As the pharmaceutical and biopharmaceutical industries head into 2023, the topic of accelerated approval continues to be a frequent source of both discussion and industry anxiety. But there are four key changes that AgencyIQ expects to occur in 2023 that companies should start preparing for now – or at least prepare for the possibility of occurrence.
FDA is scrutinizing accelerated approvals more than ever, and we expect this scrutiny to continue
- If 2021 was the year when the FDA first started to scrutinize accelerated approvals of products, 2022 was the year when that scrutiny endured and spread. The FDA withdrew 7 indications for oncology drugs with accelerated approval in 2022 – the same number as it did the year prior. That’s notable because between 2011 and 2020, the FDA withdrew a total of 8 indications for oncology products.
- Another notable addition has been the spread of FDA’s scrutiny of accelerated approvals. Throughout 2022, and as part of FDA’s Project Confirm, the agency has launched webpages related to accelerated approvals broken down into three different categories: Products for which beneficial outcomes have been verified; products once granted accelerated approval but with approvals now withdrawn; and products for which confirmatory data has not yet been obtained. Originally, these data were only collected for oncology products, but in September 2022 the FDA launched similar webpages for products with infectious disease indications as well. To AgencyIQ, the infectious disease withdrawals are indicative of the FDA’s focus on accelerated approvals expanding beyond the watchful eye of its Oncology Center of Excellence. Mylan, for example, recently withdrew its accelerated approval for Sulfamylon, and FDA withdrew two accelerated approval indications for Levaquin in 2021.
- But perhaps the biggest change has been FDA’s shifting expectations for accelerated approval confirmatory studies. In a notable press release in November, ADC Therapeutics announced that the FDA “provided strong guidance that, for it to consider an accelerated approval path, a randomized confirmatory Phase 3 study must be well underway and ideally fully enrolled at the time of any Biologics License Application filing” for the company’s investigational drug, Cami. That’s notably because, according to the company, efforts to reach this phase of development would take an additional two years. FDA’s willingness to delay a company’s filing for several years is notable, and especially notable since the entire premise of the accelerated approval program is to accelerate the development of products for critical, unmet needs. While we don’t imagine that the FDA is going to start requiring this for every product for which accelerated approval is sought, the agency’s regulators clearly seem willing to take this approach in additional circumstances. This approach was made clear in an October 2022 perspective published in the New England Journal of Medicine in which regulators from FDA’s Oncology Center of Excellence pointed to data showing that when confirmatory studies were ongoing at the time of accelerated approval, their benefits were typically verified within 5 years; for drugs for which confirmatory studies were not ongoing at the time of accelerated approval, it took longer to both verify clinical benefit and to withdraw oncology indications. FDA’s insistence that ADC have a confirmatory study underway and enrolled at the time of approval is also notable since Congress has proposed to give the agency explicit authority to require confirmatory studies to be underway at the time of approval (see below). But based on this recent action, FDA is already acting as if it has this authority, even if it’s somewhat tenuous.
- What the FDA still doesn’t have is the ability to force companies to take action. To date, the FDA has largely taken actions to achieve voluntary indication withdrawals by industry.. FDA has asked, pleaded, cajoled or strongly encouraged companies to take their products off the market. It’s done this through behind-the-scenes discussions, public meetings and letters. And most of the time, this approach is successful. Most companies would prefer to avoid the limelight – and certainly a reputation-damaging advisory Committee meeting – and maintain their reputation with regulators. But on occasion, companies are also willing to fight the FDA. And even if the FDA ultimately prevails in the fight, the effort may take years, as in the case of Covis Pharma Group’s Makena, which FDA has been trying to remove from the market for more than two years without success.
- What we’re watching for: The FDA is likely to expand its scrutiny of drugs with accelerated approval in 2023. We’re expecting additional pilot programs, more companies to experience developmental setbacks related to confirmatory study requirements at the time of approval, and additional drugs outside of the oncology space to face withdrawal requests (there are three vaccine indications, five infectious disease drugs, and 8 additional products for which confirmatory studies are years overdue – although some only slightly).
PDUFA VII changes are going into effect
- Some of the changes the FDA plans to make in 2023 and beyond that will affect companies seeking accelerated approval for their products will come from the Prescription Drug User Fee Act (PDUFA) Commitment Letter, which was signed into effect in September 2022 by President Biden. That letter, negotiated between the FDA and industry, contains several measures that will change – and potentially improve – the process by which sponsors and FDA interact on Post-Marketing Required (PMR) studies.
- PMRs are an essential condition of approval for drugs granted accelerated approval. A drug granted accelerated approval will almost always have, as a condition of approval, a requirement to conduct a confirmatory study on a key endpoint that is not a surrogate, such as overall survival. Historically, decisions regarding this PMR were challenging, and could potentially serve to delay an application. But under the PDUFA VII Commitment Letter, discussions about PMRs are now a standard part of the mid-cycle communication process between FDA and sponsors – and subject to standardized timelines for the first time. According to the letter, the FDA review team will coordinate a mid-cycle meeting with a sponsor to discuss the need for any PMR study.
