European Commission Clears up Questions on Orphan Drug Regulation

Regulatory NewsRegulatory News | 05 January 2017 |  By 

Following a public consultation in November 2015, the European Commission (EC) has released a new communication intended to clarify some lingering questions about the EU's Orphan Regulation.

The consultation sought to address five issues that have arisen since the Orphan Regulation came into effect in January 2000:

  • Clarifying the meaning of "significant benefit"
  • How to apply the Orphan Regulation to emerging diseases, such as Ebola, that are not present within the EU
  • Whether flexibility should be applied in granting orphan designation in cases where two products for the same indication are assessed in parallel
  • How to reassess a product's orphan designation when a sponsor extends the use of its product after the initial marketing authorization
  • Clarifying the process of transferring orphan designations between sponsors

According to Jordi Llinares, head of the department for scientific and regulatory management at the European Medicines Agency (EMA), the agency is working to implement the changes brought on by the communication.

Significant Benefit

To qualify for orphan designation, a medicine must treat, diagnose or prevent a serious or life threatening condition that affects fewer than 5 in 10,000 people in the European Union.

Additionally, there must not be any "satisfactory" treatment for the condition within the EU, or the medicine must be shown to demonstrate significant benefit to patients over existing options.

According to the communication, sponsors must demonstrate significant benefit based on clinically relevant advantages such as improved efficacy or a better safety profile compared to existing treatments, or a major contribution to patient care, such as a new pharmaceutical form that is demonstrated to improve adherence.

However, the communication clarifies that significant benefit should not be based on:

  • "Possible increased supply/availability due to shortages of existing authorised products or to existing products being authorised in only one or a limited number of Member States. (Exceptions may be made if the sponsor has evidence of patient harm);
  • enhancement of the pharmaceutical quality of a product in compliance with relevant Committee for Medicinal Products for Human Use (CHMP) guidelines – this is an obligation for all marketing authorisation holders; or
  • a new pharmaceutical form, a new strength or a new route of administration, unless it brings a major contribution to patient care; or
  • an alternative mechanism of action per se. However, in exceptional cases consideration may be given to those developments at the time the designation is granted. At the time the criteria are reviewed for the purposes of granting the marketing authorisation, this must translate into a clinically relevant advantage or a major contribution to patient care."

The communication also establishes that drugs prepared by hospitals or pharmacies under Article 3(7) of Directive 2001/83/EC "should not be considered a satisfactory method of diagnosis, prevention or treatment of a condition" for the purposes of establishing significant benefit over existing treatment options.

Prevalence Outside the EU

Another question addressed by the communication has to do with how the orphan designations for conditions that do not affect people within the EU are handled.

The question was raised in light of the 2014-2015 Ebola outbreak, which affected tens of thousands of people in West Africa, but was not transmitted within the EU.

According to the communication, such diseases do qualify for consideration as orphan products as the prevalence of the disease outside of the EU is not a consideration for orphan designation.

"A medicinal product intended to diagnose, prevent or treat a condition which affects a large number of people in certain non-EU countries, but which has a low prevalence or a prevalence of approximately zero in the EU, may be eligible for designation as an orphan medicinal product with respect to the prevalence criterion, and if all other criteria are met, eligible for the benefits set out in the Regulation," the communication states.

However, for conditions with zero prevalence within the EU, the Commission notes that sponsors should account for the risk that people within the EU may be affected by the disease in the future.

Parallel Orphan Applications

The communication also clarifies questions about maintaining orphan designation in cases where two products for the same orphan indication are being assessed by EMA at the same time.

"Where two applications for marketing authorisation for the same condition have been received by the European Medicines Agency at the same time, they might not remain in parallel. In such cases, it may be difficult for the second product to show significant benefit as compared with the first product due to the limited information available," the Commission writes.

In such cases, the Commission says the sponsor of the second product will not be required to demonstrate significant benefit over the first product.

However, the Commission says that the sponsor of the second product will need to demonstrate significant benefit over the first product if the notification of marketing authorization for the first product has already been published in the Official Journal of the European Union by the time the Committee for Orphan Medicinal Products (COMP) re-evaluates the second product's designation criteria, though the Commission notes that this may be done using an indirect comparison.


The Commission has also clarified that an orphan product's designation must be reassessed when there is a change to its indication, such as a new indication, type-II variation or extension of the marketing authorization.

This verification, the Commission says, will be done "to ensure that the variation of the terms of the orphan marketing authorisation complies with Article 7(3)," which establishes that the marketing authorisation for an orphan product may only cover indications that meet the criteria for an orphan product.

Transfer of Orphan Designation Between Sponsors

While Article 5(11) of the Orphan Regulation allows an orphan designation to be transferred between sponsors, the Commission has clarified that "it is not possible to transfer an orphan designation to a sponsor who already has a marketing authorisation for the same medicinal product and condition."

European Commission


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