for GDUFA II, FDA began the reauthorization process with a public meeting. The first public meeting was held on 15 June 2015, prior to negotiations with industry, to allow the public to present its views on the reauthorization, including specific suggestions for changes. In October 2015, FDA began negotiations with industry and monthly discussions with patient and consumer groups concurrently to determine proposed recommendations for the next GDUFA program and these discussions concluded in August 2016. The second public meeting was held on 21 October 2016, after negotiations with industry, to allow the public an opportunity to see and comment on the recommendations developed by FDA and industry prior to the recommendations being sent forward to Congress.

Lessons learned from GDUFA I and GDUFA II ¹

GDUFA I ANDA review goals were extremely complex, arcane and widely differential treatment for different cohorts and “tiers” of submissions whereas proposed GDUFA II ANDAs and ANDA amendments fall within a single, consolidated review goals scheme.

There were large gap between negotiated GDUFA I goals and stakeholder expectations whereas proposed GDUFA II has reauthorized to reduce gap between goals and stakeholder expectations.

The GDUFA I commitment letter described ANDA review procedures at a high level of generality whereas proposed GDUFA II ANDA review procedures are much more specific and programmatic than corresponding features of GDUFA I.

Complex products pose distinct scientific and regulatory challenges whereas proposed GDUFA II recommended pre-ANDA process for complex products.

Features of GDUFA II

The GDUFA II goals letter represents the product of FDA’s discussions with the regulated industry and public stakeholders, as mandated by Congress. The performance goals and program enhancements specified in this letter apply to aspects of the generic drug review program that are important for facilitating timely access to quality, affordable generic medicines. Main features of GDUFA II are mentioned below:

submission review performance goals;

Submission review performance goals ²

In GDUFA II commitment letter, submission review performance goals set as 90% within timeline for all types of submissions (see Table 1). GDUFA II derived two terms, i.e. standard and priority type of submissions.

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Table 1.

Submission review performance goals timeline

Submission type	90% goal timeline	Remark
Standard original ANDAs	10 Months	–
Priority original ANDAs	8 Months	If the applicant submits Pre-Submission Facility Correspondence two months prior to submission
	10 Months	If the applicant does not submit Pre-Submission Facility Correspondence two months prior to submission
Standard major ANDA amendments/unsolicited ANDA amendments	8 Months	If pre-approval inspection not required
Priority major ANDA amendments/unsolicited ANDA amendments	6 Months	If pre-approval inspection not required
	8 Months	If pre-approval inspection required and the applicant submits Pre-Submission Facility Correspondence two months prior to submission
	10 Months	If pre-approval inspection required and applicant does not submit Pre-Submission Facility Correspondence two months prior to submission
Standard and priority minor ANDA amendments/unsolicited ANDA amendments	3 Months	–
Standard PASs (Prior Approval Supplement)	6 Months	If pre-approval inspection not required
	10 Months	If pre-approval inspection required
Priority PASs	4 Months	If pre-approval inspection not required
	8 Months	If pre-approval inspection required and the applicant submits Pre-Submission Facility Correspondence two months prior to submission
	10 Months	If pre-approval inspection required and applicant does not submit Pre-Submission Facility Correspondence 2 months prior to submission
Standard PAS major amendments/unsolicited PAS amendments	6 Months	If pre-approval inspection not required
	10 Months	If pre-approval inspection required
Priority PAS amendments/unsolicited PAS amendments	4 Months	If pre-approval inspection not required
	8 Months	If pre-approval inspection required and the applicant submits Pre-Submission Facility Correspondence two months prior to submission
	10 Months	If pre-approval inspection required and applicant does not submit Pre-Submission Facility Correspondence two months prior to submission
Standard and priority minor PAS amendments/unsolicited PAS amendments	3 Months	–
Type II API DMF	Initial completeness assessments within 60 days of the later of the date of DMF submission or DMF fee payment	–
Standard controlled correspondence (CC)	60 Days	–
Complex controlled correspondence	120 Days	–
Standard/complex controlled correspondence	FDA will respond to clarify ambiguities in the CC request within 14 days	–

Standard – means submissions not affirmatively identified as eligible for expedited review pursuant to the CDER (Center for Drug Evaluation and Research) Prioritization MAPP (Manual of Policies & Procedures) ³ .

Priority – means submissions affirmatively identified as eligible for expedited review pursuant to CDER’s MAPP 5240.3, prioritization of the review of original ANDAs, amendments and supplements.

