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Pink Sheet – Off The Clock? The New Timelines Of “Real-Time Review”

Pink Sheet – Off The Clock? The New Timelines Of “Real-Time Review”

Executive Summary

When is a two-week review not a two-week review? When it is part of the US FDA’s Oncology Center of Excellence “real-time review” pilot program. The “left shifted” review pilot is off to a good start, but it may be time to rethink the concept of FDA review clocks.

Novartis AG, Amgen Inc., and Seattle Genetics Inc. have all had a common experience in 2018: each sponsor has received US FDA approval for a supplemental application less than a month after completing the submission – before they would normally even have been notified that the filing was accepted.


Seattle Genetics is the current record holder, with the Nov. 16 approval by FDA of a new indication for Adcetris (brentuximab vedotin) for use in peripheral T-cell lymphoma. The approval, FDA said, came just two weeks after the supplement was filed (announced by Seattle Genetics on Nov. 5.).


Eleven days to review a supplemental NDA based on a 452-patient study that ran for more than five years? Even in a period of hyper-fast reviews, that is astonishingly fast.


Of course, FDA did not actually review the supplement in just two weeks. In fact, FDA began its review before the application was submitted, using the new “real time oncology review” (RTOR) pilot program initiated by the Oncology Center of Excellence earlier this year.


Seattle Genetics is the fourth sponsor to gain approval under the pilot, which was highlighted as part of the Friends of Cancer Research annual meeting just three days before the news. (Also see “Reliance On ‘Digitized Paper’ Is Slowing Drug Development – US FDA’s Woodcock” – Pink Sheet, 14 Nov, 2018.)


Novartis’ Kisqali was the first product approved under the pilot, receiving an expanded breast cancer indication in April, just three weeks after the SNDA was filed. (Also see “Keeping Track: US FDA Approvals For Tibsovo, Kisqali And Second Neupogen Biosimilar” – Pink Sheet, 22 Jul, 2018.)


Amgen’s Kyprolis also received a hyper-fast approval under the pilot for a new, once-weekly dosing regimen in August, one-month after the submission of the application. In between, Merck & Co. Inc. received approval of an application to convert Keytruda’s accelerated approval status in lung cancer to full approval – though that took a relatively leisurely five months. (More on that below.)


The pilot allows sponsors to share pivotal trial data with FDA prior to the formal submission of the regulatory dossier. At least for now, the pilot is limited to supplements with “Breakthrough” level benefits, using well understood endpoints and straightforward trial designs. The clinical data review, in other words, is the review.


Under RTOR, the FDA review starts before the application is submitted. Or, as Office of Hematology & Oncology Products acting Deputy Director Gideon Blumenthal described it during the FOCR meeting, the RTOR pilot amounts to “left-shifting the review clock” by allowing FDA (and the sponsor) to get a head start on the key clinical data analysis for the proposed filing.

What Does The Review Clock Even Mean Now?

That, however, begs the question of what the “review clock” really means in that context. Indeed, the user fee era reliance on the review clock is starting to feel a bit quaint, at least in contexts like “Breakthrough” oncology drugs.


That continues a trend in emphasizing the pre-filing parts of the application process as critical to a smooth and rapid review. Under the “program” for new molecular entity reviews in the latest user fee reauthorization, there is a two-month “filing review” period built in at the start of the review period. Most observers simply elide that into a new “clock” and say that FDA has eight months to review Priority applications and 12-month for Standard filings.


But there is also an earlier milestone embedded in the process in the form of the “pre-NDA/pre-BLA meeting” – which is not mandatory, but clearly a vital step in most contexts – that occurs at least 60 days before the application is submitted. To say nothing of all the other meetings along the development pathway that could be make-or-break for a successful application.


For now, at least, there seems to be no argument but that the new processes are paying off on the only clock that truly matters – for sponsors but especially for patients – which is the time a new product can enter the market (or a new use can be added to approved labeling).


To take the latest Adcetris approval, the study for the PTCL indication (ERAGON-2) was only completed in August (last patient visit) – and the top line data were only announced Oct. 1. FDA’s work on reviewing the data presumably began around that time, setting a de facto six-week review (or perhaps a bit longer if FDA actually began to see the data even before the press release went out).


There is no question that is a hyper-fast turnaround from study completion to new label.

Did RTOR Help Keytruda?

The other cases aren’t quite so fast in that context. Amgen’s ARROW study of the once-weekly dosing of Kyprolis, for example, was completed in June of 2017 and the company issued a press release on the results in October – a full year before the new label was approved by FDA. It is safe to assume the RTOR process did not begin until much later.


The timeline for the Kysqali RTOR experience is included in the FOCR meeting materials, so there is more detail to draw on. That review actual started as a typical “pre-NDA meeting” in January 2018, after which FDA offered Novartis the chance to engage in RTOR (which had not even been publicly announced as an option at the time). That discussion came on April 6, with the first data submission coming to FDA on April 24. The approval was granted on July 18, about three months after FDA began working on the supplement. That is still impressively fast – but not quite what the three-week “review time” suggests.


And then there was Merck’s supplement for Keytruda, which was actually the first application accepted for the pilot, even though approval did not come until after the Kisqali supplement. According to the FOCR timeline, Merck first informed FDA of the clinical trial results in January, and FDA proposed the RTOR approach in February. Merck made its first submission to FDA on Feb. 27.


In that case, though, the approval itself came a full five months later, on Aug. 20. That was still one month ahead of the official “review clock” – but it is fair to ask whether the extra up-front work by FDA and the sponsor actually made any difference overall.


It is certainly understandable the first test of a new approach may not provide the most dramatic results, and Merck officials at the FOCR meeting remained enthusiastic about the experience and eager to use the pilot again.


But it does at least raise the question of whether there could be a loss of accountability when the review clock is “left shifted.” In the current FDA climate, there is no doubt that approvals are in fact coming sooner than used to be conceivable. But FDA hasn’t always been as efficient as it is today – and even with the best intentions sometimes it is dangerous to try to do too much off the clock.…