ODAC meetings are usually few and far between – and rarely come with good news for the sponsor. Below are some lessons learned from the bounty (three!) held this week.
The US Food and Drug Administration’s Oncologic Drugs Advisory Committee is always fodder for interesting discussion, given that any application that Oncology Center of Excellence Director Rick Pazdur brings to committee comes with valuable “lessons learned” – not only for the sponsor under the spotlight, but for anyone else that follows.
And those lessons are not just for oncology drug developers: The newly named Office of Oncologic Diseases (which Pazdur also heads in an acting capacity) is known for being out in front on regulatory policy, and is often the recipient of envious comments from sponsors in other therapeutic areas, who question (much to the consternation of some) why their review divisions cannot be more like OOD.
ODAC is the main public forum for oncology regulatory policy, and the way many FDA observers parse where OOD – and by extension FDA – is headed. Stakeholders were privy to a bounty of ODAC meetings this week, including one that was scheduled and promptly canceled. There was plenty of drama to go around. Below are four key takeaways:
The first surprise was FDA’s decision to convene ODAC at all. The agency announced four 11th hour applications to bring to the advisory committee, two of which – AstraZeneca PLC’s Lynparza (olaparib) for pancreatic cancer and Merck & Co. Inc.’s Keytruda (pembrolizumab) for an expanded bladder cancer indication – were scheduled outside the typical 15-day filing requirement “due to technical issues.” (Also see “Lynparza, Keytruda Supplemental Indications Face US FDA Panel Review” – Pink Sheet, 2 Dec, 2019.)
FDA said it added an extra day to the ODAC schedule given that the committee was already confirmed for a 18 December meeting (which had been scheduled just three days prior) and because members said were available to attend. That notice was published just inside the 15-day window; Bristol-Myers Squibb Co./Accleron Pharma’s BLA luspatercept was slated for the morning agenda, followed by Epizyme Inc.’s NDA tazemetostat.
In another twist, less than a week later, FDA decided it would not need to bring luspatercept to committee after all – the companies were informed of the change at a late-cycle meeting on 4 December. ODAC’s consideration of Epizyme’s NDA was then moved to the morning slot on 18 December. Luspatercept’s user fee deadline remains 4 April 2020.
So, four (and then three) late-breaking meetings for an advisory committee that had only seen three applications in all of 2019. Those, we should note, had mixed results: Karyopharm Therapeutics Inc.’s Xpovio for multiple myeloma (received accelerated approval); Daiichi Sankyo Co. Ltd.’s Turalio for symptomatic tenosynovial giant cell tumor (regular approval); and Daiichi’s quizartinib for acute myeloid leukemia (complete response letter).
Inaugural Use of “Point/Counterpoint”
Pazdur does not call advisory committees lightly: he has made clear in recent years that ODAC is most often used for “problem” applications where there are serious issues to discuss. The review team, he has said, generally skips the committee stop in the interest of acting as quickly as possible on the application to serve an unmet need.
So it was not a good sign that FDA decided at the 11th-hour to bring three applications to the committee – including two supplemental indications (Lynparza and Keytruda) for which much is known about the benefit-risk profile. Keytruda, for example, was up for its 16th oncology indication and the 17 December meeting was the first advisory committee stop for the oncologic since it was initially approved in 2014. (Also see “Lynparza, Keytruda Supplemental Indications Face US FDA Panel Review” – Pink Sheet, 2 Dec, 2019.)
The reason for the Keytruda meeting, however, became obvious as soon as the briefing documents were released: FDA had chosen the pembrolizumab sBLA to pilot its new “Point/Counterpoint” program. Pazdur had announced the program, in which FDA and the sponsor submit a single unified briefing document to ODAC, at the Friends of Cancer Research annual meeting and mentioned it would be used on an upcoming application. (Also see “Oncology Pilot To Highlight Disagreements Between US FDA And Sponsor For Advisory Committees” – Pink Sheet, 14 Nov, 2019.)
