The European Commission Proposes First Major Overhaul of the EU Medicines Regulatory Framework in 20 Years: Orphan Medicines

Background

We recently published an alert in relation to the European Commission’s legislative proposals to replace the current EU regulatory framework for all medicines (including those for rare diseases and for children). One of the major elements of the proposals is a change to the legislation governing orphan medicines for rare diseases, which we examine in more detail in this article.

Current Orphan Medicine Regime

Under the current regime in the EU, the European Commission will grant an orphan designation in respect of a medicine if its sponsor can establish that: (1) the medicine is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition; (2) either (i) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (ii) it is unlikely that the medicine, without the benefits derived from orphan status, would generate sufficient return in the EU to justify the necessary investment in its development; and (3) there is no satisfactory method of diagnosis, prevention, or treatment of such condition authorized for marketing in the EU, or, if such a method exists, the medicine would be of significant benefit to those affected by that condition.

Orphan medicines benefit from 10 years of market exclusivity once they receive a marketing authorization. Market exclusivity is an orphan incentive awarded by the European Commission to a specific therapeutic indication with an orphan designation. Each therapeutic indication with an orphan designation confers 10 years' market exclusivity for the particular indication. A medicine that has multiple orphan designations for different conditions will benefit from separate market exclusivity periods pertaining to its different orphan designations.

Proposed Orphan Medicine Regime

The key points under the new orphan medicine regime are as follows:

• Orphan Designation Criteria
  • The orphan designation criterion on the basis of return on investment has been abolished (limb 2(ii) of the current orphan designation criteria mentioned above).
  • The European Medicines Agency (EMA) may set alternative orphan designation criteria for certain orphan conditions, if necessary (e.g., due to specific characteristics of certain conditions or any other scientific reasons). Such criteria will be laid down in legislation.
• Orphan Designation Validity
  • An orphan designation will be valid for seven years. A marketing authorization holder (MAH) will therefore have seven years in which to submit a marketing authorization application for a medicine falling within the scope of that designation in order for that medicine to benefit from the 10-year market exclusivity period. This is in contrast to the current rules that mandate no timeframe for the validity of an orphan designation. The validity may be extended based on a “justified request” if the orphan medicine developer can provide evidence that the relevant studies supporting the use of the designated orphan medicine in the applied conditions are ongoing and promising with regard to the filing of a future marketing authorization application. There is no guidance yet as to what is meant by “promising” in this context.
• Market Exclusivity Periods
  • Orphan medicines addressing high unmet medical needs will benefit from 10 years of market exclusivity. Orphan medicines are considered to address a high unmet medical need if: (1) there is no authorised medicine for the condition, or the new medicine brings exceptional therapeutic advancement; and (2) the new medicine results in a meaningful reduction in disease morbidity or mortality. There is no guidance yet as to what is meant by “exceptional therapeutic advancement” and “meaningful reduction” in this context.
  • Well-established use orphan medicines (e.g., when an active ingredient of a medicine has been used for more than 10 years and its efficacy and safety have been well-established as evidenced by appropriate scientific literature) will benefit from five years of market exclusivity.
  • All the other orphan medicines will benefit from nine years of market exclusivity.
  • The market exclusivity periods described above may be extended in the following circumstances:
    • +1 year for orphan medicines continuously supplied in EU Member States: The market exclusivity period can be extended by one year if an MAH can show that, within two years of receiving a marketing authorization, the MAH has released and continuously supplied a sufficient quantity of the medicine in the presentations necessary to cover the needs of patients in those EU Member States where the marketing authorization has been granted.
    • +1 year for one or more new therapeutic indications for a different orphan condition: The market exclusivity period can be extended by one year if an MAH obtains a marketing authorization for one or more new therapeutic indications for different orphan conditions at least two years before the end of the exclusivity period. This extension may be granted up to two times. However, this would relate only to market exclusivity, not data exclusivity. If an orphan medicine benefits from this extension, the orphan medicine will not be entitled to benefit from the additional one year of data exclusivity based on the authorisation of an additional therapeutic indication that brings a significant clinical benefit in comparison with currently approved therapies. This is in contrast to the current rules, under which each therapeutic indication for a different orphan condition benefits from a separate orphan market exclusivity period.
      
      Note: The extensions to market exclusivity described above will not apply to well-established use orphan medicines.

Practical Implications

The EMA has the power to set alternative orphan designation criteria for certain orphan conditions (e.g., due to specific characteristics of certain conditions or any other scientific reasons).

The conditions for market exclusivity under the new regime lack clarity in some places. For example, elements of the high unmet medical definition are unclear, including what is meant by “exceptional therapeutic advancement” and “meaningful reduction in disease morbidity and mortality”.

As a final note, if (1) an orphan designation and (2) a marketing authorization are granted to a medicine before the new regime enters into force, that medicine will benefit from the current regime. A medicine with an orphan designation that has not received a marketing authorization before the new regime enters into force will benefit from the new regime (e.g., its orphan designation will be valid for seven years).