Publication date: December 17, 2025
One of the characteristics of diseases and conditions is that different illnesses often affect people to completely different degrees and with completely different frequencies. With the advancement of modern medicine, organizations have begun to take a more serious look at the problem of rare diseases. However, the diagnosis and treatment of such diseases are still highly problematic. One of the problems associated with this is the low revenue from such drugs. Due to the fact that some diseases are very rare, the cost of the process of developing and introducing them to the market is disproportionate to the expected sales of such drugs. This happens because of a very narrow group of people affected by such diseases. Drugs for these rare diseases are called orphan drugs or orphan medicinal products (Orphan medicinal products).
The problem of lack of access to costly medicinal products was recognized by the European Community approximately 30 years ago. Guided by the principles of patient equality and following the examples of the United States and Japan, the Community adopted Regulation No. 141/2000, which aims to support and encourage research and development of medicinal products for patients with rare diseases. The Regulation unified the Community procedure for orphan designation. This procedure was supplemented with a system of market protection and research and development incentives for drugs intended for the treatment of orphan diseases. Furthermore, the Regulation established the Committee for Orphan Medicinal Products, operating under the European Medicines Agency.
Regulation No. 141/2000 of the European Parliament and of the Council
A medicinal product is defined as any substance intended for the treatment, prevention, or use in treating human disease.[1] This definition is therefore very broad. A medicinal product may be designated as orphan if it is demonstrated that it is intended for the diagnosis, prevention, or treatment of a life-threatening or health-threatening disease affecting no more than five in 10,000 people in the European Union at the time of application.[2] An alternative criterion for orphan designation is to demonstrate that, without adequate incentives, it is unlikely that the product will generate a sufficient return on investment once it is marketed. Commission Regulationestablishes the factors to be taken into account when implementing Article 3 of Regulation No 141/2000. Under Article 3(1)(a), this means full documentation confirming the rarity of the disease, a list of similar medicinal products, scientific studies, documentation of costs incurred by the sponsor, estimated income, and much more.
In both cases, it is also necessary to demonstrate that there is no satisfactory treatment for the condition in question or, if one exists, that the product provides “significant benefit” to patients suffering from the condition.[3] The burden of proof rests with the sponsor, i.e., the natural or legal person operating within the EU seeking designation.[4] The criterion of “significant benefit” is defined as a clinical advantage or a significant contribution to patient care.[5] This criterion must be met by comparison with products already on the market, but only if there is a satisfactory treatment for the condition in question.[6] The European Commission has identified cases in which a presumption of significant benefit exists. This presumption may be based on the expected benefits for a subset of patients, particularly those refractory to existing treatments for the condition. A presumption of significant benefit may also result from: “serious and documented” difficulties with the formulation or route of administration of products available on the market; limitations in product availability due to specific storage requirements; and insufficient quantities of available medicinal products.[7]
The Regulation establishes the Committee for Orphan Medicinal Products ( COMP ), which operates within the European Medicines Agency (EMA).[8] The COMP is the body responsible for reviewing applications for orphan medicinal product designation. Before submitting an application, a sponsor may request advice from the EMA regarding trials and studies on a given medicinal product.[9]
An application may be submitted to the EMA at any stage of product development, but prior to submitting a marketing authorization application.[10] The application must include the name and address of the sponsor, the product’s active ingredients, the proposed therapeutic indications, a justification for meeting the criteria in Article 3 of the Regulation, and a description of the development stage.[11]
The EMA verifies compliance with the formal criteria and prepares the application for the COMP, which issues an opinion within 90 days of receiving the application. If a positive opinion is received, the EMA forwards the application to the European Commission, which makes a decision within 30 days. A negative opinion is forwarded to the sponsor, who has the right to appeal the COMP opinion within 90 days of its receipt. The opinion is reconsidered at the next COMP meeting and is not subject to appeal. The designated medicinal product is entered in the Community Register of Orphan Medicinal Products. The sponsor is required to submit an annual report to the EMA on the status of the product’s development. Transfer of the orphan medicinal product designation to another sponsor is possible upon submission of an appropriate application. The designation is removed from the register at the sponsor’s request; if, before marketing authorization, the product fails to meet the criteria of Article 3 of the Regulation; or after the period of marketing exclusivity expires.
Persons responsible for marketing an orphan medicinal product have access to significant simplifications in obtaining a marketing authorization. Article 7(1) of the Regulation allows such persons to benefit from the so-called Centralized Procedure. A medicinal product registered under this procedure grants marketing authorization throughout the European Union simultaneously. Eliminating the need to apply for separate authorizations is a significant convenience for drug manufacturers, which also translates into an improvement in the situation for patients with rare diseases. However, a marketing authorization issued for an orphan medicinal product only covers therapeutic indications that meet the criteria set out in Article 3 of the Regulation. Additionally, the EMA has the means to waive registration fees paid by sponsors.
