A new untitled letter sent by the US Food and Drug Administration (FDA) to Teva Neuroscience has found that an article detailer intended to help the company promote its Clozapine tablets is misleading, explaining that it makes unsubstantiated superiority claims while simultaneously omitting facts and minimizing associated risks.
Clozapine in an antipsychotic approved for the treatment of the symptoms of schizophrenia, but comes with some fairly extensive warnings. The product can, for example, cause serious blood conditions (including agranulocytosis), and requires lab testing prior to commencing treatment, during treatment and for four weeks after stopping treatment. Other serious potential adverse events include seizures, myocarditis, fainting, and death in older adults.
And therein lies the problem for Teva. Its article detailer is relatively short as far as promotional items go--just four pages in which regulators expect it to cover in full the product's relevant details in a truthful and accurate manner.
But perhaps four pages were not enough to go over the considerable number of warnings required of Clozapine. FDA's Untitled Letter, an expression of the agency's sense that a particular action or advertisement does not meet its standards, notes that the promotional materials omit "material facts" and minimize risk.
"Specifically, the article detailer fails to disclose that clozapine is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of the drug," FDA explained. "Furthermore, the article detailer also omits material information from a number of risks associated with clozapine, including QT interval prolongation, hyperglycemia and diabetes mellitus, NMS, TD, cardiomyopathy, fever, pulmonary embolism, hepatitis, anticholinergic toxicity, and interference with cognitive and motor performance."
Failure to include relevant warnings and contraindications would render Clozapine misbranded were the promotional materials to be disseminated, FDA said.
Fair Balance in the Eye of the Beholder
FDA's Untitled Letter also shows the agency's continuing eye for aesthetics, and particularly how they relate to risk. Take a look at the points Teva wants to highlight, FDA observed. Those spaces are marked by prominent text, colorful photos and graphics, and lots of white space that serve to accentuate the points made there. In contrast, the risk information is crammed together, has no headers to distinguish sections, is in black and white, and is otherwise difficult to read.
"The overall effect of this presentation undermines the communication of important risk information, minimizes the risks associated with clozapine, and misleadingly suggests that clozapine is safer than has been demonstrated," FDA wrote.
Fair balance, in other words, applies to graphical presentation of both benefits and risks.
Elsewhere in the promotional material, Teva's language creates misleading claims by virtue of its presentation of claims, FDA alleged. For example, regulators said Teva's materials state or otherwise imply that Clozapine is superior to other studied drugs like olanzapine, risperidone and haloperidol based on its "purported improvement in the excitement symptom cluster."
"These claims, however, are not supported by substantial evidence or substantial clinical experience," FDA wrote. That would require a head-to-head clinical trial to substantiate, it continued, which Teva had not conducted. Instead, the company had only looked at retrospective data to support its claim, which FDA deemed insufficient.
Similar troubles were raised throughout the piece, with FDA taking issue with several of Teva's claims that it said promoted the idea that Clozapine was superior to its competitors based on several "symptom clusters," which-like previously-had not been adequately proven through vigorous testing.
FDA said it was requesting that Teva "immediately cease and desist the dissemination" of the article detailer and submit a written response by 22 April 2013.
In a response to Regulatory Focus shortly after this article's publication, Denise Bradley, vice president of corporate communications for Teva Pharmaceuticals' Americas division, said use of the promotional piece had already been discontinued as of October 2012.
"We want to emphasize that Teva takes the issuance of
the FDA letter very seriously," Bradley said. She added that the company is now reviewing other promotional materials for Clozapine tablets to "ensure that all such material addresses the issues recently raised by FDA."
"Our commitment is to work cooperatively with FDA in resolving all the issues outlined in the letter as quickly as possible," she added.
FDA's Untitled Letter to Teva
The Promotional Materials