This newsletter summarises key regulatory and legal developments in the pharmaceuticals sector and healthcare industry in Europe.

Europe

EudraCT guidance for paediatric clinical trials

Spain

New court ruling on the pharmaceutical patent system in Spain

Royal Decree 1345/2007

United Kingdom

Reform of the regulation of unlicensed medicinal products

Europe

EudraCT guidance for paediatric clinical trials

The European Commission has published draft guidance on the information relating to paediatric clinical trials that is to be entered into the EU database on Clinical Trials ("EudraCT") and on the information to be made public by the European Medicines Agency ("EMEA").

Article 11 of Directive 2001/20/EC requires information on clinical trials to be submitted to EudraCT and to be made accessible to competent authorities of the Member States.  Article 41 of Regulation 1901/2006 as amended on medicinal products for paediatric use provides that information on paediatric clinical trials should also be submitted to EudraCT and further, that some of this information should be made public.  The aim of publishing this information is to increase the availability of information on use of medicinal products in the paediatric population and to avoid unnecessary repetition of studies.  The Commission's guidance sets out the nature of the information to be entered into EudraCT, the information to be made accessible to the public, the clinical trial results to be submitted and made public and on the responsibilities of the EMEA in relation to these activities.

Information relating to the protocol of a paediatric clinical trial should be submitted prior to its commencement, including descriptions of the trial protocol, the investigational medicinal product, therapeutic indication, trial population, the trial authorisation and the current status of the trial.  Following completion, a summary of the results and conclusions should also be submitted.  It is the obligation of the sponsor of the trial or the holder of the relevant paediatric investigation plan or marketing authorisation to submit this information to EudraCT.
 
The guidance contains lists of the information relating to the protocol and results of a trial that is to be made public.  Protocol-related information will be published automatically once it has been validated in EudraCT, even if the trial has received a negative opinion from an ethics committee.  Results of a trial are published once they have been validated by the relevant national competent authority or the EMEA.  A dedicated public website will be established for publication of this information.

The guidance has been released for consultation until 18 April 2008.  A copy can be obtained from the Commission's website.

For further information on this article, please contact Paul Hawkins or Beatriz Araujo of the London office.

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Legal proposals to combat counterfeit medicines

The European Commission has issued a consultation document setting out its key ideas to amend the regulatory framework for medicinal products in order to prevent counterfeiting.  The Commission has launched this consultation because of the increasing threat to public health that has occurred in recent years as a result of counterfeit medicines.  As described in the consultation, the numbers of seizures of counterfeit medicines at EU customs borders increased by 384% between 2005 and 2006.  In addition, counterfeiters are increasingly targeting life-saving medicines such as treatments for cancer and heart disease, whereas previously, the focus had been towards 'lifestyle' medicines such as weight-loss treatments.  Furthermore, the licensed distribution chain, including authorised wholesalers, parallel traders and pharmacies are being used increasingly by counterfeiters in addition to the internet.

The Commission has identified a number of factors that may have contributed to a rise in counterfeiting.  These include, uncertainty as to whether pharmaceutical legislation applies to certain participants in the distribution chain, a lack of transparency as to whether wholesalers and other participants in the distribution chain comply with good distribution practice, difficulties in conducting targeted product recalls, uncertainty regarding the application of pharmaceutical legislation to imports for the purpose of export and differing practice between Member States in this regard and active substances not being manufactured in accordance with good manufacturing practice.  Furthermore, it appears that enforcement action taken by different Member States may have resulted in differences in the level of protection of health and safety.

The Commission suggests that changes to the regulation of the manufacture, trade and distribution of medicinal products may need to be made by amending EU legislation including Directive 2001/83/EC relating to medicinal products and Commission Directive 2003/94/EC relating to good manufacturing practice.  The Commission stated that the key areas of regulation that could be improved to protect against counterfeit medicines are:

1. strengthening requirements for manufacture, placing on the market of medicinal products and inspections;

2. strengthening requirements for the import/export/transit (transhipment) of medicinal products; and

3. strengthening requirements for manufacture, placing on the market of active substances and inspections.

The consultation document sets out the Commission's ideas on how these regulatory changes can be implemented.  Comments on these ideas may be submitted to the Commission until 9 May 2008.  A copy of the consultation is available from the Commission's website.

For further information on this article, please contact Paul Hawkins or Beatriz Araujo of the London office.

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Guidance for manufacturers of medical devices utilising animal tissues

The European Commission has published a revised version of its guidance on the interpretation of Commission Directive 2003/32/EC (the "Directive") which provides for the management of risks associated with medical devices that utilise tissues originating from animals for which there is a suspected risk of Transmissible Spongiform Encephalopathies ("TSE").

The Directive provides that such medical devices should be subject to a risk management scheme incorporating a risk assessment.  Manufacturers are also required to submit risk assessments to a Notified Body for evaluation.  The Directive applies to medical devices that utilise tissue from various animal species and for which the tissue may have a variety of uses, such as comprising a substantial part of a device (e.g., replacement cardiac valves or bone for orthopaedic surgery), as a coating of a product or as part of a stage of manufacture of a device.

The revised guidance includes a new section explaining the obligations of manufacturers to inform Notified Bodies of any changes to the sourcing, collection, handling or inactivation/elimination of animal tissue that may modify a device's risk assessment profile.  Such changes must be approved by the relevant Notified Body before they are implemented.  Furthermore, any new information on TSE risk of a device must be sent to the relevant Notified Body.

The revised guidance also sets out details of what must be included in an updated risk assessment at the time when a conformity assessment is renewed (usually every 5 years).  This will include assessment of any significant changes in the TSE risk profile of a device.  In addition, the revised guidance includes new sections explaining the procedures that should be followed for manufacturers of medical devices that incorporate an ancillary medicinal substance that utilises material from TSE species.  The guidance also explains what a manufacturer must do if an existing medical device that was thought to be outside the scope of the Directive is subsequently found to utilise material of TSE susceptible species.

A copy of the revised guidance is available from the website of the European Commission. 

For further information on this article, please contact Paul Hawkins or Beatriz Araujo of the London office.

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Germany

Federal Administrative Court permits mail order businesses to cooperate with pharmacies

The Federal Administrative Court in Leipzig (Bundesverwaltungsgericht - "BVerwG") ruled on 13 March 2008 that cooperation between mail order businesses and pharmacies for the purpose of ordering and supplying medicinal products to consumers is permitted under the provisions of the German Act on Medicinal Products (Arzneimittelgesetz - "AMG") and the German Pharmacy Act (Apothekengesetz - "ApoG").

The AMG has permitted medicinal products to be supplied by mail order businesses since 1 January 2004. Based on this, the Dutch mail order pharmacy, Europa Apotheek Venlo, concluded an agreement to cooperate with the German pharmacy chain, dm-drogerie. Under this cooperation, orders from consumers for medicinal products can be deposited at a pharmacy operated by dm-drogerie and then collected after 3 days.  However, the municipal government in Düsseldorf prohibited this practice in 2004.  dm-drogerie successfully applealed against this prohibition at the Administrative Court of Appeal in Münster in 2006.  This appeal has now been upheld by the Federal Administrative Court in Leipzig.

The Federal Administrative Court justified its decision on the basis that the distribution of medicinal products by collection from a designated pick-up point is a common business method for mail order companies. Thus, this form of distribution comes within the term "mail order business" under section 43(1) of the AMG and section 11a no. 1 of the ApoG. The court held that the "order-and-collect" form of mail order did not involve any higher safety risks when compared to a classical mail order business where the products are delivered directly to the consumer.  Therefore, the AMG and the ApoG did not prohibit this form of distribution.  However, the court also stated that, in an "order-and-collect" form of mail order, the role of the pharmacy should be limited to a logistical service only.  Consequently the pharmacy should not give the impression that it is dispensing the relevant medicinal products or that the consumer is entering into a contract with the relevant pharmacy.  Furthermore, any advertisements conveying these impressions should not be used.

For further information on this article please contact Kirsten Plassmann of the Frankfurt office.

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Spain

New court ruling on the pharmaceutical patent system in Spain

A ruling of the Provincial Court of Barcelona has confirmed that pharmaceutical companies in Spain are not permitted to manufacture generic versions of pharmaceutical products manufactured by other pharmaceutical companies.  Whilst this ruling does not create new legal rights, it does widen the scope of the existing law (see below for further background on the product patent system in Spain).

When Spain joined the EU it enacted legislation creating a patent system.  This did not, however, offer patent protection for pharmaceutical products.  As a result, European patents for pharmaceutical products were also unenforceable in Spain.  Subsequently, Spain became part of the World Trade Organisation and ratified the TRIPS/ADPIC Agreement which provided minimum standards of industrial protection between the ratifying states.  The TRIPS/ADPIC Agreement entered into force in Spain on 1 January 1996.

The pharmaceutical industry in Spain had argued that the TRIPS/ADPIC Agreement altered the Spanish patent system and, thus, revoked the restriction on patentability of pharmaceutical products.  This argument was supported by the Barcelona court which ruled that product patents will be enforceable in Spain even if they had been requested prior to October 1992 (i.e. prior to the end of the restriction on patentability of pharmaceutical products).  Furthermore, the court established that patents that had been granted before the TRIPS/ADPIC Agreement entered into force will also be enforceable.  The court stated that, "we consider that the TRIPS/ADPIC Agreement cannot be ignored in Spain".  The ruling also established a "supervened patentability" for those patents that fall under the protection of the TRIPS/ADPIC Agreement.

For further information on this article, please contact Cecilia Pastor or Ester Navas of the Madrid office.

Background to product patents in Spain

March 1986.  Legislation created a patent system in Spain.  This, however, provided that pharmaceutical products were not patentable.  European patents granted for pharmaceutical products were not enforceable.  The legislation only protected patents for the manufacture of medicinal products.

October 1992.  The restriction on patents for pharmaceutical products was removed.

April 1994.  The TRIPS/ADPIC Agreement was ratified under the Treaty that established the World Trade Organisation.  This established a minimum protection in terms of intellectual property and industrial rights for all member states.  Article 70 provided that the TRIPS/ADPIC Agreement, "does not create obligations related to acts carried out before the date of ratification by any State", but, "it does develop obligations related to all existing issues as of the date of application of such agreement".  There was disagreement over interpretation of this article in Spain.  The TRIPS/ADPIC Agreements entered into force in Spain on 1 January 1996.

2008-2012.  Patents for approximately 20 medicinal products will expire during this period. According to the pharmaceutical industry, such patents are due to expire 3 years earlier in Spain compared to equivalent patents in other European countries and this could have a negative impact on the Spanish pharmaceutical industry.

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Royal Decree 1345/2007

Royal Decree 1345/2007 of 7 December 2007 regarding the authorisation, registration, and conditions for dispensing industrially produced medicines for human use (the "Royal Decree") completes the implementation of Directive 2004/27/EC in Spain. Directive 2004/27/EC amends Directive 2001/83/EC, which establishes a Community-wide code for medicines for human use. The fundamental aspects of Directive 2004/27/EC are implemented in response to a need to improve authorisation procedures for medicines. The Royal Decree revises national authorisation procedures, particularly mutual recognition and the decentralised procedure. Furthermore, it contains precise, detailed provisions for the practical application of the provisions of Law 29/2006, of 26 July 2006, on guarantees and rational use of medicines and medical devices.

A key development is the establishment of greater clarity in examining application files. Article 22 of the Royal Decree establishes that the Spanish Medicines and Medical Devices Agency will ensure access (i) to its decisions on authorisation or rejection of applications for marketing authorisations; and (ii) on changes, suspensions, and revocations of marketing authorisations, provided that such decisions are final. Access to technical data sheets for medicines (although this information was already public) is also confirmed. Evaluation Reports will also be made public, once confidential commercial information has been removed, and this may be of great use to third parties without being detrimental to applicants.  These changes will help to avoid any type of arbitrary non-scientific decision being issued.

The Royal Decree makes the following changes in relation to processing of applications:

• Greater clarity for some aspects and a greater specification of deadlines: previously, the health authorities had 210 days to decide on the authorisation of a medicine; in the new regulations, these 210 days include not only the decision but also service of notice of the decision to interested parties. This establishes deadlines similar to those in Law 30/1992 (which regulates the Legal System with the Public Administration and the Common Administrative Procedure).

• Article 62.2 of the Royal Decree establishes an obligation to respect continuity of supply. Once an authorisation to market a medicine has been granted, there will be an obligation to supply the market with the medicine without interruption.

• An application for a generic medicine may be filed eight years after the original medicine is authorised. As a result, a generic medicine may be marketed twenty years after the relevant patent application or twenty-five years later if a Supplementary Protection Certificate has been issued.

• Generic medicines may be sold under a brand name provided that there is no confusion with an official Spanish name or a common international name and no confusion is caused regarding the therapeutic value or the nature of the medicine.

• A new decentralised procedure through which application for registration of a medicine may be made simultaneously in all Member States. This development may shorten deadlines for the approval of registration, streamlining of the process and unifying the evaluation requirements for authorisation.

• Special Medicines.  Regulations applicable to certain medicines have been repealed. These relate to vaccines, medicines of human origin (derivatives from blood plasma and other substances of human origin), radiopharmaceutical products, homeopathic medicines, immunological medicines and medicinal gases. As a consequence, the regulation of these types of medicine has become very general. Further regulations are likely to be enacted to develop these aspects of the Royal Decree.

• Traditional plant-based medicines. Directive 2004/24/EC of the European Parliament and the Council of March 31 as regards traditional herbal medicinal products is also implemented. The Royal Decree establishes a simplified registration procedure for traditional plant-based medicines. The peculiarity of this procedure lies in the fact that, to register a traditional plant-based medicine, its traditional use will be taken into account. Therefore, the clinical and pre-clinical trials usually required for medicines for human use will not be necessary, although the competent authorities may request additional information to evaluate a product's safety. A transitional period for the commercialisation of traditional plant-based medicines under the previous regulatory system is in operation until 30 April 2011.

For further information on this article, please contact Montserrat Llopart or Ariadna Casanueva of the Barcelona Office.

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United Kingdom

Reform of the regulation of unlicensed medicinal products

The Medicines and Healthcare products Regulatory Agency ("MHRA") has published an informational consultation document examining the possible reform of the UK regulatory arrangements that allow authorised healthcare professionals to commission an unlicensed medicinal product for individual patients. 

At present, these activities are regulated by the Medicines for Human Use (Marketing Authorisations Etc) Regulations 1994 (SI 1994/3144) as amended (the "MA Regulations").  Schedule 1 of the MA Regulations allows unlicensed medicines (commonly referred to as 'specials') to be supplied to individual patients to meet a special clinical need without requiring the medicine to have a marketing authorisation.  This supply is subject to certain conditions, including, that there is a bona fide unsolicited order and that the product is formulated in accordance with the requirements of a doctor or dentist registered in the UK who will be directly responsible for the patient's use of the product. Also, if a 'special' is manufactured in the UK, the manufacturer must hold a manufacturer's (specials) licence, and any importation of a 'special' must be notified to the MHRA.

A 'special' may need to be used in a variety of situations, such as when there is no equivalent licensed medicinal product available in the UK to meet the 'special need' of a patient, where a licensed medicine is not available in a suitable formulation or if a licensed product is not available because of commercial considerations.

The present review has been launched because the existing regulation of 'specials' has been in place for a considerable time during which there have been many developments in the regulation of other medicinal products and in healthcare systems generally.  In addition, while the MHRA operates a pre-vetting scheme for imported 'specials', no equivalent system applies to 'specials' that are manufactured domestically.  Similarly, the MHRA can object to the importation of a 'special' on safety grounds alone, but cannot do so in relation to 'specials' that are manufactured in the UK.  There are also gaps in the legislation that have resulted in the MHRA not being required to hold data on the number of 'specials' manufactured in the UK and, although there is a limit on the volume of products that are permitted for each import notification, the legislation does not prohibit multiple notifications.

The MHRA's consultation contains a series of questions and comments to help assess the possibilities for regulatory reform.  In addition to the issues above, the consultation will examine whether further safeguards should be imposed in relation to the use of 'specials'.  These may include addressing safety issues relating to use of products that have been refused a marketing authorisation or relating to whether patients are provided with appropriate information to ensure safe use of a 'special'.

The consultation is open until 30 June 2008 and copies of the relevant documentation can be obtained from the MHRA's website.

For further information on this article, please contact Paul Hawkins or Beatriz Araujo of the London office.

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MHRA recommends use of brand names for prescribing biosimilar medicinal products

In the February 2008 edition of the Drug Safety Update published by the Medicines and Healthcare products Regulatory Agency ("MHRA"), the MHRA has recommended that biosimilar medicinal products should be prescribed by their brand names.  The MHRA states that this will prevent automatic substitution of a biosimilar when a biological medicine is dispensed by a pharmacist.  The MHRA also states that reference biological medicinal products and the relevant biosimilar medicinal products are not to be presumed to be identical due to their complexity even if they have the same international non-proprietary name.

The MHRA's Drug Safety Update also stresses the importance of assigning any adverse drug reaction to the correct product in the context of use of biosimilars.  For this reason, the MHRA has recommended that adverse drug reactions involving a biosimilar should be reported using the product name rather than the substance name.

A copy of the February 2008 edition of the Drug Safety Update can be obtained from the MHRA's website.

For further information on this article, please contact Paul Hawkins or Beatriz Araujo of the London office.

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Disclosure of data from clinical trials

The Medicines and Healthcare products Regulatory Agency ("MHRA") has called for new legislation to strengthen the obligations of pharmaceutical companies to disclose data and information from clinical trials.  This move has arisen after the publication of the MHRA's report into the anti-depressant drug Seroxat.

The MHRA would like additional clarity in relation to the information that is required to be submitted to regulatory authorities, including whether information should be submitted that arises from use of a medicinal product outside the EU, from use outside the terms of a product's marketing authorisation, use in clinical trials in addition to use that is in accordance with a product's marketing authorisation.  The MHRA would also like clear timescales for when this information must be supplied and sanctions for any failure to comply.

The MHRA has also stated that, "all companies have a responsibility to patients and should report any adverse data signals as soon as they are discovered".  Health minister Dawn Primarolo has supported this confirming that, "pharmaceutical companies should disclose any information they have that would have a bearing on the protection of health."

For further information on this article, please contact Paul Hawkins or Beatriz Araujo of the London office.

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