An upcoming FDA draft guidance on fair balance in promotional materials could benefit manufacturers following a spate of warning letters from the agency's ad division citing the prominence of risk information.

The Division of Drug Marketing, Advertising & Communications previously announced plans to issue the draft guidance on "Achieving Fair Balance in Print and Broadcast Advertisements" in 2005.

The ad division has released five letters - three of them warning letters - since mid-July. A common complaint by the agency is the balance of risk information with efficacy claims.

Zyvox Nets Letter Despite Brief Summary Use

A Pfizer professional journal advertisement for the injectable antibiotic Zyvox (linezolid) was cited in a July 20 ^FDL-1 warning letter for several violations, including "lack of fair balance."

The ¹ four-page spread includes the wording: "MRSA [methicillin-resistant Staphylococcus aureus] meets its match" and "Serious infection. Serious results."

Five lines of risk information appear at the bottom of the third page with the recommendation "see brief summary of prescribing information on adjacent pages." The full-page brief summary includes sections from Zyvox labeling on indications and usage, contraindications, precautions and adverse reactions.

Although risk information is presented, FDA argues that the prominence is inadequate.

"Throughout the three main pages of the four-page journal ad, effectiveness claims for Zyvox are presented using large, colorful, bolded headers as well as a colorful chart."

"In contrast, all of the risk information is relegated to page three of the four-page piece and is presented in very small font in a single-spaced paragraph at the bottom of the page, below the indications for use, without additional presentation elements that indicate to the reader that it is important risk information."

The letter does not mention the inclusion of the brief summary page.

The agency is preparing a final guidance on brief summary alternatives. The draft guidance released in 2004 proposed a bulleted "highlight" section for risk information (² Also see "Risk Information “Window” Proposed By FDA For DTC Print Ads" - Pink Sheet, 9 February, 2004., p. 4).

Ad Division Keeps Attention On Efficacy Claims

The ad division's warning letter to Pfizer also charges the ad campaign with making an unsubstantiated superiority claim and with broadening the indication.

The chart with data comparing linezolid with vancomycin does "not constitute substantial evidence or substantial clinical experience," FDA said. The studies "are not two adequate and well-controlled studies, but rather one study that was conducted prior to marketing and continued as a post-marketing study."

Further, "the presentation in the ad is based on a post-hoc analysis; p-values are meaningless in this situation and cannot be used to demonstrate statistically significant differences between treatment groups."

The letter also asserts that Pfizer is broadening Zyvox' indication with the statement "MRSA meets its match."

Pfizer's clarification of the indication in small print is not sufficient to "correct the misleading suggestion conveyed by the ad as a whole that Zyvox is indicated for the treatment of all MRSA infections," FDA said. Zyvox' two MRSA-specific indications are for nosocomial pneumonia and complicated skin and skin structure infections.

Pfizer said it will pull the ad. The firm has alternative ads for Zyvox that it can run in its place.

Abbott Gets Letter For Mailer, Not Ad

A July 19 ^FDL-2 letter to Abbott's Ross Products division finds similar breaches in a direct professional mailer for bovine pulmonary surfactant Survanta (beractant).

FDA targeted the ³ mailer's balance of risk and benefit: The mailer "present[s] effectiveness claims using large, colorful, bolded headers as well as colorful charts, bullet points, and a significant amount of white space."

"In contrast, all of the risk information...is relegated to page three of the four-page piece and is presented in small font in two lines at the very bottom of the page, below both the references and footnotes."

Abbott boasts improved survival in premature neonates weighing less than 600 grams that receive Survanta to treat respiratory distress syndrome, compared with those receiving Forest's Infasurf (calfactant).

FDA argued that "these claims...are not adequately supported and are inconsistent with the" labeling.

"The precautions section of the PI specifically states: 'Use of Survanta in infants less than 600 g birth weight...has not been evaluated in controlled trials,'" the letter notes. Further, "we are not aware of any substantial evidence or substantial clinical experience demonstrating this effect of Survanta."

Tracleer Website Cited

In another warning letter, the ad division cited Actelion on June 20 for a web page promoting the firm's pulmonary arterial hypertension therapy Tracleer (bosentan). The site made unsubstantiated superiority claims and omitted material facts, including risk information, FDA said.

The "product page and the five links...found on the page fail to include any information on the risks associated with the use of Tracleer," FDA said.

"Your omission of this important risk information raises serious public health and safety concerns." Tracleer's labeling includes a "black box" with a warning about potential liver injury and a contraindication for use during pregnancy.

Also in July, Roche received a letter citing sales reps' statements on Fuzeon , and Cytogen got a warning letter for various promotions of Quadramet .

[Editor's note: Complete coverage of each of the July ad division letters appeared in ⁴ "The Pink Sheet" DAILY . To read the articles and sign up for a free trial, visit our website, ThePinkSheetDAILY.com.]

The agency appears on pace for another significant jump in ad citations this year (⁵ Also see "FDA Ad Warning Letters On Track For Significant Increase In 2005" - Pink Sheet, 16 May, 2005., p. 24). In 2004, the ad division released 12 warning letters for the year; previous years have seen only four or five warning letters sent (⁶ Also see "Drug Ad Warning Letter Rate Jumps; FDA Vows Action To Ensure Compliance" - Pink Sheet, 7 February, 2005., p. 29).

FDA Commissioner Crawford has expressed repeated concerns about direct-to-consumer ads, although he has emphasized his support for the general idea of consumer promotion.

Only some of the recent batch of ad division letters cited DTC promotions, and each had significant lead time because of review by the chief counsel's office, but their release around the Senate vote to confirm Crawford as permanent commissioner suggests that advertising enforcement will continue to play a prominent role at FDA.

WLF Wants More Guidance From FDA

The rise in advertising letters may have helped give rise to Washington Legal Foundation's "DDMAC Watch," a program launched in June to respond to letters from the ad division and track all letters for trends that could be arguable in court (⁷ Also see "WLF Questions Ad Division Allegations; “DDMAC Watch” Starts With Strattera" - Pink Sheet, 27 June, 2005., p. 21).

WLF is urging FDA to release guidances on promotion rather than issue policy in ad letters.

In its response to the Survanta letter, DDMAC Watch charges that FDA's "allegations of insufficient risk disclosure" are "untenable."

"Federal law clearly contemplates that FDA will provide notice and a meaningful opportunity for affected parties to comment before articulating regulatory expectations for the first time."

"FDA has issued a draft guidance document on the...brief summary requirement for prescription drug advertisements, and has announced its intention to develop an additional guidance document on fair balance," WLF noted.

"But we have seen nothing suggesting that the agency plans to develop guidance on how manufacturers can present risk information with sufficient prominence and readability to satisfy DDMAC."

WLF also argues that Abbott's mailer is considered labeling and not advertising.

FDA labeling regs "nowhere purport to require disclosure of risk information in promotional labeling, like the mailer, 'with a prominence and readability reasonably comparable' to the prominence and readability with which effectiveness claims are presented."

"Whether or not DDMAC's interpretation of that particular drug advertising regulation is sound, the Division should not advance it in the drug labeling context in an untitled letter."

FDA Ad Division Letter Surge Shows Focus On Prominence Of Risk Information

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