By Kristen BoothThroughout 2017, the FDA focused its attention on the regulation of generic drug products. In 2015, the Agency issued only two generic-related guidance documents. In 2016, there were seven. In 2017, there were 15 guidance documents (including final, draft, and revised guidance documents) issued regarding ANDAs and/or generic drug products. Even more noteworthy is the fact that 11 of these 15 documents were issued after October 1st. Furthermore, the FDA published it’s first generic-related guidance document of 2018 in the first week of the year.
What is the story behind the FDA’s recent focus on generic products? Why has there been so much activity surrounding generics lately? There are a few likely reasons for this, and here’s what we think they are:
Reauthorization of the Generic Drug User Fee Amendments (GDUFA)
On August 18, 2017, the FDA Reauthorization Act (FDARA) was signed into law, officially reauthorizing GDUFA through September 30, 2022. The reauthorization, known as GDUFA II, took effect on October 1, 2017, and is intended to supplement congressional funding for the Agency’s review of generic drug applications.
There were three key changes introduced with the reauthorization of GDUFA, which are a large reason for the abundance of generic-related final and draft guidance documents that have been published since GDUFA II took effect. These changes include:
- Fee structure
- Review of priority submissions
- The introduction of Pre-ANDA programs
A majority of the fees are the same in both GDUFA I and II; however, it is important to note a few major differences, which include:
- Contract manufacturing facilities are now included in the facility fee.
- Facility fees for contract manufacturing facilities are 1/3 of the amount of the fee for non-contract manufacturing facilities
- The fees for foreign facilities is $15,000 higher than those for domestic facilities
- Prior approval supplement (PAS) fee has been eliminated
- New program fee for all approved ANDAs has been added
- The ANDA program fee assesses a fee to generic drug makers based on the number of approved ANDAs they held as of the October 1st due date
- ANDAs for which a written request for withdrawal of approval is submitted by April 1st of the previous FY are not included in the total ANDA number
- The penalties imposed on sponsors who fail to pay fees remain the same with the following additions:
- Sponsor will now be added to the publicly available arrears list
- FDA will refuse to receive (RTR) any future ANDAs from that sponsor
- Any and all drugs marketed under an approved ANDA held by the sponsor or its affiliates will be deemed misbranded
Review of Priority Submissions
Under GDUFA II, ANDA submissions and amendments, as well as PAS submissions and amendments are categorized as either standard or priority. The reauthorization brakes down the different submissions into more refined categories, allowing the Agency to set appropriate review times for each subset of submissions depending on what it is, how important it is for public health, and how lengthy the submission is.
GDUFA II also provides detailed overview of the timeframes in which the FDA will review these submissions, which have been shortened in an attempt to improve patient access to generic products. This is important, as it will help hold the Agency more accountable, and it will help to eliminate the FDA’s backlog of ANDAs and prevent such a backlog from occurring in the future.
The Pre-ANDA program was created to clarify regulatory expectations for potential applicants early in the development process. For complex generic products, sponsors can now request a Pre-ANDA meeting. During this meeting, the sponsor will meet with the Agency to discuss and review its product’s development and receive advice from the FDA regarding ANDA development programs. Meetings can be held prior to submission of the ANDA to discuss the content and format of the application, or mid-review to discuss any deficiencies, concerns, or next steps that have been identified by the Agency.
In addition to the Pre-ANDA program, an ANDA review program was also established. This program was developed with the goal of expanding the frequency and scope of reviewer-sponsor communication. Under this program, FDA will allow sponsors to have an opportunity to correct deficiencies by communicating any issues in the middle of the review process rather than at the end in the Complete Response Letter (CRL).
Although there were only three major changes implemented within GDUFA II, there are a lot that goes along with each of these changes. As such, a great number of 2017’s guidance documents, specifically those issued after October 1st, are a direct result of the reauthorization of GDUFA.
Efforts to Reduce ANDA Backlog
It is widely known that the FDA has had a backlog of ANDA submissions for quite some time now. The size of the backlog has varied over time, reaching nearly 2,900 pending applications at the height of the issue back in 2012. Since then, the Agency has taken extreme measures to reduce the overflowing queue of pending applications. Although these efforts have been successful, there are still more applications awaiting review than the Agency would like to have on its desk at any given time. As such, reducing, and ultimately eliminating, this backlog is still a primary goal of the FDA. With this still on the Agency’s to do list, it is to be expected that there would be some extra attention being paid to generic drugs, resulting in an above average amount of relevant guidance documents being released.
