EU Orphan Drug Regulations Haven’t “Failed” But Reforms Needed, Says CEO Of European Rare Disease NGO
Parents hold their child, who suffers from spinal muscular atrophy.

European legislation on drugs for rare diseases is “far from perfect”, but it is not a ‘failure’ given the amount of private sector investment it has attracted in the past two decades, says Yann Le Cam, CEO of EURORDIS – Rare Diseases Europe, a non-profit alliance of some 930 rare disease patient organisations across 72 countries, in an interview with Health Policy Watch

He was responding to a report published in The BMJ last week by a Dutch group of investigative journalists that said European orphan drug regulations have “failed” to incentivize R&D for rare diseases. The report also said the regulations, which offer new orphan drugs ten years of “market exclusivity”, had created a ‘corporate cash machine’ allowing biopharmaceuticals to reap ‘billions’ in profits. 

The investigative report largely based on an interim European Commission review, also notes that two thirds of orphan drugs have been developed for diseases that are already treatable – implying that most orphan drug investment is redundant.

Cam, however, said the report’s conclusions are simplistic, ignoring the big achievements that have been made since the regulations were put in place two decades ago.

“Twenty years ago, pulmonary arterial hypertension used to be fatal. Today, 7 treatments are approved in Europe, largely because of EU and US orphan drug regulations. The life of patients has changed,” he said. 

He said that the deeper problem is the lack of collaborative action among European member states on the orphan drug front, particularly in post-marketing research into the long-term benefits of newly approved drugs, which can further define their long-term value – and thus market price potential.  

The investigative report also claims that only 18-24 of the 142 orphan drugs that had been approved between 1999 and 2017 were developed as a result of the EU Orphan Regulation. However, there is “no data” to back up this “opinion”, said Le Cam.

Le Cam also added that 50% of orphan products in the EU market (65) can be sold as generic treatments because their ten-year period of market exclusivity has run out – according to an internal analysis by EURORDIS, which has not been published.

The Investigative Desk’s Analysis Is ‘Rigorous’, But Some Interpretations Are Misleading  

Although The BMJ analysis is rigorous, some of its interpretations are misleading because they suggest that rare disease R&D is redundant, among other issues, said Le Cam.

“Over time, the [EU orphan drug] regulation seems to have become less effective in directing research to areas where there are no treatments….95% of rare diseases remain still without a treatment”, said the interim version of the European Commission review.

Yann Le Cam, CEO of EURORDIS – Rare Diseases Europe

However, that ignores the fact that new treatments which have been approved often target the most prevalent diseases, said Le Cam. And rare disease prevalence can differ by a factor of 3,000. For instance, cystic fibrosis affects about 30,000 people in Europe, while some rare immune-deficiencies only affect 10 newborns a year.

“When you look at the numbers, it’s true that 95% of rare diseases are not treatable. What’s usually not mentioned is that two-thirds of orphan drugs developed so far treat the 400 most prevalent diseases. Deriving estimates from data can offer useful starting points, but they can also be misleading.”

The 95% figure is also an underestimate of the real unmet medical needs, as “very few” existing treatments are curative. For most rare diseases – such as hemophilia, cystic fibrosis, or seizure disorders – people are still living with a “dreadful disease”.

Finally, he notes that the conclusions of the BMJ investigative report are largely based on an interim version of the European Commission review,to be published in final form only later this summer. Until then, the underlying data upon which the report was based isn’t really available.  

“The BMJ article doesn’t provide any analysis or rational ground to claim that EU Orphan Regulations failed. They refer to a report by the European Commission which is not yet published, hence we don’t know how this number was derived. This is not a fact or a demonstrated analysis, it is a mere opinion,” he said. 

Rare diseases are defined as ones that affect less than 5 in every 10,000 people. It is estimated that at least 30 million people in the EU are affected by a rare disease.

European Incentives Have Provided Value – However Market Exclusivity Invites Misuse Of The Rules

Ellen ‘t Hoen, Director of Medicines, Law & Policy and a long-standing advocate of strong medicines access policies, offers a rather nuanced view of The BMJ report’s conclusions – and on Europe’s incentive schemes. 

“The number of orphan drugs registered has risen sharply in 20 years thanks to European incentive schemes. However, the market exclusivity for 10 years leads to high prices and invites ‘drug pirates’ to misuse the rules,” she told Health Policy Watch, referring to a recent article she co-authored and published in the Dutch medical journal.

“I recognise that there is a need for incentives to develop orphan drugs – but the current regulation is in need of urgent revision,” she added, pointing to a Briefing Document by Medicines, Law & Policy published last year, which concluded that while the EU regulations had been abused, its ‘incentives have undoubtedly contributed to a huge increase in the level of engagement of pharmaceutical firms with orphan diseases, which has led to many new orphan medicinal products being introduced to the European market’.

Now, however, “the time has come to critically evaluate the EU Orphan Drug Regulation for effectiveness and to develop new innovation models for diseases for which the pharmaceutical industry is not showing interest,” said ‘t Hoen. “The European Commission and the Member States urgently need to take measures to stop improper use of the Orphan Medicinal Products Regulation.” 

She said she was awaiting the full report by the European Commission to see what remedies it recommends. 

