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Tuesday 5 March 2019

Where did the EpiPens go?

  • Adrenaline auto-injectors are essential items for people across the globe who have serious allergies. But, last year, the world ran out of them.
  • The global shortage was caused when safety concerns emerged about one brand – EpiPen – which has a dominant market share. Competitors could not fill the gap while they sorted their production problems out.
  • The case highlights how having a few dominant market players in essential medical products can be bad for competition – but also potentially dangerous if they have supply problems.

By Jack Kessler

Your throat closes. Your heartbeat races. Your blood pressure crashes. You can’t breathe. Your first step to survival is to inject adrenaline into your thigh. Anaphylaxis is terrifying – and attack triggers are both everywhere and hard to avoid.

Natasha Ednan-Laperouse, a 15-year-old from London, died in the summer of 2016 after eating a Pret a Manger sandwich; its label had failed to note that it contained sesame, an ingredient that triggered her fatal attack.

In England, 325,000 adrenaline auto-injectors were dispensed in 2016 – an emergency treatment in case of an anaphylactic attack. The product is a pre-loaded syringe of adrenaline (also known as epinephrine) designed to be used in seconds.

Zack Howes, aged five, is typical. He is allergic to a range of foods, including fish and nuts. And wherever he goes, he or his parents must carry two auto-injectors – the second being necessary in case one breaks or misfires, or another injection is necessary before an ambulance arrives.

Auto-injectors are essential. They are the devices that allow millions of people around the world to live a normal life. For sufferers, a world without auto-injectors is potentially worse than a world without antibiotics.

The problem was that last year the world was running out.

Natasha Ednan-Laperouse

At any one time, there are about one million auto-injectors in circulation in the UK. Last year, however, there was a global shortfall – a gap of 150,000 injectors in Britain.

In September 2018, the Department of Health and Social Care (DHSC) wrote to pharmacies and healthcare professionals across the UK. It warned that the most popular auto-injector for children was out of stock and that there would be limited availability of all injectors for the rest of 2018. The timing could scarcely have been worse. With children returning for a new school year, many parents were concerned that they would be sending them off without an auto-injector.

Adrenaline has a short shelf-life, but the Medicines and Healthcare products Regulatory Agency (MHRA), the UK’s medicines regulator, agreed to extend the expiry dates of certain batches of auto-injectors by four months to ease supply problems. But in a letter issued to pharmacies in October, the NHS admitted that this action was “not foreseen to be sufficient to fulfil normal demand”.

The shortage is still not over. The DHSC says that supply of auto-injectors is improving and “all patients who require an adrenaline auto-injector should now be able to obtain a device from their pharmacy”. But pharmacies are still suffering shortages, and report significant supply issues.

One London pharmacist said: “Stock is coming in and out. We might have one for a few weeks and then it’s gone. We’re like our customers – completely in the dark.” Another said: “It used to be someone came in with a prescription and we either had it in stock or we’d get it for them in a couple of days. Now it’s still as if it’s in shortage.”

Chelsea Hollie is one of many people who is still struggling to get a replacement. “The only response I get from the pharmacist is ‘there is still a shortage’ or ‘pop in another day’. They don’t seem to know why there is a shortage or when it will stop. The out-of-date pens may still be effective, but of course I don’t know for sure, and hope not to find out.”

The auto-injector shortage seems somehow implausible. How can the world run out of something that is both relatively low-tech and utterly essential?

The answers to this question tell you a lot about flaws in the structure of global healthcare. They tell you about how regulation in the heavily supervised medical products sector may not be considering all the risks. There is public disquiet about how allowing a few players to dominate markets permits high prices – but not enough interest in the supply vulnerabilities that it creates.

The auto-injector shortage was made possible because of the outsized market share of one producer who, it turns out, had serious problems.

Even if you do not know someone who carries an auto-injector, you may have heard of EpiPen. Like Hoover, it is a brand synonymous with the product. Owned by Mylan, a global pharmaceutical company, EpiPen made up around 70 per cent of auto-injectors in the UK at the start of 2018. But that dominant position meant any challenges in the production line would be likely to be felt by users.

When Pfizer, to whom Mylan had subcontracted the manufacturing process, ran into difficulty, that is exactly what happened.

