Advertising Citations Reach Record High: Another Way To Regulate Pharma?

FDA's Division of Drug Marketing, Advertising and Communications has sent half of this year's citations for misleading advertising in the past month.

Since Sept. 25, the division has sent seven letters, including four warning letters, to pharmaceutical companies. The recent deluge ties the record for the greatest number of citations the division has sent in one month, the previous being from Nov. 5, 2002 through Dec. 3, 2002. But with a few more weeks left in October, it would be no surprise if that record is surpassed.

The pace of citations is even more remarkable given the sustained drop in violation notices that has occurred recently (see chart: " ¹ FDA Broadens The Scope Of Its Advertising Citations "). According to FDA's most recent statistics on advertising letters, released in CDER's ² report to the nation, citations had been falling for each of the past three years.

But just a little over a month ago DDMAC Director Tom Abrams said that Congress' and the Department of Justice's interest in drug industry promotional issues seems to be increasing, along with funding for his staff (³ (Also see "DoJ, Congress Want Ad Oversight: FDA Sounds Ready To Respond" - Pink Sheet, 15 Sep, 2008.) p. 19). His comment was one of several from FDA's top ad officials at the Food & Drug Law Institute advertising and promotion conference that suggested more enforcement activity was coming in the promotional arena.

The change in tone, not just volume, of citations could also be concerning to firms planning marketing campaigns. Many of the letters sent in the DDMAC reawakening have cited firms for broadly describing the disease the product is indicated for, rather than tailoring the communication to the specific endpoints that were used in the approval studies.

The five letters citing attention deficit/hyperactivity disorder drugs that were issued Sept. 25 all emphasized this concern to varying degrees (⁴ (Also see "FDA’s Advertising Enforcement Turns Its Focus To YouTube, ADHD Drugs" - Pink Sheet, 6 Oct, 2008.) p. 12).

Shire's promotion for Adderall XR (amphetamine salts), for example, described the negative effects of ADHD, such as poor job and school performance and problems with social and emotional development. But since the company's trials were not designed to gauge those effects (approval studies focused on issues such as fidgeting and talking), the agency argues, it cannot claim to alleviate them.

That means that firms cannot describe characteristics of a disease without having specific endpoints for those elements, suggests McDermott, Will & Emery attorney Arnold Friede.

If the letters do represent a philosophical shift on how FDA is enforcing promotions, it seems to be one in line with the new REMS powers that the agency has been granted as part of the FDA Amendments Act of 2007.

The Risk Evaluation and Mitigation Strategies that FDA can now impose are designed to ensure that only appropriate, well-informed patients receive potentially risky products, and the recent advertising enforcements also try to push communication - and thus implicitly use - toward only the populations that have been carefully studied.

Driving Prescribing Decisions

If firms were unable to use promotions to help nudge their products' populations a bit larger without trials, it would have profound implications for lifecycle management.

"Patient demographics and co-morbidities are very important drivers of prescribing decisions," David Godolphin, VP of Equinox Group, said at the Pharma Forecasting Summit in Boston on Oct. 2. Switching patients from competing therapies and driving maintenance become increasingly important as a product ages.

Godolphin suggests companies break out their sales by patient demographics: Who is included in your initial patient population? Who do you take away from competing therapies? When do naive patients begin treatment? Who uses the drug as maintenance therapy or re-starts therapy altogether?

"In order to make sure that you don't miss an opportunity or threat to maximize or exploit the drug's strengths and weaknesses as you're going into late development, you need to have an understanding of the makeup of your key populations."

Mirapex Pharmacy Piece Needs To Take A Rest

FDA's Sept. 29 ⁵ warning letter regarding Boehringer-Ingelheim's restless leg syndrome drug Mirapex (pramipexole) continued the theme of drawing a clear distinction between the disease as generally understood and the disease as documented in the label.

According to the warning letter, a "professional labeling piece" notes "up to 10 percent of the U.S. adult population is affected by mild, moderate or severe symptoms of RLS, which often goes undiagnosed," but the piece fails to note that Mirapex is only indicated for moderate-to-severe RLS.

