28 November 2019

Menopause

Solving the great HRT mystery

A shortage of menopause drugs has affected hundreds of thousands of women. But what caused the sudden drought – global forces, disaster capitalism, or sheer British incompetence?

By Emma Hartley

About a year ago, like hundreds of thousands of British women of her age, Michelle Watson became affected by an unexplained medical drought.

Michelle, 55, an airline account manager and Marie Curie volunteer, lives in Finchley, London, with her husband, David, and her nine-year-old Tibetan terrier, Chino. After an accumulation of unpleasant symptoms, including memory loss, she had been prescribed Hormone Replacement Therapy treatment, which suddenly vanished over a year ago.

“I was on FemSeven patches, which I was really happy with,” she said. “Then about a year ago – around October 2018 – I couldn’t get them anymore. I went to several pharmacies but just couldn’t find them.

“So my GP switched me to Evorel, which was not as good, because you have to change them twice a week rather than once. My night sweats came back again and my mood was affected. One minute I was fine and the next I was in tears or screaming at my husband, which was confusing for both of us. Not good.

Applying post-menopause hormone gel

“Before I’d started HRT I’d also been having memory problems. It was so bad I was wondering if it was some kind of early onset dementia: I would forget words or the names of clients I had been seeing for years. It really scared me until I realised it was connected with the menopause. I had thought it could have been something much, much more serious.

“Now Evorel is out of stock as well and although I managed to convince my GP to write a prescription for six months’ worth the last time I saw him, I’m worried about what will happen in January when I need more.”

One million women 

I became aware of the UK’s HRT shortage earlier this year. I’d met several medics and research scientists who had strongly advocated for the medication as a way of reducing the long-term risk of cardiovascular disease, osteoporosis, arthritis, diabetes, obesity, depression and many other health conditions that disproportionately afflict older women.

Instead of focusing on the shorter-term symptoms of hot flushes and night sweats, these scientists changed the way I thought about the medicine and made me appreciate its political significance; there is no equivalent treatment for men because the “male menopause” is regarded largely as a scientific myth.

The HRT shortage of the past year – and HRT itself – should be a feminist cause célèbre and yet, oddly to me, it has not yet achieved that status. On the face of it, there is a lazy chauvinism within an medical establishment that does not educate GPs properly on the treatment of menopausal symptoms and an NHS which – at the very least – has failed in its supply of information to take older women’s health seriously.

It is estimated that just over a million women in the UK take HRT – or at least they used to before the shortages – and many of the major brands have been affected. So the shortages have affected hundreds of thousands of people at a conservative estimate. I wanted to know why this had happened.

This investigation took me on a fascinating journey, via Morpeth in Northumberland, that revealed the links between the US’s trade war on China and the UK HRT market, as well as the murky and self-serving nature of the pharmaceuticals industry. I looked at import data from Her Majesty’s Revenue and Customs that shone a light on supply shortages and the swooning value of the Pound as Brexit uncertainty persists. Finally, I unearthed an NHS document that seemed to solve the mystery, revealing what seemed to be a spectacular own-goal by the Department of Health and Social Care. But let me start at the beginning.

The drought begins

The HRT that Michelle Watson was on at first, FemSeven, was made for Theramex by a different pharmaceutical company called Mylan. After October 2018 she was no longer able to obtain FemSeven.

Then, in spring 2019, Elleste Duet pills, also made by Mylan, fell into short supply. Janssen, which makes Watson’s second choice of HRT patches, Evorel, which had a 40 per cent market share of the UK HRT market, has said that scarcity on UK shelves was a result of increased demand as women prescribed now unavailable HRT products swapped to Evorel.

By the summer of 2019 shortages were being reported by the British Menopause Society across a wide range of HRT products, apparently as a result of this domino effect as women switched to alternative drugs. Throughout, there was very little specific information about what was causing the crisis.

So what caused the shortages? Since Mylan appears to be most closely involved in the origin of the problem, why not start there?

“Supply-chain issues”

There were intriguing rumours about unspecified supply-chain issues in China. But when I looked at the patient leaflet for Elleste Duet, it clearly said that Mylan manufactured it in Morpeth, Northumberland, at an Indian-owned factory called Piramal.

So I contacted the managing director of the factory, Rob Haxton, and asked him directly: where was the blockage in the supply chain?

He referred me to the Mylan press office (which failed to respond). He also confirmed that Piramal was the UK manufacturer of Elleste Duet. I then paid a visit to the factory in Morpeth – but Haxton wouldn’t meet me. He sent me an email saying: “Piramal package the product, the tablets being supplied to us from a Mylan source. We are not in a position to comment on behalf of the product owner who in this case is Mylan.”

