The European Union has been slow to implement an orphan drugs policy, but finally adopted one in April 2000. Neil Jenkins analyzes how to obtain protection, and reveals some lessons from the first year of filings

EU Orphan Drug Designations (ODDs) became a reality in April of last year when the Committee for Orphan Medicinal Products (COMP) established under the auspices of the European Medicines Evaluation Agency (EMEA) started to receive applications for ODDs from pharmaceutical and biotechnology companies.

The EU has in fact been relatively slow in implementing an orphan drugs policy compared to the other two major pharmaceutical product markets of the US and Japan. In the US, the Orphan Drug Act was introduced nearly two decades ago in 1983 and has resulted in the designation of around 1,000 substances as orphan drugs. Orphan drug policies have also been adopted more recently in Australia and Singapore.

In all three major markets, ODDs now sit alongside the two other forms of non-patent protection for pharmaceutical products namely, patent term extensions (or supplementary protection certificates in the case of the EU) and regulatory data protection as a further encouragement to the innovative pharmaceutical and biotechnology sector.

The primary legislation implementing the EU's orphan drugs policy is contained in Regulation no 141/2000 on Orphan Medicinal Products of December 16 1999. This Regulation was adopted on April 27 2000 with the publication of the secondary legislation containing the implementing regulations (namely, Regulation no 847/2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts "similar medicinal product" and "clinical superiority" of April 27 2000).

What is an orphan drug?
The discovery that a particular substance has therapeutic properties is merely the first stage in the development of a safe and efficacious drug. Before the substance can be placed on the market, it has to be approved and before it can be approved, the developer has to submit the results of pre-clinical and clinical tests in order to demonstrate to the regulatory authorities the quality, safety and clinical effectiveness of the substance in question. These tests are extremely expensive to conduct involving as they do clinical trials on patients. In the case of a rare disease, regardless of the clinical effectiveness of the drug, the size of the patient population for the disease in question will simply not be sufficiently large to justify the cost of carrying out those tests. An orphan drug therefore is one whose existence is known and whose effectiveness is predicted but whose future development life cannot be sustained because the large development cost is not warranted by the small anticipated economic return on the sales of the drug to such a small patient population.

In the EU legislation itself, an orphan drug is defined in terms of both patient population ie, one that "is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than 5 in 10 thousand persons in the Community when the application is made" and also economic return ie, one that "is intended for the diagnosis, prevention or treatment of [such a condition] and that without incentives it is unlikely that the marketing of the [drug] in the Community would generate sufficient return to justify the necessary investment".

To obtain an ODD, however, the sponsor of the drug must also establish that either that "there exists no other satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized or if such a method exists, that the medicinal product will be of significant benefit to those affected by the condition".

How to obtain an orphan drug designation
At the centre of the ODD scheme is the Committee for Orphan Medicinal Products or COMP. The COMP whose secretariat is provided by the EMEA has the task of examining the applications for ODDs and forming a view on whether to give a positive opinion ie, one in favour of an ODD, to the Commission. The membership of the COMP comprises representatives from each of the 15 member states plus three patient representatives plus three EMEA/Commission representatives. It has an elected chairman and makes recommendations on the basis of a two-thirds majority decision. The COMP also has the power to appoint an expert to assist it in reaching an opinion on each application. The COMP meets once a month and the minutes of its monthly meetings are posted on the EMEA website.

The procedure for obtaining an ODD for a given drug for a given indication is relatively straightforward.

