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Regulatory Focus™ > News Articles > Untitled Letter Cites BMS for Alleged Misbranding

Untitled Letter Cites BMS for Alleged Misbranding

Posted 18 July 2012

Pharmaceutical manufacturer Britsol-Myers Squibb was the recipient of an Untitled Letter from the US Food and Drug Administration's (FDA) Office of Prescription Drug Promotion (OPDP) regarding marketing materials for its drug Ixempra (icabepilone).

In the Untitled Letter, FDA calls a sales aid for Ixempra, submitted to the agency for review by BMS, as misleading due to "unsubstantiated efficacy claims" and an implied indication broader than the one approved by the agency.


Ixempra was approved by FDA in 2007 for the treatment of advanced breast cancer in patients with metastatic or locally advanced breast cancer who have not responded to anthracycline, a taxane or capecitabine. Despite the approval, FDA acknowledged the product's "significant side effects, including bone marrow suppression, muscle pain, vomiting, cardiovascular events and peripheral neuropathy. As a result of a potentially deadly contraindication with capecitabine and bilirubin, the product also received a black box warning.

BMS would later submit an Form FDA 2253 to the agency for review of a sales aid of Ixempra. The 38-page booklet is primarily data-driven, with several pages at the end presenting "hypothetical patient profiles" for several women with breast cancer who might stand to benefit from the drug.

Untitled Letter Alleges Misbranding

FDA's letter goes on to take issue with BMS's sales piece on several points.

"The sales aid presents numerous claims that overstate the efficacy of Ixempra," writes FDA. "Specifically, pages five and 11 of the sales aid, which discuss the pivotal studies for Ixempra's monotherapy and combination therapy indications, respectively, make claims regarding stable disease, stable disease ≥6 months, and progressive disease."

"These efficacy claims are misleading as they are not supported by substantial evidence or substantial clinical experience," FDA explained. The studies actually looked at different things-progression-free survival and overall response rate-but neither looked at the stable disease, stable disease at more than 6 months or the progressive disease and were "not pre-specific endpoints in the pivotal studies for Ixempra's" indications.

"Therefore, the pivotal studies do not provide substantial evidence to support these efficacy claims," wrote FDA.

Even if the pivotal trial did prove such a thing, FDA said it "does not consider stable disease to be a valid endpoint for the measurement of response in these patients because it reflect, in part, the natural history of the disease rather than any effect of the drug."

FDA also took issue with a similar "collection of retrospective subgroup analyses performed using pooled sets of clinical data collected from multiple trials with differing clinical endpoints." The agency said these studies "do not constitute substantial evidence to support efficacy claims," and are "misleading."

A Broadened Indication

BMS's sales ad tagline, "What do you do after the taxane fails?" was cited by FDA as evidence of the company seeking to broaden the indication of the product. By excluding capecitabine from the tagline, the ad by "suggesting that prior therapy with capecitabine is optional for all of the indicated uses, when this is not the case."

While the agency acknowledged that the drug's "full indication is presented at the bottom of the cover of the sales aid," which contains the tagline, it "does not mitigate the misleading impression that Ixempra may be given as monotherapy without first having failed treatment with capecitabine.

FDA called on the company to cease the dissemination of the sales aid immediately and submit a response to FDA. In a statement to Regulatory Focus, BMS said it is "committed to working with the FDA's Office of prescription Drug Promotion to ensure that the issues raised in the Untitled Letter for Ixempra are fully resolved."

However, BMS spokeswoman Sarah Koenig also said the company believes the "claims in question are accurate and consistent with our obligations under the law," and that the company "operates its business with high standards of business integrity and ethics."

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