Regulatory Background

• What is the Office of Information and Regulatory Affairs (OIRA)? OIRA sits within the White House Office of Management and Budget (OMB), where it serves as the “central authority for the review of Executive Branch regulations, approval of Government information collections, establishment of Government statistical practices, and coordination of federal privacy policy.” To ensure consistency in the overall federal approach to policy issues, OIRA reviews drafts of proposed and final regulations, including certain FDA guidance documents, as part of its charge of overseeing all major regulatory actions before their release.
• Regulatory review is typically the last step before a rule or guidance can be released. After FDA transmits its policies to OIRA for its regulatory review, and if OIRA determines that the policy is consistent with the broader federal approach (or that economic assumptions are in line with what the agency expects), the policy is typically “cleared” for publication – at which point the agency can issue the guidance or regulation, barring any internal delays.
• What is Accelerated Approval? FDA may grant accelerated approval to products intended to treat serious or life-threatening diseases/conditions for which adequate therapies are lacking, based on “adequate and well-controlled” clinical trials. A unique characteristic of the Accelerated Approval Program (AAP) is that FDA may evaluate a product’s effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (i.e., an intermediate endpoint). According to FDA, “A surrogate endpoint used for accelerated approval is a marker – a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.” The majority of accelerated approvals have been granted for oncology and hematology indications. FDA estimates the AAP is responsible for access to life-saving anti-cancer therapies a median of 3.4 years before they would have been available otherwise.
• Products granted accelerated approval are required to conduct confirmatory studies to verify their clinical benefit. These postmarketing required (PMR) studies are usually agreed upon at the time of the marketing application review and approval. However, these requirements can prove underwhelming for the FDA for several reasons. Companies typically face delays in running these studies (e.g., find it difficult to complete enrollment), while other companies find that their studies were insufficient to confirm the benefit and may seek to run additional studies. In either case, products for which the benefits of the drug have not been confirmed often linger on the market for years without full (or any) confirmation of the expected clinical benefit. A  2018 annual report from the FDA showed only 69% of PMR status reports were submitted on time. In 2020, the agency published  draft guidance that aimed to help sponsors complete their requirements promptly.
• Generally, there are two types of postmarketing studies: postmarketing requirements (PMRs) and postmarketing commitments (PMCs). As the names suggest, PMRs are mandatory studies that a sponsor must conduct, while PMCs represent a request from the agency. PMRs tend to either study a known or potential risk or seek to fill in gaps in the original data. Specifically, PMRs may include pediatric study requirements to assess safety and efficacy in children, studies to confirm clinical benefit of a product granted accelerated approval or demonstrate safety and efficacy in humans when approved through the Animal Rule pathway. PMCs address more varied topics that are often smaller in scope and importance. These can include studies related to clinical efficacy, clinical pharmacology, nonclinical toxicology, chemistry or manufacturing, among other topics.
• The need for greater oversight of postmarketing studies is an increasing point of concern. In  2019, only 79% of sponsor commitments related to PMRs and 75% related to PMCs were on schedule for completion according to their agreed-upon timelines. Then-acting FDA Commissioner Ned Sharpless said in a statement that FDA was “committed to working with companies on these issues and holding them accountable for completing these important studies on time to ensure that our understanding of a drug’s safety and efficacy keeps pace with its use in all relevant populations once a product is approved.” A previous AgencyIQ  analysis examining new molecular entity approvals from 2011 to 2019 demonstrated that the overall presence and prevalence of PMRs and PMCs has remained mostly stable over the last decade. This trend is particularly interesting since our data also show that drugs are being approved based on less data than previous years. This is due to both an   increase in drugs being approved through pathways that use surrogate endpoints (such as Accelerated Approval) and an increase in the number of drugs seeking approval for rare diseases.

• The Center for Oncology Excellence launched a new initiative, Project Confirm, in October 2021 to promote the transparency of outcomes related to accelerated approval for oncology indications. Separate from the FDA’s searchable database on the status of all CBER and CDER confirmatory trials,  Project Confirm’s database, which is also searchable, provides information on drugs that have received accelerated approval, including a detailed description of post-marketing requirements. The project’s website also features questions and answers about accelerated approvals in oncology. According to OCE staff, another major goal of the project is to educate the public about Accelerated Approval, address common misconceptions about the program, and provide a context for regulatory decision-making.
• In 2022, the Center for Oncology Excellence unveiled a new initiative titled Project FrontRunner, which aims to encourage drug sponsors to develop and seek approval of new cancer drugs in an earlier clinical setting. Essentially, OCE hopes this project will encourage sponsors developing new cancer treatments to design clinical trials that enroll earlier stage patients. Currently, sponsors typically develop and seek approval of a new drug for treatment of patients who have received numerous prior lines of therapies or have exhausted available treatment options. This is especially common for Accelerated Approval studies with subsequent confirmatory trials performed in a population with less refractory disease. The Oncology Center for Excellence 2022 Report (released early February) noted that the goals for Project FrontRunner’s inaugural year were to conduct outreach and engagement of key stakeholders to assess interest in this approach, and to develop a framework for identifying clinical settings where this approach may be feasible and appropriate.