Modifications to user fee structure

GDUFA I was built on the assumption that FDA would receive 750 ANDAs per year. ANDAs are the primary workload driver of the program. Over the first four years of GDUFA I, ANDA receipts have averaged approximately 1000 per year. To address the increased workload, FDA hired additional staff and is projected to spend about $430 million in the final year of GDUFA I.

In order to maintain current productivity and implement proposed GDUFA II improvements, FDA and industry agreed that user fees should total $493.6 million annually, adjusted each year for inflation (see Table 2).

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Table 2.

Target revenue for FY 2018. ⁴

	Target revenue (%)	$493,600,000
ANDA	33	$162,888,000
ANDA program holder	35	$172,760,000
DMF	5	$24,680,000
FDF facility	20	$98,720,000
API facility	7	$34,552,000

Modifications made to the user fee structure for the implementation of GDUFA II program as per (Table 3):

To maintain a predictable fee base and better align fee responsibility with program costs and fee-paying ability, FDA and industry propose to shift the burden more towards annual program fees (PFs). Sponsors with one or more approved ANDAs would pay an annual fee.

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Table 3.

GDUFA I vs. GDUFA II fee structure ⁵ .

Fee category	GDUFA I		GDUFA II
1-Time fees:
• ANDA Application	Yes	24%	Yes	33%
• DMF Application	Yes	6%	Yes	5%
Annual program fees:
• API facility	Yes	14%	Yes	7%
• FDF facility	Yes	56%	Yes	20%
• CMO facility	Same as FDF		Yes	One-third FDF
• ANDA holder	N/A		Yes	35%
Small (1–5 ANDAs)	N/A		Yes	One-tenth large
Medium (6–19)	N/A		Yes	Four-tenths large
Large (20+)	N/A		Yes	Full fee

ANDA: abbreviated new drug application; API: active pharmaceutical ingredient; CMO: Contract Manufacturing Organization; DMF: drug master file; GDUFA: Generic Drug User Fee Act.

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Figure 2.

FDA posting information about its process on GDUFA.

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Figure 1.

CMO assessment.

Original ANDA review program enhancements

Pre-ANDA program and subsequent mid-review-cycle meetings for complex products

The goal of the pre-ANDA program is to clarify regulatory expectations for prospective applicants early in product development, assist applicants to develop more complete submissions, promote a more efficient and effective ANDA review process, and reduce the number of review cycles required to obtain ANDA approval, particularly for complex products. FDA will issue guidance describing an enhanced pathway for complex products, including policies and procedures for product development meetings, pre-submission meetings, and mid-review cycle meetings.

FDA would issue product-specific guidance for 90% of NCE NDAs approved on or after 1 October 2017, at least two years prior to the earliest lawful ANDA filing date.

By 1 October 2020, FDA will complete enhancements to the Inactive Ingredient Database so users can perform electronic queries to obtain accurate Maximum Daily Intake and Maximum Daily Exposure information for each route of administration for which data is available.

DMF review program enhancements

FDA will ensure that DMF review comments submitted to the DMF holder are issued at least in parallel with the issuance of review comments relating to the DMF for the ANDA.

FDA will grant and conduct teleconferences when requested to clarify deficiencies in first cycle DMF deficiency letters. FDA will strive to grant such teleconferences within 30 days, giving priority to DMFs based on the priority of the referencing ANDA.

Once a DMF has undergone a full scientific review and has no open issues related to the review of the referencing ANDA, FDA will issue a “First Adequate Letter”. Once a DMF has undergone a complete review and the ANDA referencing the DMF has been approved or tentatively approved, FDA will issue a “no further comment letter”.

By 1 October 2018, FDA will issue a guidance regarding post-approval changes to a Type II API DMF and submission mechanisms for ANDA applicants who reference the Type II API DMF.

Facilities

Enhanced accountability and reporting

FDA will build internal capacity to enable improved productivity and performance through regular assessment of progress towards GDUFA goals, consistent methodologies for and timely reporting of GDUFA metrics, and transparent and efficient administration, allocation and reporting of user fee resources.

FDA will publish a GDUFA 5-year financial plan no later than the second quarter of FY 2018. FDA will publish updates to the 5-year plan no later than the second quarter of each subsequent FY.

FDA will publish the information on monthly basis on its website like number of ANDAs and ANDA amendments, DMFs, CBEs (Changes Being Effected), and PASs submitted, number each of ANDAs and PASs FDA refused for receipt in the reporting month, number of final approvals, tentative approvals, complete response letters, information requests, and DRLs issued, number of first cycle approvals and tentative approvals.