Orphan drug protection: clarification needed

The most powerful exclusivity right available to medicinal products after patent protection is orphan drug status. But although the clinical benefit requirements of the EU orphan drug legislation are business critical for companies wishing to benefit from this form of protection, they are unclearly drafted. With the legislation freshly reproduced in the UK, now would be a good time to amend it.

Beyond patent protection

As medicinal product lines move through a lifecycle, from the new compound itself to narrower and narrower applications – sub-indications, dosage regimes, patient sub-populations – challenges arise in patent law to both find the technical contribution required and demonstrate infringement. As the trend towards personalised or targeted medicines continues, these challenges will continue to stretch the limits of patent protection.

As a result, whilst patents will always be the first choice of exclusivity protection used for medicinal product innovations, where possible, other forms of exclusivity protection are significant. The most powerful additional or alternative such protection, in appropriate cases, is orphan drug designation. By contrast to patents, this form of protection is not dependent on concepts of novelty and inventive step, and nor is similarity to existing orphan products necessarily a bar. Instead orphan drug designations are awarded according to the small size of the applicable patient population and their clinical benefit.

But, whilst showing clinical benefit of some kind is business critical for those companies wishing to obtain this form of protection, the provisions of the EU legislation, and now the UK legislation that has replicated it, are drafted using essentially duplicative definitions and associated guidance. This is apt to confuse and should be resolved.

Revocation and restatement in UK law

In the 27 European Member States, a stand-alone regime of market exclusivity for orphan medicinal products is provided specifically in Regulation (EC) 141/2000 on orphan medicinal products (the EU Regulation). At the end of the Brexit transition period on 31 December 2020, this was revoked and re-stated in UK law in the Human Medicines Regulations 2012 (SI 2012/1916) (the Amended UK Regulations), in particular new regulations 50G, 58C, 58D and Schedule 9A. 

The substance of the EU Regulation is largely retained in UK law – most importantly the period of 10 years market exclusivity preventing the authorisation of similar medicinal products (subject to exceptions) – although there are some changes. In particular, of course, the domestic legislation refers to the UK, and not the EU. A further key change is that orphan status is no longer assessed separately, prior to authorisation – these processes happen together.

As the Medicines & Healthcare products Regulatory Agency (MHRA) states, a UK-wide orphan marketing authorisation can only be considered in the absence of an active EU orphan designation. If a UK-wide orphan marketing authorisation is granted and the medicinal product subsequently receives EU orphan designation, the marketing authorisation holder would need to submit a variation to change this to a Great Britain orphan marketing authorisation.

The general criteria and exceptions

In order for a product to be designated as an UK orphan medicine by the MHRA it must still comply with certain general criteria under the Amended UK Regulations, inherited from the EU Regulation. These include that, where there already exists an United Kingdom authorised and satisfactory method of diagnosis, prevention or treatment of the condition in question, the medicinal product must be of “significant benefit”.

No subsequent, “similar” medicinal product to the orphan can then receive a marketing authorisation for placing on the market for the same therapeutic indication , unless an exception applies.

These exceptions include an exception permitting a similar medicinal product to be authorised if the applicant can establish that it is safer or more effective than, or “clinically superior” to, the orphan product.

The confusion arising

In Teva v European Medicines Agency (C-138/15P), however, the Court of Justice of the European Union says that the exceptions to the exclusivity rule apply, irrespective of whether or not the subsequent medicinal product is an orphan product in its own right. This appears to mean that any similar product must meet both the orphan criteria (including “significant benefit”) and the “clinically superior” exception, if it is to benefit from orphan protection itself.

But later, the Court of Justice’s Shire v EMA (C 359/18 P) decision confirms that a medicinal product may be designated as an orphan product even if a treatment already exists for the condition in question, containing the same active ingredient, provided that it represents a “significant benefit” to those affected by the condition (that is, it is an orphan drug in its own right).

What the Court of Justice does not explain, in either case, is whether one criterion would automatically satisfy the other. Is there any difference, such that some products can be authorised under the exceptions, but not qualify as orphan drugs?

This may be a point of acute risk for some companies competing in the same therapeutic area: what do you need to show to gain your own period of orphan exclusivity, and how do you avoid being excluded from the market by an existing orphan drug?