"Although the name of the product is not mentioned on the portion of the piece containing the RLS discussion, the reverse side of the piece includes a section titled 'IMPORTANT SAFETY INFORMATION ABOUT MIRAPEX,'" the letter states.

In addition to citing the labeling piece, the warning letter also notes two ⁶ consumer-directed pharmacy printouts that failed to include any risk information and were not accompanied by the drug's approved product labeling.

The first consumer-directed printout presents a list of efficacy claims, a quiz patients can take to see if they may have RLS, a toll-free number for a money-saving offer, and a statement that says Mirapex "can help relieve the frequency & severity of many of the symptoms associated with moderate to severe primary RLS, such as the urge to move."

"When a piece make claims such as those above," DDMAC writes, "it must also present risk information as necessary to ensure that the claims made are truthful and non-misleading. No such risk information is present here."

The second printout discusses common side effects, noting that they are "mild and decreased over time." It also does not include Mirapex's serious warnings and in doing so, DDMAC writes, it misleadingly suggests that it is safer than demonstrated.

FDA "Not Gonna Take" Yaz's DTC Ads

The agency's most recent letter is also in many ways its most traditional: FDA sent a ⁷ warning letter to Bayer on Oct. 3 for ⁸ two TV ads, "Not Gonna Take It" and "Balloons," which promote its birth control product Yaz (drospirenone/ethinyl estradiol).

Yaz is approved for treatment of symptoms of premenstrual dysphoric disorder, but "has not been evaluated for the treatment of premenstrual syndrome," the warning letter states.

However, the TV ads "misleadingly suggest that Yaz is appropriate for treating women with PMS, who may not be appropriate candidates for this drug," the letter states.

"We note that despite listing certain symptoms of PMDD, nowhere do the TV ads use the full phrase 'premenstrual dysphoric disorder,' to more completely distinguish PMDD from PMS, thereby increasing the likelihood that a viewer, in light of the claims and presentations described below, will understand it to be the same as, or substantially similar to, PMS."

The Yaz DTC spot "Not Gonna Take It," for example, starts by stating: "We all know that birth control is 99 percent effective and can give you shorter, lighter periods. But did you know there's a Pill that can do more?" The ad then displays images of women singing "We're Not Gonna Take It" as they kick and punch words describing symptoms such as moodiness, bloating and irritability.

The agency also charges that Bayer minimizes the drug's risk with the two promotions by including distracting visuals and scene changes during the ad's statement of risk section. While risk minimization is still a common cause for citation, over the past two years, advertising enforcement appears to have shifted away from citations involving lack of risk information and more towards presentation of efficacy (⁹ (Also see "FDA Ad Letters Focus On Superiority Claims; Oversight Critiqued On Several Fronts" - Pink Sheet, 20 Aug, 2007.) p. 13).

A Misleading Biological Comparison

CBER Advertising and Promotional Labeling Branch jumped on the advertisement citations bandwagon this month, sending one Sept. 5 to Telecris Biotherapies for its antithrombin drug Thrombate III . FDA claims Telecris makes misleading superiority and safety claims in its sell sheet. The sell sheet presents such claims versus fresh frozen plasma based on comparison of Thrombate's label with anecdotal evidence. But the agency's ¹⁰ letter points out that there are no adequate and well-controlled clinical trials or substantial clinical experience to support those superiority claims.

Specifically, the backside of the sell sheet includes a table comparing Thrombate III and FFP, with headings that read: "Thrombate III ... the Necessary Therapy" and "Fresh frozen plasma (FFP) is contraindicated for a coagulopathy when the missing protein is available as a concentrate." FDA charges that "The overall presentation of the table misleadingly suggests that Thrombate III is safer and more effective than FFP when none of these characteristics have been compared in an adequately and well-controlled manner."

Earlier in the year, FDA sent a warning letter to ZymoGenetics for implying that its recombinant Recothrom had a better safety profile versus bovine thrombin, the standard of care (¹¹ (Also see "FDA Challenges ZymoGenetics' Safety Claims" - Pink Sheet, 7 May, 2008.)).

- Lauren Smith ([email protected])