In September 2017, the US Food and Drug Administration (FDA) delivered an extraordinary “warning letter” to Pfizer. The FDA, which is responsible for regulating devices such as auto-injectors, accused the company of repeated failures.

Pfizer (or rather, Meridian Medical, its subsidiary) had failed to “thoroughly investigate multiple serious component and product failures”, which included failures linked to patient deaths and severe illness. The FDA also accused Meridian of failing to extend the scope of its investigations into serious and life-threatening failures or to take corrective actions “until FDA’s inspection”.

In February 2016, Meridian identified a defective component – a so-called “Power Pak” – in a batch of injectors. This part serves a critical role in the operation of an EpiPen, ensuring that the auto-injector fires properly and delivers the correct dose of adrenaline. However, Meridian rejected only that batch and one other associated batch. It did not study other units from the associated lot to determine if they too were suffering from the same defect.

While an investigation and actions were undertaken to fix the defect, Meridian continued to manufacture EpiPen using the same component, while the investigation was ongoing, up until October 2016.

In a fierce rebuke, the FDA accused Meridian of continuing to manufacture EpiPen “without expanding your investigation, reviewing your incoming testing procedures to determine their adequacy or… linking the known component failure with numerous complaints you received regarding ‘failure to activate’, ‘difficult to activate’, or other product activation failures.”

Protesters outside the Mylan Headquarters

Meridian also failed in its handling of complaints. Between 2014 and 2017, it received 171 complaints of EpiPens failing to activate when used correctly – potentially fatal malfunctions. Yet Meridian admitted that it had disassembled and examined only a small minority of devices.

The FDA also called Meridian’s complaints procedure “inadequate”, because it failed to prioritise complaints based on risk to patients.

Finally, the FDA concluded that the sheer number of serious component and product failures indicated that there were major issues with the ability of EpiPen to meet users’ needs.

By March 2017, Pfizer was compelled to expand its voluntary recall of select batches of EpiPen and EpiPen Jr. By May 2018 it was admitting that it could not guarantee that EpiPen would be available at pharmacies.

This might not have been a problem, but for the sheer scale of Pfizer’s dominance, and its behaviour.

Jext and Emerade, two manufacturers of alternative auto-injectors, committed to raise production to make up the shortfall. But they needed 12 weeks to do so. With only about 30 per cent of the UK market between them, plugging the gap left by EpiPen was a serious struggle. And by this time, there was already a backlog of patients waiting for their August and September prescriptions.

Sean Connor, UK general manager of ALK, a Danish-based pharmaceutical company that markets Jext, said: “Mylan were quite dismissive of the situation and didn’t appear to take the problem seriously. More warning would have helped.”

Shirin Alwash, an ambassador for the Royal Pharmaceutical Society, says that the lack of communication meant that many pharmacies were unprepared for the shortage. “It hit us in the face,” she said. “All of a sudden you came into work one day and couldn’t order the stock. Had we known it was about to happen we could have had a contingency plan in place.”

In response, Mylan said: “We have worked closely with Meridian Medical Technologies, the manufacturer, to alleviate the intermittent supply constraints, and we are seeing improvements in patients’ ability to readily access …EpiPen… in the UK.”

A Pfizer spokesperson said: “It’s not unusual to receive product complaints, and each is investigated promptly. We are very confident in the safety and efficacy of EpiPen products being produced by Meridian Medical Technologies.”

Mylan NV’s EpiPen

Being dependent on one manufacturer for the vast majority of auto-injectors increases the risk to patients in the event of a disruption to supply. But companies who enjoy a dominant market position tend to want to keep it that way.

Mylan derives its position from the patent for the EpiPen auto-injector. Patents are effectively a legal monopoly to sell a product, and this gives companies like Mylan a lot of power – particularly if customers cannot breathe without it.

Mylan has worked hard to maintain its market position. In 2015 it filed a “citizen petition” with the FDA in order to persuade it not to approve Teva Pharmaceutical’s application for a generic competitor to the EpiPen. These citizen petitions are supposed to allow individuals and community groups to request that the FDA makes changes to health policy.

