BMJ Reports Blast Pradaxa's Path to Market, Make Push for Dose Monitoring

July 23, 2014

LONDON, UK — Boehringer Ingelheim withheld important data from regulators regarding the safety of its oral direct thrombin inhibitor dabigatran (Pradaxa) as the drug was under review for approval in nonvalvular atrial fibrillation (AF), allege several of four scathing documents published today in the BMJ [1–4].

According to the reports, the company didn't share its own analysis with US or European regulators suggesting a steep drop in bleeding risk when the drug was dosed with guidance from plasma-level monitoring. That information in the hands of regulators, they contend, would have likely undermined the key dabigatran marketing message that no such monitoring would be needed—in contrast to the routine INR monitoring required of the drug it was intended to replace, warfarin.

The company, the reports allege, kept private the conclusion of at least some of its researchers that monitoring-guided dabigatran dosing "has the potential to provide patients an even better efficacy and safety profile than fixed-dose dabigatran and also a better safety and efficacy profile than a matched warfarin group."

That's critically relevant to concerns about attendant bleeding risks that have nagged dabigatran all along, especially given confusion about bleeding events in the drug's one major US trial in AF and discussions among regulators about dabigatran dosage and plasma levels. As it turns out, the reports observe, there is evidence for "a potentially higher bleeding risk with dabigatran than has been stated" in published reports coming out of that one pivotal phase 3 trial, RE-LY .

The BMJ's three reports and one editorial, detailed and wide-ranging, also blasted RE-LY's "design and oversight" as well as the US Food and Drug Administration (FDA) and, to a lesser extent, the European Medicines Agency (EMA) for conducting expeditious or incomplete reviews of the drug for its ultimate approvals for nonvalvular AF.

RE-LY investigators contacted by heartwire for comment had not responded prior to publication.

In response to the BMJ reports, Boehringer Ingelheim released a statement titled in part, "British Medical Journal publishes biased article regarding Pradaxa"[5]. Referring to parts of the reports not based on the journal's original research, the statement emphasizes that "many of the allegations made by BMJ were reported months ago in the media and have been previously addressed in full by Boehringer Ingelheim."

It continues, "Our company has provided regulators with the complete data set and analyses of clinical evidence demonstrating Pradaxa's benefits and safety, and FDA and EMA have affirmed RE-LY's conclusions. BMJ was provided this information by Boehringer Ingelheim but chose not to include it."

Lessons for All

The articles' criticisms and allegations are based partly on what is described as the journal's own independent investigation and partly on information that's already public, as detailed in two reports from BMJ editor Dr Deborah Cohen [1–2].

The reports have lessons for all involved parties, including the company, regulators, and trialists, according to Dr Rita F Redberg (University of California, San Francisco), who coauthored an accompanying editorial[3].

"They certainly raise a lot of concerns about data that seemed to be available [but] were not publicly discussed and considered in the regulatory decision," she told heartwire . By her reading of the reports, "there seem to be multiple levels of responsibility for how that happened," she said.

When concerns were raised, for example at the 2010 dabigatran FDA advisory panel hearing and similar EMA deliberations, "and not followed up on, one worries that there was a rush to get this drug on the market [without] taking the time to examine the risks and benefits."

She added, "We're not talking about an illness for which there is not available treatment. While we certainly want to get safe and effective drugs on the market as quickly as possible, we also need to take the time to make sure they are both safe and effective."

Dabigatran: First Out of the Gate

Dabigatran was the first to market among the so-called new oral anticoagulants (NOACs), prospective alternatives to warfarin for nonvalvular AF that also currently include rivaroxaban (Xarelto, Bayer) and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb). Evidence from RE-LY that the drug could entail a lower risk of fatal bleeding complications than warfarin became a prominent dabigatran marketing point for Boehringer Ingelheim.

But dabigatran's postapproval history, in particular, has been fraught with confusion about the scope of bleeding and other complications in RE-LY that haunt perceptions of its integrity and what it is qualified to say about the drug's safety. Long before the FDA's approval decision, Cohen observed, "The US agency had concerns over misreporting of events" and refused the company's application for the drug, insisting on a data review before refiling.

The danger here is that one drug is painted as 'bad' and the other NOACs as 'good.' Rivaroxaban and apixaban were also marketed on the theme that plasma-level dose adjustment was not needed.

