big pharma, yet again,again:dabigatran

the BMJ's last issue had 6 articles on dabigatran (Pradaxa), showing the malfeasance of the drug company in promoting this agent [dabigatran is a direct thrombin inhibitor, specifically marketed as a competitor of warfarin for nonvalvular atrial fibrillation, though promoted for other indications as well, with the specific selling points based on a single key trial (RE-LY, see critique below) finding slightly lower incidence of major bleeding (16.4% vs 18.15%) without the costly and inconvenient monitoring of INRs required for warfarin -- ie, the high cost of the drug was more than justified by the savings from office visits and laboratory monitoring for warfarin. the American Heart Association's atrial fibrillation guidelines that I sent out recently endorsed direct thrombin inhibitors, as has European and Canadian guidelines (eg Natl Institute for Health Care Excellence in UK, or NICE). the following issues were discovered from the drug maker (Boehringer Ingelheim), largely through internal previously confidential documents:

    --the RE-LY trial was felt to have poor design and oversight, with a Canadian agency calling for "an independent audit of RE-LY to check for irregularities in conduct, sources of bias (this was an open-labeled, not blinded trial) and the cause of the unusually high incidence of intracranial hemorrhage in the warfarin arm" (thereby exaggerating the benefit of dabigatran), requesting patient level data to be made public. the FDA specifically was concerned about the likely high frequency of errors in the data set (misreporting of events), with subsequent FDA-mandated review by the company finding a further 3848 events. of note, the increase in new MIs (n=270) found in the dabigatran​ group was dismissed as due to chance because of small numbers, but the increase in warfarin-associated intracranial hemorrhages was highlighted, even though there were many fewer of such events (n=155). the FDA found that the "blinded adjudicator of events" in fact was unblinded in 20% of the cases (eg, by seeing identifying patient information)

    ​--the drug company has settled for $650M in litigation because the evidence provided by the company was incomplete.  The lawsuit was from fatal hemorrhage cases in the RE-LY trial, cases which it turns out were not included in the RE-LY trial’s initial compilation of adverse events, nor in the FDA-mandated recalculation, which it turns out was conducted by company scientists!!  previously unreleased documents came to light through this litigation and freedom of information act

    --the drug company noted in internal documents that the risk of bleeding could have been reduced by 30-40% if plasma levels of dabigatran were in fact monitored (company's own unreleased data), and with appropriate dosage adjustment (ie undercutting their main selling point for the drug that there didn’t need to be drug level monitoring).  internal emails in the company released in the litigation showed that the company did not want this information released. both the FDA and EMA (european medicines agency, the european FDA equivalent) specifically inquired about monitoring drug levels to improve safety, and one cardiologist, an FDA advisor, expressed concern that there was a 5-fold variability in plasma levels on the 150-mg dose. with regard to this marked plasma variability, one of the company's own scientists commenting on the potential safety issues from not checking plasma levels was rebuffed by a company official noting in a 2012 internal email that "the publication [of this result] will [do] more harm than be useful for us, neither in the market but especially harmful in the discussions in the regulatory bodies", and further, "the world is crying for this information -- but the tricky part is that we have to tailor the message smart."  and "this will make any defense of no monitoring [of plasma levels] to [health authorities] extremely difficult and undermine our efforts to compete with other [new oral anticoagulants]. "

    ​--and, one of the concerns with bleeding with dabigatran​ is that there is no antidote, unlike vitamin K with warfarin overdoses

For 2 of the most relevant BMJ articles, see: dabigatran bleeding and regulators bmj 2014 in dropbox, or doi: 10.1136/bmj.g4517, and dabigatran info withheld bmj 2014 in dropbox, or doi: 10.1136/bmj.g4670

the big issue here, as mentioned in several prior blogs including a few on dabigatran​ (see below) is that we are increasingly propelled into an era of privatization and deregulation, beginning with the Reagan presidency and leading to the situation now where almost all of the studies in major medical journals are funded by the drug companies (in the 1970’s the vast majority were publicly-funded), a large percentage of guidelines now are from specialty societies (as opposed to the recent past when the NIH led most of the guideline development) and many of the leading specialists are directly supported by drug companies, and where the cash-strapped FDA is increasingly making drug companies do further studies instead of independent groups. My own bias is that we should be very hesitant in the current climate to be early-adopters of new medications, unless there is a compelling need (for example, I think there is a compelling case for the new oral hep c drugs, or new and better-tolerated hiv meds)