Apixaban Delay Prompts 'Not-Us!' Chorus

Shelley Wood

July 06, 2012

July 6, 2012 (Silver Spring, Maryland) — The announcement last week that the FDA is delaying an approval decision on apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) for the prevention of stroke in patients with atrial fibrillation while the agency acquires additional data seems to have prompted a chorus of reassurances from different parties connected to the drug's regulatory journey.

As reported by heartwire , the companies developing the new oral anticoagulant announced June 25 that they'd received a complete response letter (CRL) from the FDA requesting additional information on "data management and verification" from the ARISTOTLE trial.

Complete Confidence and a Safe Distance

The same day news of the CRL was released, Dr Robert Califf (Duke Clinical Research Institute [DCRI]) wrote about the "surprise decision" in his blog, making it clear that the DCRI had no special insights into--or culpability regarding--the "data management and verification" situation.

"I have spoken with Chris Granger and Lars Wallentin, the co-PIs [of ARISTOTLE]," Califf writes. "While DCRI did not do the data management or monitoring for this trial, we have a copy of the database, and our statisticians have performed the independent analyses. Chris and Lars have assured me that all the essential elements of a quality clinical trial are in place and robust."

Meanwhile, principal investigators for the AVERROES trial--another major part of the FDA's deliberations--have taken the unusual step of sending a letter to trial investigators also, seemingly to dispel any concerns.

"The response of the FDA appears to be unrelated to the trial results of AVERROES or ARISTOTLE," the letter from Drs Stuart Connolly, Salim Yusuf, and John Eikelboom (McMaster University, Hamilton, ON) reads. "We would like to emphasize that we have complete confidence in the data of AVERROES and ARISTOTLE showing that apixaban is effective and safe for the treatment of a broad spectrum of patients with atrial fibrillation. We believe, as do the sponsors, that the issues raised by the FDA will be successfully resolved."

Of note, the letter states that patients enrolled in the AVERROES Long-Term Open-Label Extension will continue to receive the drug "until apixaban is commercially available in the majority of the participating countries."

The rationale for sending the letter, Connolly told heartwire , was "just in case [investigators] were wondering what was going on [and] also to reassure them that our open-label long-term follow-up study is not affected."

The Transparency Hot Potato

Surprise at the FDA's decision has spurred some observers to question whether the agency is privy to information not seen in the ARISTOTLE trial, published in 2011 in the New England Journal of Medicine. ARISTOTLE was widely seen as the "most positive" data among the major randomized trials comparing new oral anticoagulants with warfarin. But the FDA's cardiovascular and renal drugs advisory committee never convened before the drug's Prescription Drug User Fee Act (PDUFA) date came and went, so there are no briefing documents summing up the FDA's review of the data in the public domain.

Dr Eric Topol (Scripps Clinic, La Jolla, CA) theheart.org editor in chief, raised the issue on his blog, decrying the "lack of transparency" and the apparent "cloaked and secretive way in which the FDA communicates with the manufacturer about a trial that is already in the public domain, in one of the world's most prestigious medical journals."

Those comments, in turn, prompted another public declaration of blamelessness, this time from the FDA's Dr Stephen M Grant (Division Cardiovascular and Renal Products).

In a post responding to the Topolog, Grant notes that while a 2010 task force initiated by the FDA recommended that contents of CRLs be disclosed at the time they are issued, this is currently not the case.

"FDA is generally prohibited by statutes and regulations from disclosing the existence, status, or contents of an investigational application submitted to the agency, until the product has been approved," Grant writes. "So not only can FDA not disclose any information related to an [new drug application] NDA for apixaban, but FDA could not even acknowledge that a complete response letter had been issued if the manufacturer had not publicly done so. However, nothing prevents the manufacturer from disclosing the contents of a complete response letter if they choose to do so."

For now, however, the companies are keeping silent. "The information included in the Bristol-Myers Squibb/Pfizer press release is all that the companies are disclosing at this point," Bristol-Myers Squibb spokesperson Chrissy Trank told heartwire yesterday. "It is our belief that the information requested does not impact the outcome measures of the trial. It's important to note that the FDA has not requested that the companies complete any new studies." 


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