FDA Advertising Enforcers Have Little Patience For "Well Tolerated" Drug Claims

Term is too vague for promotional use, regulators say, but it is not always cited as a violation, even when other aspects of the advertisement are.

Sponsors looking for a shorthand summation of a product's adverse events should avoid the phrase "well tolerated," FDA regulators suggest. But while it needs to be used judiciously, the agency does not appear to have an absolute prohibition on the phrase.

The phrase "well tolerated" is a "vague term that means different things to different people," Ele Ibarra-Pratt, chief of CBER's Advertising and Promotional Labeling Branch, said at DIA's annual meeting.

As an example of why the term is problematic, Ibarra-Pratt cited professional promotions used for ViroPharma's hereditary angioedema product Cinryze shortly after the human plasma-derived C1 esterase inhibitor was approved.

The Cinryze letter which FDA sent to the firm in 2009 states "the safety claim presented in the bag drop that Cinryze '[i]s a well tolerated treatment for routine prophylaxis against [hereditary angioedema] attacks' ... is misleading because there are serious risks associated with Cinryze that are inconsistent with the claim 'well tolerated.' According to the PI under Warnings and Precautions, Cinryze prophylaxis may result in hypersensitivity reactions, thrombotic events, or may contain infectious agents" (Also see "ViroPharma Looks To Cinryze To Drive Sales As Vancocin Faces Likely Generic Competition" - Pink Sheet, 3 Aug, 2009.).

Advertisements should "just present the adverse events factually," Ibarra-Pratt said. "To say that a product is well tolerated really doesn't give them information in terms of what to expect in regard to their risks."

FDA may be more concerned about the Cinryze promotions because of the knotty competitive terrain that various orphan products are carving out of the hereditary angioedema market (Also see "Dyax Kalbitor Is Third To Market For HAE, But First For All Acute Attacks" - Pink Sheet, 7 Dec, 2009.).

Can Market Longevity Make Something Well Tolerated?

But the timing of Cinryze's claim may be as much of a problem for FDA as the market space that it's made in. "For a product that's recently approved, you really don't have a good idea of the risk characterization," Ibarra-Pratt said.

One piece of evidence to support that theory is a notice of violation that FDA sent in the beginning of the year about Pfizer/Eisai's Alzheimer's treatment Aricept (donepezil), which has been marketed since 1996.

FDA's Aricept letter listed a number of violations (Also see "Healthiness Of Actors In DTC Spots Returns As Issue As FDA Cites Aricept Ads" - Pink Sheet, 23 Feb, 2010.); the use of the phrase "well tolerated" was not among them, even though the TV ads stated, "Aricept is well tolerated but not for everyone."

The letter, like all advertising citation correspondence, includes the qualification that "the violations discussed in this letter do not necessarily constitute an exhaustive list," but the omission of the "well tolerated" claim seems noteworthy, especially since the agency has been listing more violations per letter recently (Also see "FDA's Advertising Letters Continue To Grow, Both In Volume And Depth" - Pink Sheet, 9 Aug, 2010.).

Asked about the apparent difference in citation emphasis, FDA stated that CDER's Division of Drug Marketing Advertising and Communications and CBER's Advertising Promotional Labeling Branch "are consistent with our approach to the use of this phrase in promotion. DDMAC reviews each promotional piece in its entirety to make the assessment whether the piece provides an adequate presentation of risk information for the prescription drug."

DDMAC "cannot make an absolute statement about the use of well tolerated in promotion as we would need to see the specific ad," the agency noted. "However, we have generally objected to the phrase as it has only served to minimize the presentation of risk information in promotion."

Given that, it's impossible to say whether the difference in the citations is a function of a the nature of the products, the length of their market experience, the presence of a caveat, or just sheer exhaustion that made the DDMAC reviewer stop listing violations before getting to "well tolerated."

Regardless, cautious sponsors would be wise to avoid the phrase entirely. But that approach may not be for everyone.

[Editor's note: "The Pink Sheet" is sponsoring a webinar on how to navigate changing trends in promotion and advertising. The Oct. 21 event will feature former FDA Associate Chief Counsel Arnold Friede, who will discuss the agency's current and upcoming enforcement priorities. To register, call 800-332-2181, email [email protected], or visit http://pages.elsevierbi.net/AC090710LP.]

-M. Nielsen Hobbs ([email protected])