Mylan is the world's second-largest manufacturer of generic drugs, and though it's run from Canonsburg, Pennsylvania, its operations three hours inland from Mumbai exemplify the central role India has come to play in the global generic-drug industry

It seems that being the “manufacturer” of a medicine on a UK patient leaflet does not necessarily mean that you “manufacture” anything in the traditional sense. The Medicines and Healthcare Regulatory Agency (MHRA) addressed my confusion: “The product licence details show Piramal Healthcare as a site of batch release and therefore they can be referenced in the leaflet as the manufacturer. The definition of the manufacturer is the site of batch release in the EU.”

So Elleste Duet is tested and packaged in Morpeth, but made somewhere else. How, then, I asked the MRHA, can I find out where the Elleste Duet pills were really made? They came back to me saying that this information is not in the public domain, citing “commercial confidentiality”. Facing this level of secrecy, I was forced to look elsewhere for clues about the origins of the HRT shortage.

The Brexit factor

Could fears about a no-deal Brexit be part of the picture? In March, the Association of the British Pharmaceutical Industry (ABPI) had put that theory in play with a press release urging the government to ban so-called “parallel exporting” of medicines.

Much of the concern about medicine supplies in the UK had centred on fears of transportation delays in the event of a chaotic British exit from the EU. But the ABPI had something else in mind: what if a weakened Pound suddenly meant drugs wholesalers in the UK could make more money by selling to EU countries?

According to Haitham Hamoda, chairman of the British Menopause Society, no other European country is nearly as severely affected by HRT shortages as the UK. The fall in the relative value of the pound since the 2016 referendum has already made selling drugs abroad more lucrative for UK wholesalers – crashing out of the EU could be an opportunity for fortunes to be made.

Surely wholesalers wouldn’t do that while there were empty shelves in UK pharmacies and British women were walking from chemist to chemist clutching paper prescriptions, trying to find the HRT medications they desperately needed?

A pharmacist checks a prescription before dispensing medication

I asked for an interview with Richard Greville, director of the ABPI, and included a list of questions about “parallel exports” and whether HRT was on his list. It seemed like a long shot.

Two days later, instead of organising an interview, the ABPI’s press office sent me an embargoed press release from the Department of Health and Social Care, headlined: “Government introduces new measures to tackle HRT shortages,” complete with quotes from the Secretary of State for Health, Matt Hancock.

A  list of medicines involved showed most of them were derivatives of estradiol, the active ingredient in most HRT.

Could it really be that simple? Had the HRT shortages – which are not projected to end until the middle of 2020 at the earliest – have been caused by wholesalers hoarding medicines with the intention of doing a bit of disaster capitalism if the UK crashed out of the EU?

How would the government propose to enforce such a ban on 2,800 wholesalers? Opening lorries at warehouse gates and ports, and arresting the owners of the companies involved might work – but border agents checking every box?

There was a gap in logic here too that troubled me. The shortages were already real, not a theoretical future risk. At this stage, the jury was still out about the relevance of “parallel exports” to the HRT shortage, despite the Secretary of State for Health apparently indicating that there was a connection.

A part of me deeply resented having to do all this research when there were government bodies and pharmaceutical companies that undoubtedly already knew exactly what had caused the UK’s HRT shortages – or should have done. And yet their maddeningly opaque and obstructive attitude and apparent lack of care for the women affected made it unavoidable.

US v China

So what about this mysterious “supply-chain issue in China”? Dr Marco Marques, a teaching fellow from the Department of Biochemical Engineering at University College London, told me that all of the medicines on the UK government’s do-not-parallel-export list had a precursor called androstenedione.

When I went looking to see where it is manufactured, it appears that China is, indeed, the main source of this active pharmaceutical ingredient. At least two of the major producers – Yicheng Goto Pharmaceuticals and Hubei Danao Pharmaceuticals, both in Hubei province, had been in trouble recently with the United States Food and Drug Administration (FDA). The FDA had put products from these two factories on “import alert”, which meant their goods would be detained at the US border and that those companies had been denied legal access to the US market.

An employee at a China Grand Pharmaceutical and Healthcare Holdings Ltd facility in Wuhan, China

How would that affect the UK? The knock-on effects on the remaining handful of androstenedione manufacturers will have been considerable. And the UK imports more than three times as many hormone products from the US as it receives from the EU.

Data from Her Majesty’s Revenue and Customs shows the international hormone trade to the UK, and in particular a huge drop between 2017 and 2018 of imports from the US.

In 2017, the UK imported oestrogen and progestogen hormone products from the US worth £7,415,906. But in 2018 that dropped to £2,888,761, with no compensating imports from elsewhere.

