European Union: European Commission Publishes Revised Guideline On Criteria For Orphan Designation Of Medicinal Products

Last Updated: 5 December 2016
Article by Geneviève Michaux, Mark Mansour and Christopher M. Mikson

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.

Originally published 29 November 2016

Learn more about our Life Sciences practice.

Visit us at

Mayer Brown is a global legal services provider comprising legal practices that are separate entities (the "Mayer Brown Practices"). The Mayer Brown Practices are: Mayer Brown LLP and Mayer Brown Europe – Brussels LLP, both limited liability partnerships established in Illinois USA; Mayer Brown International LLP, a limited liability partnership incorporated in England and Wales (authorized and regulated by the Solicitors Regulation Authority and registered in England and Wales number OC 303359); Mayer Brown, a SELAS established in France; Mayer Brown JSM, a Hong Kong partnership and its associated entities in Asia; and Tauil & Chequer Advogados, a Brazilian law partnership with which Mayer Brown is associated. "Mayer Brown" and the Mayer Brown logo are the trademarks of the Mayer Brown Practices in their respective jurisdictions.

© Copyright 2016. The Mayer Brown Practices. All rights reserved.

This Mayer Brown article provides information and comments on legal issues and developments of interest. The foregoing is not a comprehensive treatment of the subject matter covered and is not intended to provide legal advice. Readers should seek specific legal advice before taking any action with respect to the matters discussed herein.

To print this article, all you need is to be registered on

Click to Login as an existing user or Register so you can print this article.

Similar Articles
Relevancy Powered by MondaqAI
In association with
Related Topics
Similar Articles
Relevancy Powered by MondaqAI
Related Articles
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Mondaq Free Registration
Gain access to Mondaq global archive of over 375,000 articles covering 200 countries with a personalised News Alert and automatic login on this device.
Mondaq News Alert (some suggested topics and region)
Select Topics
Registration (please scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of

To Use you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.


The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.


Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions