Sponsors looking for a shorthand summation of a product’s adverse events should avoid the phrase “well tolerated,” Food and Drug Administration 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 the Advertising and Promotional Labeling Branch at the FDA’s Center for Biologics Evaluation and Research, said at annual meeting of the Drug Information Association.
As an example of why the term is problematic, Ms. Ibarra-Pratt cited professional promotions that were used for ViroPharma’s hereditary angioedema product Cinryze shortly after the human plasma–derived C1 esterase inhibitor was approved.
The Cinryze letter, which the FDA sent to the firm in 2009, states that “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 package insert under Warnings and Precautions, Cinryze prophylaxis may result in hypersensitivity reactions, thrombotic events, or may contain infectious agents.”
Advertisements should “just present the adverse events factually,” Ms. 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.”
The 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.
But the timing of Cinryze’s claim may be as much of a problem for the FDA as is 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,” Ms. Ibarra-Pratt said.
One piece of evidence to support that theory is a notice of violation that the FDA sent in the beginning of the year about Pfizer Inc./Eisai Inc.’s Alzheimer’s disease treatment, Aricept (donepezil), which has been marketed since 1996.
The FDA’s Aricept letter listed a number of violations; 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.
Asked about the apparent difference in citation emphasis, the FDA stated that the Division of Drug Marketing Advertising and Communications (DDMAC) at its Center for Drug Evaluation and Research 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.”