CDER’s latest novel drug approvals report shows how the pandemic is still affecting some drug approvals

According to a report released this week describing CDER’s approval of 55 novel drugs in 2023, the agency failed to meet its goal dates under the Prescription Drug User Fee Act (PDUFA) Commitment Letter for 11% of applications – a record high. Here, AgencyIQ analyzes the root causes of these delays, and whether a trend could emerge in the coming years.

Quick background: Goal dates under the Prescription Drug User Fee Act (PDUFA)

• The FDA collects user fees as part of an essential bargain between regulators and industry. Industry wants its products reviewed quickly, efficiently and predictably. Without sufficient resources, the FDA is unable to do so. Therefore, industry pays the FDA “user fees” for nearly all applications for approval, as well as annual fees related to registration and listing. These fees help the FDA hire staff, who help to review applications more quickly. In addition, the FDA agrees to follow certain performance metrics to ensure the timely review of applications. Fees are also used for a host of other activities meant to improve the FDA’s regulatory capacity and capabilities, such as I.T. modernization efforts.
• The Prescription Drug User Fee Act (PDUFA) authorizes the FDA to collect fees from companies that submit marketing applications to the agency for certain human drug and biological products. Originally enacted in 1992, PDUFA has been reauthorized six times, each time for a five-year period. FDA received its most recent statutory authority to collect fees through PDUFA VII on September 30, 2022, when it passed user fee reauthorization as part of the Continuing Resolution to fund the federal government.
• The PDUFA VII Commitment Letter describes the agreed-upon standard review times for most drug products. For various submissions, resubmissions, and supplements, FDA intends to review and act on 90% of submissions in the specified windows. These windows depend on whether the new drug application (NDA) or biologics license application (BLA) is a new molecular entity, and if the application has received standard review (10 months, plus 2 months of administrative time) or priority review (6 months, plus 2 months of administrative time). The FDA prioritizes the review of drugs and biologics for high-need conditions that are life-threatening or debilitating.
• The goal date can be extended by the agency in two cases. First, as outlined in the Commitment Letter, “a major amendment to an original application, efficacy supplement, or resubmission of any of these applications” may add on an additional three months to the review time. The clock can only be extended once per review cycle. Second, the FDA can extend the goal date in cases where the applicant fails to provide a “comprehensive and readily located” list of manufacturing facilities, since this information is needed to schedule mandatory inspections. In these cases, the goal date can be pushed two to three months.

CDER has typically received high marks on meeting these goal dates, but 2023 was different

• According to AgencyIQ’s analysis of the past 10 years, the FDA’s Center for Drug Evaluation and Research (CDER) has not previously fallen below a 95% annual rate of meeting PDUFA goal dates for New Molecular Entities (NMEs). In fact, CDER received a perfect 100% for meeting PDUFA dates for novel drugs in 2013, 2017, 2018 and 2020. While the agency faced challenging years in 2021 and 2022 due to the Covid-19 pandemic, CDER PDUFA goal dates were met for 98% and 95% of NME approvals, respectively.
• Quick note on methods used to conduct this analysis: AgencyIQ reviews and compiles data on novel drug approvals from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Novel drug products, also referred to as New Molecular Entities, are defined as products that have never been approved for any indication. While the definition of NME has changed over the years, it can sometimes include a combination product consisting of at least one drug that has previously been approved. The data used by AgencyIQ is obtained from reports put out by CDER and CBER, as well as approval letters and review packages posted to the Drugs@FDA database.
• On January 8, CDER published a report of all novel drug approvals that occurred in 2023, including key statistics. The accompanying press release described the approvals as “a wide range of therapies” that “will help patients and consumers live better and possibly longer lives.” In total, CDER approved 55 NMEs in the calendar year. Of the lot, 51% were for rare diseases, 56% received priority review, 16% received accelerated approval and 64% were approved in the U.S. before any other country.
• One data point from the report stood out – just 89% of these NME approvals met their agreed-upon PDUFA goal dates. This means that six of the 55 NMEs were not reviewed within the targeted timeframe.
• While the six products that were approved after the goal date treat a variety of indications, they are all biologics. Per the report, the products include: Bimzelx for moderate to severe plaque psoriasis in certain adults, Loqtorzi for recurrent or metastatic nasopharyngeal carcinoma, Ngenla for growth failure, Pombiliti for late-onset Pompe disease, Rystiggo for generalized myasthenia gravis in certain adults, and Ryzneuta for neutropenia.

What led to the delays in approval for these six drugs?

