Important changes in the way that the EU deals with orphan medicines could be signalled later this year when the European Commission publishes a revised version of its 2003 Communication (policy paper) on the topic
The Commission has said it wants to ‘streamline the regulatory framework’ underpinning the assistance given to manufacturers of orphan drugs and to adapt the policy to ‘technical progress,’ and has asked for comments from the pharma industry and other interested parties on how it should proceed.
In its preliminary text put out for comments, Brussels proposes clarification of how sponsors might demonstrate a significant benefit compared with authorised medicines and where and how a new pharmaceutical form could be justified. ‘Furthermore, in view of the development and further integration of the European pharmaceutical market, it seems appropriate to remove the possibility of claiming a significant benefit based on a potential increased supply,’ states the paper, although it acknowledges that some member states had suggested that the medicinal products prepared in a (hospital) pharmacy should be considered in the assessment of the significant benefit.
The Commission, noting that it had refused orphan designation for products intended for diseases that had been declared eradicated by the WHO, comments that the outbreak of Ebola had shown that an infectious disease with a very low prevalence in the EU can very rapidly become a serious threat to public health and ‘it may therefore be appropriate to apply a risk-based approach’ for deciding what is or is not an orphan drug.
As defined by the European Medicines Agency (EMA), orphan medicines are medicines developed to treat rare diseases deemed to be life-threatening or chronically debilitating to no more than five in every 10,000 people. Given that in normal market conditions, the pharmaceutical industry has little interest in researching and marketing medicines in such relatively small quantities, the EU offers incentives to encourage their manufacture, setting strict qualification criteria. At the heart of these is the requirement that any new Orphan Medicinal Product (OMP) has to demonstrate that it offers ‘significant benefit’ to patients over and above what is already available.
Orphan designation for a condition such as Ebola would entail that eventually only one product would be available in the EU
The new Communication, which is expected to be released in the autumn, ‘is a bit of an unknown for us and maybe for the whole orphan community,’ said Kristina Larsson, EMA’s Head of Orphan Medicine. Part of the reason for that is that while the Commission has indicated how it might proceed, its final decision is far from set in stone. Moreover, there have been a wide variety of responses shown in the public consultation launched by the Commission regarding its plans. These seem to reflect the division between manufacturers, who have said they wish to avoid an ‘overly prescriptive approach,’ and the more cautious attitude of patient and medical groups.
‘If there are to be major changes in how we should deal with the procedure in terms of the interpretation of significant benefit, we would have to do that as soon as this notice comes out,’ Larsson told Manufacturing Chemist.
Between 5000 and 8000 distinct rare diseases exist, affecting 6–8% of the EU population in total — in other words, between 27 million and 36 million people in the EU. Among leading afflictions are spina bifida, cystic fibrosis, Tourette syndrome, spinal muscular atrophy, lysosomal storage disorders, patent ductus arteriosus (PDA) and familial adenomatous polyposis (FAP). Some are congenital and some diseases of this kind appear during adulthood, such as renal-cell carcinoma, glioma and acute myeloid leukaemia. The leading database for rare diseases and orphan drugs in the EU is ‘Orphanet’, which is freely accessible to the public and contains information about 6000 diseases.
Through the EMA, the EU assists with the development of OMPs, offers reduced fees for marketing-authorisation applications and provides protection from market competition once the medicine is authorised. Largely as a consequence of its role in this process, EMA has become internationally influential in the assessment and authorisation of medicines for rare diseases. It maintains a collaboration with the US Food and Drug Administration (FDA), although the two bodies have different legislations which impedes the development of closer links — although that might change if a Transatlantic Trade & Investment Partnership (TTIP) trade deal is agreed between the EU and US).
In January this year, the Commission published an inventory of incentives in the EU for making orphan medicinal products as required by the EU Regulation on Orphan Medicinal Products, (EC) No. 141/2000. It showed that at that date, upon EMA’s recommendation, the Commission had authorised 117 orphan medicines for patients suffering from rare diseases, 82% of which consisted of new active substances.
