Glaxo Gets an FDA Warning... With Teeth

Well before Vytorin became a cause célèbre — which is to say, about a year ago — GlaxoSmithKline’s Avandia was the drug getting slapped around by critics for, in that case, possible heart problems that had possibly been downplayed or ignored. That case, which led to new warnings on the drug’s label but nothing more drastic beyond a falloff in sales, played a major role in Food and Drug Administration reforms last year that handed the agency broad new powers to monitor and enforce drug safety.

In an interesting postscript, the FDA has just exercised those powers on Glaxo, issuing the drugmaker an official warning letter for failing to keep the agency up-to-date on more than 18 continuing studies of Avandia. While the agency didn’t accuse Glaxo of deliberately hiding the information, which the drugmaker eventually supplied anyway, it did hit the company for apparently not being able to track its own sprawling research effort.

That might strike many people as little more than a exercise in bureaucratic i-dotting and t-crossing, but it’s far more momentous than that. These kinds of “phase IV” post-approval studies are about the only way that FDA — or anyone else — can begin to track the safety of new drugs in any sort of rigorous way. Recall, in fact, that Avandia’s safety problems only emerged when Cleveland Clinic cardiologist Steven Nissen did his own analysis of 42 existing Avandia studies and published his results in the New England Journal of Medicine.

So if GSK can’t keep track of its studies, how can anyone else hope to keep tabs on the data that might reveal hidden safety problems? Michael McCaughan of the In Vivo Blog suggests that the FDA’s letter amounts to a shot across the drug industry’s bow, a warning that Big Pharma had better get its house in order on the drug-safety front — or else. And he’s right.

What’s more, the FDA issued a not-so-subtle reminder that it has an awfully big stick with which to get the attention of drugmakers, one substantially scarier than the relatively minor fines it can also impose (emphasis mine):

You should take prompt action to correct the violations described above. Failure to do so may result in regulatory action without further notice. These actions may include, but are not limited to, seizure and/or injunction.

Other federal agencies may take this Warning Letter into account when considering the award of contracts. In addition, any pending New Drug Applications, Abbreviated New Drug Application, or export certificate requests submitted by your firm may not be approved until the above violations are corrected.

In case you’re not up to speed on your regulatory-speak, the FDA is reminding the industry that it has the power to hold up new drug approvals if it’s not satisfied. Ouch.

One final observation: Even with the improvements that Glaxo has put in place, such as its Avandia clinical-trial registry, its post-marketing program remains huge and a pain-and-a-half to decipher, at least for people like me who aren’t already steeped in the issue. I counted 34 phase IV post-marketing studies on Glaxo’s list, and an astonishing 72 phase III trials (these are typically the “pivotal” studies required for drug approval), all involving God knows how many patients.

Worse, the FDA and Glaxo appear to differ on what makes a phase III trial different from a phase IV — at least, that’s the only conclusion I can draw from the fact that many of the trials cited by the FDA aren’t listed in the company’s registry under the same names or study codes, while many of those that do appear are often classified by the drugmaker as phase III instead of IV. I won’t belabor the point, but the complexity here is truly mind-numbing. I spent some time on the registry hoping to get a better sense of exactly what a phase IV marketing program looks like, and at the moment, I have to say I think I know less than when I started.