• According to the FDA, delays arose due to issues with international inspections during the pandemic. The report follows the metric with a note that “a number of novel drug approvals in 2023 were delayed due to COVID-19 related foreign travel restrictions, which hindered onsite inspections within the user fee review timeline.”
• As AgencyIQ has previously discussed, alternative inspection approaches were adopted during the Covid-19 pandemic. During this time, FDA relied heavily on alternative inspection tools and methods such as remote interactive evaluations (RIEs), which are one type of remote regulatory assessment (RRA). In October 2023, FDA released a draft guidance stating that beyond the public health emergency, “… FDA has determined that continued use of alternative tools, including remote interactive evaluations, based on risk and program needs, will enhance our ability to assess facilities,” [ Read AgencyIQ’s complete analysis of the guidance here.].
• Inspection delays are plausible for at least four of these applications. Pombiliti’s review materials directly reference this issue, noting that “At the time of the PDUFA date for BLA 761204, there were restrictions on travel due to the COVID-19 pandemic and the pre-approval inspection (PAI) of the drug substance and drug product manufacturing facility WuXi, Biologics, Co., Ltd, China (FEI: 3010606982) could not be performed.” Loqtorzi’s review describes delays resulting from both the resolution of a “deficiency related to inadequate virus control in the manufacturing” along with travel restrictions that prevented inspections of clinical sites in China, which were ultimately performed between August and September 2023. Ryzneuta’s Office of Pharmaceutical Quality (OPQ) review document explicitly states that travel restrictions prevented the completion of inspections at facilities in China during the initial review cycle; “therefore, FDA deferred action on the application until inspection activities were completed.” Ngenla’s review materials indicate that the BLA review was completed on April 24, one month prior to the PDUFA goal date. However, according to the OPQ reviews, approvability as of April 24 was still pending “final determination of compliance status of the manufacturing facilities” located in Ireland. OPQ ultimately recommended approval on June 24, although the exact reasons for the delayed inspection in this case are unclear.
• The other two delays appear to stem from the agency’s internal processes. The Bimzelx review materials include comments from the Office Director (or designated signatory) that the PDUFA goal date was missed as the review team and applicant resolved a “newly identified potential safety signal” that “required additional time for review and consideration.” As for Rystiggo, review materials indicate that the application was submitted in October 2022 and that the review was completed on Friday, June 23, 2023 (one day before the PDUFA goal date of June 24). However, the approval letter was not formally issued until Monday, June 26. Although this delay may have been simply due to the fact that the goal date landed on a Saturday, there is no explanation provided for this three-day delay.

Analysis

• Considering its track record over the past decade, the FDA’s 2023 performance on meeting PDUFA goal dates is a rare miss. The high rate of inspection issues occurring with this batch of NME’s will likely prove to be an outlier, but it remains to be seen if this will represent a new trend. If so, this will likely be a key point in the negotiation of the next PDUFA reauthorization, as industry relies on the predictability of these timeframes.
• It is worth reiterating that the missed goal dates were all for biologic products, which present greater quality and inspection challenges due to their complexity. At the OPQ 2023 Pharmaceutical Quality Symposium, CHRIS DOWNEY, supervisory chemist in the Office of Pharmaceutical Manufacturing Assessment (OPMA), described some considerations for inspection readiness in biologics development. According to Downey, the timeline of pre-license inspections for biologics can create challenges. These inspections occur earlier in the workstream compared to those for drugs—at the time of application—and firms (especially smaller or newer firms) may not have solidified commercial processes at this time.
• Capacity remains a large issue both at CDER and across the agency, and missed PDUFA target dates are one potential manifestation of workforce strain. As AgencyIQ has previously discussed, federal hiring is a challenge at the best of times, due to complex and outdated recruitment and interview systems, but federal hiring for extremely technical roles at the FDA has been a particular issue for several years. FDA leadership has acknowledged the issue, especially regarding steep competition from private industry. The agency committed to hire staff (and build out new programs) under PDUFA VII. According to the latest quarterly update, published at the close of FY 2023, CBER had completed 83% of its hiring under the user fee program. CDER, on the other hand, had completed just 53%.
• AgencyIQ will continue to keep an eye on FDA’s commitments under PDUFA VII, other user fee programs, legislation and more. Much of this information can be found and reviewed in our Calendars, Trackers and Explainers Curated Collection. For upcoming PDUFA target dates, specifically, see AgencyIQ’s monthly look-ahead for the FDA.

Featuring previous research by Alec Gaffney and Laura DiAngelo.
To contact the author of this item, please email Amanda Conti ( [email protected]).
To contact the editor of this item, please email Chelsey McIntyre ( [email protected]).

Key Documents and Dates

• Advancing Health Through Innovation: New Drug Therapy Approvals 2023