In some respects, the choice of Keytruda made sense, given that pembrolizumab has pioneered other FDA programs: Keytruda received the first “tissue-agnostic” indication (for MSI-high tumors) and was the first product to enter the real-time oncology review (RTOR) pilot for a new indication. The “Point/Counterpoint” approach evolved out of a shared review document (the “Assessment Aid”) piloted alongside the real-time review model.
On the other hand, it seemed an odd choice given that “Point/Counterpoint” is intended to highlight differences of opinion between FDA and the sponsor, and there was relatively little disagreement between the agency and Merck on the approvability of Keytruda’s expanded bladder cancer indication. (Also see “Keytruda Bladder Cancer Advisory Cmte. To Discuss Clinical Meaningfulness Of Complete Response Rate” – Pink Sheet, 16 Dec, 2019.)
The one issue that was highlighted by FDA was the need for a discussion on what values of complete response rate and durability would constitute a clinically meaningful result. Other than that, but for the pilot, the application looked like the kind of routine approval FDA would make with little fanfare. Indeed, if the agency had simply approved the 16th indication and issued a press release, no one would have batted an eye.
Instead, FDA brought Keytruda to committee, and Merck may have paid a (small) price as a result. The ODAC vote was surprising tight given the tone of the briefing documents (9-4 in favor), with many advisory committee members talking themselves out of recommending approval. The lack of a “Pazdur Moment” (see below) also didn’t help the application. (Also see “Merck’s Keytruda Survives ‘Conflicted’ Adcom Vote For Bladder Cancer Indication” – Pink Sheet, 17 Dec, 2019.)
“The Pazdur Moment”
A better pilot for “Point/Counterpoint” may have been the morning discussion on 17 December: AstraZeneca’s Lynparza sNDA for pancreatic cancer. FDA used the briefing documents to lay out a series of issues, including, most ominously, a “modest” improvement in progression-free survival in the face of FDA’s clear and often-stated preference of using overall survival as the primary endpoint in pancreatic cancer. (Also see “AstraZeneca’s Risky Lynparza Endpoint In Pancreatic Cancer Goes Before Advisory Cmte. ” – Pink Sheet, 15 Dec, 2019.)
ODAC discussed many of the issues outlined by FDA and appeared headed for a split or negative vote. Pazdur, who had remained quiet during much of the meeting, waited for the committee to finish their comments, and then signaled for the floor. At that point, it became clear that FDA (or at least Pazdur himself) viewed the application more favorably than the briefing documents and the agency’s oral presentation suggested.
First, Pazdur dismissed any concern with the use of PFS to support approval – or at least, in the small subset of pancreatic cancer patients with the BRCA mutation (4-7% of pancreatic cancer patients). Overall survival may well be the “gold standard,” he acknowledged, but requiring that hurdle for targeted treatments in small populations is “detrimental” to patients. FDA, he added, needs to be more flexible in its regulatory standards with applications like olaparib.
The oncology chief went on to say it would be nearly impossible to show a survival advantage in the Phase 3 POLO trial given the size of the patient population: “In this subset of patients, with this BRCA mutation, it’s going to be very difficult to show a survival advantage.” Pazdur suggested that if the sponsor were to pursue a tissue-agonistic indication for olaparib, even more regulatory flexibility might be necessary from FDA.
That four-minute “Pazdur Moment” turned at least one “no” vote into a “yes”: Committee Chair Philip Hoffman (University of Chicago) said he came to the meeting expecting to vote “no” on the application because of a lack of data demonstrating overall survival. His opinion changed, however, with the understanding that the benefit was seen in a very targeted population – “a subset of a subset,” he said, echoing Pazdur.
“I voted yes because I think that although this is a subset of a subset who has a very prolonged benefit. … I’m impressed by that benefit and would hate to think that the benefit would not be available to those patients,” Hoffman said. “That’s what Dr. Pazdur was referring to with respect to targeted therapies and the potentially very limited populations to whom they may apply.”