In fact, Cohen states, "The BMJ has learned that it has taken three reviews of the data [by Boehringer Ingelheim] to calculate the number of major and fatal bleeds among trial participants, and even today there are doubts whether all events have been properly accounted for."

So if there are other NOACs available for nonvalvular AF, and if the dabigatran evidence base is so shaky, why recommend its use at all? "The danger here is that one drug is painted as 'bad' and the other NOACs as 'good.' Rivaroxaban and apixaban were also marketed on the theme that plasma-level dose adjustment was not needed, as it is with warfarin," Cohen observed for heartwire in an email.

"More systematic and independent study is needed to establish what price, in terms of preventable hemorrhage and death, is being paid for each of the new drugs in the name of ease of use," Cohen said. "We would also benefit from independent head-to-head trials of all anticoagulants: monitored and dose-adjusted vs as currently prescribed vs well-controlled warfarin."

On the other hand, Redberg notes, warfarin itself remains a good choice in nonvalvular AF. "There have been concerns about bleeding pretty much since [dabigatran] came out. Between that and the lack of a reversal agent, and the fact that there is a very tried and true alternative already on the market, I personally have not been recommending dabigatran. And whenever patients ask me, I tell them we really need to wait until we're sure about the risk and benefit profile."

"Lack of Transparency"

Regarding confusion over the nature and scope of bleeding complications in RE-LY, an accompanying editorial[3] says the BMJ's account of events "illuminates a lack of transparency about the safety of unmonitored dabigatran, compounded by the drug's fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration."

The editorial from Redberg and Dr Blake Charlton (University of California San Francisco) continues, "Equally unsettling are data-integrity issues, which prompted the US Food and Drug Administration initially to refuse to review dabigatran" and insist on the data review. It disclosed dozens of previously unreported events, "including one stroke, one systemic embolism, and 69 major hemorrhages."

But the FDA also seemed to play a big role in the suspect state of the evidence available to support an approval for dabigatran. As Charlton and Redberg explain, "Boehringer Ingelheim applied for 'fast-track' approval premised on the novelty of fixed-dose anticoagulation." The agency granted the request, and it "meant that the FDA decision was based on a review before the completion of RE-LY rather than an assessment after the completion of two randomized clinical trials as required under standard approval procedures."

Said Redberg to heartwire , "I think the basis for a fast-track approval was pretty weak in this case, and I think the eagerness to get this drug on the market with a novel indication could have influenced the carefulness with which they reviewed the data." And as is true for every drug application, she said, it was a "bad idea" to have the sponsor involved in the adjudication of events.

What Boehringer Ingelheim May Have Known but Didn't Share

Confusion and transparency issues about dabigatran's bleeding safety profile are central to the Cohen reports' allegation that Boehringer Ingelheim failed to provide regulators on both sides of the Atlantic with its analysis that supported a dose-adjustment strategy for the drug, including monitoring of plasma levels. "The company also withheld analyses that calculated how many major bleeds dose adjustment could prevent," according to the reports.

I think the eagerness to get this drug on the market with a novel indication could have influenced the carefulness with which they reviewed the data.

"The company found that if the plasma levels of the drug were measured and the dose was adjusted accordingly, major bleeds could be reduced by 30% to 40% compared with well-controlled warfarin," according to Cohen's reports. "It has also identified the plasma levels at which the dose adjustment should occur to reduce the risk of a major bleed," Cohen writes.

In comments to heartwire , Cohen noted that "Clinicians have also been asking for the data underpinning the analyses documented in the investigation for many years because they have been concerned about the need to determine therapeutic ranges [to] maximize benefit and minimize harm. Boehringer Ingelheim should honor these requests."

She added, "The company should work with regulators and physicians around the world on concrete steps that will improve the safety profile of dabigatran. There needs to be an agreed therapeutic range, varying strengths available in all countries for dose adjustment, and physician education about the value of the plasma-level test to identify patients at high risk of bleeding."

In its public statement, a Boehringer Ingelheim officer is quoted saying the company "made a robust effort to find ways to utilize plasma levels to further improve the risk/benefit profile of Pradaxa, and it is irrational to suggest otherwise." It reiterates a point, actually disclosed by the BMJ, that "because the simulations did not offer reliable predictions of actual patient outcomes, they were not provided to regulators." However, it notes, "all of the data that were used for the simulations had already been provided."

