Marketing authorisationTime frame
How long does it take, in general, to obtain an authorisation from application to grant, what fees are payable and what is the normal period of validity of the authorisation?Medicinal products
In the centralised marketing authorisation procedure, the time limit for the evaluation procedure is 210 days, subject to extensions if additional questions need to be addressed. Within 15 days of the adoption, the European Medicines Agency (EMA) will forward its opinion to the European Commission to start the decision-making phase. Overall, the assessment of a new medicine usually takes approximately one year. Marketing authorisations granted in the European Union have an initial period of validity of five years. The EMA charges fees for marketing authorisation applications, and for variations and other changes to marketing authorisations, as well as annual fees for authorised medicines. The EMA basic fee for a marketing authorisation application for a human medicine starts at €297,400.
Under the mutual recognition and decentralised procedures, the evaluation process may take up to 210 days after the submission of a valid application under the decentralised procedure and 90 days under the mutual recognition procedure. Once all the member states involved in the procedure agree with the assessment, the procedure closes and each member state must grant a national marketing authorisation. This grant should occur within 30 days, but in practice the national phase timelines and fees for such authorisations vary as they follow national rules. Granted marketing authorisations are valid for an initial period of five years.
In principle, it may take 12 to 16 weeks to obtain a ‘CE’ marking for a medical device where this process requires the involvement of a notified body. However, notified bodies have been experiencing significant delays since the new medical device regulations became fully applicable. As a result, the timing for obtaining certificates of conformity from notified bodies may, in practice, be much longer and take one year or more. Some notified bodies offer options for expedited reviews or dedicated on-site review of design dossiers and technical files.
The certificates of conformity issued by notified bodies are valid for the period that they indicate, which must not exceed five years.Protecting research data
What protections or exclusivities apply to the data submitted by originators to gain initial approval and, on variation or new application, to add indications or pharmaceutical forms?Medicinal products
Regulation (EC) No. 726/2004 provides that medicinal products benefit from an eight-year period of data exclusivity and a 10-year period of market protection.
Directive 2001/83/EC allows an applicant for a marketing authorisation to rely on the reference medicinal product’s data only after the expiration of this eight-year period of data exclusivity. Therefore, during the eight years from the date of grant of the first marketing authorisation for the reference product, no generic application may be filed referring to the data contained in the application dossier of the reference product. After the expiry of this period, regulatory authorities may receive a marketing authorisation application and grant such an authorisation for a generic or biosimilar medicinal product relying (in full or in part) on the data of the reference product’s data package.
Such an authorised medicinal product may be placed on the market only after two years from the expiry of the data exclusivity (10 years from the reference product’s first marketing authorisation grant – market protection). This 10-year period of market protection can be extended to a maximum of 11 years if, during the first eight years, the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications that, during the scientific evaluation prior to authorisation, are held to bring a significant clinical benefit in comparison with existing therapies. This period of regulatory data protection is commonly referred to as the 8+2+1 approach.
Where a change of classification of a medicinal product has been authorised on the basis of significant preclinical tests or clinical trials, the data submitted to support that variation is protected by a standalone one-year period of data protection, during which a generic company cannot cross-refer to the data when seeking to make an application for a change in the classification of its product.
Where an application is made for a new indication for a well-established substance, a non-cumulative period of one year of data protection shall be granted, provided that significant preclinical or clinical studies were carried out in relation to the new indication.
There is no protection period for data submitted to support a ‘CE’ marking. However, the data is usually considered to be confidential, and manufacturers of similar or follow-on products cannot access such data.
Medical device manufacturers may use a device that is already on the market to demonstrate equivalence of their own device to reduce the amount of data required to obtain a ‘CE’ mark for its product. There are three equivalence criteria: clinical, technological and biological. The European Commission guidance provides details on how this should be documented and factors that could affect the demonstration of equivalence. Under the new medical device regulations, manufacturers must have a contract in place allowing access to data for competitors’ devices with which equivalence is claimed.Freedom of information
To what extent and when can third parties make freedom of information applications for copies of research data submitted by applicants for authorisation to market medicinal products or medical devices?Medicinal products
Regulation (EC) No. 1049/2001 provides EU citizens and natural or legal persons residing or having their registered office in an EU member state with the right of access to documents held by EU institutions. This right to access also concerns documents held by the EMA.
