Accelerated Removal: FDA making use of new authority to withdraw ineffective drugs more quickly

How do things work now?

• FDA-approved drug products can be removed from the market for many different reasons. For example, a company may no longer wish to sell a product due to low margins, a product may be less popular than newer, better therapeutic options, or companies may try to get ahead of their competition by marketing a newer version and phasing out an older one.
• But sometimes, the FDA wants drugs off the market for reasons of safety or effectiveness. This is especially common for drugs and biologics granted accelerated approval – a pathway that permits the FDA to rely on endpoints that stand in for clinical benefit as evidence that a drug is effective to treat serious or life-threatening conditions. Because the benefits of a drug granted accelerated approval are not yet confirmed by the time its launched, the FDA requires that companies conduct confirmatory testing of these benefits as a condition of approval.
• But some drugs initially granted accelerated approval are later shown not to be safe or effective (see chart below). In many such cases, the FDA will seek to withdraw its approval for the indications that were granted accelerated approval. Companies will generally agree voluntarily to withdraw an indication.
• For example: In March 2024, Bayer announced that it had voluntarily withdrawn its New Drug Application for Aliqopa (copanlisib) after its confirmatory trial did not verify the clinical benefit of the drug in follicular lymphoma. The company also waived an opportunity for a hearing.

Instances in which FDA has sought to withdraw accelerated approvals with the consent of the sponsor

• However: Companies can decide not to voluntarily withdraw a drug and instead choose to engage the FDA, leveraging an at-times contentious process intended to keep the drug on the market for its current indication of use. While this happens less often – we’re aware of just three instances – in these cases, it’s been remarkably difficult for the FDA to successfully remove these drugs from the market. In some respects, it is considerably more difficult for the FDA to withdraw approval for a product than it is for it to approve a product in the first place – even when it feels the drug is no longer safe or effective.

What’s the context?

• A case study in the withdrawal process: FDA’s efforts to remove AMAG Pharma’s Makena (hydroxyprogesterone caproate injection), a drug originally granted accelerated approval in 2011 and intended to reduce the risk of preterm birth. As part of Makena’s approval, the FDA required that its original sponsor, Hologic, conduct a confirmatory study to verify the drug’s expected clinical benefit. Ultimately, however, the FDA found that the trial “failed to demonstrate a statistically significant difference between the Makena and placebo arms.” Following the publication of the results of the failed confirmatory study, FDA convened an advisory committee in 2019 which narrowly (9-7) recommended that FDA pursue withdrawal of Makena from the market.
• FDA proposed to withdraw Makena in October 2020, kicking off a 914-day process of administrative hearings and review. The FDA published a final decision officially withdrawing approval of Makena on April 6, 2023. The federal docket covering the evidence behind this decision is expansive and includes more than 250 documents – memoranda, decisions, hearings, letters, Citizen Petitions, requests for correction, appeals, presentations, an advisory committee meeting, requests for extensions and more.
• This two-and-a-half-year saga highlights how difficult the FDA finds it to withdraw products once they have been granted accelerated approval. The FDA originally took 207 days to review Makena, in addition to its review for a previous unsuccessful approval bid. In other words, it took FDA more than four times as long to withdraw approval of Makena than it did to approve it in the first place.
• Congress recently granted FDA new authority under the Consolidated Appropriations Act of 2023 meant to expedite the withdrawal of certain drugs using an “expedited procedure” (Section 3210). Under the new procedure established by the law, the FDA may withdraw the approval of a product that had been granted accelerated approval under four specific conditions: First, if the sponsor of the product “fails to conduct any required postapproval study of the product with due diligence”; Second, if the confirmatory study “fails to verify” the predicted benefit; Third, if evidence other than sponsor-conducted studies demonstrates the drug to be unsafe or ineffective; or Fourth, if the sponsor “disseminates false or misleading promotional materials with respect to the product.”
• Despite its name, the expedited procedures do not actually seem to provide the FDA with much authority to actually expedite. This new process gives a drug sponsor plenty of opportunities to interact with regulators and even raise its concerns about withdrawal in a public forum. The FDA is required to provide sponsors with notice of and an explanation for the proposed withdrawal, an opportunity to meet with either the FDA Commissioner or a designee, and an opportunity for written appeal to the Commissioner or designee. In addition, the FDA must provide an opportunity for the public to weigh in on the proposed withdrawal, publish a summary of public comments and FDA’s responses to them, and convene an advisory committee (if requested, and if no specific meeting has already taken place).
• In other words, despite Section 3201 describing the procedures as being “expedited,” the legislation contains few provisions that would help the FDA further expedite the withdrawal process itself. For example, the law provided no specific timelines or due dates for the required withdrawal activities to take place. However, the FDA is required to publish a draft guidance document describing the expedited procedures no later than June 29, 2024.