OCE & Accelerated Approval: What’s the latest?

• In December 2022, the Consolidated Appropriations Act was passed into law, and with it, reforms of FDA’s Accelerated Approval program. Title three of the legislation (known as the Food and Drug Omnibus Reform Act, or FDORA), requires FDA to publish a draft guidance on how sponsor questions about novel surrogate or intermediate endpoints can be answered earlier in the development process, as well as other factors related to the accelerated approval process. The legislation also requires FDA to form a new intra-agency “Accelerated Approval Council” by the end of 2023 with the goal of ensuring “the consistent and appropriate use of accelerated approval across the FDA.” The Council should meet at least three times per year and work to develop guidance, best practices, advice and other policies. The Council is directed to publish a report on their activities within one year on the FDA website (and must continue to do so annually). [ Click here to read our analysis of the FDORA legislation.]
• New provisions in FDORA may give the FDA additional leverage to achieve the withdrawal of products whose confirmatory trials have not confirmed safety, effectiveness, or both. In the new legislation, FDA is  now required to specify the conditions for a post-approval study (or studies), “which may include enrollment targets, the study protocol, and milestones, including the target date of study completion.” Previously, FDA generally only published information about the high-level requirements of the postmarketing required study (more commonly known as a PMR).
• The agency now also has explicit authority to require that a confirmatory study be underway at the time of accelerated approval. The FDA is permitted to require, “as appropriate,” that a study or studies be underway prior to approval, or within a specified time period after the date of approval” for a product granted accelerated approval.” FDA has already  begun to require this for certain products as a condition of approval, but Congress has now granted FDA the explicit authority to do so. The language included in the omnibus also states that if the FDA does not require a postmarketing study for a drug granted accelerated approval (as is the standard), that it must publish (on its website) a “rationale for why such study is not appropriate or necessary.” However, the omnibus legislation does not indicate when this publication should occur.
• Most of the accelerated approvals the FDA has granted in the last several years have been for oncology indications, and many of these remain unconfirmed. Last year, Gautam Mehta, a clinical officer and reviewer at FDA’s Office of New Drugs (OND), shared the state of play of accelerated approvals in oncology. Accelerated approvals have made up just over a third of the oncology approvals over the last 2 years, he said – 36%, in 2020, and 33%, in 2021. In all, 167 accelerated approvals have been granted for oncology indications, with 112 of those coming in the last decade.
• Although it took almost a decade to remove accelerated products approved in the early 2000s, OCE is hastening the pace at which is scuttles unconfirmed accelerated approvals. For instance, Mylotarg (gemtuzumab ozogamicin) for acute myeloid leukemia and Iressa (gefitinib) for non-small cell lung cancer were both removed from the market approximately 12 and 11 years post receiving accelerated approval, respectively. In recent times, OCE has  withdrawn accelerated products with unproven benefits within five years or less.
• As we saw during the Advisory Committee Meetings in 2022, FDA is getting serious about reining in accelerated approvals. In 2022, the FDA continued its scrutiny of products that have received accelerated approval, some of which may have failed to confirm a favorable benefit-risk profile in confirmatory trials, either because the trials failed or because they weren’t completed. Last May, the FDA’s Oncologic Drugs Advisory Committee (ODAC) held a three-day meeting to discuss six indications for oncology drugs approved through the Accelerated Approval pathway. As AgencyIQ discussed at the time, it appeared that the committee erred on the side of maintaining market access – even when the benefit of a drug approved based on its “potential” was not technically confirmed in the confirmatory studies  [Read AgencyIQ’s analysis, “Six observations from the FDA’s ODAC meeting,” here]. In short, they tended to defer to the question of whether the information demonstrated that a drug shouldn’t be available to a patient. Additionally, the FDA  withdrew four cancer drugs with accelerated approval following an “industry-wide review” in March 2021.

Now OCE is slated to release a new guidance on accelerated approval in the coming weeks, and we have a few clues as to what it might contain

• On Thursday (March 9, 2023), the FDA sent a new guidance document entitled “ Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics” to the White House’s Office of Information and Regulatory Affairs (OIRA) for review. This guidance has never before been developed and would be a draft guidance document. Notably, this document was not included on the FDA’s various guidance agendas, and neither was it included in the Prescription Drug User Fee Act Commitment Letter.

While we don’t know what the guidance will contain, exactly, we have a few theories.

• One potential is for the guidance to address things like confirmatory studies, the timing of such studies, and how FDA will assess these factors as part of the accelerated approval process. As the FDA now has the authority to do so, we figure this authority may well factor into FDA’s guidance, even tangentially.
• Another thought is that we might see OCE use this guidance to discuss the clinical phases of development and how to promote earlier-line treatments for therapies considering accelerated approval (i.e., the goals of Project FrontRunner). However, this is perhaps less likely; The Oncology Center for Excellence 2022 Report (released early February 2023) noted that the goals for Project FrontRunner’s inaugural year were to conduct outreach and engagement of key stakeholders to assess interest in this approach, and to develop a framework for identifying clinical settings where this approach may be feasible and appropriate. A “framework” rarely means “guidance” in the FDA’s regulatory vocabulary, but instead of a discussion paper or whitepaper.
• But even outside of project FrontRunner, there’s still the possibility that OCE touches on some of the same themes. An October 2022 article authored by key OCE staff noted that, “Public discussion has focused on improving the Accelerated Approval off-ramp, suggesting specific time limits for completing confirmatory trials, patient enrollment milestones for evaluating timely trial completion, and alternative procedures for withdrawing indications. But equally important are procedures to build quality and efficiency into the AA on-ramp, which should include a prospective, comprehensive strategy detailing the sponsor’s plans for Accelerated Approval and verification of clinical benefit with an overall aim of expediting therapeutic advancement and shortening the time between a product’s initial approval and the completion of its confirmatory trials.” According to the authors, these “on-ramp considerations” include trial design, end points, study population, and timelines for obtaining data to support the Accelerated Approval and to confirm clinical benefit.
• The NEJM article goes on to suggest two options sponsors could utilize to ensure such timely generation of evidence to confirm or refute clinical benefit. First, “Rather than waiting to initiate the confirmatory trial (in a population with less refractory disease) after being granted Accelerated Approval, sponsors could pursue a single randomized trial, potentially in an earlier treatment setting, that could both support AA and subsequently verify its clinical benefit. AA could be granted on the basis of a planned interim analysis of overall response rate, and traditional approval granted on the basis of clinical benefit (usually improvement in overall survival) at the trial’s conclusion.”
• Second, “An alternative strategy is to conduct two concurrent studies: a single-group AA study examining the overall response rate in patients without other available therapies, and a randomized trial with the potential to demonstrate clinical benefit in patients who have received fewer treatments. If these studies enrolled patients around the same time, an interim analysis of safety and overall response rate in the confirmatory trial could provide supportive evidence and greater confidence for the AA based on the single-group study. A clinically meaningful effect on overall response rate in this interim or a subsequent analysis could support an additional AA indication for the randomized-trial population. In this scenario, the FDA and the sponsor would agree in advance on the criteria for attaining AA and criteria for withdrawing the indication.”
• In our experience, OCE often previews its policy shifts and guidance document topics in medical journals before publication, and so this could be an indicator of what the guidance will contain.
• Another thought is that the guidance could provide a platform for FDA to respond to feedback that was submitted on other OCE draft guidances but was ultimately omitted from finalized versions. For example, when FDA finalized its guidance on Cancer Clinical Trial Eligibility Criteria: Available Therapy in Non-Curative Settings, the Agency ultimately chose to disregard the jointly submitted request from the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) to “thoughtfully reexamine the use of prior therapy exposure as selection criteria to maximize clinical trial participation.” [ See complete AgencyIQ Analysis here]. Though excluded in the July 2022 guidance, this joint request by ASCO and FOCR suggests that cancer patients are interested in trying new therapies despite having explored another experimental treatment previously. As similar statements have been made by Director of the FDA’s Oncology Center for Excellence, Richard Pazdur, it seems probable that the Agency will address this concern in another, more suitable guidance (…perhaps one on Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics?).

https://fda.agencyiq.com/article/00000186-cede-db28-afa7-effe6c370000