What’s Inside That Black Box?


I have sat through an extraordinary number of FDA Advisory Committee meetings on a wide range of topics. During RX to OTC switch meetings, there is a great deal of fuss about the label and what it is going to say. Company sponsors have to present evidence that their label is consumer-friendly and consumer-understood, by conducting label comprehension studies. In other words, by demanding label comprehension studies, the agency wants proof that consumers will understand the instructions on the product. Inevitably, during the course of the deliberations, one advisory committee member will turn on his microphone and ask "do we know how many people actually read the label?"

But we should not only be concerned about what consumers read and comprehend, we should also be worried about physicians. The FDA uses the dreaded Black Box Warning as a staple in its stable of risk management tools. Whenever there is an aspect of a drug’s that is a cause of concern – whether an upsetting signal in pre-clinical studies or a post-marketing adverse event discovery – the agency often smacks a Black Box Warning onto the label of the product. Already in 2006, examples include Elidel Cream (pimecrolimus) and Protopic Ointment (tacrolimus) for use in the treatment of eczema and revisions to the Clozaril boxed warning. Last year, the agency added or revised at least seven Black Box Warnings to the labels of drugs.

However, in a study released late last year, it was revealed that by and large, physicians do not heed Black Box Warnings. This was a retrospective study analyzing claims from nearly 1,000,000 people in 10 geographical areas over a two and a half year period. Whenever any of these people were prescribed a drug with a Black Box Warning, it was found that 42% of the time, the label was not being followed. Physician compliance with the warnings ranged widely – from .3% to 49.6%.   Moreover, a more recent study from the Boston area indicates that physicians are not heeding the warnings. 

With results like these, one has to ask oneself whether a Black Box Warning better serves public health interests or the interests of companies with products in competition with a drug so labeled. In fact, some physicians feel that the warnings induce panic among patients who are taking a product that is black boxed, meaning that they have to spend extra time with them to reassure them. It may actually be that Black Box Warnings are not only not effective – they may have a negative effect on public health. After all, the agency hasn’t studied their effectiveness. If the warnings are not effective, the agency is managing risk by press release, not substance.

Given that the agency does have money to spend on studies (see Monday’s posting on the study that demonstrated more frequent consultation with the agency means drugs fare better through the regulatory process) one would think that they would apply some effort to discover whether their own risk management tools are, in fact, worth the time and trouble. They require comprehension studies for drug sponsors. They should apply the same standards to themselves.

It would not be costly to partner with a few professional societies conduct a comprehensive survey of physicians to find out which risk management tools are the most effective, or at the very least, try to help answer the question on Black Box Warnings. It seems like a smart company or trade association that feels that Black Box Warnings are victimizing and not useful, would want to do it. In any case, someone should do it.

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