Drug Competition Action Plan
Last but certainly not least, the final cause of the increased generic regulation is the FDA’s recent acknowledgement that there is an issue concerning drug competition and patient access to certain drugs.
High Drug Prices are Limiting Patient Access
In a blog post published by the FDA Voice on June 21, 2017, FDA commissioner Scott Gottlieb, MD stated that “too many patients are being priced out of the medicines they need.” Furthermore, he went on to note that, although the Agency is not directly involved in drug pricing, it can address the issue by “facilitating increased competition in the market for prescription drugs through the approval of lower-cost, generic medicines.” He noted that, “innovation in pharmaceutical development is essential because it creates new and sometimes life-saving therapies. But access to lower-cost alternatives, once patent and exclusivity periods lapse, also is critical to the nation’s health.”
In his blog post, Dr. Gottlieb stated that there are a number of scientific and regulatory obstacles inhibiting generic competition. As such, these barriers are delaying and, in some cases, denying patient access to more affordable drugs. This is an issue that requires immediate attention.
On June 27, 2017, a press release was issued from the FDA, announcing a number of steps the Agency is taking under its new Drug Competition Action Plan to “increase competition in the market for prescription drugs and facilitate entry of lower-cost alternatives.”
The Drug Competition Action Plan is just one part of the FDA’s solution to this problem. In addition, the FDA is also taking the following actions to solve the issue at hand:
- On July 18th, a public meeting was held by the FDA, where it asked for input on how and where the FDA’s current rules (e.g., standards and procedures related to generic drug approvals) are creating obstacles for generic drug makers.
- In an attempt to encourage the development of generic products, the FDA “posted a list of branded drugs that have no listed patents or exclusivities and for which the agency has yet to approve a generic drug application.” Furthermore, the Agency “intends to expedite the review of any generic drug application for a product on this list to ensure that they come to market as expeditiously as possible.”
- The FDA announced a change to is policy regarding the way it prioritizes the review of ANDAs that are submitted. In this announcement, the Agency stated that it “will expedite the review of generic drug applications until there are three approved generics for a given drug product.”
As the Agency works to improve patient access to generic drugs and provide patients with more cost-effective options, the amount of information being released has increased. In the form of both draft and final guidance documents, as well as the proposal of new legislation and FDA rules, and so much more, the Agency’s dedication to facilitating competition in the market is the one of the main reasons behind the increase in generic-related activity in 2017.
Draft & Final Guidance Documents Issued in 2017
It is clear that there a number of factors causing the significant spike in generic-related activity that occurred in 2017. However, we have yet to talk about the actual topics being addressed. As such, the following list includes the topic of each guidance document that was issued last year:
- 180-Day Exclusivity: Questions and Answers – Draft Guidance issued on January 12, 2017
- Referencing Approved Drug Products in ANDA Submissions – Draft Guidance issued on January 13, 2017
- Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA – Draft Guidance issued on January 13, 2017
- ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin – Draft Guidance issued on October 2, 2017
- ANDA Submissions – Refuse-to-Receive Standards: Questions and Answers – Draft Guidance issued on October 2, 2017
- ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA – Draft Guidance issued on October 2, 2017
- Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA – Draft Guidance issued on October 2, 2017
- ANDA Submissions – Prior Approval Supplements Under GDUFA – Final Guidance issued on October 4, 2017
- Completeness Assessments for Type II API DMFs Under GDUFA – Final Guidance issued on October 4, 2017
- Determining Whether to Submit an ANDA or a 505(b)(2) Application – Draft Guidance issued on October 11, 2017
- Requests for Reconsideration at the Division Level Under GDUFA – Draft Guidance issued on October 11, 2017
- Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA – Draft Guidance issued on October 13, 2017
- Controlled Correspondence Related to Generic Drug Development – Draft Guidance issued on November 2, 2017
- General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products – Final Guidance issued on November 21, 2017
- Information Requests and Discipline Review Letters Under GDUFA – Draft Guidance issued on December 15, 2017
In addition, there has also been one generic-related guidance document published so far this year. On January 3, 2018, the FDA published a draft guidance entitled “Good ANDA Submission Practices,” and if 2017 was any indication of what is to come, it is likely just the first of many more to come throughout the year.