Opioid Warning Letter To Cipher Likely Easy Call For US FDA
Executive Summary
Murky enforcement environment has probably contributed to FDA's record-low number of letters, but detailing material for ConZip failed to include risk information and important limitations of use for the tramadol extended-release product.
The US FDA Office of Prescription Drug Promotion's (OPDP) most recent enforcement letter – targeting marketing materials for a long-acting opioid that lacked any risk information – was probably an easy call for an agency whose leader has vowed it needs to be more forceful in responding to the opioid epidemic.
In an Aug. 24 warning letter, OPDP cited Cipher Pharmaceuticals Inc. for failing to include any risk information in a professional detailing aid for ConZip (tramadol extended-release). The promotional material also failed to include important limitations of use for the drug, FDA said.
As a result, ConZip is misbranded under the Food, Drug and Cosmetic Act, FDA's letter states. It requests Cipher immediately cease misbranding ConZip and develop a corrective messaging plan.
The ConZip promotion "fails to provide material information about the consequences that may result from the use of the drug and creates a misleading impression about the drug's safety, a concern heightened by the serious public health impacts of opioid addiction, abuse and misuse." – OPDP
FDA Commissioner Scott Gottlieb has vowed that the agency will take a more activist role under his watch in fighting the opioid epidemic. Since taking the agency's helm in May, he has announced a host of opioid-related measures, including the formation of a new steering committee to examine key regulatory and policy issues and the withdrawal of Endo Pharmaceuticals Inc.'s Opana ER (oxymorphone extended-release). (Also see "Opioid Policy At US FDA To Become 'More Forceful,' Gottlieb Says" - Pink Sheet, 23 May, 2017.) (Also see "Opana ER Should Come Off The US Market, FDA Tells Endo" - Pink Sheet, 8 Jun, 2017.)
Whether OPDP will play a more prominent role in the agency's efforts to tackle opioid abuse remains to be seen. Nevertheless, the warning letter to Cipher provides some very clear guidelines for opioid product manufacturers on what not to do when it comes to crafting marketing materials for their products.
Creating A Misleading Impression About Safety
Cipher is the new drug application (NDA) holder for ConZip, which was first approved in 2010. Vertical Pharmaceuticals LLC, which submitted the detailing aid for FDA review, holds the exclusive US license from Cipher to market, sell and distribute ConZip.
ConZip carries the standard indication for long-acting opioids: management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Labeling also includes the classwide limitation of use that such products should be reserved for patients in whom alternative treatments (such as non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated or otherwise inadequate to provide sufficient pain management.
Like other long-acting opioids, ConZip carries a boxed warning on addiction, abuse and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; and drug interactions, including when used with benzodiazepenes.
FDA notes the ConZip detailing aid makes various representations about efficacy, such as "All Day Pain Relief."
"However, the detail aid fails to communicate any risk information about the product," the letter states. "By omitting the risks associated with ConZip, including serious and potentially fatal risks, the detail aid fails to provide material information about the consequences that may result from the use of the drug and creates a misleading impression about the drug's safety, a concern heightened by the serious public health impacts of opioid addiction, abuse and misuse."
Omitting Material Facts
The sales aid also is misleading because it failed to provide material information about ConZip's indication, including important limitations of use, FDA said.
Specifically, the promotional piece omits language from the drug's indication that states it should only be used to mage severe pain "for which alternative treatment options are inadequate."
"OPDP requests that Cipher immediately cease misbranding ConZip and/or cease introducing the misbranded drug into interstate commerce," the letter states.
FDA requests a written response from Cipher by Sept. 8, 2017 stating whether it intends to comply with the agency's request, listing all promotional materials for ConZip that contain the violative representations cited in the warning letter, and explaining the company's plan for either discontinuing use of such materials or ceasing distribution of the drug.
Cipher said it is actively working with commercial partner Vertical to respond to FDA's warning letter by Sept. 8.
"Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials."
The corrective pieces should include a description of the violative promotional pieces and activity, a summary of the violative messages and information to correct each one, and be free of promotional claims and presentations, FDA said. "To the extent possible, corrective messaging should be distributed using the same media, and generally for the same duration of time and with the same frequency that the violative promotional material was disseminated," the letter states.
In a statement to the Pink Sheet, Cipher said "it takes all compliance matters seriously and is actively working with Vertical to respond to the FDA warning letter" by Sept. 8. "Revenues from ConZip represent approximately 2% of Cipher’s revenues in 2017," Cipher said.
One Opioid-Related Letter In 2016
The ConZip letter is only the second enforcement letter issued by OPDP this year.
In a May untitled letter, OPDP cited Orexigen Therapeutics Inc. for failing to include important risk information in a TV ad for the obesity drug Contrave (naltrexone/bupropion) and for placing the important risk information solely in the visual portion of the commercial. (Also see "Contrave TV Ad's Slimmed Down Adverse Events Draw FDA Rebuke" - Pink Sheet, 24 May, 2017.)
In 2016, OPDP issued a total of 11 enforcement letters, one of which targeted a long-acting opioid. In a September 2016 untitled letter, OPDP took issue with websites for Durect Corp. and Pain Therapeutics Inc.'s Remoxy (oxycodone extended-release), an investigational product formulated with properties intended to deter abuse. (Also see "FDA’s Promotional Enforcement Still Playing It Safe" - Pink Sheet, 14 Nov, 2016.) The sites suggested the unapproved drug is safe and effective for purposes for which it is under investigation, FDA said.
Several weeks after the untitled letter, FDA handed the Remoxy sponsors a complete response letter in which the agency requested new studies and data to support deterrence claims for several routes of abuse. (Also see "Remoxy's Woes Stoke Criticism Of FDA's Review Of Abuse-Deterrent Opioids" - Pink Sheet, 30 Sep, 2016.)