Understanding Accelerated Approval Pathways

The FDA’s accelerated approval program, launched in 1992, allows early drug approvals based on surrogate markers for unmet medical needs, particularly in oncology. While this accelerates patient access, it raises concerns due to delays in confirmatory studies and reliance on surrogate endpoints, with difficulty assessing if new drugs improve on existing treatments. An “evidentiary gap” arises as drugs approved through this pathway aren’t considered standard until full approval, enabling “fast-follower” drugs to enter the market without comparative studies. This can complicate treatment choices and hinder innovation. Adopting a model similar to the EMA’s conditional approval could address these issues by allowing accelerated drugs to be considered in new approvals, balancing quick access with strong clinical evidence. #cancer #innovation #acceleratedapproval

Yesterday was the 38th anniversary of #FDA's approval of zidovudine (AZT or Retrovir), the first drug approved to treat #HIV/AIDS. We should remember AZT not only as the first treatment for the then-33,000 patients after seven excruciating years since the first cases, but also as a historic precedent in rapid, collaborative drug development and expedited FDA review. ·      A phase 1 trial by NCI and Duke University led to a phase 2 multicenter, randomized, placebo-controlled trial of 282 patients in February 1986 halted after just months by the data safety monitoring board based on dramatic outcomes: 19 deaths among 137 control arm patients versus one of the 145 patients receiving zidovudine. Opportunistic infections developed in 45 patients receiving placebo, compared with 24 receiving AZT. ·      The patients were initially stratified by their ‘CD4 cell counts’, their T cells with CD4 surface markers, which were also measured over time. The result: a statistically significant increase in treated patients. The conclusion: while not a clinical endpoint, CD4 cell counts were a surrogate endpoint “reasonably likely to predict clinical benefit” – the conceptual foundation of FDA’s accelerated approval pathway. ·      FDA had also worked closely, if not in unprecedented ways, with Burroughs Wellcome on the trial and the New Drug Application (NDA) – foreshadowing the collaborative hallmarks of future expedited reviews. Strikingly, AZT also received #orphandrug designation in July 1985. ·      After waiving the requirement of a phase 3 trial before the December 1986 NDA submission, FDA convened its Anti-Infective Advisory Committee and took just three months to approve the drug. ·      Finally, in a precursor to expanded access, prior to approval, AZT was made available to more than 5,000 of the most severely ill AIDS patients. This achievement was not absolute: AZT had significant toxicity, was not wholly effective as monotherapy, allowing for resistance to develop. But stacking precedent upon precedent, AZT paved the way for today’s paradigm of rapid drug development and regulatory flexibility underlying contemporary #cancer and #raredisease drug development and virtually every expedited review pathway at FDA. (AZT’s high price also triggered intense scrutiny, one of a long line of prescription drug pricing controversies, yet also beneficially led to formation of a $30M Federal reimbursement program that became the life-saving #RyanWhite AIDS Drug Assistance Program (ADAP) – authored by my former boss, Henry Waxman.) But with our biomedical enterprise and #NIH currently under siege from the Administration’s extralegal actions and vertigo-inducing cuts, it is all the more important we recall the public-private collaboration that drove life science #innovation, the crucial roles of NIH and FDA, and the critical sacrifices and engagement by patients that led to AZT’s approval and our public health response to HIV/AIDS. #kendallsquarepolicy

FDA: Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway JANUARY 2025 Docket Number: FDA-2024-D-3334 Issued by: Oncology Center of Excellence For drugs granted accelerated approval, sponsors have been required to conduct confirmatory studies postapproval to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. In the Consolidated Appropriations Act, 2023 (CAA), Congress amended section 506(c) of the FD&C Act (21 U.S.C. 356(c)), to provide additional authorities to help ensure timely completion of such trials, including that 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.” This draft guidance, when finalized, will describe FDA’s interpretation of the term “underway” and policies for implementing this requirement, including factors FDA intends to consider when determining whether a confirmatory trial is underway prior to an accelerated approval action. https://lnkd.in/egj6WKUM