  • The sponsor of the drug may submit an application at any time prior to the application for marketing authorization. The application comprises the name and address of the sponsor, the active ingredient of the medicinal product, the proposed indication, (most critically) the justification that the criteria for an ODD (as outlined above) are met and a description of the stage that the development of the drug has reached and finally, the likely indications that are expected for the drug. The implementing regulation contains detailed provisions on what has to be shown by the sponsor in order to meet the criteria for an ODD: see box 1.
  • The EMEA checks the application for formalities and prepares a summary for the COMP.
  • The COMP gives an Opinion within 90 days as to whether to recommend an ODD or not.
  • If yes, the EMEA forwards the favourable opinion of the COMP to the Commission which is obliged to adopt the decision within 30 days save in exceptional circumstances.
  • If no, the sponsor is notified and has a further 90 days in which to submit grounds of appeal and the COMP is then obliged to review its previous negative decision. There is no further right of appeal.
  • Once the positive opinion has been adopted by the Commission the ODD is entered on the Community Register of ODDs which is accessible at

The COMP has emphasised the benefits in terms of the time taken to process applications of giving it advance notice of an application and also making use of pre-submission meetings with the EMEA in order to allow discussion of any difficult issues.

It is understood that in future the EMEA will publish on its website a summary of the COMPs positive and negative opinions in order to enhance further the transparency of the procedures and resulting decisions.

Box 1: What the sponsor must show to satisfy the criteria for an ODD

To obtain an ODD, the sponsor has to establish (1) the rarity of the disease to be diagnosed, prevented or treated or the lack of return on the investment needed to bring the drug to the marketplace and (2) the lack of a satisfactory alternative method of diagnosis, prevention or treatment.

To establish these criteria, the sponsor must provide the following information or documents:

Rarity of the disease

  • Authoritative references to demonstrate that the disease affects no more than 5 in 10,000 persons in the Community.
  • Authoritative references to demonstrate the life-threatening or chronically debilitating nature of the disease.
  • A review of relevant scientific literature from Community or third country database with appropriate extrapolations as required.
  • Relevant details in those cases where the disease has been considered within the framework of the Community activity on rare diseases.

Return on investment

  • Authoritative references to demonstrate the life-threatening or chronically debilitating nature of the disease.
  • Information to show the prevalence of the disease within the Community.
  • The costs incurred to date in developing the drug.
  • The provision of any grants, tax incentives or other cost recoveries.
  • Where there is more than one indication for the same drug, the justification for apportioning r&d costs between the different indications.
  • Future r&d and development costs.
  • Future production and marketing costs for first 10 years authorisation.

Lack of satisfactory alternative methods

  • Details of any existing alternative authorized methods including both medicinal products and medical devices.
  • Either a justification as to why such alternative methods are not considered satisfactory or a justification for the assumption that the drug will be of significant benefit to those affected by the disease.

The benefits of an ODD
The main practical benefit of an ODD is that once a marketing authorization has been accepted for the drug in question, the sponsor of the ODD is granted not merely data exclusivity but true market exclusivity for a period of 10 years. The way this works in practice is that the Community and the member states are obliged "not, for a period of 10 years, to accept any other applications for a marketing authorization or grant a marketing authorization or accept an application to extend an existing marketing authorization for the same therapeutic indication in respect of a similar medicinal product".

This 10-year period of market exclusivity can only be lost in the following circumstances:

  • If at the end of the fifth year, on an application from a member state, it is established that the criteria for ODD are no longer met and in particular that marketing exclusivity is no longer justified on economic grounds.
  • If the sponsor consents to a second application.
  • If the holder of the ODD is unable to supply sufficient quantities of the drug in question.
  • If the second applicant can establish that the second drug "although similar ... is safer, more effective or otherwise clinically superior".

The precise ambit of an ODD marketing exclusivity turns in particular on what is meant by the terms "similar medicinal product" and "clinical superiority". Both of these terms have been defined with some particularity in the implementing regulation: see box 2.

Box 2

The terms "similar medicinal product" and "clinical superiority" have been defined in the implementing regulation with some particularity.

"Similar medicinal product" means a medicinal product containing a similar active substance or substances as contained in a currently authorised orphan medicinal product, and which is intended for the same therapeutic indication.

"Similar active substance" means an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism.

This includes:

(1) Isomers, mixture of isomers, complexes, esters, salts and non-covalent derivatives of the original active substance, or an active substance that differs from the original active substance only with respect to minor changes in the molecular structure, such as a structural analogue.

(2) The same macromolecule only with respect to changes in the molecular structure such as:

(2.1) proteinaceous substances where:

  • the difference is due to infidelity of transcription or translation,
  • the difference in structure between them is due to post-translational events (such as different glycosylation patterns) or different tertiary structures,
  • the difference in the amino acid sequence is not major. Therefore, two pharmacologically related protein substances of the same group (for example, two biological compounds having the same International Non-proprietary Name (INN) sub-stem) would normally be considered similar,
  • the monoclonal antibodies bind to the same target epitope. These would normally be considered similar;

(2.2) polysaccharide substances having identical saccharide repeating units, even if the number of units varies and even if there are post-polymerisation modifications (including conjugation);

(2.3) polynucleotide substances (including gene transfer and antisense substances), consisting of two or more distinct nucleotides where:

  • the difference in the nucleotide sequence of the purine and pyrimidine basis or their derivatives is not major. Therefore for antisense substances, the addition or deletion of nucleotide(s) not significantly affecting the kinetics of hybridisation to the target would normally be considered similar. For gene transfer substances, unless the differences in the sequence were significant the substances would normally be considered similar,
  • the difference in structure between them relates to modifications to the ribose or deoxyribose sugar backbone or to the replacement of the backbone by synthetic analogues,
  • the difference is in the vector or transfer system;

(2.4) closely related complex partly definable substances (such as two related viral vaccines, or two related cell therapy products);


(3) the same radiopharmaceutical active substances, or one differing from the original in radionuclide, ligand, site of labelling or molecule-radionuclide coupling mechanism linking the molecule and radionuclide provided that it acts via the same mechanism.

"Clinically superior" means that a medicinal product is shown to provide a significant therapeutic or diagnostic advantage over and above that provided by an authorized orphan medicinal product in one or more of the following ways:

(1) greater efficacy than an authorized orphan medicinal product (as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative efficacy claim for two different medicinal products. Direct comparative clinical trials are generally necessary, however comparisons based on other endpoints, including surrogate endpoints may be used. In any case, the methodological approach should be justified;


(2) greater safety in a substantial portion of the target population(s). In come cases direct comparative clinical trials will be necessary;


(3) in exceptional cases, where neither greater safety nor greater efficacy has been shown, a demonstration that the medicinal product otherwise makes a major contribution to diagnosis or to patient care.

It is worth noting that the term similar medicinal drug is defined more broadly in the ODD legislation than the concept of "essential similarity" has been construed in the context of the data exclusivity legislation. This is not surprising given that the term "similar medicinal product" in effect defines the orphan drug innovator's exclusive territory and a broad definition is required in order to encourage and thereby reward orphan drug development. By contrast, the term "essentially similar" in effect defines the territory in which a subsequent generic applicant may after 10 years rely on the innovator's regulatory data in support of their own marketing authorization and a narrow definition is warranted given the balance struck by the data exclusivity legislation between the interests of the innovative sector, the generic sector and the public.

It is important to bear in mind that an ODD can be granted to different sponsors for the same or similar drugs for the same indication and that the grant of marketing exclusivity arises not merely by virtue of ODD but rather the subsequent acceptance of a marketing authorization for a previously designated orphan drug. This point raises a number of issues.

First, there has already been one case where positive marketing authorization opinions were given for similar drugs for the same indication from different applicants both of which had obtained an ODD for the same drug. It is understood that the Commission will accept the marketing authorization for each on the same day in which case the two products will each have marketing exclusivity against third parties but obviously not themselves.

Second, in the more usual case, for the second applicant for a marketing authorization to gain access to the market, they will have to establish the clinical superiority of the second drug. By way of example, in the US (whose Orphan Drug Act contains a similar clinical superiority ground on which to break the absolute monopoly granted by an ODD) Serono, the Swiss biotechnology company, is currently in the process of challenging Biogen's monopoly in respect of a multiple sclerosis treatment drug by carrying out comparative trials on both its and Biogen products.

The other benefits of an ODD are the provision of advice and assistance on the conduct of the clinical trials necessary to obtain a marketing authorization, the grant of a marketing authorization via the centralized as opposed to the national mutual recognition procedure, a reduction and/or waiver in application and renewal fees for the marketing authorization and finally, eligibility for EU R&D financial incentives intended to support research into the development of orphan drugs.

ODDs prove popular in the first year
To date, 113 applications for ODDs have been submitted, a further 58 applications are in the pipeline, the COMP has rendered 60 positive opinions and 51 ODDs have been granted by the EU Commission.

The details of the granted ODDs to date are set out in table 1.

Table 1


Therapeutic Indication


Designation Date

Somatropin Aids Wasting Ares-Serono (Europe) Ltd 8 Aug 2000
Alfa-Galactosidase A Treatment of Fabry disease TKT Europe-5S AB 8 Aug 2000
Alfa-Galactosidase A Treatment of Fabry disease Genzyme BV 8 Aug 2000
Fluorouracil Treatment of glioblastoma Ethypharm SA 18 Oct 2000
Gemtuzumab ozogamicin Treatment of acute myeloid Leukemia Wyeth Europa Ltd 18 Oct 2000
1,5 (Butylimino) - 1,5 - dideoxy, D-glucitol Treatment of Gaucher disease Oxford Glycosciences (UK) Ltd 18 Oct 2000
N-Carbamyl-L-glutamic acid Treatment of N-acetylglutamate synthetase (NAGS) deficiency Orphan Europe 18 Oct 2000
Arsenic trioxide Treatment of promyelocytic leukemia Voisin Consulting SARL 18 Oct 2000
Thalidomide Treatment of erythema nodosum leprosum (ENL) or type II lepra reactions Laboratoires LAPHAL 29 Dec 2000
Anagrelide Hydrochloride Treatment of essential thrombocythaemia Shire Pharmaceutical Development Ltd 29 Dec 2000
Busulfan (Intravenous use) Conditioning treatment prior to hematopoietic progenitor cell transplantation Pierre Fabre Medicament 29 Dec 2000
Nitisinone Treatment of tyrosinaemia type 1 Swedish Orphan AB 29 Dec 2000
Ethyl Eicosopentaenoate Treatment of Huntingdon's disease Laxdale Ltd 29 Dec 2000

Treatment of primary and of the following forms of second pulmonary hypertension:

