When a reference listed drug (RLD) product is discontinued from marketing, or if the RLD’s NDA application is officially withdrawn, we all know that the FDA must make a determination that the specific RLD was not discontinued from marketing or withdrawn for safety or efficacy reasons before it can approve an ANDA based on the RLD. The FDA makes this determination on its own initiative or based on a petition submitted specifically asking the Agency to make such a determination. In the instance we are about to discuss, Medley Pharmaceuticals Ltd. submitted a citizen petition dated June 6, 2022 (Docket No. FDA‑2022‑P‑1013) asking for the FDA to make the determination.
It is a common practice for firms to discontinue or withdrawal applications as many RLD sponsors will no longer choose to market a product if the market is no longer viable for that product. For instance, a common scenario is that the market for the product has gone 90% generic and there is no longer a business model that supports the continued commercial marketing of the RLD. There are myriad other reasons that firms discontinue or withdrawal products (especially if newer, more effective treatments for the same use are approved). Even though this is a common occurrence and a routine practice, this one FDA S&E determination has a bit of a different look than usual.
On the prepublication page of the Federal Register Notice today (here), the FDA issued its determination to the petition Medley had submitted asking that it determine that the RLD Chantix (varenicline tartrate) tablets, 0.5 mg and 1 mg, were not discontinued from marketing for safety or efficacy reasons. Why is this different than most findings? Well, in June 2021, the innovator “suspended distribution of the anti‑smoking treatment Chantix after heightened levels of the carcinogen N‑nitrosodimethylamine (NDMA) were found in some lots of the pills” (here). The FDA further discussed the issue here. But the unusual thing about the FR notice and the FDA’s determination is that the FDA made the following explanation for its decision:
“PF Prism CV [the current registered holder of the NDA] has voluntarily discontinued marketing of CHANTIX (varenicline tartrate) tablets, 0.5 mg and 1 mg. The levels of the N‑nitroso‑varenicline (NNV) impurity in Chantix exceeded the FDA’s acceptable intake limit. The FDA’s current understanding is that the NNV impurity can be controlled within the acceptable intake limit by sponsors of varenicline products within the context of their particular applications.”)
The FDA further stated, “After considering the citizen petition and reviewing Agency records and based on the information we have at this time, the FDA has determined under § 314.161 that CHANTIX (varenicline tartrate) tablets, 0.5 mg and 1 mg, has not been withdrawn for reasons of safety or effectiveness to the extent that the drug can be manufactured or formulated in a manner that satisfies any applicable acceptable intake limit for nitrosamine impurities.”
The nitrosamine impurity issue is certainly nothing new, and the concern has expanded to numerous other products. The FDA has slowed to a near halt its responses to ANDA applicants regarding pending applications if there is a possible nitrosamine issue with the proposed product. In this instance, the FDA shows through its statements in the FR notice that there is a way forward, as evidenced by approvals of other varenicline tartrate tablet products. While the impact of the FDA’s determination in this specific instance may not be a factor in resolving other product’s nitrosamine issues, it is possible that this could be a signal that resolution may be around the corner. Let’s hope the corner is not miles away!
