It’s a Cruel Summer – Two New OPDP Untitled Letters

FDA’s Office of Prescription Drug Promotion (OPDP) has issued two new Untitled Letters this summer after 5 months without any letter activity. The letters are vastly different from one another in subject matter, but together they make a cruel summer of OPDP enforcement against industry. [Editorial note – the Gen X’er included that link first – for the arguably more popular reference, read on.]

The first Untitled Letter was issued to kaleo, Inc. on July 17, 2024 for a social media post published by Instagram influencer Brittany Mahomes (who has 2 million Instagram followers) about AUVI-Q (epinephrine injection, USP) that “entirely omit[ed] all risk information” about the drug. Mahomes, spouse to Kansas City Chiefs quarterback, Patrick Mahomes, is the mother of 2 young children with severe food allergies. Presenting only information about the benefits or efficacy of a prescription drug, like AUVI-Q, without any risk information is considered a false or misleading presentation under the Federal Food, Drug and Cosmetic Act (FDCA), and is considered misbranding of the product.

AUVI-Q is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects… biting insects… allergen immunotherapy, foods, drugs, diagnostic testing substances… and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The approved labeling for AUVI-Q includes warnings and precautions regarding emergency treatment, injection-related complications, serious infections at the injection site, allergic reactions associated with sulfite, and disease interactions.

The Instagram post contained both a video portion and text portion, neither of which mentioned or included any risk information. Instead, the post focused solely on the benefits and efficacy of AUVI-Q, with statements otherwise consistent with AUVI-Q’s approved labeling, such as “Auvi-Q is the only epinephrine autoinjector out there for infants and toddlers” and “AUVI-q® (epinephrine injection, USP) is for life-threatening allergic emergencies.”  The FDA acknowledged that although the post included the statement, “For Important Safety Information, visit @auviq_IS[,]” this “does not mitigate the misleading impression created by the omission of risk information,” (emphasis added). FDA’s stated concern from a public health perspective is that the omission of risk information “fails to provide material information about the consequences that may result from the use of Auvi-Q and creates a misleading impression about the drug’s safety.”  In other words, individuals may not be as vigilant about avoiding allergens if they only hear the benefits of AUVI-Q without understanding there may be safety consequences as well.

Honestly, we are pretty shocked that this social media post slipped through the review committee.  Haven’t we all learned that celebrity endorsements for prescription drugs still need to meet traditional promotional requirements? Thank you, Kim, for paving the way here.

Moral of the story – simply referring consumers (or followers) to a drug’s website for safety information is not enough  – even if you are TSwift’s bestie.

August 2024 Untitled Letter to Mirati Therapeutics Inc.

The second Untitled Letter was issued to Mirati Therapeutics Inc. (Mirati), a Bristol Myers Squibb company, on August 1, 2024 for content on a healthcare provider branded website for its product, KRAZATI (adagrasib), which was approved under FDA’s accelerated approval pathway for patients with certain types of non-small cell lung cancer based on objective response rate (ORR) and duration of response (DOR). The FDA’s accelerated approval pathway can allow for earlier approval of drugs intended to treat serious conditions and fill an unmet medical need where approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit and the predicted clinical benefit is subsequently verified in a post-approval confirmatory trial(s). FDA notes in its letter that it received multiple complaints about the website under its Bad Ad Program.

The letter states the website makes false or misleading claims and representations about the benefits and efficacy of KRAZATI, thus misbranding the product. The website makes numerous clinical efficacy claims for the drug, including claims relating to “depth of response,” “disease control rate” (DCR), and rates of “stable disease” (SD), “partial response” (PR), “complete response” (CR), and “progressive disease” (PD) from Mirati’s KRYSTAL-1 study which was the basis for FDA’s accelerated approval of KRAZATI. However, as FDA points out in its letter, KRYSTAL-1 was a multicenter, single-arm, open-label expansion cohort study that evaluated the effect of KRAZATI on ORR and DOR and thus did not establish that the SD observed in the study was attributable to the effect of the drug; such an assessment would need to be based on the results of a randomized controlled trial. FDA noted similar findings for the website’s presentation of DCR, overall survival (OS) and progression free survival (PFS) results since the KRYSTAL-1 study design was not capable of producing interpretable results on these endpoints. The website also included claims from “data on file” that were based on “pooled DOR” information. FDA stated “[p]ooling data poses analytical problems as differences among studies and study populations can affect the validity and interpretability of such pooled analyses,” and, because the FDA could not verify the presented results, requested Mirati provide data to support its claim for FDA’s review. Additionally, Mirati included disclaimers that the data presented on the website were based on descriptive and post-hoc analyses, which FDA stated is not sufficient to mitigate the overall misleading impression created by the inclusion of the data.

The Mirati letter deals with much more nuanced issues than the letter to kaleo. When dealing with a drug that is approved via the accelerated approval pathway, can efficacy data be presented as consistent with the FDA-required labeling (CFL) and be subject to the “scientifically appropriate and statistically sound” (SASS) standard, generally thought to be a lesser substantiation standard than the traditional regulatory requirements of “substantial evidence” and “substantial clinical experience?”  Even in a CFL world, these presentations likely fall short of the SASS standard where the communication “relies on a study that is inadequate to support the representations or suggestions it presents [and] disclosure of the material limitations of that study does not correct the misleading message conveyed by the communication.”

What these bloggers find interesting about this letter (beyond the CFL analysis) is that because KRAZATI was approved under the accelerated approval pathway, Mirati would have been required to submit all promotional materials for the drug thirty (30) days in advance of the material being used. As FDA did not object to the timing of the submission in the letter, it seems that FDA (likely) received a copy of this website for review, FDA did not comment, and Mirati moved forward with publishing – only to receive an Untitled Letter months later.  Years ago, FDA had much more robust communications about promotional materials with sponsors of accelerated approval products. This Draft Guidance, withdrawn in 2015, outlines FDA’s historical intent to review submissions and provide comments in a timely manner, “usually within 15 working days of the day the materials are received by FDA.” While it is likely not reasonable to maintain this expectation given the volume of materials submitted, it begs the question:  if OPDP cannot review materials and/or provide comments within the thirty (30) day window for accelerated approval products, why bother requiring sponsors to submit their materials in advance in the first place? Just some food for thought.