In principle, all documents belonging to EU institutions and the European decentralised bodies, such as the European medical agencies, are accessible to the public. However, certain public and private interests, such as the privacy and integrity of the individual – in particular in accordance with EU legislation regarding the protection of personal data, or the commercial interests of a natural or legal person – shall be protected through exceptions in line with the provisions of Regulation (EC) No. 1049/2001.
The Court of Justice of the European Union has recently issued a series of rulings regarding access to documents held by the EMA.
Given that notified bodies are private entities, they are not subject to the freedom of information legislation. As such, there is very limited ability to request access to the technical information relating to an application for ‘CE’ marking held by the notified bodies.Regulation of specific medicinal products
What are the specific requirements and processes for marketing approval of the major categories of regulated products?
EU law sets out requirements for certain specific areas, such as medicinal products for rare diseases (the Orphan Drugs Regulation (EC) No. 141/2000) or medicines for children (the Paediatrics Regulation (EC) No. 1901/2006). The basic procedures for authorisation of those medicinal products are the same as for standard products. However, there are additional requirements or incentives that may apply to such products.
The EMA recommends orphan medicinal product designation for products intended for life-threatening or chronically debilitating conditions that affect not more than five in 10,000 persons in the European Union, provided that the product in question offers a significant clinical benefit. Medicines that have been granted an orphan designation benefit from financial incentives such as a reduction of fees or fee waivers and 10 years of market exclusivity following marketing authorisation. Each indication with an orphan designation confers 10 years of market exclusivity on the particular indication.
Marketing authorisation applications for medicines must include consideration of use of that product in children. Products that are granted a marketing authorisation on the basis of the paediatric clinical trials conducted in accordance with a paediatric investigation plan are eligible for a six-month extension of the protection under a supplementary protection certificate (if the product covered by it qualifies for one at the time of approval). The EMA offers scientific advice and protocol assistance free of charge for questions relating to the development of paediatric medicines. Medicines developed specifically for children that are already authorised but are not protected by a patent or a supplementary protection certificate are eligible for a marketing authorisation for paediatric use. If such an authorisation is granted, the new data submitted to support the authorisation of the product will benefit from 10 years of market protection.Post-marketing surveillance of safety
What pharmacovigilance or device vigilance obligations apply to the holder of a relevant authorisation once the product is placed on the market?Medicinal products
Under the EU legal framework of pharmacovigilance, the marketing authorisation holder must collect information on the risks of medicinal products as regards patients’ or public health. That information must refer in particular to adverse reactions in patients arising from use of the medicinal product. The requirements include risk management plans, post-authorisation studies, signal detection and management at the EU level, periodic safety update reports, and assessment and reviews of medicines through referrals. Marketing authorisation holders are also required to maintain a pharmacovigilance system master file that is permanently available for submission or inspection by the national competent authority.
The process of reporting adverse drug reactions is centralised through electronic submissions to the EudraVigilance database. As of 30 June 2022, it is mandatory to report side effects to EudraVigilance using a data format based on international standards set by the International Organization for Standardization.
Manufacturers of medical devices are required to plan, establish, document, implement, maintain and update a post-market surveillance system in a manner that is proportionate to the risk class of and appropriate for the type of device. The post-market surveillance system is an integral part of the manufacturer's quality management system, and monitors the clinical performance and clinical safety of each device.
The new regulations also provide obligations on vigilance, whereby the manufacturer must report to the regulatory authorities any serious incidents or field safety corrective actions in respect of devices made available on the EU market.Other authorisations
What authorisations are required to manufacture, import, export or conduct wholesale distribution and storage of medicinal products and medical devices? What type of information needs to be provided to the authorities with an application, what are the fees, and what is the normal period of validity?Medicinal products
According to Directive 2001/83/EC, the manufacturing and importation of medicinal products requires a specific authorisation issued by the national competent authority of the member state where these activities are carried out. Importers are responsible for ensuring that the third-country manufacturers from whom they are importing comply with good manufacturing practices. Marketing authorisation applicants must ensure that the proposed manufacturing sites included in the marketing authorisation application comply with good manufacturing practices.
To obtain such an authorisation, manufacturers and importers must comply with several requirements, including to:
- specify the medicines that are to be manufactured or imported and the place where they are to be manufactured or controlled;
- have at their disposal suitable premises and control facilities; and
- have at their disposal the services of at least one qualified person.