“The [European] Commission commissioned a study of the orphan drug regulation and has it at its disposal – for some time now but has not made the study public. Word on the street is that it is forthcoming. This study is carried out by Technopolis and addresses the effectiveness of the regulation. It will be important to know the conclusions and recommendations made by the researchers. The study is part of the pharmaceutical incentives review the Council asked for in 2016.”

Importantly, EU Regulation needs to have a “corrective mechanism for misbehaviour”, emphasized Hoen, who received a royal prize for her work on access to medicines a few months ago. 

Among the recommendations made by her NGO a year ago, would be the introduction of a so-called ‘‘sufficiency test’, which would shorten the ten year period of market exclusivity if sufficient return on investment is proven for a given orphan drug.

According to recent data, a ten-year period of market exclusivity has been granted in 99.96% of orphan drugs in the EU based on the so-called ‘prevalence threshold’, which assumes that investment in diseases affecting less than five in ten thousand people is not profitable. This assumption is needing ‘urgent revision’, said ‘t Hoen.

European Collaboration To Drive Down Prices Of Orphan Drugs  

Child with Williams syndrome in Russia

Le Cam agrees that in some cases, a ten-year period of market exclusivity or more is excessive given the rewards the drugs may bring.

But he stresses that more European collaboration not only on R&D but also with respect to price negotiations, would help improve access and lower prices of many orphan drugs, referring to the findings of a 2018 EURODIS analysis.

If Member States were to collaborate more closely on post-marketing R&D, they would be better positioned to negotiate drug prices, as well as agreements to ensure access to drugs in smaller countries and specific demographic groups. 

He explains that in the case of many orphan drugs, treatments are “stabilizing” rather than “curative”. And given the small numbers of patients involved, post-market evaluation of the real value of new rare disease treatments is critical. It can also ensure that treatments cater to the broad range of clinical symptoms reported by patients with rare diseases – a highly heterogeneous group. 

“Today, data collected in the region is not robust enough to allow different treatments to be compared between each other and to determine which product is the most suitable for which age, in which situation, in which combination and which regimen”, said Le Cam. “Pooling data across Europe with the same research questions and protocols would be good science and better use of your money.”

“We can blame the private sector as this report does, but we also need to blame member states for their fragmented approach to generating evidence on orphan drugs after they’re approved. As a result, we still don’t know the real-life value of treatments in patients and are unable to adjust prices accordingly.”

Given that some patients fail to respond to specific treatments, having several drugs for the same disease up our sleeves is crucial – and it can also drive down their price due to competition. Developing such data would also enable orphan drugs to be priced more fairly, as their cost would reflect their ‘real-life value in patients’.

Le Cam also added that European member states tend to negotiate orphan drug prices on an individual basis rather than on a regional level, leaving smaller nations – such as Denmark, Belgium of the Netherlands – standing in the queue for “years” until they gain access, although the same treatment may be available in a larger country right next door.

In 2017, about a quarter of Europeans with a rare disease said their treatment had not been available in their country over the previous year, according to a EURORDIS survey co-funded by the EU.

A Structured & Collaborative Approach To Price Negotiations 

In 2018, EURORDIS urged member states to jointly negotiate a ‘European Transactional Price’ for orphan drugs to account for the fact that preliminary treatments are still ‘‘approximates” rather than ‘curative’ treatments. The Paris-based NGO also called on countries to collaboratively generate robust value assessments for orphan drugs – thus empowering the region to renegotiate the Transactional Price in a way that it reflects the value of the treatment provided. 

The mechanisms proposed by EURORDIS would reduce fragmentation of the European market and allow patients to have immediate access to lifesaving drugs while reducing prices, Le Cam says.

“Offering immediate access to patients and predictability of revenue will attract private sector investment, while also reducing prices and expanding getting access to patients.”

The industry is ready to compromise prices in return for better access to patients and market predictability, he said. However, Member States have acted as the main bottleneck in past decades, and must collaborate for better price negotiation and access.

Today, collaboration is limited to a handful of initiatives, but “the intent is there”. These include the so-called ‘BeNeLuxA’ initiative from 2015, where Belgium, the Netherlands, Luxembourg, Austria, and Ireland came together to kick start negotiations for medicines, including orphan drugs.

More recently in 2017, other member states – Malta, Romania, Greece, Cyprus, Italy, Spain, Portugal and Ireland – agreed to jointly negotiate orphan drug prices in the Valletta Declaration, which covers some 160 million Europeans, or about 32% of the EU’s population.

In 2017, ten European Member States signed the Valletta Declaration to improve access to medicines, including orphan drugs

The General Consensus – ‘Urgent’ Action Is Needed

Despite lively debates over The BMJ investigative report, there seems to be a growing  consensus that both the European Commission and Member States need to take urgent measures to improve access to patients with rare diseases.

The debates over medicines access and pricing raised by COVID-19 may even help accelerate action on the rare disease front as well. 

Says Le Cam: “European Member States have never been able to put their act together because there was a lack of support from the European Commission that didn’t want to put their finger in supporting Member States to collaborate on price negotiation and access. Now, this is changing completely with COVID-19.” 

Image Credits: EURORDIS – Rare Diseases Europe, EURORDIS – Rare Diseases Europe, EURORDIS – Rare Diseases Europe, Valletta Technical Commitee.

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