‘Dangling’ Accelerated Approval Reviews Expand At US FDA
Executive Summary
The oncologic drugs advisory committee’s upcoming reviews are moving beyond the PD-1/PDL-1 inhibitor class – and to a very different type of sponsor.
The US Food & Drug Administration’s Oncologic Drugs Advisory Committee is slated to review the status of three more Accelerated Approval marketing applications over the course of the fall – but only two of three should be considered as part of the broader effort to address so-called “dangling” approvals.
ODAC met in April to discuss six indications for checkpoint inhibitors where confirmatory trials have not yet demonstrated clear clinical benefit. That meeting was a kick-off effort for the Oncology Center of Excellence’s plan to systematically review the status of AA indications in an effort to shore up public confidence in the pathway. (Also see "ODAC Report Card: Six Takeaways From Accelerated Approval Reviews Of Checkpoint Inhibitors" - Pink Sheet, 30 Apr, 2021.)
Of the three new ODAC reviews, the first – an 28 October meeting on the continued marketing status of Oncopeptides AB’s Pepaxto (melphalan flufenamide) – should not be considered on par with the other “dangling” Accelerated Approval reviews in 2021.
The other reviews (six checkpoint inhibitor indications discussed the end of April; two blood cancer indications set for December) are part of an effort by the oncology review group at FDA to enhance the oversight of AA and assure that post-marketing commitments are met – and product labels are appropriately matched to current therapeutic options.
The Pepaxto review is a more urgent matter, and one that would likely have triggered an advisory committee even without the broader AA review.
Pepaxto was approved earlier this year (February) for use in refractory multiple myeloma based on overall response and duration of response in a single arm open label trial in a highly refractory population. The sponsor was directed to complete a randomized comparative study, and the “OCEAN” trial – comparing Pepaxto to pamalidomide – was ongoing at the time of approval.
However, FDA placed a partial clinical hold on the trial in July, because the study (“OCEAN”) showed an increased risk of death compared to pomalidomide. Based on FDA’s analysis of the data at that time, the hazard ratio was 1.104 for risk of death on Pepaxto in the 495 patients in the trial – though the difference was not statistically significant at that point. FDA also suspended enrollment in all other Pepaxto trials. (Also see "Pepaxto’s Accelerated Approval In Myeloma May Sink On OCEAN Trial's Adverse Survival Data" - Pink Sheet, 28 Jul, 2021.)
The December meeting does, however, represent the next phase of the FDA Oncology Center of Excellence’s efforts to assess “dangling” Accelerated Approval indications – and expands on the prior focus on the PD-1/PDL-1 checkpoint inhibitors in several respects.
The meeting, set for 2 December, expands into new cancer types (multiple myeloma and acute lymphoblastic leukemia) – but also into new sponsor types. While the April review involved three of the largest oncology companies in the world – Merck & Co., Inc., Bristol Myers Squibb Company and Genentech, Inc. – the December meeting involves two smaller sponsors – Secura Bio, Inc. for Farydak (panobinostat) originally approved in February 2015, and Acrotech Biopharma LLC for Marqibo (vincristine sulfate liposome) originally approved August 2012.
Perhaps as significantly, it involves applications that have transferred ownership since AA was initially granted, raising another factor to complicate timely completion of the regulatory commitments. Farydak was originally a Novartis AG product and was acquired by Secura in 2019; Marqibo was owned by Spectrum Pharmaceuticals Inc. at the time of approval and then acquired by Acrotech, also in 2019.
Last but not least, both applications had a difficult path through FDA in the first place, and they may help explain why they are an early focus of the expanding review of “dangling” Accelerated Approval applications.
On the surface, Marqibo is a relatively straightforward case of apparently overdue confirmatory trial results. The application was initially approved in 2012 with a requirement to complete a confirmatory randomized trial by 2017 (with the final report submitted in 2018). The lack of a conversion to full approval three years later makes the product a clear example of a “dangling” approval.
The tortured regulatory history of the application, however, likely also flagged it for attention. Marqibo was first submitted for approval in 2004, and was rejected at that time, with OCE Director Richard Pazdur (then a relatively new head of FDA’s oncology division) declaring clear frustration with the attempt to use AA as a short-cut.
The episode helped build a portrait of Pazdur in the eyes of FDA’s critics (notably the Wall Street Journal) as bent on “raising the bar” in oncology. (Also see "The Greatest FDA Advisory Committees, Part II: The Birth Of The ‘Pazdur Moment’" - Pink Sheet, 2 Sep, 2020.)
The drug was rejected a second time in 2011 before finally gaining approval. It is no surprise that OCE would want to keep tabs on the commitment to complete confirmatory trials, particularly as it moves across ownership.
Farydak had a less torturous path to approval, but the application was initially rejected by an FDA advisory committee as a candidate for full approval based on PFS in myeloma. The rejection reflected FDA’s reservations about the meaningfulness of the benefit in a category with multiple options – and concerns about toxicity potentially reflecting too high a dose.
However, FDA ultimately granted Accelerated Approval based on the interpretation that other agents with the same refractory indication were still under Accelerated Approval at the time and so would not be considered “available” therapy.
Somewhat unusually, Novartis had two post-marketing obligations to fulfill – the first related to optimizing the dosing before the second, more traditional confirmatory clinical trial obligation. (Also see "FDA Used Regulatory Loophole To Save Novartis' Farydak" - Pink Sheet, 17 Aug, 2015.)
According to the approval letter, the dose-finding study was due to be completed by 2018 with the final report submitted in 2019. The clinical confirmatory trial was to use a dose selected based on an interim analysis of the earlier trial, with a target completion date of February 2021. The final study report is not due until December of this year.
That timeline makes it unusual for FDA to be asking whether the indication should be retained at this point. Regardless, revisiting the dosing issues with Faradyk may be an end in itself, giving the oncology group another chance to highlight its effort to advance new paradigms for dose finding in the field (“Project Optimus.”) (Also see "Pazdur To Oncology Drug Developers: Step Back, Slow Down – And Find The Right Dose" - Pink Sheet, 13 Aug, 2021.)
[Editor’s note: This story has been updated to clarify that FDA placed a partial clinical hold on the OCEAN trial. The trial is not completely halted; patients have the opportunity to reconsent if they’re deriving clinical benefit.]