‘The number of products authorised has grown with time (which is encouraging for the future), but remains limited, bearing in mind the existence of 5000 to 8000 distinct rare diseases. We can conclude that just 1% of these are currently covered by authorised medicinal products in the EU,’ the Commission said in an associated note. Incentives were therefore essential to facilitate pharmaceutical development: ‘The most frequently authorised medicinal products are treatments for pulmonary arterial hypertension, acute myeloid leukaemia, cystic fibrosis, multiple myeloma and acute or chronic lymphoblastic leukaemia,’ it said.
In March this year, the Commission published responses to its announcement that it would review the 2003 Communication.1 These comments were enlightening, signalling how the pharma sector would like the Commission to proceed. Among the main comments was a memo from the Joint Task Force on Rare Diseases and Orphan Medicinal Products formed by the EFPIA (European Federation of Pharmaceutical Industries and Associations) and EuropaBio (European Association for BioIndustries), a European alliance of more than 45 member companies committed to the development of orphan drugs and improving the lives of patients with rare diseases. In their joint comment, the two bodies recalled that the European Commission had underlined that it was ‘not appropriate to lay down overly prescriptive requirements.’ They said they were ‘concerned that the draft notice moves away from this understanding and seems more concerned by completeness rather than appropriateness of data requirements.’
It was essential in these discussions to keep the reality of OMP development in mind and, in particular, the specificities of rare diseases. ‘Far from all OMP designated products will be successfully developed and introduced into the market. Pharmaceutical development is characterised by high attrition; in the case of rare diseases, development can be complicated by a lack of scientific knowledge on the disease and by small patient populations. It is important to consider the feasibility of some of the data requirements. A designation provides a tool to access resources (such as scientific advice by the EMA) and incentives to try and increase the possibility of developing successful treatments for rare diseases. A designation will not necessarily result in the development of a successful product,’ the joint task force said.
On the question of demonstrating significant benefit compared with authorised medicines, the EU’s orphan regulation aims at facilitating the placing of innovative products ‘with a significant benefit compared with existing products’ on the EU market. The Commission said in its draft suggestions for public consultation that ‘15 years of experience has shown that the significant benefit is one of the key criteria for the application of the regulation,’ and ‘it appears useful to clarify how the sponsors need to demonstrate a significant benefit compared with authorised medicines’.
The joint task force comment said that while it was useful to show significant benefit, ‘we also believe that a cautious approach is warranted when defining the level of evidence/proof required from developers’. Conclusive data might not be available until very late in the development of a product, ‘so that requesting such data already at the time of designation could result in the delay of a request for designation until the development programme is almost complete. As a result, the use of protocol assistance (PA) and scientific advice (SA) to ensure that the development programme will address the expectations for demonstrating SB [significant benefit] may no longer be viable and this would seem to go against the view of the Commission that PA and SA should be used more extensively in the development of OMPs,’ said the joint task force.
Responses were received from a large number of health, academic and industrial bodies, including the Dutch government, which said among other things that ‘the use of the OMP Regulation to promote the development of medicinal products or vaccines targeting highly contagious communicable diseases needs serious consideration.’
In such circumstances, the Dutch government also questioned whether the system should be used to help pharma companies develop products that are patent protected and hence not as widely available as they could be. Some of the benefits of the Regulation could be of great added value for the development of these products in the form of protocol assistance and reduced fees, etc. ‘but from a public health perspective, the benefit of market exclusivity is not desirable,’ it said.
‘Orphan designation for a condition such as Ebola would entail that eventually only one product would be available in the EU, which creates dependence of EU member states towards one marketing authorisation holder. If the orphan condition suddenly evolves into a highly prevalent disease within the EU, it is doubtful whether production can follow suit. In such cases it is desirable that several manufacturers can develop the product.’
The Dutch government added that ‘the market exclusivity for the orphan medicinal product also means that any similar medicinal product that may have been developed in third countries, which is equally effective but (much) less costly than the orphan medicinal product, can’t enter the EU market.’ When large numbers of citizens were affected and mass vaccination was required ‘the price levels for such an orphan product may pose an unacceptable barrier to public health’.
Considering the regulation in general there was growing concern in the Netherlands and in other European countries that ‘this legislative framework also has some unintended and/or unwanted adverse consequences that challenge its purpose and that may jeopardise future availability and affordability of orphan medicinal products for EU citizens,’ the Dutch government said. ‘Orphan medicinal products that benefit from market exclusivity enter the EU market — almost without exception — at very high price levels compared with medicinal products with a ‘normal’ marketing authorisation.
‘Governments are willing to pay for medicinal products that provide effective treatment for patients with serious chronic or life threatening conditions. However, various recent studies in the Netherlands have highlighted the growing influx of new OMPs that reach the market with limited added value for the patient and an increasingly greater budgetary impact,’ it added.
In its comments on the Commission’s reform plans, Israel-based generic pharma giant Teva said that the Commission suggestions made thus far do ‘not provide additional clarity to the meaning of significant benefit, in particular no further guidance is provided as to the data requirements to substantiate a claim for significant benefit for a new pharmaceutical form of a medicinal product’.
In relation to current delay of market entry of generic products, Teva said it was important to address the situations ‘wherein generics of orphan medicines are blocked after the period of market exclusivity for that orphan product has expired as a result of a similar drug product, approved as an orphan product during the first exclusivity period, being granted a further 10 years of market exclusivity’. This was an ‘evergreening strategy’ that had been used before, said Teva, quoting the imantinib/Nilotinib case.
In the UK, the Royal College of Physicians noted ‘the difficulty in generically defining the significant benefit upfront as it will usually be disease specific. If there is no approved drug already in existence, one would equate this to statistically significant differences in the primary outcome measures of the treated arm over placebo. ‘There is an important question as to how the significant benefit will be defined for a specific disease, including whether patients would be involved. Our experts agree that a potential increase in drug supply does not provide a significant benefit in clinical terms.’
The use of the OMP Regulation to promote the development of medicinal products or vaccines targeting highly contagious communicable diseases needs serious consideration
Larsson was broadly upbeat about the state of research into orphan diseases in the EU at present, but added that ‘one could hope that there might be a little bit more in the field where it would be very useful to have more research in rare diseases, where there are currently no authorised products’. She explained: ‘What we see is that especially for some rare diseases, in particular in oncology, there is a lot of research going on, but then there are already quite a lot of products available to the patient. These can be improved but it would be more beneficial to do more research in areas where there are no products approved at all — for some metabolic diseases, for example, where there are no treatments, though there are of course for some variants. There’s quite a lot of interest in the orphan field right now and that’s why this is being discussed now.’
Clearly, whatever emerges from the Commission review will have to tackle what Larsson cites as the perennial problem faced by researchers in this field — the lack of a large patient base for clinical studies. The official orphan definition was five in 10,000 cases but there was a big variation between this and the 'ultra rare' cases of one in 10,000.
She said the EU was going in the right direction for finding and approving medicines for rare diseases ‘and I think the orphan legislation and the incentives that it gives has been fundamental in this’. But she noted that there had been criticism of the way in which some orphan products come to the market. ‘Legislation has been criticised by some because people have to pay for them, because many of the orphan products are really very expensive,’ she said.
‘But the point I want to make is that when an orphan product gets its 10-year market exclusivity, it is a reward for development in a rare disease and there is no regulatory link between granting an orphan product a marketing authorisation and a specific price. It is not within the remit of the EMA to set a price — that’s strictly a national matter — but just because the product is orphan doesn’t mean it should automatically have a high price because it’s not always that the development has been substantial,’ she said.