Pfizer Inc.’s outcomes trial comparing its non-steroidal anti-inflammatory drug Celebrex (celecoxib) to ibuprofen and naproxen may not be perfect, but it may be FDA’s best shot at truly understanding whether the three NSAIDs come with different cardiovascular safety profiles, FDA advisors said.

There was no formal vote on the topic at the Feb. 10-11 joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee, but no panelist spoke up to urge discontinuation of the study.

The PRECISION trial should not be halted based on meta-analyses and other observational data that some have interpreted as giving naproxen a safety advantage, members added.

FDA’s epidemiologist Andrew Mosholder had recommended discontinuing PRECISION – Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen – in briefing documents leading up to the committee meeting to avoid exposing patients to undue risks, citing the lesser cardiovascular risk seen with naproxen in meta-analyses and observational data Also see "NSAID Panel Could Give Naproxen Labeling Edge" - Pink Sheet, 5 February, 2014..

Pfizer initiated the study in patients at high risk of heart disease in 2005 at FDA’s request Also see "Celebrex Heart Risk To Be Assessed By Cleveland Clinic In Pfizer-Funded Study" - Pink Sheet, 19 December, 2005..The trial was initially expected to complete in 2013 but due to slow accrual that date has been moved to mid-2016.

Since 2005, NSAIDs have had a boxed class-wide warning for cardiovascular risk Also see "Celebrex, NSAID Labeling Must Include Skin Reactions Warning, FDA Says" - Pink Sheet, 20 June, 2005.. FDA reconvened its advisors to determine whether newly available data should result in changes to NSAID labeling.

Committee members disagreed with Mosholder that the data presented was sufficient to conclude that naproxen had a clear advantage, voting 16-9 that available data do not support a conclusion that naproxen has a lower risk of CV thrombotic events as compared to other NSAIDs.

“How Do You Present Drift In A Regulatory Statement?”

The majority of nay voters said they were concerned about the quality of the meta-analyses and observational data presented. The data, while informative, was not credible and reliable enough to make a regulatory change.

There were too many methodological problems in the data that was presented, Linda Tyler, University of Utah College of Pharmacy said. She concluded there was not sufficient data to make a decision of a clinically significant difference between naproxen and other NSAIDs.

“When I look at all the data I see overlapping confidence intervals for all the data on all the analyses,” Tyler said. “We see huge variability both in terms of the doses and the types of studies that are combined in the meta analyses that have been presented. So with those overlapping confidence intervals what you do see is what I’m going to call drift. You see naproxen drifting to the more safe and celecoxib to the non-safe side. … So the question becomes how do you present drift in a regulatory statement and then that’s crux of the difficulty.”

Members argued continuing PRECISION was ethical and would provide FDA its best shot at understanding the safety differences among NSAIDs.

Even members that voted yes – that naproxen has a lower CV risk – favored keeping the PRECISION trial ongoing. Notably most of these yes voters did not feel that the data the distinguished naproxen’s differentiated risk warranted a strong labeling claim.

“I think the best chance to characterize the differential risk among non-steroidals is the PRECISION trial, for all it warts. ... I’m very careful when I say it’s the best chance, it might not be the perfect opportunity, but it is the best opportunity we have,” Sanjay Kaul, cardiologist at UCLA School of Medicine, said.

Kaul, who voted no on naproxen’s differentiated CV risk, said there are challenges with the conduct of PRECISION including with retention and event accrual as well as the timeliness of the trial, but also acknowledged the sponsor has disclosed many of these concerns. And importantly he added, “I don’t believe there is a loss of equipoise,” Kaul added.

Kaul said FDA should not repeat its past mistake where it put a hold on the TIDE trial, which was designed to establish the comparative CV safety of diabetes drugs rosiglitazone (GlaxoSmithKline PLC’s Avandia and generics) and Takeda Pharmaceutical Co. Ltd.’s Actos (pioglizatone) in 2010 Also see "FDA Replaces Avandia REMS Distribution Restrictions With Prescriber Training" - Pink Sheet, 26 November, 2013..“The best chance to characterize the drugs was lost,” he said.

Many panel members also cited the presence of an independent un-blinded Data Monitoring Committee as assurance that PRECISION could continue.

“Now that the study is launched, we have a DMC that is responsible for making sure that if there is a substantial balance in events between two arms or the study will be stopped. … In my mind that also reinforces my comfort with that study and equipoise because for those patients in the study there is no substainal signal of harm or the study would have been stopped by now,” Dean Follman, Chief, Division of Clinical Research in the Biostatistics Research Branch at the National Institute of Allergy and Infectious Disease at NIH.

Advisors also pointed out that FDA will lose other valuable data about adverse events with NSAIDs if the study stops early.

Clarify Labeling On Latency of CV Risk

Committee members also cast a 14-11 vote that the weight of evidence supports reconsideration of advice regarding the latency of CV thrombotic risk. FDA said current class labeling implies that the CV thrombotic risk is not substainal with short treatment courses.

Nearly all panelists, regardless of vote said they wanted it to be made clear that there was no latency of risk. Some voted no on the question because they thought the label already made clear that the risk could be immediate and all panelists emphasized the importance of new labeling conveying this immediate risk with the drugs.

NSAID Safety Review: FDA Panel Seeks Continued PRECISION From Pfizer

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