- FDA is also set to establish processes to support the “consistency and predictability” of the PMR process for sponsors. The FDA will be required to “communicate details on anticipated PMRs” that it will require for accelerated approval drugs between 6 weeks (for priority review New Molecular Entities, or NMEs) and 8 weeks (for standard review NMEs). However, these deadlines may not apply “if a major safety issue which requires a PMR is identified based on data submitted subsequent to submission.”
- These PMR-related goals for NMEs are set to start going into effect in FY2023, when the FDA expects to communicate anticipated PMRs to the applicant within the 6/8 week timeframe 60% of the time. This goal will increase to 70% in FY2024 and 80% for FY2025-2027.
- For non-novel drugs (i.e., ones which have already been approved for another indication of use), applicants will be able to request a review of existing PMRs “for release” – in other words, to ask FDA to find that a PMR is no longer necessary. Upon submission of the request, the FDA will then have 45 days to notify the sponsor of the need for any additional data to evaluate the request, and 60 days from the date of submission to respond to the request. This approach could help sponsors of existing PMRs for accelerated approval products to request the cancellation of their existing obligations – although there’s no indication the FDA will be willing to do this on a consistent basis.
- What we’re watching for: 2023 will be a building year for the FDA as it works to implement the PDUFA VII agreement. Some companies will likely benefit from FDA’s more predictable process for PMR reviews, especially if the agency is asking for more robust information and commitment prior to a drug’s approval.
Congress could take action as soon as next week
- A quick reminder: Throughout much of 2022, Congress was working to negotiate a significant package of legislative reforms that would have affected the FDA’s regulation of a wide range of programs. These reforms were originally intended to be passed as part of the reauthorization of FDA’s user fee programs, but they were ultimately left behind as part of a “skinny” reauthorization. Still, these reforms had passed in the House of Representatives.
- Among the negotiated reforms was a series of provisions related to reforming the FDA’s accelerated approval process. Both the House and Senate versions of these reforms were largely – though not entirely – similar. Both bills would have permitted sponsors of drugs granted accelerated approval to use real-world evidence as part of a post-approval study (PAS). Both bills would require that a PAS/PMR be agreed to at the time of approval, including specific enrollment targets, protocols, milestones and completion dates. FDA would be able to require that a study begin prior to approval. Companies would need to report on the progress of their studies every 180 days. FDA would be given authority to expedite the withdrawal of a product granted accelerated approval if its confirmatory data are unacceptable.
- There were a few key differences between the bills as well. The House bill would have required specific labeling for drugs granted accelerated approval regarding lingering uncertainties about the drug’s effects. The Senate bill, meanwhile, would have made the failure to conduct a PAS with “due diligence” a prohibited activity (it already is, though).
- What we’re watching for: Congress is expected to potentially pass these accelerated approval reforms as part of a year-end omnibus package as early as next week (December 23rd). While it remains to be seen if these reforms ultimately make it into the final package – and how existing differences between the House and Senate versions of these reforms are resolved – it’s likely that FDA will enjoy some additional authority related to accelerated approval in 2023.
Keep an eye on CDER’s guidance agenda
- An ominous guidance: The FDA’s Center for Drug Evaluation and Research (CDER) oversees drug regulation at the FDA, and each year it publishes an agenda of the guidance documents that it has under development. For several years, this guidance agenda has included an ominous inclusion: a guidance document entitled Civil Monetary Penalties for Failure to Meet Accelerated Post Marketing Requirements.
- Under the FDA Amendments Act of 2007, the FDA already has the authority to require PMRs for certain drugs and biologics (notably including those granted accelerated approval), and to levy fines on companies that do not meet their required obligations. These fines, however, aren’t especially steep – just $250,000 per violation, and not more than $1 million for all prior violations. For active, ongoing violations, though – the sort that might occur if a PMR is actively not being met – then the FDA would be able to levy penalties of up $250,000 for the first month of the violation, and then $1 million per month thereafter, up to a maximum of $10 million.
- But according to some reports, the FDA has never before imposed a civil monetary penalty for a delay related to a PMR, despite the fact that there are at least 15 drugs for which accelerated approval has been granted with overdue confirmatory studies.
- What we’re watching for: The FDA has made clear in 2021 and 2022 that there are consequences for failing to conduct confirmatory studies, or for companies with unfavorable confirmatory data. We might expect the agency to expand upon this approach in 2023 with the long-awaited publication of this guidance to make clear that the consequences of inaction aren’t limited to public shaming or market withdrawals, but also civil monetary penalties as well.
To contact the author of this analysis, please email Alec Gaffney ( [email protected])
To contact the editor of this analysis, please email Kari Oakes ( [email protected])