In the space of one year, imports from the US dropped by 61 per cent – and all UK hormone imports fell by 51 per cent. The first of the two Chinese factories put on import alert received their letter in November 2017 and the second in August 2018. It is hard to resist the conclusion that this is at least a partial explanation for the HRT shortages.

When I showed him the HMRC data, Haitham Hamoda, the chair of the British Menopause Society, expressed frustration with the lack of a proper explanation for the UK’s HRT shortages from the companies directly involved.

“If this table includes the import of products containing estradiol, then the drop in imports between 2017 and 2018 could only have had an impact on the HRT market,” he said. “There is no good reason for the level of secrecy we have been experiencing from the pharmaceutical companies involved in the shortages: Janssen has told us that the shortages of Evorel have been to do with increased demand. But that’s just not very plausible from a company of that size.

“What you are showing me here is a very viable explanation for the shortages and I would like to hear the responses of the pharmaceutical companies to this 60 per cent drop in hormone imports from the US. One of the difficulties in trying to understand what has been going on here is that we don’t know conclusively where the specific drugs are manufactured.”

A Chinese worker looks on as a cargo ship is loaded at a port in Qingdao

Would he call on the UK’s MHRA to make that information available on patient leaflets? “Definitely,” he said. “Everyone is entitled to know where their drugs are manufactured.”

And yet… if a drop in US imports were the full explanation for our HRT shortages, surely the whole of the EU would have been in the same position? But there is no evidence that anywhere has been as badly affected as the UK.

Who knows?

There is one company that is in a far better position than any other to explain what has been going on in the UK’s HRT market over the last couple of years – and that is Mylan because they part-own the manufacturing process for the two products that vanished from the UK market first.

They have more information about what has occurred here than any other company. And yet they have simply chosen not to explain.

Several weeks after first requesting a response from Mylan to the questions raised here about its products, I finally received this email from a PR called Georgie Phipps at an external communications agency called Speed. “Hi Emma, Thank you for contacting Mylan re some HRT enquiries. At this point, Mylan will not comment beyond the information that is available on the BMS website.”

A Mylan facility in Morgantown, West Virginia

Mylan told the British Menopause Society in September it had experienced an “interruption in production” in 2019 and would be would be transferring production to a Mylan-owned and operated facility and expected supply to resume in the second half of 2020.

And yet knowing about the dubious recent corporate history of Mylan still does not explain why the UK should be worse hit by HRT shortages than the rest of the EU. This, on the other hand…

A problem made in Britain?

Five months before the first HRT product vanished from the shelves, the UK government issued an update to its drugs pricing policy, which was sent to me by a source.

Page three of the 996-page document shows that 15 HRT products, including the FemSeven and Evorel products used by Michelle Watson, were added on 1 June 2018.

The drugs tariff is a mechanism for keeping the NHS’s medicines bill under control by specifying the prices payable to pharmacies for them. It now appears to me that everything up until this point in my investigation would be best described as global context: this document finally seems to explain why only the UK has been so badly affected.

When the Department of Health and Social Care (DHSC), in consultation with the Pharmaceutical Services Negotiating Committee (PSNC), an arms-length agency operating from Hosier Lane in the City of London and led by Simon Dukes, changed the tariff for these HRT products it did so, the DHSC press office has since told me, because there were pricing fluctuations on the world market.

By pegging the UK price at a certain level it was hoped that the NHS would be able to minimise its bill for these medicines in the face of market uncertainty.

However, what appears to have happened is that the price was pegged at a level where it was simply unattractive for the pharmaceutical companies involved to sell to the UK – and the invisible hand of the market has done the rest.

The time-lag between the update in June 2018 and the beginning of the shortages in October 2018 is likely to represent how long it took for wholesalers’ shelves to empty.

Hemant Patel, secretary of the North East London Pharmaceutical Panel explained: “The drug tariff sets out the prices the NHS will pay for medicines to pharmacies. It used to be that the price paid to the pharmacy would be slightly more than the price paid to the wholesaler but now there are a lot of drugs in Category C of the NHS tariff on which pharmacists are losing money because the DHSC takes a long time to reflect market prices. Sometimes, something costing 90p can suddenly cost over £30, due to the market being manipulated by wholesaler and the manufacturer.”

At the heart of a problem so ferociously complex that many in the pharmaceutical industry even have trouble understanding it, could this be a simple case of incompetence? Since the 1 June 2018 update (which names the Secretary of State for Health at the time – Jeremy Hunt – as directly responsible for the decision-making it contains) the drug companies appear simply to have been selling to countries where they can get more money for their medicines.

Jeremy Hunt may have been in charge when the update was made, but Matt Hancock became secretary of state for health on 9 July 2018 and was therefore the person responsible when the shortages began – and which have continued to the present day. If the DHSC is a ship of state, was Hancock asleep in the wheelhouse?

Matt Hancock, UK health secretary, left, and Jeremy Hunt, his predecessor

Pharmacists familiar with the NHS’s drug tariff agree that the change in the drugs tariff is the best explanation they’ve seen for the UK’s HRT shortages. Patel said: “Yes. The likeliest explanation for the drug shortage is adding the drug to Category C designed to manage NHS costs. The inadvertent effect of the transfer to category C is shortages in supply which have caused avoidable additional work in pharmacies and deep concerns and frustration to patients. The demand for the drug… is unsatisfied due to NHS pricing policies.”

Leanne Sinclair, clinical pharmacist at The Independent Pharmacy, said: “The beginning of the HRT shortages appears to coincide with the change in the reimbursement mechanism of certain medicines within this category. A combination of the new fixed-pricing system and the falling value of the pound may mean that the UK is a less valuable market for manufacturers to allocate stock, leading to shortages.”

Rod Tucker, a pharmacist researcher at Robert Gordon University in Aberdeen, and Scott McDougal of The Independent Pharmacy agreed with this analysis.

Professor David G Taylor, professor of pharmaceutical and public health policy at UCL, explained the impact the drug tariff can have: “If you control the price of a drug so it is lower than in other markets, the other markets will get preference. The NHS has a cost-limiting culture that is always just on the edge of pushing things too low: I’m talking about labour costs and drugs. There is an element of NHS management that cares more about budget control than about patient care.”

I also showed my workings to Dr Peter Greenhouse, a Bristol-based menopause specialist, who said: “This is an enormously impressive piece of research. It clearly shows cock-up on a grand scale: incompetence from the DHSC and either incompetence or ignorance from their political masters. This needs to reach a much wider audience, preferably before the election.”

Dr Anne Henderson, a Harley Street gynaecologist and menopause specialist, said: “The HRT shortages have had a devastating impact on my patients, some of whom have completely run out of medication resulting in adverse side-effects which are not straightforward to rectify. I’m concerned about the absolute lack of transparency from the Department of Health and Social Care and pharmaceutical companies involved.”

There appears to have been an institutional failure to care about the HRT shortages, she said, asking who, if anyone, in the government takes responsibility for women’s health. “I have repeatedly tried to contact the relevant team at the health ministry and the various drug companies but, with the exception of Novartis, I have not had any useful feedback. I think the current situation is quite disgraceful and that the millions of women involved have not been properly considered either by the DHSC or the drug companies.

“Many of my patients have travelled abroad to buy patches, for example in Spain, Belgium and France. They have been able to obtain large volumes without any difficulties.”

The health secretary, Matt Hancock, said in February this year that UK drug shortages are “very much not out of my hands” and, when asked about HRT, claimed that “we are working on it daily as a department”.

When asked for a response to this article on 29 October (the day that a bill legislating for an early general election began its passage through parliament) a spokesman for the DHSC said: “The benefit of adding a medicine like HRT to this particular part of the tariff (category C) is that it means that the price is fixed at a certain rate (its list price) when pharmacists are reimbursed for purchasing it.

“It is in no way linked to the global shortage, which is due to manufacturing issues outside of the UK government’s control. Manufacturing issues can include difficulty accessing raw ingredients, problems with machinery and batch failures, for example. It’s a highly regulated process so if something goes wrong, it can take a while to fix. I’m very concerned at your suggestion that the two are linked. They are not related in any way and I’m struggling to understand your reasoning for why you believe they are?”

I supplied my reasoning.

On 6 November, following the completion of the early general election bill’s passage on 31 October, parliament was dissolved and I received this message from the DHSC press officer. “As I explained on the phone earlier, we are not able to issue an on-the-record DHSC statement as your article will be published during Purdah and pre-election rules apply to civil servants. However, I would urge you to contact CCHQ for a political statement from the Conservative party.”

At the time of publication, the Conservative Party had failed to respond.

All photographs Getty Images

Further reading

Malcolm Gladwell’s landmark New Yorker essay on the origin story of the Pill is still regularly referenced almost 20 years later.

For a more academic take on a similar subject, Is Menstruation obsolete? by Eslimar Coutinho argues that regular monthly bleeding is not the “natural” state of women, and that it puts them at risk of several medical conditions.

If you want to understand just how pervasive overt and unconscious bias against women can be, see Caroline Criado Perez’s  Invisible Women which reveals the imbalance in everything from bulletproof vests to office temperature controls.

Emma Hartley, the author of this investigation, wrote a great piece for The Sunday Times about the pioneering work being done to ‘postpone’ the menopause.