One of the greatest privileges afforded to orphan medicinal products is market exclusivity. If a marketing authorization has been granted through the centralized procedure or all Member States have granted marketing authorizations in accordance with mutual recognition procedures, and provided that this does not violate intellectual property rights or any other provisions of EU law, an orphan medicinal product enjoys market exclusivity for a period of 10 years from the date of marketing authorization. [12]This means that Member States and the European Union are obligated not to accept another marketing authorization application, issue an authorization, or renew an authorization for a similar medicinal product for the same therapeutic indication. A similar medicinal product is a product containing identical active substances or active substances with similar molecular structural characteristics to those contained in an already approved orphan product.[13]
As an exception to the rule in paragraph 1, a similar medicinal product may be granted a marketing authorisation if: the marketing authorisation holder for the original orphan medicinal product obtains consent; the marketing authorisation holder for the original orphan medicinal product is unable to supply sufficient quantities of the product; or the second applicant can demonstrate that the second medicinal product possesses clinically superior characteristics over the original product. [14]Clinical superiority is defined as a significant therapeutic or diagnostic benefit over the original orphan medicinal product, through greater efficacy, greater safety in the target patient group, or other significant contribution to diagnosis or patient care. [15] In a recent ruling, the CJEU confirmed that these criteria are not cumulative, so it is sufficient to meet only one of them to establish clinical superiority.[16] Furthermore, regarding Article 8(3), the CJEU ruled that the application of this article does not exclude the application of Article 8(1) of the Regulation.[17] This means that a marketing authorisation granted for an orphan medicinal product for the same therapeutic indications as the original product, even under Article 8(3), leads to ten years of market exclusivity.[18]
The period of market exclusivity may also be shortened to six years if, at the end of the fifth year, it is demonstrated that the orphan medicinal product no longer meets the definition set out in Article 3 of the Regulation.[19] An example of such a situation would be the product’s profitability, which would justify the lifting of market exclusivity. This procedure is initiated by the EMA at the request of a Member State. The European Commission recommends that, at the end of the fifth year of market exclusivity, the relevant authorities in the Member States conduct appropriate reviews of the marketing authorizations.[20]
The exclusivity period may also be extended to twelve years if the marketing authorization application for an orphan medicinal product includes the results of all studies conducted in accordance with an approved clinical investigation plan involving the pediatric population. [21]This measure is intended to further support the development of medicines for rare diseases, particularly those affecting children.
Article 8(1) of the Regulation clearly states that the orphan medicinal product designation system operates in parallel with the intellectual property protection system. In practice, this means that the market exclusivity system does not affect patent protection. The patent protection system, particularly for medicinal products, is regulated by other legal acts at both the national and EU levels. A significant difference lies in the scope of protection between the two systems – market exclusivity merely prohibits the registration of orphan medicinal products by Member States. A patent, on the other hand, typically allows for the exclusive commercial use of the protected product for a specified period of time . This is therefore much broader in scope.
Article 9 of the regulation establishes a system of incentives created by the Community and Member States to support research and development aimed at developing and making available orphan medicinal products. The issue of reimbursement and access to drugs and therapies intended for the treatment of rare diseases is a very complex issue. The reimbursement system for products used to treat rare diseases has not been harmonized at the EU level. In 2024, approximately 49 orphan drugs were reimbursed in Poland, representing approximately one-third of all products registered in the EU. [22]The reimbursement system fully covers only the treatment of cardiovascular diseases, where only one orphan drug is currently registered. [23]Given that the costs of treating rare diseases significantly exceed the income of the average household in Poland, the current reimbursement system for orphan drugs provides limited assistance to patients. Importantly, in May of this year, a draft amendment to the Reimbursement Act was submitted for public consultation. This draft was intended to provide faster access to therapies for patients with rare diseases. However, at the time of writing, the draft had not yet been voted on in the Sejm.
The Orphan Drug Regulation was undoubtedly a significant step forward in the regulation of pharmaceutical law in the European Union. However, over 20 years have passed since the last amendment to these regulations. Recognizing the technological progress and social changes occurring in Europe, the European Commission published the Pharmaceutical Package in 2023, responding to new needs in pharmaceutical law. The Package aims to introduce regulations on competition in the pharmaceutical market, but also on access to drugs for rare diseases.[24]
On December 11, 2025, European Union lawmakers reached a preliminary agreement on new regulations in pharmaceutical law. The planned changes will also affect the system for designating orphan medicinal products. Information provided by the European Parliament indicates that the changes will affect a significant portion of the current system, starting with the definition of an orphan medicinal product. The new definition removes the second part of Article 3(1)(a) of the regulation, which refers to the lack of prospects for a sufficient return on investment.[25]
There are also plans to add a new designation of a “breakthrough” orphan medicinal product (Breakthrough Orphan Medicinal Product), which would designate a medicinal product for an orphan disease for which there are currently no treatments, and the use of that product would result in a “clinically significant” reduction in morbidity and mortality in patients. [26]The period of market exclusivity is also to be changed. The standard period is to be 9 years. [27]Breakthrough orphan medicinal products will receive 11 years of exclusivity, while products registered under the previous regulation will receive only 4 years. [28]It should be noted that the above-mentioned changes are only a draft currently undergoing the ordinary legislative procedure, so they may be subject to significant changes in the future.