  • connective tissue disease pulmonary hypertension
  • drug induced pulmonary hypertension
  • portopulmonary hypertension
  • pulmonary hypertension associated withcongenital heart disease
  • chronic thromboembolic pulmonary hypertension
Schering AG 29 Dec 2000
Xaliproden hydrochloride Treatment of amyotrophic lateral sclerosis Sanofi-Synthelabo 17 Jan 2001
Lusupultide Treatment of Acute Respiratory Distress Syndrome Byk Gulden 17 Jan 2001
Arsenic trioxide Treatment of acute promyelocytic leukaemia Pharmacie Centrale des Hopitaux de Paris 17 Jan 2001
Recombinant human acid - glucosidase Treatment of Glycogen Storage Disease type II (Pompe's disease) Genzyme 14 Feb 2001
Bosentan Treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension Actelion Pharmaceuticals France 14 Feb 2001
Ibuprofen Treatment of patent ductus arteriosus Orphan Europe 14 Feb 2001
Imatinib mesylate Treatment of chronic myeloid leukaemia Novartis Europharm Limited 14 Feb 2001
Laronidase Treatment of Mucopolysaccharidosis type I Genzyme 14 Feb 2001
Pegvisomant Treatment of acromegaly Pharmacia and Upjohn 14 Feb 2001
Ribavirin Treatment of Haemorrhagic Fever with Renal Syndrome ICN Pharmaceuticals Ltd 14 Feb 2001
N-acetylgalactosamine-4-sulfatase Treatment of Mucopolysaccharidosis type VI (Maroteaux-Lamy Syndrome) Clin Trials Research Limited 14 Feb 2001
L-Lysine-N-acety-L-cysteinate Treatment of cystic fibrosis SMB Technology SA 14 Feb 2001
Ibuprofen Prevention of patient ductus arteriosus in premature neonates of less than 34 weeks gestational age Orphan Europe 5 March 2001
Inolimomab Treatment of Graft versus Host Disease OPI Orphan Pharma International 5 March 2001
Ribavirin Treatment of adenovirus infection in immunocompromised patients ICN Pharmaceuticals Ltd 8 March 2001
8-cyclopentlyl-1,3-dipropylxantine Treatment of cystic fibrosis SciClone Pharmac. Italy Srl 29 March 2001
Arsenic trioxide Treatment of myelodysplastic syndromes Cell Therapeutics (UK) Ltd 29 March 2001
Arsenic trioxide Treatment of multiple myeloma Cell Therapeutics (UK) Ltd 29 March 2001
Ranpirnase Treatment of malignant mesothelioma Dr E Morgenstern 29 March 2001
Gusperimus trihydrochloride Treatment of Wegener's granulomatosis Euro Nippon Kayaku GmbH 29 March 2001
Levodopa and Cardidopa(gastroenteral use) Treatment of advanced idiopathic Parkinson's disease with sever motor fluctuations and not responding to oral treatment NeoPharma Production AB 10 May 2000
Recombinant human C1-inhibitor Treatment of angioedema caused by C1 inhibitor deficiency Pharming NV 11 May 2000
Humanised Anti-HM 1.24 Monoclonal Antibody Treatment of multiple myeloma Chugai Pharma Europe Ltd 10 May 2000
Retroviral g c cDNA containing vector Treatment of severe combined immunodefieicny (SCID)-XI disease Genopoeitic SA 30 May 2000
Ecteinascidin 743 Treatment of soft tissue sarcoma Pharma Mar SA 30 May 2000
Fomepizole Treatment of methanol poisoning IDIS Ltd 30 May 2000
Recombinant human alpha-1-antitrypsin (respiratory use) Treatment of emphysema secondary to congenital alpha-1-antitrypsin deficiency Bayer AG 30 May 2000
Human engineered monoclonal antibody specific for Trasforming Growth Factor b2 Prevention of scarring in glaucoma filtration surgical procedures Cambridge Antibody Technology 30 May 2000
Human Milk Globule 1/Human Milk fat Globule 1 -S- p-isothiocyanatobenzyl-diethylenetriaminepentaacetic acid for use with Yttrium Treatment of ovarian cancer Antisoma PLC 30 May 2000

Source: Life Science Law Review

It is understood that in the first year of operation, of the applications which did not succeed, seven applications were withdrawn after an evaluation, four were withdrawn spontaneously by the sponsor and three received negative opinions. It is further understood that there were two main reasons for a lack of success. First, the failure to define clearly the orphan disease as a result of "salami slicing" a larger indication. Second, the failure to consider all forms of existing treatment and not merely pharmaceuticals when justifying a significant benefit for the potential new drug.

Although the grant of an ODD is no guarantee of success in obtaining a marketing authorization and still less a successful pharmaceutical product, the high level of interest in ODDs in the first year of operation strongly suggests that it will not be long before the first ODDs become available on the market and begin to make a real impact on the diagnosis, treatment and prevention of at least some the rarer diseases within the EU.

First published on in November 2001.

Important - The information in this article is provided subject to the disclaimer. The law may have changed since first publication and the reader is cautioned accordingly.