FDA flexes its new accelerated approval authorities, hoping to accelerate access to confirmatory data

How do things work now?

• Accelerated approval allows for an expedited regulatory review process – for some products. The FDA can use the accelerated approval pathway to speed the approval process of a qualifying new drug or biologic based on the use of a “surrogate” or “intermediate” endpoint that is “ reasonably likely” to predict the clinical benefit of the product. A key component of accelerated approval is the requirement that the drug’s sponsor conduct “confirmatory studies” that are meant to confirm the drug’s expected benefits after its initial accelerated approval, providing evidence of efficacy that allows the accelerated approval to be converted to full approval.
• The pathway is intended for treatments of diseases and conditions that are “ serious or life-threatening.” To achieve earlier patient access to potentially meaningful medicines, the FDA is willing to allow sponsors to use endpoints that may not accurately predict clinical benefit.
• The FDA’s decision to grant accelerated approval to a new drug product is based on a combination of objective and subjective criteria. Under the statutory criteria underlying the pathway, regulators are supposed to take into account the extent to which the surrogate or intermediate endpoint is likely to predict clinical benefit of the disease. FDA is also required to account for the severity, rarity, or prevalence of the condition, as well as the availability (or lack thereof) of alternative treatments, as well as the extent to which the new product offers a meaningful advantage over any available therapy. Critically, the FDA holds products under review for accelerated approval to the same statutory standard (“substantial evidence” of safety and efficacy, based on adequate and well-controlled clinical investigations) as products granted traditional approval.
• The FDA has acknowledged that this approach has some risks beyond those in a traditional approval. The primary risk associated with the pathway is that the surrogate endpoint won’t actually be linked to clinical benefit in practice, meaning the drug would be ineffective – or worse, harmful – for patients. “In addition, there generally will be fewer, smaller, or shorter clinical trials than is typical for a drug receiving traditional approval, which may generally mean there is less information about the occurrence of rare or delayed adverse events,” the FDA wrote of the accelerated approval pathway in a May 2014 guidance document on its various expedited programs.
• These surrogate or intermediate endpoints are often clearly related to the primary endpoints they’re standing in for. The FDA’s database of surrogate endpoints that have been used for drug approval or licensure includes endpoints related to response rates (the proportion of patients showing some response to treatment), progression-free survival (PFS, where disease remains stable), and reductions in a specific measurement considered to be meaningful (e.g., reduction in amyloid beta plaque in patients with Alzheimer’s disease), and more.
• Still, there are recent experiences with drugs granted accelerated approval that haven’t shown clinical benefit in their confirmatory testing. The best-known example of a product granted accelerated approval that ultimately didn’t demonstrate benefit was Genentech’s Avastin (bevacizumab). According to the FDA, an initial accelerated approval for Avastin to treat metastatic breast cancer was based on the surrogate endpoint of PFS, with data showing an estimated 5.5-month PFS benefit for Avastin combined with the drug paclitaxel when compared to taking just paclitaxel. However, subsequent confirmatory studies showed that the drug did not ultimately result in improved overall survival (OS), which is a measure of how long patients live following either diagnosis or the start of treatment. In addition, the drug was later found to contribute to increased serious adverse events in patients, with “Avastin-related deaths” observed in 1.2% of patients enrolled in trials. As a result, the FDA ultimately withdrew approval and ordered the drug withdrawn the drug from the market.
• Given these risks, confirmatory studies are a key component of the accelerated approval pathway. These requirements, also known as postapproval study conditions or Postmarketing Requirements (PMRs), generally include a requirement to complete a specific study, to ensure adequate enrollment, and to follow patients for a specific period of time.

What’s the context?

