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One of my favorite Jerry Seinfeld jokes is about airplanes: “And what’s the deal with the Black Box? It’s the only thing that survives the crash. Why don’t they build the whole airplane out of the black box?” Black Box is also a popular 90s band, an important device in computers and engineering, and even a wine distributor. But in medicine, a black box can mean the demise of a drug that could otherwise have made a difference for patients one way or another.

The FDA uses the black box, or “Boxed Warnings,” to identify the most serious type of warning on the front and center of a drug’s package insert, on the FDA’s website, and on the corresponding pharmaceutical company’s website. These are generated when some adverse event(s) in clinical research or development leads to concerns for risks of serious or even life-threatening consequences. Anyone who has been in research knows that a flare of the disease being investigated is listed as an adverse event, along with colds and flu, tripping on the sidewalk, and everything in between.

According to the FDA, the boxed warning is applied to promote awareness when the risks may outweigh the benefits, when serious adverse events (SAEs) may be prevented or their risks decreased with lab monitoring and/or choosing the right patient, or when drug was approved with restrictions or safety guidelines. As a result, physicians are supposed to inform patients about the relevant risks of a boxed warning drug before prescribing it. The flip side is there is nothing to prevent anyone from writing such drugs in the interest of practicing good medicine or doing what is best for patients. But despite the stigma and label of a drug having a black box warning, isn’t “what the doctor ordered”—with acceptance of the risks and benefits—going to eventually help patients in need? Or is the emphasis on sales because patients and/or doctors are scared off by the boxed warnings? I think the main question comes back to fundamentals: are black box warnings really helpful and worthwhile—or more of a CYA and rinse-repeat?

Think of some of the most recognized medications that are routinely prescribed every day, which many of us did not know had black box warnings: Pradaxa, Adderall, Xanax, Vicodin, Zoloft, and even Synthroid. In dermatology, there are warnings for the topical calcineurin inhibitors, many biologics, and most recently Siliq (brodalumab), Regranex (becaplermin) gel, acitretin and isotretinoin, clindamycin, and of course, Botox (onabotulinumtoxinA injection). Do we remember the genesis of the black box warnings linked to any of these agents when we are using them? Are we hesitating when it’s time, or making sure the best needs of the patient are met?

I am always curious about who brings black box warnings to our attention, and if they are used as marketing tools against the guilty drug. Is it right for us to be influenced when the risk of the medication comes from mice getting lymphoma when they were fed 30 times the topical dose, or when the unfortunate stories of attempted or completed suicides are unclearly linked to the time course on the medications in a trial, enough so that it is even stated in the package insert despite the warning?

Then there are the conspiracy theorists who believe that the box warnings to Novartis for (pimecrolimus) Elidel and Valeant for (brodalumab) Siliq were to punish bad behavior, such as excessive direct-to-consumer advertising or the games played with share prices that everyone remembers from recent news. Even more interesting are the theories that many new or “designer” drugs are made to create diseases and an “unmet need” (I hate that phrase). An article published in in Forbes1 by a former Pfizer executive took that issue head on, but as Led Zeppelin eloquently told us, “and it makes me wonder.” The unfortunate consequence in this era of social media medicine (not to mention the era of guilty before proven innocent), is that it is next to impossible to erase stigmas and have reasonable discussions with minds that are already made up…usually blended with futile attempts to do what is best for patients and avoid the next bad review.

Suggestion pads are losing ground to the will of the customer, so it is up to us to stay connected to the facts. But if we don’t continue to think outside the box, particularly the black box, we will continue to lose our edge and become formulary jockeys. “Do no harm” doesn’t have to mean do not deviate, it means do your best. We live in a time where everything we eat has a disclosure of some kind, so imagine the scrutiny on pharmaceutical agents. Our responsibility is to balance efficacy, safety, and, of course, access when we prescribe...this means also balancing all elements of risk with benefit, for the benefit of patients, of course.

https://www.forbes.com/sites/johnlamattina/2018/06/20/there-go-those-drug-companies-inventing-new-diseases-again/#638946d834bb

Winterfield, L, Vleugels, RA, Park, K, “The Value of the Black Box Warning in Dermatology,” J Drugs Dermatol, 2015, Vol 14(7):660-6

—Neal Bhatia, MD

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