It continued, "The truth is the totality of scientific evidence does not support dosing decisions for Pradaxa based on blood levels. The research shows that individual patient characteristics, such as kidney function and certain medications, are critical factors in contributing to the risk of bleeding."

Monitoring-Guided Dosing

The reports contend that releasing data showing the benefits of plasma-level monitoring to regulators and clinicians would have challenged the company's steadfast message that dabigatran therapy didn't need monitoring. "This is considered to be a substantial advantage over warfarin," the reports note. "At every stage in dabigatran's evaluation, licensing, and marketing, the claim that there was no need to monitor drug levels has been central."

And the information would certainly have been of interest to the EMA and FDA advisory panel members, at the very least, who mulled over the drug's apparent bleeding risks and at least considered that plasma-level monitoring with dabigatran therapy might be appropriate. As heartwire reported in September 2010, the panel unanimously recommended the FDA approve dabigatran for AF. But the reports describe only limited follow-up by either agency on concerns raised about not requiring at least some degree of monitoring guidance for dosing.

On that issue, another of the four BMJ reports[4], by Dr Thomas J Moore (Institute for Safe Practices, Horsham, PA) and associates, reviews the considerations and decisions of the FDA and EMA, whose evaluations of dabigatran were "a study in contrasts."

FDA's "Strange Tunnel Vision"

The FDA "pursued a policy making the new drug easier to use with just one primary dose, even though it would increase the risk of hemorrhage in older patients." But the agency also thought it "might slightly improve the efficacy of dabigatran in preventing stroke," they write.

"The EMA, by contrast, showed continuing concerns about reducing the risk of bleeding and pursued multiple risk-reduction policies. But neither agency insisted on the most effective step to reduce bleeding risk—optimizing the drug's anticoagulant effect in each patient."

The FDA "showed a strange tunnel vision in pursuing a reduction in stroke rates of a fraction of 1% on the basis of a single trial whose data quality the agency had already challenged. Its model of the trade-offs between stroke and bleeding focused on fatal and life-threatening bleeds, which excluded 91% of bleeds in RE-LY," according to Moore et al.

"The cost of these decisions was sometimes doubling or tripling the risk of severe bleeding in older patients, patients with impaired kidney function, low body weight, those who were taking aspirin, or who for other reasons ended up with excessively high plasma levels."

By the end of 2011, the group writes, there were alarming reports of a postmarket jump in cases of major bleeding in the US, Europe, and Japan, in the US often in "older patients taking dabigatran at the 150-mg dose," the only dosage from RE-LY that the FDA approved (a second 75-mg twice-daily dose, not studied in RE-LY, was approved for patients with severe renal impairment). The FDA and EMA examined the cases.

A review of the EMA meeting materials shows that the company slide presentation did not include all their relevant data on plasma-level variability of dabigatran.

"The FDA's primary response to the bleeding reports was to launch an observational study comparing warfarin with dabigatran using its pilot postmarket surveillance system called Mini-Sentinel," according to Moore et al. As heartwire reported, the agency ultimately concluded that dabigatran-associated bleeding rates during the surveillance period didn't seem higher than those pegged to warfarin.

"The EMA, on the other hand, considered whether to require plasma-level testing for dabigatran. . . . An ad hoc advisory committee of experts met in March 2012 to consider whether to require testing and whether additional safety measures to reduce bleeding risk were required."

But Boehringer Ingelheim made a case against the need for routine monitoring. "The meeting minutes show the company position was accepted and no further action was recommended on monitoring," according to Moore et al. "However, a review of the EMA meeting materials shows that the company slide presentation did not include all their relevant data on plasma-level variability of dabigatran."

The authors conclude, "The safety of dabigatran in nonvalvular atrial fibrillation can be substantially improved in both the US and [European Union]. The manufacturer, the FDA, and EMA need to agree on a therapeutic range and recommend initial dose adjustment based on plasma measurements" and should stipulate plasma-level testing in all recipients, they write.

Cohen, Charlton, and Redberg declared no relevant competing interests. Moore discloses working " as [a] consulting expert in litigation against drug companies brought by government entities and private plaintiffs"; disclosures for his coauthors are in the report.

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