Between 2004 and 2005, FDA required 91 products to carry "black boxes"—the agency's most serious level of patient warning.
That was more than double the 45 black boxes required during the 25 years from 1975 to 2000.
Brands with black-box warnings face unique challenges when communicating with potential customers: Promotion for black-box
products must always include a prominent display of the warning and full prescribing information. In addition, reminder advertising
cannot be used. But these challenges do not mean the products cannot be successful. In fact, more than 300 active ingredients
with black-box warnings are currently on the market. (For a complete list, see
http://formularyproductions.com/blackbox.) Many are thriving, including Altace, Celebrex, Fortamet, and Paxil.
How has that success been possible? The answer most likely can be found in the way these drugs were marketed: They shared
information to ensure patient safety and employed marketing strategies crafted to drive appropriate use.
Sometimes an entire class of drugs carries a black-box warning. All ACE inhibitors, for instance, carry a warning for increased
risk to the fetus during pregnancy. Similar class-based black boxes can be found on SSRIs, NSAIDS, beta blockers, and angiotensin
II antagonists. Other products might be the single agent or one of a few agents in its therapeutic class to be restricted
by a boxed warning. Remicade (infliximab), for example, carries warnings on increased rates of infection, risk of tuberculosis,
and the potential for T-cell lymphomas. Competitor Humira carries a similar but less detailed boxed warning, while Enbrel,
a similar compound, has no such warning.
With a class-based black-box warning, the communications challenge is to differentiate the brand on its efficacy advantages
while communicating class-effect language in its safety messages. Altace, for instance, has a benefit its fellow ACE inhibitors
don't have: It lowers the risk of heart attack. The brand has used this benefit to approach the market by partnering with
the American Heart Association in providing information on the risk of heart attack.
The challenge is more complex when the warning applies to a single drug. Take, for example, GSK's recent activities in support
of Avandia. Following the May 2007 publication of a meta-analysis in the New England Journal of Medicine concluding that Avandia increases cardiovascular (CV) risk, the company had to quickly and clearly communicate a significant
amount of information. Company representatives positioned GSK's own RECORD study as the best available information on CV risk.
They challenged the methodology of the meta-analysis, including questioning the fact that only 65 percent of the conclusions
were consistent with the results of prospective, randomized, large-scale controlled studies. In short, GSK both disseminated
information regarding RECORD and interpreted and managed other sources of information.
Novartis' Zelnorm, which recently reentered the market following its safety-related withdrawal (due to increased risk of heart
attack, stroke, and unstable angina), also provides an interesting case study. Recognizing that for certain patients the benefits
outweigh the risks, FDA announced in July 2007 that it would permit restricted use of Zelnorm under a treatment investigational
new drug (IND) protocol to treat irritable bowel syndrome with constipation and chronic idiopathic constipation in women younger
than 55 who meet specific guidelines and for whom physicians determine the drug is medically necessary. Importantly, patients
must sign consent forms ensuring they are comprehensively informed about Zelnorm's potential risks and benefits.
What both brands have in common is the amount of information they have communicated to prospective customers, as well as the
factual manner in which they have communicated that information. Demonstrating that the benefits of these therapies outweigh
the risks has been key to continued marketing of the products. Clinical rationale, relevant disease information, appropriate
drug usage, patient selection, compliance, and physician and consumer responsibility are other types of information that help
offset concerns raised about boxed warnings.