58 69 Success of the European Orphan Medicines Regime.Fm

Cross-border Life Sciences 2003

The success of the European orphan medicines regime

Peter Bogaert, Covington & Burling

www.practicallaw.com/A27971

In April, 2000, a totally new European orphan medicines regime 2309/93 - entitles an applicant to obtain a marketing authorisa- came into effect. This was many years after adoption of a similar tion if the application complies with the requirements set out in incentive scheme in the US and examples in other countries, that legislation (see, for instance, the decision of 7th December, such as Japan. The rules are intended to provide incentives for 1993 of the ECJ in Pierrel SpA and others v Ministero della research and development of medicines intended for the Sanità, Case C-83/92). treatment, prevention or diagnosis of rare disorders that otherwise would not be pursued by industry in light of the limited Preparatory policy work carried out between 1993 and 1996 chances of return on investment. It is estimated that there are ultimately resulted in a formal Commission proposal for a between 5,000 and 8,000 such rare disorders in the world, the European orphan medicines regime in August 1996. Following a majority of which are of a genetic origin, and that up to 30 million highly efficient and constructive legislative procedure, on 16th people affected by one of these rare diseases live in the EU. December, 1999 the European Parliament and the Council adopted the basic text (Regulation No. 141/2000 of the The regime is intensively used by industry and overall is quite European Parliament and the Council of 16th December, 1999 successful, although it has not yet reached full maturity. Its on orphan medicinal products, OJ 2nd January, 2000, L18/1) success has also helped the thinking on other regulatory (the Regulation). It became applicable on 27th April, 2000,

Cross-border incentive schemes, like a new paediatric exclusivity regime which when the first implementing Commission Regulation was currently is under review by the European Commission. adopted (Commission Regulation No 847/2000 of 27th April, 2000, Official Journal 28th April, 2000, L 103/5) (the This article examines: Implementing Regulation).

■ The background and status of the European orphan medi- Objectives. The objectives of the Regulation are: cines regime. ■ To establish an EU procedure for identifying medicines that ■ How orphan medicines are designated. are intended to treat, prevent or diagnose rare diseases (orphan medicines); and ■ Market exclusivity issues. ■ To provide for a EU wide ten-year market exclusivity incen- ■ Regulatory assistance for sponsors. tive to attract the necessary investment in research, development and marketing efforts. The market exclusivity is BACKGROUND intended to allow companies to charge higher prices, and thus to increase the chances of a proper return. The US adopted the Orphan Drug Act in 1983 with the intention of stimulating the development of medicines for treatment of rare The regime is not intended to be exclusive, and the Regulation diseases by means of tax credits and a seven-year market specifically invites the EU and the member states to provide for exclusivity for approved orphan medicines. The act has proven to additional orphan medicine incentives. be very effective, and over 220 orphan drugs have received approval. Legal status. Although the original intention was to prepare EC legislation in the form of a directive, the first preliminary draft Slowly, pressure developed for similar incentives in Europe, proposal released by the Commission was presented in the form which led to limited national measures. These included, for of a regulation, and that legal form was maintained in the final example, the procedure for exceptional temporary marketing version. The use of a regulation, which, in accordance with article authorisations in France (autorisations temporaires d’utilisation 249 of the EC Treaty, has direct effect in all the member states, or ATU) and administrative measures by the European Medicines is more efficient but it also means that the text cannot be further Evaluation Agency (EMEA) (accelerated review and partial or fine tuned at the stage of implementation into national law (as is total waiver of fees). often the case with a directive).

The main incentive, however, in the form of market exclusivity, In addition, the Regulation is intended to provide an incentive for had to be adopted at EU level because EC pharmaceutical mainly innovative companies to commit substantial resources to legislation - in particular Directive 2001/83 (codifying a number the development of orphan medicines, and it is likely that in of earlier directives, including Directive 65/65) and Regulation several cases the commercial success of companies or joint

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venture projects will depend on the reliability of the exclusivity any stage of the development of the product, until an application rights under the Regulation. It can therefore be expected that the for marketing authorisation is filed (article 5.1, the Regulation terms of the Regulation will be the subject of litigation, although and article 2.4(a), the Implementing Regulation). that does not yet seem to have occurred. The application is submitted to the EMEA (which should in Scope. The Regulation covers medicinal products for human use principle be informed in writing at least two months in advance). (as defined in article 1 of Directive 2001/83). Because orphan The EMEA assesses the application and forwards it, together with medicine status must be applied for before an application for a a summary report, to the Committee for Orphan Medicinal marketing authorisation is submitted, the regulation does not Products. The Committee consists of 21 members (one member apply to products that were approved or for which an application nominated by each member state and six members nominated by for approval was pending before 27th April, 2000 (except for new the Commission, of which three represent patients’ organisa- orphan indications of an existing product (article 2.4(a), the tions). Implementing Regulation)). During the legislative process, a proposal was made to allow products that were in the process of Within 90 days, the committee adopts, by consensus or by being approved to also benefit from the Regulation, but this was majority vote, an opinion on the application, which is then not accepted. transmitted to the Commission for a decision, normally within 30 days. Main provisions. The Regulation provides for: An orphan medicine designation must refer to either the

■ Criteria and a procedure for designating orphan medicines. prevalence criterion or the potential return on investment criterion (article 2, the Implementing Regulation).

