The price of access: Can the NHS afford Orkambi?

The impasse over access to Vertex’s Orkambi for cystic fibrosis patients in England and Wales has revealed the cracks in the NHS’ regulatory system. Matt Fellows explores where the core issues lie in the debate, and what can be done to prevent future breakdowns in communication for the good of patients.

Pricing is an issue that is rarely out of the news, and it’s not difficult to see why: health is an issue for literally every single person on the planet, and to bring money into the equation as a requisite for accessibility was never going to go well. But medicines must be developed and delivered within the existing national or international framework, and that naturally renders any access efforts vulnerable to conflicts of interest and financial concerns.

The issue inspires intense debate for this reason alone, but on a deeper level, requiring stakeholders to debate and affix a price tag on a medicine only invites or even requires them to court the unavoidably subjective notion of the intrinsic value of a drug. What value can it bring? How many lives will it save? How can its benefits for patients be neatly quantified and monetised? How can it make a return on investment? It’s seems an almost inherently self-defeating discussion when you have two parties on either end of the negotiating table whose primary [modus operandi] is to protect their own interests within strict red lines.

Of course, this is perhaps slightly more applicable to the system in the UK than in, say, the US, which faces entirely unique problems within its own highly-publicised debate on pricing and the value of drugs. While some of the most prominent Big Pharma CEOs lined up in February before US Congress to justify the high prices of their medicines – a line-up which included AbbVie’s Rick Gonzalez, Pfizer’s Albert Bourla, Bristol-Myers Squibb’s Giovanni Caforio, MSD’s Kenneth Frazier, Sanofi’s Oliver Brandicourt, and Johnson & Johnson’s Executive Vice President Jennifer Taubert, who stood in for Chief Executive Alex Gorsky – the UK’s cystic fibrosis (CF) community has been grappling with a crisis of its own, and one that is emblematic of the wider pricing and access debate.

NICE has been locked in negotiations with Boston-based Vertex for a number of years, negotiations which have starkly highlighted the distance between the two organisations’ stances on the perceived valuation of the medicine. And with these discussions at a stalemate, approximately half of the 10,000 eligible patients in dire need of an effective treatment for the debilitating condition are denied access until the stand-off is resolved.

But the story stretches back even further than that. [Pharmafocus] spoke to Nick Medhurst, Head of Policy and Public Affairs at the Cystic Fibrosis Trust, to get the full picture that has led to this point.

"The story really starts back around 2012 with Kalydeco, Vertex's first medicine in CF and the first drug in CF to target the root cause by modulating the cystic fibrosis transmembrane-regulating (CFTR) protein. It's why this category of drugs is so innovative in CF: Kalydeco when it was first licensed was only available for one specific CF-causing mutation, which only 5% of the UK CF population had," he explained. "We could probably get bogged down in the detail of how that got reimbursed but it basically rose up through the gap when the Health and Social Care Act came in, and specialised medicine commissioning moved from being the domain of the Advisory Group on National Specialized Services (AGNSS) to NICE. It was effectively approved within six months for routine commissioning by NHS England, and then in 2015 Orkambi was licensed, and Orkambi expanded the treatable population to more than 50% of people with cystic fibrosis, because it targets people who have two copies of the most common CF-causing mutation.

"In 2018, a new iteration of that medicine was licensed: Symkevi, which slightly expanded the treatable population again, but is effectively a demonstration of a rolling pipeline of medicines being released by Vertex, but we hit the buffers back in 2015; we're expecting in the middle of this year data for a Phase 3 trial to be released by Vertex on what is known as a triple combination therapy – the drug compounds that are in Symkevi, which are Kalydeco, another compound called tezacaftor, and another compound which has yet to receive a name. That drug is likely to expand the treatable population to 90% of people with CF in the UK, and the Phase 2 data and four weeks of the Phase 3 data show that that is creating a really transformational benefit almost immediately in patients who are able to access it.

"That's been part of the story basically ever since 2012, with obviously increasing certainty of the fact that these drugs will make it through their Phase 3 hurdles; We've seen Orkambi pass that phase, Symkevi pass that phase, and we have every expectation that the triple therapy will pass that phase later this year, start to be licensed in North America and Europe as early as 2020."

SUB-HEADING: The price of good health

There is currently no cure for the genetic condition, which can cause breathing difficulties due to a build-up of thick mucus, frequent lung infections, and infertility in males, while life expectancy for patients in the developed world tops out at just 50 years. The need for more effective therapies to treat CF is without question, but what makes Orkambi so essential for these patients in need?

"The specific innovation in Orkambi is that it isn't something which is symptom-managing. Lots of treatments in CF, particularly for the respiratory system, are to dampen down respiratory infections, or mucolytics to loosen mucus to help people to clear the thick, sticky mucus which is characteristic of CF and is fertile ground for infections to take hold that lead to the respiratory failure which is the main cause of death in CF," Medhurst explains. "These are just pills for people to take, morning and night, and they have a multi-systemic effect; because there are treating the disease at the cellular level, they are able to have a positive impact on CFTR function in the lungs, in the gut, and elsewhere, where it helps people to stay well in the respiratory health and feel more comfortable in their digestive health, gain weight more easily, and generally feel more stable, stronger and resilient. That's the particular importance of these medicines, quite aside from the fact that they're easy to take – they are remarkably potent versus the type of treatments that people have been burdened with in the past."

The negotiations between NICE and Vertex came to a head after 12 months in July 2018, when the UK watchdog published what it called its "fair and final offer" to secure the drug, an offer which was thought to be around £500 million for all of the company’s approved medicines, as well as any which may secure approval in future. Vertex rejected that offer.

"It’s not that we won’t take that offer, it’s that we can’t," said Vertex Chief Executive Officer Jeff Leiden at the time. The company is asking for £105 000 per patient per year; NICE’s offer amounts to around just £10,000 per patient per year. Health Secretary Matt Hancock called the offer "incredibly generous" as said that the firm were "profiteering off the back of the NHS."

Leiden asserted: "We have made an offer to NHS England that is the best in the world, for all of our medicines and all patients, and their response has been to offer us a fraction of what other countries pay for our medicine." Were the company to agree to the offer, he said, it would not secure the return on investment necessary to continue to develop the next generation of cystic fibrosis drugs, while also criticising NICE’s 25-year-old decision-making process, calling it unfit for purpose.

Come 2019, little has changed. With progress stalled, the plot thickened with the news in February that Vertex had doubled its Q4 profits for the year from $158 million to $337 million, which the company specifically put down to "the strong growth in total CF product revenues". Needless to say, this only inflamed tensions that were already running high; Shadow Health Secretary Jon Ashworth remarked in response: "Those living with CF who are currently denied this life-saving drug will be disgusted at these profits. This big pharma firm, by refusing to play fair with the NHS, is holding lives to ransom. The price they want for Orkambi is simply unjust." And as the icing on the cake, the company confirmed in response to questioning from Dr Sarah Wollaston MP on 25 March that it had destroyed almost 8,000 packs of the drug – around 600 years’ worth of treatment – after they had passed their expiry date.

Valuation and funding

The stalled negotiations today are clearly the result of fault on both sides of the aisle, with neither truly exempt from liability in the lack of progress on the issue, but where does the true crux of the problem lie?

"I think, quite simply, it's an issue of pricing, and to be more specific, it's about the two parties' considerations of the value of the drug," Medhurst notes. "We've seen various iterations of this being played out in public, most recently with the Health and Social Care Committee, that there is no disagreement that these are effective medicines; nobody's saying that people with CF don't need these medicines, or that they're not going to have a significant benefit to the UK population. It's the disagreement over their reimbursement for risk and innovation that Vertex would suggest, versus concerns over budget impact and opportunity cost that the NHS will highlight as a key problem.

"It's clear that our current system for jumping over regulatory hurdles creates some barriers to the subsequent cost-effectiveness evaluation when the primary target is safety and efficacy. With EMA, the more nuanced questions of value are left to a secondary level," he continued. "It is, of course, very challenging, and currently very expensive and potentially impractical, to capture in a short-term trial a medicine designed for a chronic condition, and to capture a level of nuance that would be important for a healthcare system, or indeed for a society, to put a valuation on it itself.

"We find ourselves kind of caught in what really should be the past of arguing about the cost and the need to get Orkambi to individuals. Of course, in that time – three, maybe four years – the benefit that could have been conferred to that patient population has not been; people in the UK will receive these drugs, and potentially the more powerful potent triple therapy, from a lower starting base than counterparts in, for example, Germany, Holland, Ireland, where the population that has been treated with these drugs will be healthier."

So, at its core, this is a debate about how we value medicines like Orkambi, and how we translate medical benefit into a monetary measure. Of course, in situations like this, the manufacturer is going to look out for its own interests and financial feasibility must be taken into account on their side, so seeing eye-to-eye with the health service is unlikely to be a common occurrence. But this is compounded by a much deeper issue: the NHS cannot negotiate a price approaching the level that manufacturers expect and require if it simply does not have the funding to do so.

"To be very clear, our experience is that there is not sufficient investment on behalf of the NHS or NICE or the UK Government in creating a dynamic negotiating environment; since the 2012 Health and Social Care Act, there's been a trend of medicines that get a negative recommendation from NICE falling into a black hole of responsibility," remarks Medhurst. "The recommendation for Orkambi described it as an important, effective medicine that was not cost-effective. That's duty discharged, and there's no requirement for a dynamic negotiation process after that.