The impact of a “Pazdur Moment” cannot be understated. In his 20 years at FDA, Pazdur has often used ODAC as a forum for expounding on important themes or messages that reach beyond the review at hand. The moment where he joins the conversation often feels like a turning point in the fortunes of the sponsor – for good (like Lynparza) or for bad (like quizartinib).
A Response To FDA Critics
FDA appears to have brought the olaparib sNDA to the advisory committee for two reasons. First, to receive feedback on questions that were debated internally about the use of PFS and whether the data support approval; but also (and this is where “Pazdur’s Moment” comes in), to explain what Pazdur appeared to have already concluded: that regulatory flexibility would be needed for olaparib given the small patient population.
But Pazdur’s comments on Lynparza appeared to have a third objective: to answer critics who claim FDA is lowering its standards by approving expensive drugs with meaningless endpoints and short, small trials that do not demonstrate efficacy.
Pazdur is sensitive to that criticism, and the olaparib meeting was not the first time he (or other senior FDA officials) has spoken out recently in response to critics. (Also see “US FDA Pushes Back Against Critics: Breakthrough Is Not A Drug ‘Beauty Contest'” – Pink Sheet, 10 Dec, 2019.)
Whether olaparib was the perfect example to use to quiet those critics is debatable. FDA has never cleared a pancreatic cancer therapy using PFS as a primary endpoint without data showing a survival benefit. Both FDA and the committee expressed concern with the “modest” benefit (a 3.6 month improvement in PFS) seen in a small number of patients (154, with 92 patients on olaparib). And like all new oncology drugs, Lynparza is expensive: the drug costs about $13,000 a month for its approved indications in breast and ovarian cancer.
That type of price tag may be what is driving the criticism, Pazdur believes. That was one of his main messages at a Friends of Cancer Research Senate briefing on 10 December: Recent criticism in the mainstream media and in academic journals about FDA approval standards, he said, may be more a reaction to high drug prices than how the agency is reviewing drugs.
The critics, Pazdur said at the briefing, “have confused several issues,” believing that FDA has authority over things like drug prices. “They look at price, and want higher standards because of the prices of these drugs. This is something that we simply don’t look at.”
FDA does not make approval decisions (nor can it) based on the price that a sponsor may give a newly approved drug, he said. “We have no idea whatsoever what the price of these drugs … will be after approval.”
It is clear that Pazdur is both fed up with those that say FDA has lowered its standards – the science has changed, not FDA, he would say – and also incredibly sensitive to it. Thus, ODAC’s third committee session this week, for Epizyme’s tazemestostat, presented him with a perfect opportunity to defend the agency’s high standard when it comes to accelerated approval, and its determination to protect the designation.
Tazemetostat demonstrated the traditional reason for bringing an application to ODAC: Pazdur wanted to air concerns with the proposed application for accelerated approval, which was based on an open-label, non-randomized study. The sponsor has a confirmatory study planned in combination with doxorubicin, but with a timeline that appears to be slipping. (Also see “Epizyme’s Tazemetostat Faces US FDA Doubts About Efficacy In Epithelioid Sarcoma” – Pink Sheet, 17 Dec, 2019.)
Pazdur was relentless in his criticism, first obtaining a commitment from Epizyme to start work on the confirmatory study, and then to question ability to demonstrate in that study a significant effect on progression-free survival (15 months) despite a low response rate (15%).
He based his skepticism based on his two decades at FDA. “One of the reasons I am bringing this up is, having been in this chair for 20 years, I have heard many companies say that they are going to be doing trials.”
In the case of tazemetostat, it was positive assessments by two sarcoma specialists serving as temporary members that change the course of the meeting. While the FDA questions about the feasibility of the confirmatory trail dominated the early part of the morning discussion, the committee appeared headed to a negative vote, but ended up 11-0 in favor.
In the end, however, Pazdur got what he wanted: a public commitment by Epizyme to complete the trial.