“Tongue and Done” – Just . . . No.

Yesterday’s FDA Warning Letter, Press Release, and accompanying public relations campaign related to AcelRx’s promotional material for Dsuvia (sufentanil) are remarkable for exactly the reasons FDA intended them to be remarkable: these actions all signal to industry that despite anemic levels of FDA enforcement related to Rx drug promotion, when it comes to opioids, FDA is paying attention and ready to take action.  In addition to the Press Release, FDA’ers tweeted about the Warning Letter, including the following tweet (of three) by Dr. Janet Woodcock:  “False or misleading promotional communications will not be tolerated.  The agency is focused on reducing harm by decreasing exposure to opioids, while still enabling appropriate access for patients with medical need.”  FDA, in what appears to be a new approach, has already updated the OPDP 2021 Warning Letter website to include CDER’s press release, in addition to posting the Warning Letter and underlying promotional material.

It should come as no surprise that the media blitz and OPDP’s first letter of 2021 relate to opioid promotion.  Before retirement, Tom Abrams, former Director of OPDP, regularly stressed OPDP’s enforcement priorities and, included among them, was promotion for drugs that have serious risks.  Just last month, Acting Director of OPDP, Katie Gray, provided an interview where she explicitly stated, in response to a question on which promotional materials were priorities, that OPDP would focus “on promotional materials for high-risk drugs, such as opioids. We want to make sure the promotional materials accurately convey the risks associated with these drugs, convey responsible use of opioids, and do not inadvertently contribute to the opioid epidemic.”  The last time an OPDP Warning Letter was accompanied by an FDA Press Release was back in December 2019, relating to a treatment intended to prevent relapse to opioid dependence.

Back to the Dsuvia Warning Letter – there are a number of key takeaways for industry.  It is apparent that the letter was triggered, in this particular instance, by the use of the pithy tagline, “Tongue and Done” that emphasizes simplicity in administration.  Given FDA’s history with this product, and that administration was one of the issues cited as part of a complete response letter – it is not surprising that this type of promotion was likely to garner the agency’s attention.  (As an aside, knowing how much former FDA Commissioner Scott Gottlieb enjoys our song references, these bloggers spent an inordinate amount of time looking for clever references to music videos that would relate to this tagline.  Not surprisingly, after watching a few too many Kiss videos – featuring Gene Simmons – we abandoned the exercise.  Hence the name of this blogpost.)

Putting the tagline trigger aside, FDA also called out the company’s failure to include information on the maximum dosing within a 24 hour period, despite otherwise calling out the ability to re-dose Dsuvia within an hour.    This is a practical concern, not simply for opioids, as there is a safety suggestion implied with re-dosing statements.

Industry should pay close attention to other FDA comments in the Warning Letter with regard to the presentation of risk and benefit information.  The allegations relating to how the company presented the full indication and limitations for the product, as well as Important Safety Information, should be scrutinized as the techniques employed are often used by others.   From the Warning Letter:

“the full indication with the limitations of use are intermingled with risk information in a paragraph format in a much smaller font size and a plain white background, and are accessible only if viewers “scroll” down the banner. Therefore, this does not mitigate the misleading impression.”

These bloggers find it shocking that FDA would object to presenting the full indication, particularly one that is longer and includes limitations of use, with safety information and that FDA would particularly call out that it was against a plain white background.  One of the core tenets of any ad is ensuring that the full indication and safety information are legible – and FDA has a long history of calling out instances when safety information was minimized because it was presented against a colored background.   In fact, this very issue was addressed in FDA’s Draft Guidance on Presenting Risk Information, dating back to 2009, in a section on Contrast:

“Contrast between text and background should not highlight the benefit information more than the risk information. Example 18: If benefit information in a piece is presented in white letters on a black background, risk information should be presented with similar contrast. If the piece presents risk information in a way that would make it difficult to discern (e.g., using white letters on a light gray  background or gray letters on a black background), the presentation may be considered false or  misleading. Even if the background is a color designed to attract attention, the contrast influences the prominence of the words once attention has been gained. In fact, printing words in some attention-grabbing colors (e.g., red) may make the words difficult to read.  Similarly, the placement of risk information over pictures or other visual elements with multiple colors can cause this information or portions of this information to lack prominence and be difficult to read. Furthermore, a print piece that superimposes risk information over a visual image could compromise the accuracy of the piece as a whole by drawing attention away from the risk information.

While it may be fair to point out in the Warning Letter that the safety information was only visible after scrolling within the digital banner ad, it is absurd to think that by providing safety information in black font against a plain white background that the company has somehow minimized risk.

In looking at the banner ad, it looks like the company employed a “20%” approach to the inclusion of safety information.  This approach includes a scroll bar for the user to obtain additional safety information, but devotes 20% of the visual field to safety information as balance.  In this Dsuvia banner ad, that amount of space was not enough to present the full, all caps title from the Boxed Warning.  Although somewhat consistent with how industry treats digital banner ads (although arguable that 20% of an ad would be sufficient balance for an opioid with significant safety concerns and a REMS), companies should be mindful, not only of spacing, but of the substantive safety information in view.

FDA also cited both the digital banner as well as a print flyer for failing to present information relating to the Boxed Warning, Contraindications, Warnings and Precautions, and Adverse Reactions “with a prominence and readability reasonably comparable with the presentation of information relating to the benefits” of the drug.  FDA cites “typography, layout, contrast, headlines, paragraphing, white space, and other techniques” as affecting readability and emphasis. FDA also highlights that “risk information is relegated farther down in paragraph format with less prominence.”

The key takeaways here are not new:  minimizing safety, particularly for a drug with serious risks, will likely trigger FDA enforcement (no matter how sleepy OPDP may seem).  The issues cited by OPDP are those clearly outlined in its 2009 Draft Guidance – which was not exactly revolutionary at the time it was originally published and simply summarized points made in prior DDMAC Warning and Untitled Letters.  Many of the techniques utilized by AcelRx, and objected to by OPDP, are those employed across industry.  One has to question whether lack of OPDP enforcement has led, to a certain degree, to industry falling back into old habits –  with safety information “below the line,” at the end of a piece, in small font with running text.  While it may have been the nature of this promotion in the midst of the opioid crisis that stirred FDA to action, the issues OPDP called out are nevertheless ones even non-opioid manufacturers might want to reconsider in light of this letter.