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Hundreds of EpiPen users complained about problems with the lifesaving device. It still took 3 years and a top regulator stepping in before serious change — with potentially deadly outcomes

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Hundreds of EpiPen users complained about problems with the lifesaving device. It still took 3 years and a top regulator stepping in before serious change — with potentially deadly outcomes

EpiPens weren’t working.

Complaints about the devices were piling up with the product’s manufacturer, a unit of the drug giant Pfizer called Meridian Medical Technologies, in 2013 and 2014. Patients said their EpiPens were hard to activate or activated before they could use them, arrived leaking, or came with bent needles or discolored solution.

Drug inspectors from the US Food and Drug Administration in 2014 warned of shortcomings with the company’s process for investigating patient complaints. Despite the warnings, Meridian didn’t make significant changes to its complaint-investigation process until about three years later, after a major voluntary recall of EpiPens.

Patients with severe allergies rely on the devices to inject a life-saving dose of epinephrine and halt allergic reactions. Food allergies, which affect about 5% of children and 4% of adults in the US, are a common reason to carry an EpiPen.

Meridian failed to thoroughly investigate product failures or take appropriate corrective action, the FDA told the company in a September 2017 warning letter. New processes put in place as a result of that warning letter affected manufacturing capacity, Pfizer has acknowledged, resulting in an ongoing shortage of the lifesaving devices that’s continued for almost a year.

Business Insider is the first to report on the FDA’s warnings to the company that date to 2014, the subsequent action from Meridian, and critical details of how Meridian handled the complaints that would lead to a large voluntary recall. This article is based on hundreds of pages of documents obtained in a public-records request.

“You failed to thoroughly investigate multiple serious component and product failures for your EpiPen products, including failures associated with patient deaths and severe illness,” the FDA wrote to Pfizer’s Meridian unit in September 2017, in a rebuke that the regulator released publicly.

“You also failed to expand the scope of your investigations into these serious and life-threatening failures or take appropriate corrective actions, until FDA’s inspection,” the FDA wrote.

Food allergies, which affect about 5% of children in the US, are a common reason to carry an allergic-reaction treatment like an EpiPen.
Getty

Meridian launched a voluntary recall of EpiPens in early 2017 and, in response to FDA warnings, began an effort to overhaul its manufacturing process.

Pfizer said in a statement to Business Insider that the company is “very confident in the safety and efficacy of EpiPen products being produced at the site.”

“Pfizer assessed the FDA’s observations, and submitted a comprehensive response, which included a detailed corrective and preventive action plan,” the company said. “Since the inspection in 2017, the Meridian manufacturing site has been diligently implementing all commitments made to the FDA.”

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‘A matter of public safety’

The EpiPen is an important, even iconic product. It was brought to market decades ago by Meridian, then called Survival Technology. Meridian licensed out the device’s marketing and distribution rights to a Merck subsidiary, and later Mylan. Pfizer acquired Meridian in 2011, according to an expansive history published in the Cornell Law Review. For the more than 25 years that EpiPen has been sold in the US, it has been the top-prescribed device of its kind, according to Mylan.

But the allergic-reaction treatment became a poster child for corporate greed in recent years after Mylan hiked its price more than 500%, to more than $600 for two devices. Mylan was raising the EpiPen’s price even as concerning complaints about the product were on the rise. The complaints were typically routed through Mylan first, according to the documents reviewed by Business Insider. Mylan later introduced a generic EpiPen at around half the price.

Mylan did not return Business Insider’s requests for comment.

The price of the EpiPen, a lifesaving allergic-reaction treatment, went up more than 500% between 2007 and 2016, which sparked controversy. After the outcry, the seller, Mylan, introduced a cheaper generic EpiPen at around half the price.
Samantha Lee / BI Graphics

The EpiPen is a relatively minor product for Pfizer. Its $290 million in sales in 2017, for example, was dwarfed by bestsellers such as the $4.5 billion pain and seizure medication Lyrica. But in recent years, troubled factories have been a headache for the drugmaker, with FDA inspectors repeatedly citing violations, for instance, at a Kansas plant of one of its subsidiaries, Hospira.

Pfizer told Business Insider in a statement that it is working to address those issues, adding: “We stand behind the products manufactured there and are very confident in their safety and efficacy.”