• Even as FDA imposes requirements that confirmatory studies be completed by a specific time, in practice these confirmatory studies are often completed years late – if at all. According to a September 2022 report by the HHS Office of Inspector General (OIG), of all drugs granted accelerated approval (278), 104 had incomplete confirmatory trials at the time of publication, and 35 had at least one trial past its original planned completion date. Four drug applications were more than 5 years behind schedule on their confirmatory studies.
• As a result of these concerns, in late 2022 Congress granted the FDA new authorities related to accelerated approval as part of the Consolidated Appropriations Act of 2023. Section 3210 of the law made several significant changes to the underlying statute governing the pathway, including one requirement that the FDA “may require, as appropriate, a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product” (emphasis added).
• This specific authority that FDA “may require” that studies be “underway prior to approval” was intended to ensure that companies were serious about their confirmatory studies and would be more likely to finish them on time.
• Since obtaining this authority, FDA has taken additional steps to clarify how it plans to use – and define – it. In March 2023, FDA released a draft guidance document on “ Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics,” which recommended that randomized controlled confirmatory trials for accelerated approval “be well underway, if not fully enrolled, by the time of the accelerated approval action.” In addition, it wrote that such confirmatory trials “should be underway when the marketing application is submitted.” [ Read AgencyIQ’s analysis of this guidance]

What’s new?

• The FDA has now shown that it is upholding this expectation, and is even willing to reject drugs on a temporary basis to enforce it. In a March 25, 2024 press release, Regeneron Pharmaceuticals announced that the FDA had issued two Complete Response Letter (CRLs) related to its Biologics License Applications for its biologic odronextamab in relapsed/refractory (R/R) follicular lymphoma (FL) and in R/R diffuse large B-cell lymphoma (DLBCL).
• Quickly: A Complete Response Letter (CRL) is, conceptually, the opposite of an approval letter. It is an FDA communication to a sponsor that their application is not able to be approved in its current form as the result of one or more reasons. It is not a finding that the drug cannot be approved, but rather that an application cannot be approved without additional information or evidence. To support application sponsors’ ability to generate this information, CRLs will generally also include “recommended actions” the sponsor could take to address FDA’s stated concerns. Of the many reasons FDA may send a sponsor a CRL, three are most common: A lack of data (i.e., not enough trials were run or patients enrolled), inadequate data (i.e., there were deficiencies in the application), or FDA finding that the data provided do not support the proposed indication.
• FDA’s rationale for these new CRLs to Regeneron, however, is quite unusual – and perhaps unprecedented. According to Regeneron, the CRLs “did not identify any approvability issues with the odronextamab clinical efficacy or safety, trial design, labeling or manufacturing.” Rather, they were related to an ongoing study that includes both a dose-finding element (intended to optimize the dose given to patients to minimize side effects) and a confirmatory element. While the dose-finding part of the study had begun, the confirmatory portion had not. As Regeneron explained, “the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion be agreed prior to resubmission,” indicating that enrollment had not begun for the confirmatory portion of the study.

What are the implications?