■ A ten-year market exclusivity period (subject to revision after Cross-border six years). Designated products are entered in a Community Register of Orphan Medicinal Products. Since March, 2002, the EMEA has

■ Regulatory assistance to companies developing orphan med- published summaries of the opinions on designation (see http:// icines (in the form of protocol assistance and guaranteed www.emea.eu.int/index). access to the centralised marketing authorisation procedure). An application for designation may also be submitted for a new therapeutic indication for an already authorised medicinal ORPHAN MEDICINE DESIGNATION product. In this case, the marketing authorisation holder must apply for a separate marketing authorisation to cover just the orphan indication. The sponsor of an orphan medicine must establish a number of criteria for a medicine to be designated as an orphan medicine. An application for orphan medicine designation must: The sponsor is the natural or legal person, established in the EU, seeking to obtain or having obtained the designation of a ■ Contain details of the sponsor. medicinal product as an orphan medicinal product (article 2, the Regulation). ■ Specify the active ingredient(s) of the product and the proposed therapeutic indication. First the sponsor must establish one of the two following criteria:

■ Justify that the criteria for designation are met. ■ That the orphan medicine is intended for the diagnosis, prevention or treatment of a life-threatening or chronically The criteria for designation. The Implementing Regulation 847/ debilitating condition affecting not more than five in 10,000 2000 and Commission guidelines (updated in October, 2002) people in the EU when the application is made (the “preva- specify in more detail what information must be submitted. lence criterion”). For an application based on the prevalence criterion, the informa- ■ That the orphan medicine is intended for the diagnosis, pre- tion must include, among other things: vention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the EU and that ■ Appropriate details on the condition intended to be treated without incentives it is unlikely that the marketing of the and a justification of the life-threatening or chronically medicinal product in the EU would generate sufficient debilitating nature of the condition supported by scientific return to justify the necessary investment (the “return on or medical references. investment criterion”). ■ Authoritative references which demonstrate that the disease In addition, the sponsor must establish that there is no satisfac- or conditions for which the medicinal product would be tory method of diagnosis, prevention or treatment of the administered affects not more than five in 10,000 people in condition in question already authorised in the EU or, if such the EU at the time at which the application for designation method exists, that the medicinal product will be of significant is submitted. benefit to those affected by that condition (article 3.1, the Regulation). ■ A review of the relevant scientific literature and information from relevant databases in the EU, if available. Where no An application for orphan medicine designation can be made at database in the EU is available, reference may be made to This article was first published in the Global Counsel Life Sciences Industry Report 2003 and is reproduced with the kind permission of the publisher, Practical Law Company. For further information or to obtain copies please contact [email protected], or visit www.practicalllaw.com/lifesciences GLOBAL COUNSEL HANDBOOKS www.practicallaw.com/lifesciences 59 Cross-border Life Sciences 2003

databases available in third countries, provided the appropri- ■ All cost and revenue data must be determined in accordance ate extrapolations are made. with generally accepted accounting practices and be certi- fied by a registered accountant in the EU.

■ Where a disease or condition has been considered within the framework of other Community activities on rare diseases, ■ Information on the prevalence and incidence in the EU of this information must be provided. In the case of diseases or the condition for which the medicinal product would be conditions included in projects financially supported by the administered at the time at which the application for desig- EU, a relevant extract from this information, including nation is submitted. details of the prevalence of the disease or condition in question, should be provided. The Implementing Regulation further defines “significant benefit” (of the proposed orphan medicine over existing The Commission guidelines also provide that when the proposed therapies) as “a clinically relevant advantage or a major contribu- therapeutic indication refers to a subset of a particular patient tion to patient care”, and requires the following information to be population, a justification of the medical plausibility of this submitted on existing therapies: population-sub-set should be provided. This aims to exclude “salami-slicing” of indications to fit the prevalence criterion. ■ Details of any existing diagnosis, prevention or treatment Additional general guidance is also contained in a guideline methods of the condition in question that have been author- issued by the Committee for Orphan Medicinal Products in March ised in the EU must be provided, making reference to scien- 2002 (COMP/436/01). tific and medical literature or other relevant information. These may include authorised medicinal products, medical devices or other methods of diagnosis, prevention or treat- The prevalence criterion is in practice clearly the preferred route ment which are used in the EU. for companies. The published summaries of designation opinions show that the prevalence of the diseases in question varies ■ Either a justification as to why the methods referred to above widely, for instance from about 750 non-ketotic hyperglyci- are not considered satisfactory or a justification for the naemia patients to 170,000 patients suffering from ulcerative assumption that the medicinal product for which designa- colitis. The maximum allowed is about 187,000 patients in the tion is sought will be of significant benefit to those affected

Cross-border current Union of 15 member states. by the condition.

For an application based on the return on investment criterion, Since the Regulation is intended to stimulate investment in new the information required includes among other things: products, the “significant benefit” criterion should not be applied too strictly. Before a decision to invest in a product is ■ Appropriate details on the condition intended to be treated made, only limited data will be available to demonstrate an and a justification of the life-threatening or seriously debili- expected significant benefit. Fortunately, the revised version of tating or serious and chronic nature of the condition sup- the guidelines now recognises that the potential availability of an ported by scientific or medical references. orphan medicine may be taken into account in finding that it will be of “significant benefit”, in particular when an existing therapy ■ Data on all costs that the sponsor has incurred in the course is approved only in a limited number of member states. of developing the medicinal product. Different sponsors can obtain an orphan medicine designation for

■ Details of any grants, tax incentives or other cost recovery medicines that contain the same (or essentially the same) active provisions received either within the EU or in third countries. ingredient and are intended for the same therapeutic indications (article 2.4(b), the Implementing Regulation). The first product that obtains approval will then block approval of the other (see ■ Where the medicinal product is already authorised for any below “Market exclusivity: Practical application of the exclusivity indication or where the medicinal product is under investiga- provisions” and also, for a list of orphan medicines designated tion for one or more other indications, a clear explanation of, until the end of December, 2002, see box “Designated orphan and justification for, the method that is used to apportion medicines and marketing authorisations”). the development costs among the various indications.