What’s new?

• A new case study could provide a view into what “expedited” means in practice: The FDA recently announced that it had successfully withdrawn Oncopeptides AB’s Pepaxto, and the agency’s efforts show that it is capable of moving considerably faster to withdraw products than it did for Makena. On February 23, 2024 the FDA issued a final decision to withdrawal approval of Pepaxto (melphalan flufenamide), a cancer drug approved in February 2021 under the accelerated approval pathway as a fifth-line treatment for adult patients with relapsed or refractory multiple myeloma. The drug’s original approval had been based on two surrogate endpoints in the HORIZON trial: overall response rate (ORR) and duration of response (DOR).
• As part of the drug’s accelerated approval conditions, Oncopeptides AB was required to conduct a confirmatory study – a randomized Phase 3 clinical trial comparing Pepaxto to a standard of care therapy and assessing both progression-free survival (PFS), ORR and overall survival (OS). This trial, known as the OCEAN trial, was intended to account for some of the limitations with HORIZON, which was a single-arm Phase 2 study.
• However, that confirmatory study “did not achieve its pre-specified primary endpoint of improvement in PFS, showing instead a detrimental effect on OS,” the FDA wrote in its decision memo. In other words, not only did Pepaxto not extend survivability – it actually reduced it (“an increased risk of death”), providing the FDA with an acute safety concern to contend with. As a result, the FDA issued a public warning to patients and health care professionals, and noted that it was requiring Oncopeptides to suspend enrollment in the trial. The agency also convened an Advisory Committee hearing in September 2022 to discuss the trial and to vote on one important question: Is the benefit-risk profile of Pepaxto favorable for the indicated patient population? In a 14-2 vote, the committee voted that there was not a favorable benefit-risk profile, indicating to the FDA that the product’s accelerated approval should be withdrawn. [ Read AgenccyIQ’s analysis of this advisory committee hearing.]
• As a result, on July 7, 2023 the FDA proposed to withdraw accelerated approval of Pepaxto, directly citing the company’s failed confirmatory study. It’s worth noting that this proposal was issued eight months after the passage of the Consolidated Appropriations Act of 2023, the law which granted FDA the supposed “Expedited” withdrawal procedure authority, making it the first time that FDA had sought to impose a withdrawal on a sponsor since obtaining this authority.
• In response to FDA’s proposal, Oncopeptides submitted an appeal of the proposed decision and requested a meeting with the FDA Commissioner (note: Many of these actions occurred prior to the public announcement of FDA’s proposed withdrawal). Ultimately, PETER MARKS, the Director of FDA’s Center for Biologics Evaluation and Research (CBER) – a division which regulates biologics and did not participate in the original review of Pepaxto – was chosen to lead FDA’s evaluation of Oncopeptides’ appeal.
• The FDA’s process to withdraw Pepaxto took a total of just 232 days – dramatically faster than it took the agency to withdraw Makena (914 days). However, there are several key differences which appear to have contributed to the different speeds of withdrawal.
• First, let’s look at a timeline for the withdrawals of both Makena and Pepaxto, relying upon public documents available in each product’s respective dockets:

