Out of the Black Box: Marketing a Product with a Warning Box

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.

Kathy Magnuson

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 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.

Information Management

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.

Marketing Considerations

The strategies employed by successful black-box and postwithdrawal brands suggest a three-part approach to marketing these drugs.

First, disseminate information appropriately. The controlled dissemination of information and education provides the cornerstone of promoting brands hindered by the presence or prospect of a black box. It is crucial to fully disclose clinical studies' results, appropriate use data, patient types, and clear, concise information on risks.

Brands that try to downplay or withhold negative information will ultimately be found out. One has only to look at Vioxx, or even the recent Avandia news, to see that complete disclosure coupled with information on managing the risks is the best approach.

Full disclosure can optimize brand efficacy through proper usage and compliance, underscore corporate responsibility, develop good will across constituencies, and engender customer loyalty.

Second, develop deep, diverse customer relationships. Customer loyalty, important for any brand, is crucial for brands with black-box warnings, including those that have been reintroduced following a safety-related withdrawal or suspension. It was, after all, largely due to consumer demand that FDA reexamined Tysabri after it was initially withdrawn.

Developing deep and meaningful relationships across multiple constituencies can have a major impact on receptivity to a brand as well as to its long-term success. Taking the time to listen and respond to the input of patient advocacy groups helps engender goodwill and a powerful voice in support of appropriate use of a brand.

Regulatory bodies are also key customers. Sharing information throughout the process helps nurture a strong tie with FDA and DDMAC that can inform the decision-making process and allow the brand team to be a proactive partner that contributes to the outcome. Depending on the brand, other constituency groups, such as payers and pharmacies, may also be relevant and therefore crucial to include in the brand's partnership strategies.

Third, review ongoing brand performance. To create the types of relationships described above, it is imperative that a brand behave in an actively responsible way, from allocating resources to tracking the performance of the brand and the perceptions of its customers. In addition to the typical sales tracking, brand teams must develop an ongoing dialog with all constituents to learn how messages are received so they can be adjusted accordingly.

Listen to prescribing physicians. Formally collect feedback from sales representatives. Talk to patients and their advocates. Make sure that educational programs are effective in how they communicate the risks and benefits of the brand. Do follow-up surveys to ensure the testing required is being done and information is being reported back to both the pharmaceutical company and the proper regulatory bodies. Taking control of the flow of positive and negative information will demonstrate a corporate commitment to ensuring patient safety and appropriate use of the brand.

It is also important that these efforts be consistent across the life of the brand. Trying to court goodwill when safety or other problems arise won't work if the information delivered hasn't been consistently honest and up-front from the conception of promotional efforts.

Finding the Silver Lining in Those Black Boxes

The notion of risk versus benefit poses an age-old dilemma, one that requires careful consideration. For many patients, therapies that carry a black-box warning can open up possibilities to live more fully, more freely. Pharmaceutical marketers have a significant responsibility to provide the full story to enable patients and their physicians to make the most informed decision possible about their treatment.

As pressure to ensure the safety of drug treatments while continuing to provide cutting-edge therapies increases for the industry as a whole—and FDA in particular—the demand for full disclosure will increase. The use of new technologies for disseminating the information will allow for greater reach of risk-and-benefit messages to key customers, building the customer relationships necessary to be successful.

Kathy Magnuson is executive vice president and managing director at Brand Pharm. She can be reached at kathy.magnuson@brandpharmusa.com