The European Medicines Agency estimates that 30 million people living in the European Union suffer from a rare disease. Orphan drug designation can be awarded to a product which treats conditions affecting fewer than 5 people in 10,000 – or to a drug which is unlikely to generate ‘sufficient returns to justify the investment needed for its development’. Between 5,000 and 8,000 distinct rare diseases exist – 80% of them have genetic origins – and affect 6-8% of the population. However, fewer than 1,000 diseases ‘benefit from even minimal amounts of scientific knowledge’, the EMA says.
In other words, there are significant gaps – and this is where pharma manufacturers come in. As the regulator implies, developing drugs intended for small numbers of patients has little commercial incentive under normal market conditions – it is a long, expensive and insecure undertaking. “In England, one of the biggest barriers to access is the uncertainty and the long duration of the process that needs to be followed in order to get a novel therapy routinely commissioned,” says Alastair Kent, director of Genetic Alliance UK.
The number of rare diseases for which no treatment is currently available is estimated to be between 4,000 and 5,000 worldwide. Incentives to find treatments include the EMA carrot of market exclusivity for a set period – but even if your drug does work, there is no guarantee of reimbursement.
Unfortunate message
Some of these thorny problems were encapsulated in uniQure’s recent decision not to seek an extension to its five-year European marketing authorisation – which expires in October – for Glybera, the expensive gene therapy developed for a small subset of patients with the rare familial lipoprotein lipase deficiency (LPLD). The single dose treatment costs more than €1 million per patient – although very few have actually received it. The company’s chief executive Matthew Kapusta said simply: “Glybera’s usage has been extremely limited and we do not envisage patient demand increasing materially in the years ahead.” In other words, the decision makes commercial sense. However, for Kent it is a disappointment.
“It sends an unfortunate message to companies who might think they have something which works,” he says. “The crucial issue is how we create more certainty that if you produce a therapy for a very small population it is likely to get through to patients.”
While there are undoubtedly challenges, independent health economist Leela Barham believes companies need to take advantage of opportunities for more efficient trials and real-world evidence – both of which are now significant for marketing authorisation and HTA/payer approval. Digitisation of healthcare, including linking registries, as well as social media, can help engage with the very patients needed to participate in trials and whose views must play a role in informing company decisions to continue development, regulators’ decisions to authorise and HTA/payers’ decisions to fund, she says.
Ambitious strategy
“Companies need to set an ambitious strategy for pricing and market access early on,” Barham continues. “But the successful ones will be fleet of foot and able to adapt the strategy as they engage and understand what patients, regulators, HTA/payers need to see in the evidence package and a price that will be tolerated across a region and for individual countries.”
When it comes to how these brands actually get to patients, payers (whether at national, regional or hospital level) are the key access and pricing stakeholders, concerned with the value proposition way beyond the product’s clinical profile. Rare diseases as a bundle can be up to 10% of a prescribing budget, so success in this area requires a real understanding of stakeholders’ perspectives and roles and how access pathways work.
The process of assessment varies in Europe. In France, for example, the Autorisation Temporaire d’Utilisation (ATU) system enables access and reimbursement before marketing authorisation for treatments for serious or rare disease, if there is an absence of suitable therapeutic alternative and where it looks like the benefit/risk is positive. “To avoid perverse incentives there are some checks and balances in the system,” explains Barham. “Companies have to have already applied, or commit to applying, for marketing authorisation in a defined time period. There’s a protocol for how data will be collected, and with the potential for a payback should the reimbursed price agreed later be lower than the price during ATU.” In Germany, meanwhile, drugs with the orphan designation are excluded from early benefit assessment if their turnover is less than €50m a year. “Where they are subject to early benefit assessment they will automatically be given the ‘additional benefit’ label,” Barham continues. “Companies can launch with a price and then assessment takes place a year later.”
SKC’s white paper ‘Orphan Drugs in Germany – lessons learned from AMNOG, best and worst practices and strategic implications’ (Kirchmann et al, 2017) offers pharma manufacturers a few pointers for successful orphan drug market access in the country. These include a reminder that companies have to prove additional benefit against a comparator therapy if turnover exceeds €50m a year. The authors add: “A comprehensive value story and an explanation of the burden of disease is very important in case of a debatable degree of innovation or very high-priced drugs.”
Under fire
Some observers feel that Germany and France provide relatively wide access to orphan drugs, certainly compared to England. NICE, which has its own Highly Specialised Technology (HST) assessment process, has come under fire for the change in April 2017 to the way it assesses therapies to treat the rarest of diseases. A new threshold for ultra-orphan drugs is achieved via weightings, with the potential for NICE to recommend an ultra-orphan drug with a cost per QALY of £300,000.
It is too early to judge the impact, but as Barham points out: “The challenge for companies is understanding not just the headline number but instead how committees will apply the weighting criteria needed to allow for a higher cost per QALY.” Managed entry agreements are still likely to be needed.
“Companies will still need to work hard to win a NICE ‘yes’ recommendation, and may still yet have to accept optimised – as NICE calls them – or restricted – as industry calls them – recommendations,” Barham adds.
A NICE spokesperson told PME: “These drugs will now be evaluated against a sliding scale, so that the more additional QALYs a medicine offers, the more generous the cost per QALY level it will need to meet in order to be recommended for routine commissioning, starting at £100,000 per QALY, rising to a maximum of £300,000 per QALY. This is ten times higher than the normal limit applied by NICE.”
Kent believes NICE’s decision will only make things more difficult for patients with rare conditions to access innovative medicines.
“None of the four therapies approved to date under the NICE HST process would meet the criteria,” he says. “The opportunity to introduce a delay of up to three years, even when approved, is also unacceptable as it puts financial issues ahead of patient benefit – not a good move when disease progression may be an issue, and not a good prospect even if the condition is stable.”
Numbers game
The number of orphan drugs actually being approved in Europe is hard to quantify. It is possible to calculate from, say, Orphanet lists how many products have been given the orphan drug designation and approval by EMA in the past and currently have the designation. “But if approval means achieving both marketing authorisation and price and reimbursement approval – which is, after all, what matters most to patients, clinicians and companies for different reasons – it is difficult to find summary stats on that,” Barham says.
While it seems unlikely that there will ever be a blueprint that will always work, optimising the pricing and market access strategy is a continuous activity and companies should always consider the increasing number of opportunities for early engagement with agencies – not all will make sense but companies could miss an opportunity if they don’t consider them, she adds.
“There is scope for more imaginative structures for market access agreements,” suggests Kent. “For example, repayment over time rather than in one hit. That is indicative of the way things will have to go.”
“No system is perfect,” Barham concludes. “But there is scope for improvements in all countries to try to reach a balance of early access, revenue for the company and price flexibility for the payer over time, which is particularly important for rare diseases.”