Bibliography :
Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (C 178/02 29/7/2003).
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311 , pp. 67–128).
Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ L 18/1, 22.01.2000).
Commission Regulation (EC) No 847/2000 of 27 April 2000 laying down provisions for compliance with the criteria for designation of medicinal products as orphan medicinal products and the definitions of the concepts of “similar medicinal product” and “clinical superiority” (OJ L 103, 28.4.2000 , p. 5).
Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 378, 27.12.2006, p. 1).
Commission notice on the application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products (2016/C 424/03).
C ‑237/22 P, Mylan IRE Healthcare v Commission (2024) ECLI:EU:C:2024:850 .
T-140/12, Teva Pharma BV and Teva Pharmaceuticals Europe BV v European Medicines Agency (EMA) (2015) EUCLI: EU:T :2015:41.
A Kalinowska- Sługocka , J Sługocki , Health care problems of people suffering from rare diseases on the example of regulations concerning so-called orphan medicinal products (2012).
A. Zimmermann, R Zimmermann, Orphan medicinal products (2009).
European Commission, Pharmaceutical package: new EU rules on medicines < https://www.consilium.europa.eu/pl/policies/pharma-pack/#what > accessed 8/12/2025.
Oleksandr Shtyka , Orphan drugs and their availability in Poland (2024) < https://www.urtica.pl/o-nas/aktualnosci/leki-sieroce-w-polsce.html > accessed 8/12/2025.
Parliament European , Background note: pharmaceutical package provisional agreement elements < https://www.europarl.europa.eu/news/en/press-room/20251209IPR32111/background-note-pharmaceutical-package-provisional-agreement-elements > obtained accessed 16/12/2025.
[1]Article 1(2) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311 , pp. 67–128).
[2]Article 3 paragraph 1(a) Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ L 18/1, 22.1.2000).
[3]Article 3 paragraph 1(b) of Regulation No. 141/2000.
[4]Art. 2 paragraph d Regulation No. 141/2000.
[5]Article 3(2) Commission Regulation (EC) No 847/2000 of 27 April 2000 laying down provisions for compliance with the criteria for designation of medicinal products as orphan medicinal products and the definitions of the concepts of “similar medicinal product” and “clinical superiority” (OJ L 103, 28.4.2000 , p. 5).
[6]Commission notice on the application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products (2016/C 424/03).
[7]ibid.
[8]Art. 4, paragraph 1, Regulation No. 141/2000.
[9]Article 6(1) of Regulation No 141/2000.
[10]Art. 5 paragraph 1 of Regulation No. 141/2000.
[11]Art. 5, paragraph 2, Regulation No. 141/2000.
[12]Article 8 paragraph 1 of Regulation No. 141/2000.
[13]Article 3 paragraph 3 (b) and (c) of Commission Regulation 847/2000.
[14]Article 8 paragraph 3 of Regulation No. 141/2000.
[15]Article 3(3)(d) of Commission Regulation 847/2000.
[16] C ‑237/22 P, Mylan IRE Healthcare v Commission (2024) ECLI:EU:C:2024:850 §77.
[17]T-140/12, Teva Pharma BV and Teva Pharmaceuticals Europe BV v European Medicines Agency (EMA) (2015) EUCLI: EU:T :2015:41, §78.
[18]ibid.
[19]Article 8 paragraph 2 of Regulation No. 141/2000.
[20]Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (C 178/02 29/7/2003).
[21]Article 37 of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 378, 27.12.2006, p. 1).
[22] Oleksandr Shtyka , Orphan drugs and their availability in Poland (2024) < https://www.urtica.pl/o-nas/aktualnosci/leki-sieroce-w-polsce.html > accessed 8/12/2025.
[23]ibid.
[24]European Commission, Pharmaceutical package: new EU rules on medicines < https://www.consilium.europa.eu/pl/policies/pharma-pack/#what > accessed 8/12/2025.
[25] Parliament European , Background note: pharmaceutical package provisional agreement elements < https://www.europarl.europa.eu/news/en/press-room/20251209IPR32111/background-note-pharmaceutical-package-provisional-agreement-elements > obtained accessed 16/12/2025.
[26] ibid.
[27] ibid.
[28] ibid.