"What has become clear, in the Orkambi case, is that it has taken political intervention to bring the parties back to the table, but political intervention is quite different to guidance from the minister on what to invest in, but just creating that dynamic of negotiating has required that intervention. If that's compared to, for example, the German system, where companies enter into discussions with the German authorities knowing that there is a process that will, if all else fails, lead to binding arbitration to settle a cost. The Cystic Fibrosis Trust believes that that model could prove fruitful in the UK, having a situation where there is some kind of backstop, or at least a safety net that would stop these types of standoffs occurring in the first place, because actually, as the company continues to turn a profit, and the NHS continues to protect its budget, the only people who have suffered in this standoff are people with CF and their families; nobody else bears that burden of harm in this sorry tale."

As Medhurst notes, political intervention has unfortunately been necessary once again in order to push negotiations forward, with Vertex CEO Jeff Leiden meeting with representatives from NICE and NHS England in March. Around the same time, a petition demanding access for patients surpassed 117,000 signatures, and it’s clear there is more work to be done. NICE is expected to revisit the case in July this year.

Breaking the deadlock

It’s clear that the NHS is not able to deliver on its remit of protecting public health if it cannot come to the negotiating table with the ability to propose realistic offers in line with other comparable countries. And besides that, NICE’s regulatory system is currently lacking in its ability to facilitate access for certain groups of patients. In stand-offs like the case with Orkambi, there is obviously responsibility on both sides to put the patient first, but, in lieu of a full overhaul of the system, what can be done to refine the [status quo] in order to prevent such deadlocks occurring in future and denying patients access to the medicines they need? Medhurst and the Cystic Fibrosis Trust have some ideas.

 "From 2015 onwards, we have spoken about the power of the UK CF registry, which is a consented, anonymised healthcare, clinical and demographic database of more than 90% of people with CF in the UK," he explains. "We've argued that that resource, which is hosted and managed by the Cystic Fibrosis Trust, is incredibly important for the long-term follow-up and assessment of real-world value of these medicines. It's a resource and an asset that's already used by EMA for pharmacovigilance and by NHS England to determine payments to providers based on a tariff model of disease severity; it's a hugely well-respected and hugely well-established assets that's community owned, that can go a significant way to arbitrating that uncertainty or drawing out a more nuanced understanding of value in an assessment of these medicines. We actually have quite a good example through the data that has been collected on Kalydeco of enriching that trial data with real-world data, so we can talk about its impact on a number of exacerbations: we can talk about its impact on median FEV, but also the risk of death or risk of needing transplant, and a host of other important indicators of value and efficacy.

"Aside from our guidance on the use of the registry, we're looking to long-term as well with investment in a clinical trials accelerator platform, to a network of principle sites for clinical trials in the UK, which we hope will make the development of future therapies more efficient, cost-effective, and avoid some of these challenges in the longer term. We also have research programmes looking at patient-centred outcomes and quality of life to provide new tools for healthcare systems to understand and appraise the value of new medicines.

"That's all for the longer term. What we have right now is the need to get the key protagonists in the room negotiating, and finding the compromise which, in the short-term, enables people to benefit from these medicines, because I think it is not acceptable for the NHS to say ‘sorry, the price is too high’ and walk away from the table, and it's clearly not acceptable for the company to say ‘we are not prepared to find a price that this country can afford to pay.’

"I think, in a top-line sense, there has to be an acceptance and responsibility taken for fact that these issues will recur for at least the next 10 years, and we need to be thinking about stemming that particular flow," Medhurst continues. "I think that the government's Accelerated Access Review dabbled in that area and provides useful recommendations for how we can improve that translational science from the lab and perhaps make development of new innovative products cheaper and more efficient, and de-risk the current pharmaceutical and biotech development models, which may go some way to allowing for more affordable prices to be proposed by companies. But at the moment, there is a situation where companies already have enormous sunken costs, either on products that weren't able to make it to market, or indeed in products which they are currently in the throes of investing in - anything which has got to Phase 2 is already at that point. Perhaps we need to think of a short-term strategy on this, and that may involve the government being realistic about what it needs to invest in, or indeed be more targeted and specific with what investment needs to be drawn back in, but I think the goal has to be for there to be a private, public, and perhaps third-sector collaboration to enable more affordable, sustainable prices in the longer term.

"There aren't any easy answers today; if there were they'd have already been proposed, and there probably aren't easy answers in the medium-term either, but we can work hard and collaboratively to properly understand those longer-term challenges and mitigate them now, because that's where that work has to start."

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