The problems at Pfizer’s manufacturing facilities represent a wider problem for the US health system. Drug shortages have declined from peak levels, but last year there were many new shortages that seriously affected patients and doctors, including for the EpiPen, Douglas Throckmorton, the deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, has said.

It’s common for manufacturing problems identified during FDA inspections to lead to a drug shortage because those problems can take time to resolve, David Gaugh, a senior vice president of sciences and regulatory affairs at generic-drug industry group Association for Accessible Medicines, told Business Insider.

Pfizer previously said that new processes put in place after the FDA’s September 2017 warning letter have had “some impact on manufacturing capacity,” as has supply of third-party components.

But EpiPen availability is critical for those with food allergies, and “a matter of public safety,” Lisa Gable, the CEO of the advocacy group Food Allergy Research and Education, said in a statement to Business Insider.

“These shortages not only create unnecessary stress, but families and adults managing potentially life-threatening food allergies rely on epinephrine auto-injector devices for rapid, dependable administration of epinephrine, the first-line treatment for anaphylaxis,” she said. “Instances in which auto-injectors are not functioning properly also carry potentially life-threatening consequences.”

Read more: An EpiPen is 500% more expensive than it was in 2007

Complaints on the rise

Those who get severe allergic reactions to foods such as peanuts, stings, or bites from insects such as bees, wasps, and mosquitoes depend on the EpiPen to inject epinephrine into the outer thigh, where it works quickly to counteract the attack.

Since at least 2013, patients had been increasingly complaining about their EpiPens, including that they didn’t always work, FDA inspection documents and correspondence between Pfizer’s Meridian and the regulator show. Business Insider obtained the documents in a public-records request.

Complaints in the US rose 13% from 2012 to 2013, and the company was also getting more reports of serious side effects with the device, rising from three in 2010 to nearly 50 in 2013.

Patient complaints about products not activating, arriving with atypically colored or cloudy solution in them and activating spontaneously were emerging as popular, an FDA inspection report found.

“It’s not unusual to receive product complaints, especially when the product is frequently administered by non-medically trained individuals,” Pfizer said in a statement. The company added that it has shipped more than 30 million EpiPens globally since 2015.

FDA inspectors told Pfizer’s Meridian that it wasn’t properly investigating complaints as far back as the start of 2014.

Read more: The strange history of the EpiPen, the device developed by the military that turned into a billion-dollar business and now faces generic competition between Mylan and Teva

More than half of about 400 complaints the firm received about EpiPens were for the aforementioned issues and products arriving with bent needles, but the firm still hadn’t figured out by that fall what was causing many of the complaint types, another 2014 FDA inspection report found.

When Meridian’s investigations didn’t confirm the problems, Meridian didn’t implement significant changes to address them, according to the documents Business Insider reviewed. That is a theme in Meridian’s hundreds of pages of correspondence with US drug regulators between 2014 and 2018.

Statistics paint a stark picture. From 2014 to early 2017, patients submitted more than 200 complaints that they were unable to activate their EpiPens. In internal investigations into those complaints, the company only confirmed that two EpiPens had problems.

In correspondence with the FDA, Meridian explained the discrepancy this way: Not every patient submitted a sample of the product, and of those who did, Meridian employees were able to get the samples to work in the lab. Others — even though the patients said they hadn’t worked — arrived in an activated state, suggesting they had worked. In still other cases, lab testing contradicted the complaint.

Diana Zuckerman, the president of the National Center for Health Research, a consumer-advocacy group, questioned whether it was appropriate for a company such as Pfizer’s Meridian — which makes a product intended for consumers to use — to blame its customers for problems.

Zuckerman told Business Insider that she’s previously seen, in the case of reports about a defective implant, other companies blaming surgeons for errors.

“That’s the bottom line: You can’t sell life-saving products intended to be used by patients if you can’t consider why patients might not be able to use it,” she said.

Meridian would end up making a change to how it investigated complaints of product failures.

FDA calls an investigation ‘deficient’

Meridian was catching plenty of defective EpiPen units before they got to market, reports from FDA inspectors visiting its plants in 2014 show. But that wasn’t setting off any alarms at Meridian because the company didn’t have a “meaningful” internal limit for an acceptable number of manufacturing defects, according to the FDA reports.