But manufacturers like Mylan file the vast majority of these so-called citizen petitions, with the FDA denying over 90 per cent of them. In a report to the US Congress, the FDA stated its belief that these petitions are intended “primarily to delay the approval of competing drugs products and not raise valid scientific issues”. A 2015 study by Michael Carrier and Carl Minniti describes these petitions as stalling tactics, which “play a crucial role in delaying generic entry”.

Another tool of the big pharmaceutical companies is what Dean Baker, co-director at the Centre for Economic and Policy Research, calls “pay to delay” tactics, where they make bogus patent claims. “There is an incredible asymmetry,” he says. “Pfizer has much more to gain from keeping a new entrant out than the competitor has getting in. The incumbent firm is happy to go to court and hope the generic competitor will go away.”

At the same time, Mylan has used its market position to raise prices. Between 2007, when it acquired EpiPen, and 2016, the cost of a two-pack of pens in the US increased from $100 to more than $600. Meanwhile, Mylan chief executive Heather Bresch’s total remuneration increased from $2.5m to nearly $19m between 2007 and 2015.

At a hearing in front of the House Committee on Oversight and Government Reform in 2016 to discuss the rising cost of EpiPen, Congressman John Duncan denounced Bresch in stark terms. “The greed is astounding… I am a very pro-business Republican but I am really sickened by what I have heard today.”

Heather Bresch, chief executive officer of Mylan

Furthermore, adrenaline is not a new drug that Mylan invented and brought to market after painstaking years in laboratories and billions of dollars spent in research and development. Mylan didn’t discover it at all – it purchased the EpiPen brand only 12 years ago, and adrenaline was discovered more than 100 years ago.

There is some encouraging news for consumers. In August 2018, the FDA approved a generic adrenaline auto-injector, marketed by Teva. FDA commissioner Scott Gottlieb said the approval meant that “patients living with severe allergies who require constant access to life-saving epinephrine should have a lower-cost option, as well as another approved product to help protect against potential drug shortages”.

As a result of a 2012 law that allowed the FDA to levy a fee on generic drug makers to spend on hiring additional staff, waiting times have improved. In fiscal year 2018, the FDA approved a record 971 generic drugs, breaking the record set the previous year. But the EpiPen example shows there is a long way to go.

The EpiPen shortage has put tremendous strain on the millions of people around the world who are at risk of anaphylaxis. Many have had to live in fear of going into anaphylaxis without a pen, or that their expired pens may not work when they need them.

Sarah Howes, Zack’s mother, complained of a lack of understanding from some quarters: “I was very annoyed that the doctor and some pharmacists didn’t care or see the emergency of it.”

A Pfizer spokesman stressed the delays were temporary, “due to supply of certain third-party components, along with process changes”.

An auto-injector is not a “normal” product. Most things we buy are not intended for use in potentially fatal situations. But the EpiPen shortage tells a story of markets where one company holds a dominant position, and regulators have waited for it to run into trouble.

Angela Waters runs the #alwayscarrytwo campaign, which encourages people at risk of anaphylaxis to carry the recommended two auto-injectors. She worries that some doctors are not giving patients the right information.

Waters has also been told by parents that some general practitioners (GPs) are not prescribing a second auto-injector because they say there is one in school. This misses the point. People at risk of anaphylaxis must carry two pens at all times, and GPs, the type of doctors who deal with such prescribing in the UK, cannot guarantee that all schools will have spares.

“A GP said to me because my daughter didn’t use her auto-injector last year, she didn’t need a new one this year. I said just because we haven’t been in a car accident doesn’t mean you throw away your seatbelt.”

Further reading

  • This article by Business Insider goes into great detail on the EpiPen defect and the regulatory back and forth with the FDA.
  • “Tashi, I love you so much, darling. I’ll be with you soon. I’ll be with you.” This Guardian article starts with the heartbreaking words that Tanya Ednan-Laperouse said to her daughter as she was dying hundreds of miles away in a French hospital.
  • This Bloomberg piece tells you about the tools drug companies use to keep less expensive alternatives away from patients.
  • Take a couple of minutes and watch this clip of Mylan CEO Heather Bresch being grilled by the US House Committee on Oversight and Government Reform about the rising cost of EpiPen.