The Tuesday warning letter noted that the manufacturer had received 171 complaints about products that failed to activate between 2014 and 2017, but did not disassemble “the vast majority” of the units as part of its investigation. The device is designed to inject epinephrine to halt dangerous allergic reactions.
“In fact, your own data show that you received hundreds of complaints that your EpiPen products failed to operate during life-threatening emergencies, including some situations in which patients subsequently died,” the FDA letter said. The product flaws included the device not functioning properly when needed and the injector not having drug left when needed.
“Many of the complaints related to product activation failures, including failures to activate when the user followed the operating instructions, as well as failures for products that spontaneously dispensed epinephrine drug prior to use so that the drug was no longer available when the user attempted to activate the product,” the letter said.
The warning letter was sent to the company following an FDA inspection of operations at the Missouri-based plant.
Annual prescriptions for EpiPen products have more than doubled over the last decade to 3.6 million, according to IMS Health data.
Meridian Medical Technologies recalled certain lots of the auto-injectors in March, shortly after the inspection concluded.
FDA spokeswoman Theresa Eisenman said in a statement Thursday that the agency “was not aware of defective EpiPens currently on the market.”
Pfizer said in a statement that the company has “no information to indicate that there was any causal connection between these product complaints and any patient deaths.”
The company also offered assurances about the effectiveness of the devices on the market.
The company is “very confident in the safety and efficacy of EpiPen products being produced” at the facility where the problems were found in February and March, the statement said.
Despite those reassurances, however, organizations focused on drug safety said the FDA letter should stir concern.
“I think it would be an understatement to say that the results are disturbing,” said Michael Carome, director of the health research group at Public Citizen, a watchdog focused in part on drug safety. “The findings of the letter reflect a reckless disregard for public safety and patient health.”
He said that patients should check whether their EpiPen was included in the previous recall. He noted that even if the product wasn't recalled, concerned patients could consult with their health-care providers if they are worried.
During the course of the inspection, the FDA found that Meridian Medical Technologies had discovered that a critical component of the auto-injector product failed last year in a sample unit.
The company rejected two lots of that component and asked the manufacturer of the part to do an investigation, but continued to make the drug — without “linking the known component failure with numerous complaints you received regarding 'failure to activate,' 'difficult to activate,' or other product activation failures,” the Tuesday letter said.
Diana Zuckerman, president of the National Center for Health Research, said that the strongly worded letter was unusually blunt and straightforward, and will raise concerns for parents and patients who depend on the EpiPen.
“It may well be a very small number, relatively speaking, of EpiPens that are likely to be problematic, and it may be that those have been recalled. But the parents and patients don't know that,” Zuckerman said. “This is a product where you don't know, until you use it, whether it works or not. I think it's safe to say no patient — and no parent — wants to find out the hard way that the product that they have isn't effective.”
Pfizer said in a statement that the complaints were not unusual, “especially when the product is frequently administered by non-medically trained individuals.”
EpiPen is stocked in many schools and is often used by parents, children or others who may not be medical professionals.
The FDA, however, noted that some problems had previously been identified at the facility as early as 2014.
“These repeated failures demonstrate that your facility's oversight and control over the manufacture of these products is inadequate,” the letter said.
“We note that Pfizer’s recall several months ago of certain lots of EpiPen Auto-Injector was taken as a proactive and precautionary measure with FDA in relation to these issues,” Mylan spokeswoman Nina Devlin said in an email.
“Mylan has an unwavering commitment to quality and patient safety and we are confident in the safety and efficacy of EpiPen products being produced at the site. Further, we do not currently anticipate any supply issues as a result of the warning letter.”
The letter requires the company to provide a comprehensive review of investigations and a plan for patient safety and assessing quality risks for products still in distribution.