Two important developments occurred in mid-November 2016 for the pharmaceutical industry in Europe: the European Commission (the “Commission”) published a revised guideline on orphan medicinal products and launched a public consultation on the Paediatric Regulation. This Legal Update covers the revised guideline on orphan medicinal products. Another Legal Update will cover the public consultation on the Paediatric Regulation.

On November 18 2016, the Commission published a notice on the application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products (the “Notice”). This is the Commission's first step in revising the guidelines on orphan medicinal products. The Commission has now turned to the guideline on similarity, the revised version of which should become available soon.

In the European Union (the “EU”), Article 3 of Regulation (EC) No 141/2000 on orphan medicinal products (the “Orphan Regulation”) sets out two conditions for the granting of an orphan designation, each of which is twofold:

  • The product is intended for the diagnosis, prevention or treatment of a rare condition (“prevalence criterion”), or the marketing of the product intended for the diagnosis, prevention or treatment of a life-threatening or serious condition would not generate sufficient return to cover the investment made (“financial criterion”); and
  • There is no satisfactory treatment for the condition in the EU, or if there is, the future medicinal product will be of significant benefit to patients affected by that condition (“significant benefit”).

The Notice updates and replaces a Commission communication of 2003 that further explained those conditions as well as the procedure for orphan designation and market exclusivity. The Notice covers the same topics except market exclusivity.

The most interesting points developed by the Notice are the following.

Prevalence of a condition outside of the EU. The Notice reiterates that treatments for communicable diseases with very low or close-to-zero prevalence in the EU, such as the Ebola and the Zika virus diseases, are also eligible for orphan designation in the EU. Where the prevalence in the EU is approximately zero, the eligibility is based on the risk of EU residents becoming affected by the disease. In other words, the Orphan Regulation supports the development of medicinal products for highly deadly diseases that only exist outside of the Europe but could spread thereto.

Subset of a condition. Where the proposed orphan indication (i.e., treatment, prevention or diagnosis) refers to a subset of a condition rather than to a condition, the company must justify such restricted use of the product. The Notice stresses that patients in the subset should present distinct and unique evaluable characteristics that have a plausible link to the condition and are essential for the efficacy of the product. The genetic subtype/profile and pathophysiological characteristics associated with the subset should be so closely linked to the action of the product that their absence renders the product ineffective in the rest of the population suffering from the condition. Moreover, “subsetting” a condition with the use of biomarkers will not be acceptable unless the sponsor demonstrates that the activity of the product would not be shown on the larger population.

Satisfactory method authorized in the EU. Satisfactory methods include authorized medicinal products, even if they are only authorized in one EU Member State; off-label use is not considered a satisfactory method. According to the Notice, the products have to be authorized for the treatment of the disease as such or, at the very least, address exactly the same set of symptoms.

The Notice specifies that commonly used methods of diagnosis, prevention or treatment that are not subject to marketing authorization (e.g., surgery, radiotherapy, medical devices) may be considered satisfactory. Scientific evidence of their efficacy and safety could result from clinical guidelines from European medical societies or published scientific evidence. In certain cases, medicinal products prepared for an individual patient in a pharmacy according to a medical prescription (“magistral formula”) or according to the prescriptions of a pharmacopoeia and intended to be supplied directly to patients served by the pharmacy (“officinal formula”) may be considered satisfactory treatment, provided that they are well known and safe and that this is a general practice in the EU. On the other hand, a product prepared in a hospital under a hospital exemption scheme should not be considered a satisfactory method.

One may wonder about the rationale for differentiating between, on the one hand, magistral and officinal preparations, and, on another hand, hospital preparations. Is the Commission’s objective not to impede the development of ATMPs for rare diseases? One may also wonder why a medicinal product that is authorized, produced industrially and distributed “professionally” is not, from a patient perspective, preferable over magistral and officinal preparations.

Significant benefit. “Significant benefit” is established by comparing the future medicinal product and existing authorized medicinal products or methods, not just by assessing the intrinsic qualities of the product in question. The Notice specifies that “[t]he purpose of the legislation is to encourage and reward innovative treatments. These require investment in research and in the development of potential improved medicinal products that can bring meaningful advantages for patients.” On that basis, significant benefit may no longer be based on a possible increased supply/availability due to shortages of existing authorized products; existing products being authorized in only one or a limited number of Member States (except evidence of patient harm); or a new pharmaceutical form, a new strength or a new route of administration, unless it brings a major contribution to patient care.

Maintenance of orphan designation at the time of marketing authorization—evidence. The Commission specifies that the orphan designation criteria must continue to be met when the product is granted the marketing authorization as an orphan medicinal product and requires that at that time the significant benefit be demonstrated by means of comparative data rather than mere assumptions (which are sufficient at the time of the granting of the orphan designation, subject to a minimum of non-clinical and/or clinical data).

Confirmation of the COMP practice. The Notice confirms the practice of the COMP with regard to the evidence of significant benefit at the time of marketing authorization. First, any advantage of the future orphan product is to be considered in the context of experience with authorized products in the orphan condition, even if comparative clinical studies are not possible. In exceptional cases, if it is not possible to generate a sample big enough to provide sufficient comparative evidence, alternative methods (e.g., indirect comparisons with external data) may be used.

Second, insofar as granting a marketing authorization for a new pharmaceutical form of an existing medicinal product could prevent the entry of generics, the major contribution to patient care of the new pharmaceutical form should be justified with relevant data showing meaningful benefits for patients. In practice, the COMP is very demanding with regard to such evidence.

Third, in cases where sponsors seek a conditional marketing authorization, the limited package of data may not be sufficient to confirm significant benefit, and as a result, the orphan designation may not be confirmed. The sponsor therefore may want to seek protocol assistance before considering a conditional marketing authorization.

Simultaneous applications for marketing authorization. The Notice addresses the issue of simultaneous applications for marketing authorization. When two applications for marketing authorization for the same condition have been received by the European Medicines Agency (the “EMA”) at the same time, they usually remain in parallel. In such a case, the sponsor of the second product is not able to show significant benefit as compared with the first product due to the lack or limited information available. On that basis, the Commission considers that, when two applications are assessed by the CHMP at the same time, the sponsor of the second product should not be required to show significant benefit over the first product. This evidence, however, is required if the notification of marketing authorization has been published in the Official Journal of the European Union at the time of the re-evaluation of the designation criteria by the COMP. In practice in such a case, the significant benefit may only be demonstrated by means of an indirect comparison, and in most cases, that indirect comparison will be limited to the SmPCs and EPARs of the two products.

Number of orphan designations. The Notice stresses that a sponsor can receive only one orphan designation per condition for any given medicinal product. However, it does not specify the condition is not the rare disease itself but the treatment, prevention, or diagnosis of the rare disease. The difference is important because a sponsor that has developed a product for the treatment of a rare disease would otherwise have no incentive to develop the same product for the prevention of the rare disease.

The Notice mentions but does not discuss the application of Article 5(1) of the Orphan Regulation, which requires that the orphan designation be applied for before the application for marketing authorization. The Commission considers that this article prevents the validation by the EMA of an application for orphan designation filed for a same active substance and medical condition which are the same as those of an authorized medicinal product. As a result, the innovator of a medicinal product for a rare disease that was authorized before the entry into force of the Orphan Regulation (April 2000) may not benefit from an orphan designation for any new development of its product; third parties may, though.