Timeline of the withdrawal process for Makena and Pepaxto

• How did the FDA manage to expedite the withdrawal of Pepaxto? There are a few key factors. First, the agency did not have to conduct a second advisory committee hearing to support its decision to withdraw. Because the Consolidated Appropriations Act only permits a sponsor to request a public hearing “if no such advisory committee has previously advised the [FDA] on such issues with respect to the withdrawal of the product prior to the sponsor’s request,” the FDA was able to skip this part of the process. Ordinarily, convening an advisory committee adds many months to the withdrawal process.
• FDA also just seemed to move more quickly during this withdrawal. For example, FDA received the sponsor’s appeal to its proposal to withdraw Makena on December 4, 2020. It didn’t hold an advisory committee hearing on the matter until October 17, 2022 – almost two years later. Now compare that timeline to Pepaxto, for which FDA received a formal appeal on August 4, 2023 and issued a substantive response on September 8, 2023.
• Of course, there’s another handy explanation that might account for some of the delays as well: The FDA was in the midst of addressing the Covid-19 pandemic at the time that it had proposed to withdraw Makena from the market, with staff and senior officials in particular having little excess capacity to address matters not related to the pandemic. For example, CELIA WITTEN, who was one of the top administrative officials on the Makena withdrawal and who oversaw the Makena advisory committee hearing as Presiding Officer, was serving as Deputy Director of CBER during the pandemic – a position which meant that she was effectively responsible for reviewing applications related to Covid-19.
• There are plenty of other differences between these two processes that likely had an impact as well. There were hardly any public comments (FDA noted just four) on FDA’s proposal to withdraw Pepaxto. Meanwhile, there was a sustained public pressure campaign against the FDA related to its efforts to withdraw Makena, and in particular related to the significant impact that preterm birth has on Black patients. AMAG Pharmaceuticals presented a consistent, hard-fought case against FDA’s efforts to withdraw its product all along, while Oncopeptides had actually originally submitted a request in October 2021 to the FDA to withdraw its application for Pepaxto but rescinded that request in January 2022. Makena continued to be marketed throughout the withdrawal proceedings, whereas Oncopeptides declined to market the drug during its withdrawal proceedings. Pepaxto had been approved recently enough that FDA’s review staff was still familiar with the product, whereas Makena had been approved more than a decade prior. FDA reviewers noted almost no safety concerns with Makena, whereas they had significant concerns about overall survival (which decreased), which FDA considers to be a safety endpoint.

What are the implications?

• “Expedited” doesn’t necessarily mean “fast.” While the FDA was able to withdraw Pepaxto from the market more quickly than it had withdrawn Makena, the entire process still took nearly 8 months, and there was still a considerable gap between the FDA’s advisory committee vote and its proposed withdrawal order being published (289 days). FDA doesn’t use its withdrawal authority that often, and so it’s going to take time to determine if the FDA is able to expedite this process even further – or if this is about as fast as the agency is able to go using its current regulatory mechanisms.
• While we’re awaiting FDA’s draft guidance document on how it plans to handle expedited withdrawals, the case of Pepaxto could provide life sciences companies and policymakers with some practical insights. In particular, the FDA seems keen on expediting internal processes to accelerate the process overall, based on the timeline above. If the agency is able to figure out how to expedite calling advisory committees and assigning senior staff to work on withdrawals, it might be able to expedite this process further. And as noted by Hyman, Phelps & McNamara attorneys Mark Tobolowsky and Michelle Butler, FDA has also shown a willingness to combine certain work products and set prompt deadlines as part of this process, which has also expedited the withdrawal process.
• There are still inherent incentives for companies to fight to the end instead of acquiesce. In both cases of Makena and Pepaxto, the sponsors had adopted a two-part argument. Part one involved arguing that the FDA shouldn’t withdraw their product from the market; Part two involved arguing that a narrower indication for the drug should be preserved, even if most of the original indication was withdrawn. While these arguments weren’t successful in either case, it’s one that we expect will likely be employed in future cases as well. In addition, companies are still legally permitted to sell their products throughout the entirety of the hearing procedures. In the case of Makena (and its generics), that meant nearly three years of additional sales that they would have lost out on had they not fought the FDA.
• This effort to speed things up also lines up closely with other reforms to FDA’s accelerated approval process. For example, the FDA has recently begun to require that sponsors of new drugs and biologics seeking accelerated approval have their confirmatory studies be “underway” and mostly enrolled prior to approval, and has also emphasized that studies should be “underway when the marketing application [for approval] is submitted.” Ultimately, these efforts may be even more effective at expediting withdrawals than any other changes made under the Consolidated Appropriations Act of 2023. Faster access to confirmatory data means that FDA can expedite decisions to withdraw products regardless of how long the withdrawal process takes. It also reduces the chance that companies will act in bad faith and not take serious steps to collect confirmatory data.
• And, as in the case of Pepaxto, starting confirmatory studies earlier can mean that confirmatory data are available soon after approval, ensuring that ineffective or unsafe drugs don’t linger long on the market. In the future, then, we’re more likely to see more withdrawals that are similar to Pepaxto, for which confirmatory data was available relatively soon after approval, allowing FDA to take prompt action.

To contact the author of this analysis, please email Alexander Gaffney ( [email protected])
To contact the editor of this analysis, please email Kari Oakes ( [email protected])

Key Documents

• Accelerated Approval Withdrawal Statute
• Makena Docket
• Pepaxto Docket
• Consolidated Appropriations Act of 2023 (Page 1365)