• FDA’s willingness to issue CRLs for products with confirmatory trials planned but not yet ‘underway and mostly enrolled’ is likely to lead to some short-term disruption, including some potentially delayed approvals in the oncology space. For companies hoping to make use of the accelerated approval pathway, FDA’s guidance and actions demonstrate that companies will need to invest serious time and resources into ensuring that they are not just ready to run a trial, but that the trial has already begun. It’s worth noting that to date the FDA has not offered any guidance or specifics regarding what it considers to be “ mostly enrolled,” which could make some trial sponsors nervous.
• Instead of running separate confirmatory studies, some companies may wish to run a single trial spanning Phase 3 into Phase 4. In its March 2023 draft guidance, the FDA said it would accept this approach, with some caveats. For example, oncology sponsors would need to preserve the “integrity of the trial” since the initial analysis and evaluation of the data could potentially introduce bias. Given the costs and time associated with starting up a separate, additional study to confirm efficacy, this approach could be preferable for sponsors hoping to accelerate the confirmatory process and reduce the likelihood that FDA would delay or reject their application for approval. However, some companies and advocacy groups have said this approach may not be as realistic as the FDA hopes. “Sponsors may be hesitant to invest resources to conduct a single trial due to the large number of patients required to be appropriately powered. This approach holds greater risk and higher investment up front than a two-trial approach and may be more appropriate for certain indications due to availability of supportive clinical data (e.g., supplementary versus first-in-class original application),” wrote Friends of Cancer Research, a nonprofit cancer advocacy organization that works closely with both FDA and industry, in comments on the draft guidance document.
• In general, the FDA – with the help of Congress – seems to have closed down many of the mechanisms by which companies previously delayed their confirmatory studies, either by accident or on purpose. By requiring studies to be underway, FDA is ensuring firms can no longer wait for months or years after approval to begin confirmatory trials. By wanting studies to be mostly enrolled, FDA is fighting back against companies who complained they were unable to fully enroll these studies after approval. Further, while companies can still tout potential benefits even if their confirmatory studies have less-than-stellar results, FDA now has the legal authority (also under the Consolidated Appropriations Act) to expedite the withdrawal of products that were initially granted accelerated approval.
• But these CRLs (and future actions like them) may also raise concerns about the way FDA is deploying its new authority. FDA’s delay of an accelerated approval for a drug that is otherwise approvable based on its safety and efficacy could touch a nerve among legislators who originally voted for the accelerated approval reform package in 2023. Regulators’ actions are intended to drive companies to speedily generate confirmatory data about the actual efficacy of their drugs – and therefore also help keep taxpayer dollars from paying for ineffective drugs. But that’s not necessarily an easy thing to explain to policymakers who may soon be hearing a simpler story from affected drugmakers: This policy is resulting in delays in approval for some cancer drugs that are likely effective. And for a program that is intended to accelerate drug development, delays may be difficult for the FDA to defend, and especially from desperate patients who care only that they aren’t able to readily obtain a likely effective medication. For supporters and detractors of the 2022 accelerated approval reforms, we suspect these CRLs will serve as a starting gun for a fierce debate about whether these reforms are having the intended effects.
• This debate is likely to extend beyond oncology to the cell and gene therapy space as well. Accelerated approvals also are common for cell and gene therapies to treat rare diseases, a scenario where timelines are long, trial enrollment is challenging, and stakes are high. The director of FDA’s Center for Biologics Evaluation and Research, PETER MARKS, remarked last fall that “accelerated approval is going to be the norm, I think, for a lot of our approvals, or at least our initial approvals of a gene therapy.” The FDA’s Center for Biologics Evaluation and Research (CBER), the division which regulates biologics and gene therapies, may well take a different approach to confirmatory trial expectations for rare, genetic diseases and conditions. It’s also worth noting that FDA’s March 2023 draft guidance was the work product of only one FDA center: It’s Oncology Center of Excellence (OCE), which regulates oncology drugs and medical products. Neither CBER nor FDA’s drugs division, the Center for Drug Evaluation and Research (CDER), signed onto the guidance, indicating that they may approach confirmatory trials differently than the OCE.
• There’s another line of attack that we anticipate may emerge, and that is related to disparities of impact on drug developers. Regeneron is a large company, with more than $100 billion in market capitalization. It is so large, in fact, that the CRLs it received this week barely even registered in its stock price. And as a company, it is well able to afford a confirmatory study in support of this drug before any sales are made. But many developers of medicines are far smaller and far less well-capitalized than Regeneron. For them, FDA’s new authorities and guidance may impose financial challenges and lead to different decisions with respect to market access choices.
• The key question we imagine some companies will be asking is this: Does the company have enough resources to run a confirmatory trial for a year in advance of an approval decision? And depending on the answer, we suspect some companies will need to obtain additional funding, partner with larger companies, or halt development entirely. Or, as Regeneron noted in its press release, companies may look forward to obtaining approval for these products first in foreign markets (such as Europe) and using those data to support subsequent FDA approvals – which, if it becomes a pattern, is likely to draw the ire of the U.S. Congress.

To contact the author of this analysis, please email Alexander Gaffney ( [email protected])
Featuring additional insights from Laura DiAngelo ( [email protected])
To contact the editor of this analysis, please email Kari Oakes ( [email protected])

Key Documents and Dates

• Regeneron Statement
• Accelerated Approval Statute
• FDA Webpage on Accelerated Approvals
• FDA Database of Postmarketing Requirements
• FDA Guidance on Expedited Programs for Serious Conditions, including Accelerated Approval
• Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics