First published in our Biotech Review of the year – issue 9.
December 2020 marked the 20th anniversary of the EU Orphan Regulation, which aims to encourage the development and commercialisation of medicines to treat rare diseases that otherwise would not be developed by providing incentives for sponsors and developers. The large number of medicines approved to treat rare diseases in the last 20 years is proof of the success of the Regulation.
In the framework of the European Commission’s examination of the impact of pharmaceutical incentives on the availability and accessibility of medicines for rare diseases, the strengths and weaknesses of the EU regulatory framework governing orphan medicines were reviewed. The evaluation of the effects of the Orphan Regulation shows that the Regulation stimulated research and development of medicines to treat rare diseases, but at the same time some shortcomings were identified.
The fact that 95% of rare diseases still have no treatment option has been widely used by those who think that the Regulation has not met its purpose, but this figure needs to be understood in the wider context: the burden of disease is unevenly distributed across the 7-8,000 rare diseases. Indeed, 10.9% of the most prevalent rare diseases account for 98.6% of the patients with rare diseases. Many are of the view that the Regulation fosters innovation to the benefit of many patients. In any event, there are some undeniable shortcomings that can be improved.
What shortcomings are specific to biotech products?
Some contend that the Regulation has fallen short of providing the necessary stimulus to develop medicines in areas of unmet medical needs and that there is an uneven availability and accessibility of medicines across Member States in the EU once they are authorised. These are general issues that affect all types of medicines. Having said that, some issues are very specific to biotech products. Indeed, the Regulation was designed bearing in mind the approaches to developing and authorising medicines that prevailed just over 20 years ago. For biotech products this poses some challenges.
Advanced therapy medicinal products may be approved with a limited clinical dataset if they are granted a conditional marketing authorisation (CMA). The CMA may make it difficult for the EMA’s Committee for Orphan Medicinal Products to assess whether the medicine offers significant benefit over existing treatments, and whether orphan designation can be confirmed and the product can profit from orphan market exclusivity.
Certain diseases have been better defined and their molecular causes better understood thanks to the important progress made in the field of genomic research over the last 20 years. The identification of subtypes of new diseases which were previously considered as a part of a broader disease is clearly beneficial to patients and researchers. Similarly, personalised medicine has shown to be highly cost-effective. Whereas personalised medicine does not change the definition of the disease, it better targets the patient population responding to a certain medicine. The European Commission is concerned that the developments in personalised medicine should not lead to unnecessary multiplication of rare diseases out of common diseases with the duplication of market exclusivity periods.
Advances with biomarkers also put the orphan medicines framework to the test. They are used more and more in tissue-agnostic development in oncology, where the product development is not focused on patients with a particular type of cancer, but rather on any patient expressing particular biomarkers, independent of the tissue or origin of the cancer. Treatments developed as a result can act against multiple types of cancer or their subsets, which would require changes to the policy on defining the orphan condition and on which subset(s) should be taken into consideration when applying for orphan designation. Biomarkers can define a valid sub-set of a condition acceptable for orphan designation, but showing significant benefit in the defined condition may be a challenge.
What solutions are being proposed?
Given that the above challenges will increase as technology advances, the European Commission proposes to review the Regulation, as updates to the guidelines will probably just provide limited improvements when trying to adapt to said advances. In its Inception Impact Assessment related to the revision of the EU legislation on medicines for children and rare diseases, the European Commission puts forward four different options for the modification of the current system of orphan designation and incentives.
As a common element to the four options the European Commission advocates increased flexibility of the criteria for orphan designation: it advocates leaving behind the central rule of “disease” which exists in the current regime, but avoiding the misuse of a potential new regime that could lead to unnecessary duplications of rare diseases derived from common diseases. In other words, the European Commission wants to avoid the grant of orphan designation for subsets of common diseases.
The four options that the European Commission tabled to change the current regime are:
- In the first option, the Commission advocates for retaining the prevalence of the condition to be less than 5 in 10,000 for the purpose of obtaining orphan designation. The main incentive will still be the orphan market exclusivity. However, the proposal is to have a variable duration of the orphan market exclusivity period, depending on the type of development (innovative products, re-purposed products, products with a second or multiple indications) and the maximum length would continue to be of 10 years.
- Building on option 1, the Commission proposes to change the criteria for designation to better identify rare diseases. This option would include a proposal to change the current threshold of total number of cases of a disease at a specific point in time, but there is no suggestion of what the new threshold or time period would be. The Commission also proposes to include a different criterion for orphan designation to identify specific rare diseases like rare cancers consisting of incidence, that is, taking into account the number of people that got the disease during a specified period of time, with different criteria applying depending on the type of the disease.
- Building on option 2, this third option adds an alternative incentive. In particular, for products addressing an unmet medical need in rare diseases and rare paediatric diseases a new incentive is proposed. This incentive could either complement the existing incentive or replace it. Possible novel rewards could consist of the extension of regulatory data protection or transferable vouchers like priority review or regulatory rewards vouchers.
- The last of the options proposed by the Commission would be the most disruptive of all in terms of the incentives offered: not all medicines for rare diseases would have orphan market exclusivity. Instead only medicines treating unmet medical needs in rare diseases and rare paediatric diseases would benefit from market exclusivity.
What will happen next?
Developers need to factor in the unavoidable changes to the incentives system. According to the European Commission Work Programme 2022, a revision of the Regulation is expected in the last quarter of 2022. This may get delayed but the Commission has come this far and it is highly unlikely that changes to the incentives will not take place.
It is undeniable that there are still unmet medical needs in the EU. EFPIA is of the opinion that “[w]here unmet medical needs remain, more incentives are needed, not less” and so the association is in favour of new incentives to boost attractiveness.
Predicting how far the Commission will get in view of the four options available is difficult, but our bet is that the new framework will lie somewhere between options 2 and 3: orphan market exclusivity will continue to be the main incentive, but it is possible that additional orphan indications will get less or no exclusivity. In order words: the possibility of having separate market exclusivity periods of 10 years for the same product with multiple orphan designations for different conditions could cease to exist in the future, further to some alleging that it constitutes an “evergreening” of orphan market exclusivity. The Commission seems keen on having more flexible criteria for designation, so it is probable that option 2 will materialise in changes to Article 3 of the Orphan Regulation. We hope that an alternative incentive for products addressing unmet medical needs in rare diseases and rare paediatric diseases will be created, but it should complement the existing orphan market exclusivity rather than replace it. A “bonus” seems to be the most attractive way of incentivising the development of these medicines, and removing the orphan market exclusivity as we know it would be a harmful setback in the development of new treatments for rare diseases in view of all of the progress made in the last 20 years.
 Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products.
 Nguengang Wakap, S., Lambert, D.M., Olry, A. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 28, 165–173 (2020).
 European Commission Joint evaluation of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and Regulation (EC)
No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products
 Ref. Ares(2020)7081640 – 25/11/2020.
 The European Commission’s work programme for 2022 can be accessed here: https://ec.europa.eu/info/publications/2022-commission-work-programme-key-documents_en
 EFPIA’s response to the public consultation on the review of the Orphan and Paediatric Regulations.