Detailed information on the designation procedure, including the ■ A statement of, and justification for, all development costs Commission guidelines and an application format, are available that the sponsor expects to incur after the submission of the on the website of the Pharmaceutical and Cosmetics Unit of the application for designation. Commission (www.pharmacos.eudra.org/orphanmp/index.htm) and of the EMEA (http://www.emea.eu.int/index). ■ A statement of and justification for all production and marketing costs that the sponsor has incurred in the past and Losing orphan medicine status. A product is removed from the expects to incur during the first ten years that the medicinal register of orphan medicines when it is established, before the product is authorised. product receives a marketing authorisation, that the criteria for orphan medicine designation are no longer met (article 5.12, the ■ An estimate and justification for the expected revenues from Regulation). The prevalence criterion, however, is not to be sales of the medicinal product in the EU during the first ten reassessed since it applies at the time of application for designa- years after authorisation. tion. This can have severe consequences for the sponsor and This article was first published in the Global Counsel Life Sciences Industry Report 2003 and is reproduced with the kind permission of the publisher, Practical Law Company. For further information or to obtain copies please contact [email protected], or visit www.practicalllaw.com/lifesciences 60 GLOBAL COUNSEL HANDBOOKS www.practicallaw.com/lifesciences Life Sciences 2003 Cross-border

undermine the basic intention of the Regulation, which is to is applied for by the sponsor of the orphan medicine. If the provide incentives for research and development. The research application is submitted by a third party, however, it is advisable and development expenditure is, of course, primarily (or at least to submit written evidence that the sponsor recognises that the significantly) made before the application for a marketing author- application relates to the product for which he holds the orphan isation, but the incentive can be taken away during the approval medicine designation. This makes it clear that the marketing procedure even if approval is ultimately granted. authorisation triggers the exclusivity.

It is, for instance, possible that a sponsor obtains orphan The exclusivity rights are not unlimited. The scope of the medicine designation for a product for a specific application exclusivity is restricted to “similar medicinal products” and the because there are no existing approved therapies for that indica- exclusivity can be ignored or broken in a number of specific tion, but a similar product is being used off label. If in such circumstances. circumstances a marketing authorisation holder for such a similar product can obtain approval for a variation extending the indica- Scope of exclusivity. The exclusivity protects against a similar tions to include the orphan medicine indication (without, for medicinal product with the same therapeutic indication. instance, himself seeking orphan medicine status), this can undermine the investments made by the sponsor of the orphan A “similar medicinal product” is further defined in the medicine. This is not hypothetical since the active ingredients of Implementing Regulation as a medicinal product containing a orphan medicines may be well known substances (see box similar active substance or substances (a substance with physio- “Designated orphan medicines and marketing authorisations”). logical or pharmacological activity) as contained in a currently This can be unfair, particularly when the sponsor is unaware of authorised orphan medicinal product, and which is intended for the attempts of the other entity to seek approval (which is not the the same therapeutic indication. case in the situation of two competing products that both Cross-border obtained orphan medicine status, which is made public) or when A similar active substance means an identical active substance, the variation to the existing product is granted on the basis of a or an active substance with the same principal molecular somewhat incomplete file. structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism. In this context, the principle that at least a single national This includes: approval should not be considered as a “satisfactory” existing therapy, or that at least an orphan medicine that is expected to ■ Isomers, mixture of isomers, complexes, esters, salts and become centrally approved will offer a “significant benefit”, is of non-covalent derivatives of the original active substance, or even higher importance than at the time of application of the an active substance that differs from the original active sub- orphan medicine designation. stance only with respect to minor changes in the molecular structure, such as a structural analogue. MARKET EXCLUSIVITY ■ The same macromolecule or one that differs from the original macromolecule only with respect to changes in the The cornerstone of the Regulation is the market exclusivity for ten molecular structure. years granted to approved orphan medicines. The exclusivity means that the member states, and the Community, will not, for The Implementing Regulation does not provide further rules on a period of ten years, “accept another application for a marketing the same therapeutic indication. In order to give useful effect to authorisation, or grant a marketing authorisation or accept an the Regulation, the phrasing should not be interpreted literally, application to extend an existing marketing authorisation, for the but should be read taking into account what medically consti- same therapeutic indication, in respect of a similar medicinal tutes the same indication. product.” (The term “extend an existing marketing authorisation” refers to approval of a new indication for an already approved Breaking the exclusivity. The exclusivity can be broken in any of product by means of a variation instead of a new marketing the following scenarios: authorisation). This is intended to guarantee a sufficient return

to justify investment in the development of orphan medicines. It ■ With the consent of the marketing authorisation holder of is independent of any other exclusivity under intellectual property the original orphan medicine. rights (in particular patents and supplementary protection certif-

icates) or data exclusivity (under article 8 of Directive 2001/83). ■ If that marketing authorisation holder cannot supply sufficient quantities of the medicine (which is not related to the Exclusivity is only triggered when the orphan medicinal product price at which that person markets the product, but only is approved, either under the centralised procedure (a marketing covers a general inability to arrange for adequate supplies). authorisation issued under Regulation 2309/93) or, in all member states, under the decentralised procedure (15 national ■ When a new product, although similar, is safer, more effec- marketing authorisations, issued in accordance with the relevant tive or otherwise clinically superior. provisions of Directive 2001/83). As a rule, however, sponsors of orphan medicines choose the centralised procedure which is The Implementing Regulation defines “clinically superior” as automatically available to them (see below) and which is easier meaning that a medicinal product is shown to provide a signifi- to manage in this context. cant therapeutic or diagnostic advantage over and above that provided by an authorised orphan medicinal product in one or The Regulation does not require that the marketing authorisation more of the following ways: This article was first published in the Global Counsel Life Sciences Industry Report 2003 and is reproduced with the kind permission of the publisher, Practical Law Company. For further information or to obtain copies please contact [email protected], or visit www.practicalllaw.com/lifesciences GLOBAL COUNSEL HANDBOOKS www.practicallaw.com/lifesciences 61 Cross-border Life Sciences 2003

■ Greater efficacy than an authorised orphan medicinal prod- their marketing authorisations on the same day (4th May, 2001). uct (to be assessed by controlled clinical trials). Generally, The Commission's view is apparently that the two products, this would represent the same kind of evidence needed to because they were approved concurrently, share the market support a comparative efficacy claim for two different exclusivity rights, but there are several legal questions that can medicinal products. be raised in that regard.

■ Greater safety in a substantial portion of the target popula- The situation of alfa-galactosidase may be rare, and will even be tion(s). In some cases direct comparative clinical trials will rarer in the future since the products were in the pipeline and the be necessary. companies in question awaited the adoption of the Regulation before applying for a marketing authorisation. ■ In exceptional cases, where neither greater safety nor greater efficacy has been shown, a demonstration that the medicinal REGULATORY ASSISTANCE product otherwise makes a major contribution to diagnosis or to patient care. The Regulation provides for regulatory assistance to sponsors of orphan medicines: Finally, it is important to note that the exclusivity only protects against new marketing authorisations being granted. In practice, ■ The EMEA is expected to provide protocol assistance to in some member states, relevant sales can be made on the basis sponsors of orphan medicinal products, assisting them to of named patient sales (such as, for instance, under the broad design the tests and trials required to prepare a marketing individual importation provisions of section 73(3), the German authorisation application (see the EMEA guidance for com- Arzneimittelgesetz). panies requesting protocol assistance regarding scientific issues, 27th February, 2002, EMEA/H/238/02). Possible reduction of exclusivity. The ten year exclusivity period is subject to a reduction to six years if the criteria for orphan ■ Orphan medicines have a guaranteed access to the central- status are no longer met at the end of the fifth year following ised procedure leading to a marketing authorisation that is approval (article 8.2, the Regulation). A member state must automatically valid for the entire EU (although does not nec- inform the EMEA that the criterion on the basis of which market essarily provide automatic access to the market; several Cross-border exclusivity was granted may not be met and the EMEA will then member states still apply pricing and reimbursement initiate the procedure set out in article 5 (which is the same as approval procedures). In many instances, access to the cen- for granting orphan medicine status, but is started by a member tralised procedure would already be available under the cur- state). rent rules (the procedure is in general mandatory for the biotechnological products covered by Part A of the Annex to It is clear that a review under article 8.2 can only cover those Regulation 2309/93, and optional for new chemical entities criteria for orphan medicine designation that were relied on at the and other innovative products covered by Part B of the time of obtaining the designation. When, for instance, a product annex), but guaranteed access may constitute an additional was given orphan medicine status on the basis of the prevalence incentive. criterion, the market exclusivity cannot be reduced to six years for reasons of sufficient profitability of the product since that is only ■ The regulation also calls for a special budget being made relevant under the return on investment criterion. available for waiving (in part or in total) the fees payable to the EMEA. The budget for 2002, for instance, amounted to When reassessing the absence of an (equivalent) alternative EUR3.3 million (US$3,485,000). therapy, obviously the orphan medicine itself must not be taken into consideration. Other support. The Regulation also provides that orphan medicines are eligible for incentives made available by the EU Practical application of the exclusivity provisions. The Regula- and by member states to support research into, and the develop- tion is intended to grant an approved orphan medicine protection ment and availability of, orphan medicines (and in particular aid against subsequent approvals for products that are sufficiently for research for small and medium size enterprises). similar (as to the active ingredient and the therapeutic indication (see above “Scope of exclusivity”), unless there are overriding Member states must inform the Commission of available reasons to allow a subsequent approval (see above “Breaking the incentives, and the Commission must publish an inventory of EU exclusivity”). This protection is available against approval of a and member states’ incentives. The Commission posts on its competing product irrespective of whether that product also website an “Inventory of Community and national incentive obtained orphan medicine designation. measures to aid the research, marketing, development and availability of orphan medicinal products.” These rules can, of course, also apply to two similar products that are in a similar stage of development. An interesting example of The regulation does not, however, oblige member states or the EU two orphan medicines in that situation are the alfa-galactosidase to provide any additional incentives. In particular, there is no products developed by Genzyme (Fabrazyme) and Trans-Karyotic provision for tax incentives, which are, for instance, a crucial part Therapies (Replagal), each for the treatment of Fabbry disease. of the US regime (but according to the inventory published by the The two products were among the first three products to receive EU, France has granted special exemptions from pharmaceutical orphan designation under the Regulation in August, 2000. industry taxes and the Netherlands and the UK operate general Undoubtedly not as a coincidence, the products also received tax benefits for research and development activities). This article was first published in the Global Counsel Life Sciences Industry Report 2003 and is reproduced with the kind permission of the publisher, Practical Law Company. 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DESIGNATED ORPHAN MEDICINES AND MARKETING AUTHORISATIONS

The following products have up to December, 2002 received orphan medicine status (and where applicable, a marketing authorisation):

Register of designated Orphan Medicinal Products (by number) EU Designation Product Designated Orphan Indication Sponsor Designation date (and tradename, EU centralised number, and authorisation date where applicable) EU/3/02/127 Cholic acid Treatment of inborn errors in Agence générale des équipe- 18/12/2002 primary bile acid synthesis ments et produits de santé - Etablissement pharmaceu- tique des hôpitaux de Paris (AGEPS-EPHP) EU/3/02/126 Recombinant inhibitor of Treatment of angioedema Dyax s.a. 18/12/2002 human plasma kallikrein Cross-border EU/3/02/125 Monoclonal antibody to Treatment of post-transplant OPI Orphan Pharma Interna- 18/12/2002 human interleukin-6 lymphoproliferative disorders tional EU/3/02/123 Anti-CD147 murine Treatment of Graft versus Host SangStat UK Limited 14/11/2002 monoclonal IgM Disease EU/3/02/122 Etilefrin Treatment of low flow priapism Laboratoires SERB 13/11/2002 EU/3/02/121 5-aminolevulinic acid Intra-operative photodynamic Medac Gesellschaft für 13/11/2002 hydrochloride diagnosis of residual glioma klinische Spezialpräparate mbH EU/3/02/120 Duramycin Treatment of cystic fibrosis Dr. Gerd Döring, Hygiene- 13/11/2002 Institut, Universität Tübingen EU/3/02/119 Iodine 131 radiolabeled anti- Treatment of glioma Interface International 13/11/2002 nucleohistone H1 chimeric Consultancy Limited biotinylated monoclonal antibody EU/3/02/118 Recombinant glycoprotein Prevention of post transplanta- Henogen S.A. 22/10/2002 gp350 of Epstein-Barr virus tion lympho-proliferative disorders EU/3/02/117 Boswellia serrata resin extract Treatment of peritumoral Pharmasan GmbH 21/10/2002 oedema derived from brain tumours EU/3/02/116 Autologous renal cell tumor Treatment of renal cell Liponova GmbH 21/10/2002 vaccine carcinoma EU/3/02/115 (-)-17-(cyclopropylmethyl)- Treatment of uremic pruritus Toray Europe Limited 11/09/2002 3,14 ß-dihydroxy-4,5 a- epoxy-6ß-[N-methyl-trans-3- (3-furyl) acrylamido] morphinan hydrochloride (intravenous use) EU/3/02/114 Myristoylated-peptidyl- Treatment of paroxysmal Adprotech Limited 11/09/2002 recombinant Human CD59 nocturnal haemoglubinuria EU/3/02/113 Mitotane Treatment of adrenal cortical Agence générale des équipe- 11/09/2002 carcinoma ments et produits de santé - Etablissement pharmaceu- tique des hôpitaux de Paris (AGEPS-EPHP)

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EU/3/02/112 Doxorubicin carbon/iron Treatment of hepatocellular Interface International 11/09/2002 magnetically targeted carcinoma Consultancy Limited microparticles EU/3/02/111 Benzoic acid, sodium salt Treatment of non-ketotic Ethicare GmbH 11/09/2002 hyperglycinaemia EU/3/02/110 Thymalfasin Treatment of hepatocellular SciClone Pharmaceuticals 30/07/2002 carcinoma Italy S.r.l EU/3/02/109 Oregovomab Treatment of ovarian cancer Dorian Regulatory Affairs 30/07/2002 EU/3/02/108 Myristoylated-peptidyl- Prevention of post transplanta- Adprotech Limited 30/07/2002 recombinant SCR1-3 of tion graft dysfunction human complement receptor type I EU/3/02/107 Purified bromelain Treatment of partial deep Professor Keith Judkins 30/07/2002 dermal and full thickness burns EU/3/02/106 Antisense NF-kappaB p65 Treatment of active ulcerative InDex Pharmaceuticals AB 30/07/2002 Oligonucleotide colitis EU/3/02/105 Carbamic acid, [[4-[[3-[[4-[1- Treatment of cystic fibrosis Boehringer Ingelheim 26/06/2002 (4-hydroxyphenyl)-1-methyl- International GmbH ethyl]phenoxy]methyl]phenyl] methoxy]-phenyl]iminome- thyl]-,ethyl ester EU/3/02/104 Miltefosine Treatment of visceral leishma- Zentaris Aktiengesellschaft 12/06/2002

Cross-border niasis EU/3/02/103 Recombinant Human Porpho- Treatment of acute intermit- HemeBiotech A/S 12/06/2002 bilinogen Deaminase tent porphyria EU/3/02/102 Mitotane Treatment of adrenal cortical Laboratoire HRA Pharma 12/06/2002 carcinoma EU/3/02/101 Pseudomonas exotoxin Treatment of glioma PPD Global Ltd 30/04/2002 (domains II/III)-Interleukin 13 chimeric protein EU/3/02/100 Recombinant human alpha-1- Treatment of emphysema Baxter AG 30/04/2002 antitrypsin (respiratory use) secondary to congenital alpha- 1-antitrypsin deficiency EU/3/02/099 Bryostatin-1 Treatment of oesophageal GPC Biotech AG 30/04/2002 cancer EU/3/02/098 Epothilone B Treatment of ovarian cancer Novartis Europharm Limited 22/03/2002 EU/3/02/097 Humanised anti-KSA Treatment of renal cell Merck KGaA 22/03/2002 monoclonal antibody - human carcinoma interleukin-2 fusion protein EU/3/02/096 Nitisinone Treatment of alkaptonuria Swedish Orphan AB 13/03/2002 EU/3/02/095 Chimeric IgG monoclonal Treatment of renal cell Wilex AG 19/03/2002 antibody cG250 for use with carcinoma 131I EU/3/02/094 Chimeric IgG monoclonal Treatment of renal cell Wilex AG 19/03/2002 antibody cG250 carcinoma EU/3/02/093 Beclomethasone 17, 21- Treatment of intestinal graft- Voisin Consulting S.A.R.L. 13/03/2002 dipropionate (oral use) versus-host disease EU/3/02/092 4-(3,5-bis-(hydroxy-phenyl)- Treatment of chronic iron Novartis Europharm Limited 13/03/2002 1,2,4) triazol-1-yl)-benzoic overload requiring chelation acid therapy

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EU/3/02/091 TGF-ß2 specific phospho- Treatment of high-grade Antisense Pharma GmbH 22/03/2002 rothioate antisense oligodeox- glioma ynucleotide EU/3/02/090 Human transferrin conjugated Treatment of gliomas KS Biomedix Holdings PLC 19/03/2002 to mutant diphtheria toxin EU/3/02/089 GM-CSF receptor antagonist Treatment of juvenile British Biotech Pharmaceuti- 18/03/2002 myelomonocytic leukaemia cals Ltd EU/3/02/088 Colistimethate sodium Treatment of Pseudomonas Forest Laboratories UK Ltd 19/02/2002 aeruginosa lung infection (including colonisation) in cystic fibrosis EU/3/02/087 Eflornithine hydrochloride Treatment of Familial ILEX Services Limited 19/02/2002 Adenomatous Polyposis (FAP) EU/3/02/086 Porfimer sodium (for use with Treatment of high-grade Axcan Pharma International 06/03/2002 photodynamic therapy) dysplasia in Barrett´s BV Esophagus EU/3/02/085 Carmustine (solution for Treatment of glioma Icon Clinical Research UK 05/03/2002 intratumoral injection) Ltd EU/3/01/084 Azacitidine Treatment of myelodysplastic Pharmion Limited 06/02/2002 Cross-border syndromes EU/3/01/083 Adenovirus-mediated Herpes Treatment of high-grade Ark Therapeutics Limited 06/02/2002 Simplex Virus-thymidine glioma with subsequent use of kinase gene ganciclovir sodium EU/3/01/082 2-chloro-9-[2-deoxy-2-fluoro- Treatment of acute lymphob- Bioenvision Limited 05/02/2002 ß-D-arabinofuranosyl]adenine lastic leukaemia EU/3/01/081 Fumagillin Treatment of diarrhoea associ- Sanofi-Synthelabo 04/02/2002 ated with intestinal microsporidial infection EU/3/01/080 Human engineered Treatment of Systemic Genzyme Europe B.V. 04/02/2002 monoclonal antibody specific Sclerosis for Transforming Growth Factor ß1 EU/3/01/079 Sinapultide, dipalmitoylphos- Treatment of acute lung injury Discovery Laboratories Inc. 04/02/2002 phatidylcholine, palmitoyloleoyl phosphatidylglycerol and palmitic acid EU/3/01/078 Iduronate-2-sulfatase Treatment of Mucopolysac- TKT UK Ltd 11/12/2001 charidosis, type II (Hunter Syndrome) EU/3/01/077 [gly2] Recombinant human Treatment of Short Bowel PAREXEL International 11/12/2001 glucagon-like peptide Syndrome Limited EU/3/01/076 Octovalent Pseudomonas Prevention of Pseudomonas Orphan Europe 11/12/2001 aeruginosa O-polysaccharie- aeruginosa infections in toxin A conjugate vaccine patients with cystic fibrosis EU/3/01/075 Denileukin diftitox Treatment of cutaneous T-cell Ligand Pharmaceuticals UK 11/12/2001 lymphoma Ltd EU/3/01/074 Halofuginone Hydrobromide Treatment of Systemic PPD Global Ltd 11/12/2001 Sclerosis EU/3/01/073 Recombinant human Treatment of invasive fungal NeuTec Pharma plc 05/12/2001 monoclonal antibody to infections hsp90

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EU/3/01/072 Apomorphine (oromucosal Treatment of off-periods in Orion Corporation 05/12/2001 use) Parkinson’s disease not responding to other oral treatment EU/3/01/071 Stiripentol Treatment of severe myoclonic Laboratoires BIOCODEX 05/12/2001 epilepsy in infancy EU/3/01/070 Celecoxib Treatment of Familial Pharmacia-Pfizer EEIG 20/11/2001 Adenomatous Polyposis EU/3/01/069 Phenylephrine Hydrochloride Treatment of ileal pouch anal S.L.A. Pharma (UK) Limited 20/11/2001 anastomosis related faecal incontinence EU/3/01/068 Thalidomide Treatment of Multiple Kendle International Limited 19/12/2001 Myeloma EU/3/01/067 Thalidomide Treatment of Multiple Pharmion Limited 20/11/2001 Myeloma EU/3/01/066 Thalidomide Treatment of erythema Pharmion Limited 20/11/2001 nodosum leprosum (ENL) or type II lepra reactions EU/3/01/065 Deoxyribose phosphorothioate Treatment of Multiple Aventis Pharma S.A. 20/11/2001 (5´-tct-ccc-agc-gtg-cgc-cat- Myeloma 3´) EU/3/01/064 Abetimus sodium Treatment of lupus nephritis Icon Clinical Research UK 20/11/2001 Ltd

Cross-border EU/3/01/063 Deoxyribose phosphorothioate Treatment of chronic Aventis Pharma S.A. 20/11/2001 (5´-tct-ccc-agc-gtg-cgc-cat- lymphocytic leukaemia 3´) EU/3/01/062 Idebenone Treatment of Friedreich’s Laboratoires Takeda 20/11/2001 ataxia EU/3/01/061 Imatinib mesilate Treatment of malignant Novartis Europharm Limited 20/11/2001 gastrointestinal stromal tumours EU/3/01/060 Pemetrexed disodium Treatment of malignant Eli Lilly Nederland BV 17/09/2001 mesothelioma EU/3/01/059 Dexrazoxane Treatment of anthracycline TopoTarget A/S 19/09/2001 extravasations EU/3/01/058 Repertaxin L-lysine salt Prevention of delayed graft Dompé s.p.a. 19/09/2001 function in organ transplant EU/3/01/057 Porcine lung surfactant Treatment of acute lung injury Leo Pharmaceutical Products 19/09/2001 EU/3/01/056 Recombinant human acid Treatment of Niemann-Pick Genzyme B.V. 19/09/2001 sphingomyelinase Disease, type B EU/3/01/055 Cladribine (subcutaneous Treatment of indolent non- Lipomed GmbH 18/09/2001 use) Hodgkin’s lymphoma EU/3/01/054 Sinapultide, dipalmitoylfos- Treatment of Meconium Discovery Laboratories Inc. 19/09/2001 fatidylcholine, palmitoyloleoyl Aspiration Syndrome fosfatidylglycerol and palmitic acid EU/3/01/053 Beraprost sodium Treatment of pulmonary Aventis Pharma S.A. 18/09/2001 arterial hypertension and chronic thromboembolic pulmonary hypertension EU/3/01/052 Seocalcitol Treatment of hepatocellular Leo Pharmaceutical Products 31/07/2001 carcinoma

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EU/3/01/051 1,3-Propanedisulfonic acid, Treatment of Systemic Quintiles Limited 31/07/2001 disodium salt Secondary Amyloidosis EU/3/01/050 Zinc acetate dihydrate Treatment of Wilson’s disease Orphan Europe S.a.r.l. 31/07/2001 EU/3/01/049 Ramoplanin Prevention of invasive Biosearch Italia S.p.A. 09/07/2001 infections due to Vancomycin Resistant Enterococci (VRE) in colonised patients deemed at risk of infection EU/3/01/048 Ziconotide (intraspinal use) Treatment of chronic pain Elan Pharma International 09/07/2001 requiring intraspinal analgesia Ltd EU/3/01/047 Thalidomide Treatment of Multiple LAPHAL DEVELOPPEMENT 09/07/2001 Myeloma EU/3/01/046 Thalidomide Treatment of Graft versus Host Laboratoires LAPHAL 09/07/2001 Disease EU/3/01/045 Betaine anhydrous Treatment of homocystinuria Orphan Europe 09/07/2001 EU/3/01/044 Human Alpha1-Proteinase Treatment of emphysema Aventis Behring, GmbH 09/07/2001 Inhibitor (respiratory use) secondary to congenital alpha 1-antitrypsin deficiency Cross-border EU/3/01/043 Human Milk Fat Globule 1 / Treatment of ovarian cancer Antisoma Plc 30/05/2001 Human Milk Fat Globule 1 - S-p-isothiocyanatobenzyl- diethylenetri- aminepentaacetic acid for use with 90Yttrium EU/3/01/042 Human engineered Prevention of scarring in Cambridge Antibody 30/05/2001 monoclonal antibody specific glaucoma filtration surgical Technology for Transforming Growth procedures Factor ß2 EU/3/01/041 Recombinant human alpha-1- Treatment of emphysema Bayer AG 30/05/2001 antitrypsin (respiratory use) secondary to congenital alpha 1-antitrypsin deficiency EU/3/01/040 Fomepizole Treatment of methanol IDIS Ltd 30/05/2001 poisoning EU/3/01/039 Ecteinascidin 743 Treatment of soft tissue Pharma Mar SA 30/05/2001 sarcoma EU/3/01/038 Retroviral gamma-c cDNA Treatment of Severe GENOPOIETIC S.A.S. 30/05/2001 containing vector Combined Immunodeficiency (SCID)-Xl Disease EU/3/01/037 Humanised Anti-HM1.24 Treatment of Multiple Chugai Pharma Europe Ltd 10/05/2001 Monoclonal Antibody Myeloma EU/3/01/036 Recombinant human C1- Treatment of angioedema Pharming Group N.V. 11/05/2001 inhibitor caused by C1 inhibitor deficiency EU/3/01/035 Levodopa and Carbidopa Treatment of advanced NeoPharma Production AB 10/05/2001 (Gastroenteral use) idiopathic Parkinson’s disease with severe motor fluctuations and not responding to oral treatment EU/3/01/034 Gusperimus trihydrochloride Treatment of Wegener’s Euro Nippon Kayaku GmbH 29/03/2001 granulomatosis EU/3/01/033 Ranpirnase Treatment of malignant Dr. Erika Morgenstern 29/03/2001 mesothelioma

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EU/3/01/032 Arsenic Trioxide Treatment of Multiple Cell Therapeutics (UK) Ltd 29/03/2001 Myeloma EU/3/01/031 Arsenic Trioxide Treatment of myelodysplastic Cell Therapeutics (UK) Ltd 29/03/2001 syndromes EU/3/01/030 8-cyclopentlyl-1,3-dipropylx- Treatment of cystic fibrosis SciClone Pharmaceuticals 29/03/2001 anthine Italy S.r.l. EU/3/01/029 Ribavirin Treatment of adenovirus ICN Pharmaceuticals Limited 08/03/2001 infection in immunocompro- mised patients EU/3/01/028 Inolimomab Treatment of Graft versus Host OPI Orphan Pharma Interna- 05/03/2001 Disease tional EU/3/01/027 Ibuprofen Prevention of patent ductus Orphan Europe 05/03/2001 arteriosus in premature neonates of less than 34 weeks of gestational age EU/3/01/026 L-Lysine-N-acetyl-L- Treatment of cystic fibrosis SMB Technology SA 14/02/2001 cysteinate EU/3/01/025 N-acetylgalactosamine-4- Treatment of Mucopolysac- Dr Gertrud Thormann 14/02/2001 sulfatase charidosis, type VI (Maroteaux-Lamy Syndrome) EU/3/01/024 Ribavirin Treatment of haemorrhagic ICN Pharmaceuticals Limited 14/02/2001 fever with renal syndrome EU/3/01/023 Pegvisomant Treatment of acromegaly Pharmacia and Upjohn 14/02/2001 Cross-border (Somavert EU/1/02/ 240/...; 13/11/ 2002) EU/3/01/022 Laronidase Treatment of Mucopolysac- Genzyme B.V. 14/02/2001 charidosis, type I EU/3/01/021 Imatinib mesylate Treatment of chronic myeloid Novartis Europharm Limited 14/02/2001 leukaemia (Glivec EU/1/01/ 198/...; 27/08/ 2001) EU/3/01/020 Ibuprofen Treatment of patent ductus Orphan Europe 14/02/2001 arteriosus EU/3/01/019 Bosentan Treatment of pulmonary Actelion Registration Limited 14/02/2001 arterial hypertension and chronic thromboembolic (Tracleer EU/1/02/ pulmonary hypertension 220/...;15/05/ 2002) EU/3/00/018 Recombinant human acid Treatment of Glycogen Storage Genzyme Europe B.V. 14/02/2001 alpha-glucosidase Disease type II (Pompe’s disease) EU/3/00/017 Arsenic Trioxide Treatment of acute promyelo- Agence générale des équipe- 17/01/2001 cytic leukaemia ments et produits de santé - Etablissement pharmaceu- tique des hôpitaux de Paris (AGEPS-EPHP) EU/3/00/016 Lusupultide Treatment of Acute Respira- ALTANA Pharma AG 17/01/2001 tory Distress Syndrome EU/3/00/015 Xaliproden hydrochloride Treatment of amyotrophic Sanofi-Synthelabo 17/01/2001 lateral sclerosis

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EU/3/00/014 Iloprost Treatment of primary and of Schering AG 29/12/2000 the following forms of secondary pulmonary hypertension: connective tissue disease pulmonary hypertension, drug-induced pulmonary hypertension, portopulmonary hypertension, pulmonary hypertension associated with congenital heart disease, chronic thromboembolic pulmonary hypertension EU/3/00/013 Ethyl Eicosopentaenoate Treatment of Huntington’s Laxdale Ltd 29/12/2000 disease EU/3/00/012 Nitisinone Treatment of tyrosinaemia Swedish Orphan AB 29/12/2000 type I EU/3/00/011 Busulfan (Intravenous use) Conditioning treatment prior Pierre Fabre Médicament 29/12/2000 to hematopoietic progenitor

cell transplantation Cross-border EU/3/00/010 Anagrelide Hydrochloride Treatment of essential Shire Pharmaceutical 29/12/2000 thrombocythaemia Development Ltd EU/3/00/009 Thalidomide Treatment of erythema Laboratoires LAPHAL 29/12/2000 nodosum leprosum (ENL) or type II lepra reactions EU/3/00/008 Arsenic Trioxide Treatment of acute promyelo- Cell Therapeutics (UK) 18/10/2000 cytic leukaemia Limited (Trisenox EU/1/02/ 204/...;05/03/ 2002) EU/3/00/007 N-carbamyl-L-glutamic acid Treatment of N-acetylgluta- Orphan Europe 18/10/2000 mate synthetase (NAGS) deficiency EU/3/00/006 1,5-(Butylimino)-1,5- Treatment of Gaucher Disease Oxford GlycoSciences (UK) 18/10/2000 dideoxy, D-glucitol Ltd (Zavesca EU/1/02/ 238/...;20/11/ 2002) EU/3/00/005 Gemtuzumab Ozogamicin Treatment of acute myeloid Wyeth Europa Limited 18/10/2000 leukaemia EU/3/00/004 Fluorouracil Treatment of glioblastoma Ethypharm S.A. 18/10/2000 EU/3/00/003 Alpha-Galactosidase A Treatment of Fabry disease Genzyme Europe B.V. 08/08/2000

(Fabrazyme EU/1/ 01/188/...;04/05/ 2001) EU/3/00/002 Alpha-Galactosidase A Treatment of Fabry disease TKT Europe-5S AB 08/08/2000

(Replagal EU/1/01/ 189/...;04/05/ 2001) EU/3/00/001 Somatropin AIDS wasting Serono Europe Ltd 08/08/2000

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