In at least two instances, the FDA thought the company wasn’t putting the pieces together when evidence suggested that more defective devices might be making it out the factory’s doors to market. One of the firm’s investigations, into a customer report of a broken EpiPen, did not connect the issue to the product’s manufacturing process, in which 4,432 units made at the same time had been rejected for defects, FDA inspectors said.

For that reason and others, they described the investigation as “deficient.”

A crucial component, with a defect

About two and a half years later, in the spring of 2017, Pfizer’s Meridian unit committed to overhauling the way it handled complaints about its products.

It came on the heels of a major event: The company’s US recall of an estimated 260,000 EpiPens because of a defective part.

Called a Power Pak, the component plays a crucial role in making sure the EpiPen fires correctly and delivers the right amount of lifesaving epinephrine. It’s made by a third party, and Meridian’s investigation had concluded that the problem originated with the supplier.

The supplier isn’t revealed in the documents obtained by Business Insider as they were redacted in part to protect trade secrets and other information.

Meridian identified the Power Pak issue in February 2016 and sent back some batches of the component.

Meridian later heard two complaints from customers, in April and December 2016, about problems activating EpiPens, which its own investigations confirmed. Both involved issues with the Power Pak component. The two complaints came from outside the US and, in both cases, the patients used another EpiPen — the product is sold in packs of two — that did work, Pfizer said.

But even though its internal investigation suggested more EpiPen lots could be affected, the company downplayed the two complaints as not significant enough for a recall, calling one complaint “low level,” its correspondence with US regulators shows.

The firm expanded its investigation and issued recalls only after an FDA inspection and “after multiple discussions with FDA,” the regulator said. In March 2017, the company decided to voluntarily recall 13 EpiPen lots sold between late 2015 and mid-2016 in the US, and 81,000 devices outside the US.

Pfizer told Business Insider that its investigations were in line with, or better than, industry and regulatory standards.

Manufacturing issues identified in FDA inspections can commonly lead to drug shortages, because they may take some time to get resolved, one expert told Business Insider.
Samantha Lee / BI Graphics

In a September 2017 warning letter, the FDA told the company that the failure of its EpiPen products could have caused patient deaths, and it chastised the company for poorly investigating patient complaints.

“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 said.

“You did not thoroughly investigate these complaints. Moreover, we note that your follow up did not include removing potentially defective products from the marketplace, even though you had identified a defect in one of the critical components used to manufacture these products and even though you ultimately confirmed the same or similar component defect as the root cause for multiple complaints.”

That’s when Pfizer’s senior management got involved, the documents show.

The company responded to the FDA in September 2017, saying that “no evidence has been found of a causal link between patient deaths and reports of failure of EpiPen units to activate.”

The firm said it confirmed only two patients’ complaints about its product. Both were from a single manufacturing lot of EpiPens that had already been recalled earlier that year, it added, presumably referencing the April and December 2016 complaints.

Meridian came up with what’s called a compliance action plan that year to address the FDA’s many observations, setting up different commitments and deadlines for them. The 38-page plan had about 142 commitments in late July 2017, which ballooned to 270 almost a year later.

Importantly, the firm said it would require a more thorough examination when patients complained that EpiPens weren’t working.

Other parts of the plan could affect EpiPen supply, the documents show, with one portion of it postponed to mid-October 2017 to prevent or minimize stockouts.

Read more: There’s a shortage of EpiPens in the US

A Pfizer representative previously said that new processes implemented as a result of the FDA warnings had “some impact on manufacturing capacity,” with supplies of third-party components also playing a role. The company is still shipping the medicine and expects supply to improve in the coming months.

FDA inspectors had raised other concerns with the company’s complaint-investigation process.

Complaints weren’t given priority status linked to the amount of risk involved, according to an early 2017 FDA inspection report, with categories such as “spontaneous activation” labeled as normal, as was “container broken/cracked/leaking prior to use.”

Pfizer said that would change starting in September 2017, and Meridian has continued to be in communication with the FDA about manufacturing changes.

A recent correspondence, dated October 2018, laid out a timeline for further fixes, which extended through at least the end of this month.

(This story was updated with a new photo showing the EpiPen.)

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