On Wednesday, the US Food and Drug Administration (FDA) released the text of a new Untitled Letter sent to Johnson & Johnson - the second sent in as many months to the same company - regarding promotional material for its blockbuster anticoagulant Xarelto (rivaroxaban), alleging that the company failed to present the risks of the drug in a fair and balanced manner.
Untitled Letters are less serious than the more widely-known Warning Letters, which indicate that failure to take action will lead to regulators taking enforcement action. Instead, the Untitled Letter calls for a correction (typically in an advertisement or other promotional material), but almost always stops short of indicating that enforcement action will be forthcoming if changes aren't made.
J&J's subsidiary Janssen received a similar Untitled Letter earlier in May 2013 regarding promotional materials hosted on the company's website for its anticancer drug Doxil (doxorubicin).
That letter references claims made against the drug's label for ovarian cancer, a condition for which it has received FDA approval. The problem, regulators said, it that the marketing materials for the drug contain an entire section claiming an association between levels of a biomarker (the CA-125 biomarker) and clinical responses to Doxil therapy.
Such an association had "not been demonstrated by substantial evidence or substantial clinical experience," regulators wrote. Janssen's materials reference several retrospective evaluations of primary data that did not meet federal standards for evidence.
FDA's Office of Prescription Drug Promotion (OPDP) called for Janssen to immediately cease the dissemination of the marketing claims. As of 7 June 2013, that webpage had been removed in its entirety, though a link to a non-existent webpage on the topic still exists here.
Now J&J's regulatory staff at Janssen are getting their second Untitled Letter in as many months, with FDA releasing one for Xarelto on 19 June 2013 that covers another aspect of allegedly deficient promotional practices: fair balance.
The letter refers to a direct-to-consumer print advertisement shown in the January/February issue of WebMD magazine. Regulators contend that the print ad minimizes Xarelto's risks and makes a "misleading claim," rendering the ad itself "false or misleading."
The problem is a familiar one as far as Untitled Letters go. FDA said the company failed to exhibit its risk and benefit information using the principles of fair balance. Under FDA regulations, companies are required to give equal treatment in all respects to the risks and benefits of a drug. This means that if the benefits are shown in size-18 green, comic-sans font, your risks must be as well.
In Janssen's case, FDA points to numerous benefits of the drug, which areaccentuated using bold text. For example:
"…With XARELTO, there's no routine blood monitoring-so you have more time for yourself. There are no dietary restrictions, so you're free to enjoy the healthy foods you love. And there are no dosage adjustments, which means you can manage your risk with just one pill a day, taken with your evening meal. Learn how XARELTO can help simplify your AFib-related stroke risk treatment…."
The risks section, however, failed to include this same selective bold-text strategy, making the overall presentation "misleading." The benefit information is also contained on a page with graphics, a photo and colorful text. The problem, noted FDA, was that the same page contained no risk information whatsoever, and that all risk information was contained within subsequent pages. [See the advertisement here]
The company was further chided by FDA for including the statement: "And there are no dosage adjustments…"
Regulators said this claim "misleadingly suggests that dosage adjustments are not necessary with Xarelto," even as some patients - those with renal impairment, for example - may need to lower the dose in response to increasing liver damage or toxicity.
FDA said the company has until 20 June 2013 to reply to the agency regarding its intended actions, which could include corrective advertisements to be run in WebMD magazine.