Fees vary per country. Both fees and the validity periods for manufacturing or importing authorisations are set out at a national level.
Directive 2001/83/EC provides that a specific authorisation is required to engage in activity as a wholesaler in medicinal products, stating the premises located on their territory for which it is valid. However, possession of a manufacturing authorisation includes authorisation to distribute by wholesale the medicines covered by the authorisation.
Where the manufacturer of a device is not established in an EU member state, it must appoint an authorised representative based in one member state of the European Union or the European Economic Area (EEA) to place the device on the EU market.
Importers of medical devices from outside the European Union or EEA are not required to obtain an import authorisation but are subject to several obligations under the new regulations. This is a relevant change introduced by the MDR and IVDR, as the previously applicable directives did not specifically regulate the role and obligations of importers.
Importers assume the obligations incumbent on manufacturers if they make available on the EU market a device under their name, registered trade name or registered trademark, except in cases where they have entered into an agreement with the manufacturer whereby the manufacturer is identified as such on the label and is responsible for meeting the requirements placed on manufacturers in the MDR or IVDR.
No authorisation is required to distribute medical devices that have been lawfully placed on the EU market.Sanctions
What civil, administrative or criminal sanctions can authorities impose on entities or their directors and officers for breach of the requirements concerning controlled activities?Medicinal products
The enforcement of the pharmaceutical legislation is mainly carried out at a national level, although EU law states that in determining penalties member states should ensure that they are effective, proportionate and dissuasive.
National authorities have broad enforcement powers and may issue administrative fines, revoke or suspend authorisations or licences, suspend the reimbursement of a medicine and shut down facilities. Failure to comply with the medicinal product regulatory regime may also entail criminal or administrative penalties for the manufacturer or the marketing authorisation holder. At the EU level, Regulation (EC) No. 726/2004 provides for EU financial penalties, according to which the EMA may investigate and report on alleged breaches of the EU pharmaceutical rules by holders of a marketing authorisation for centrally authorised products. The European Commission can then adopt decisions imposing significant financial penalties of up to 5 per cent of their annual turnover on infringing marketing authorisation holders.
The new regulations on medical devices require EU member states to lay down the penalties applicable for infringement of their provisions and take all necessary measures to ensure that they are implemented. The new regulations establish that the penalties provided for shall be effective, proportionate and dissuasive. National competent authorities have a range of investigatory and enforcement powers to ensure the safety and quality of devices. Competent authorities assess allegations of non-compliance, monitor the activities of the notified bodies designated by them, investigate medical devices as a result of adverse incident reports and carry out proactive risk-based projects with other EU member states to identify emerging risks. As with medicines, national penalties may be imposed on individuals and entities found to be in breach of the legislation and primarily involve administrative or, in some member states, criminal fines.Exemptions
What, if any, manufacture and supply of medicinal products is exempt from the requirement to obtain an approval to market?
Directive 2001/83/EC provides certain exemptions from the requirement to obtain approval to market a medicinal product, including:
- any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (commonly known as the magistral formula);
- any medicinal product prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and intended to be supplied directly to the patients served by the pharmacy (commonly known as the officinal formula);
- medicinal products intended for research and development trials;
- intermediate products intended for further processing by an authorised manufacturer;
- any radionuclides in the form of sealed sources;
- whole blood, plasma or blood cells of human origin, except for plasma that is prepared by a method involving an industrial process; and
- advanced therapy medicinal products prepared on a non-routine basis and used in a hospital for an individual patient (commonly known as the hospital exemption).
Are imports allowed into your jurisdiction of finished products already authorised in another jurisdiction, without the importer having to provide the full particulars normally required to obtain an authorisation to market? What are the requirements?Medicinal products
Parallel importation is the importation from an EU or EEA member state of origin to a member state of destination of a medicinal product that is essentially similar to a product already authorised in the destination member state. Parallel importers must submit an application to the national competent authority of the destination member state for a parallel import authorisation prior to any importation.
Parallel distribution is the distribution of a centrally authorised medicinal product from one member state to another by a pharmaceutical company independent of the marketing authorisation holder. Parallel distributors must submit a notification of intention to parallel distribute to the EMA prior to any importation.
EU law does not restrict individuals importing medicines into an EU member state from a third country, provided that they are strictly for use by that person or a member of their immediate family.
Once a medical device has been ‘CE’ marked, it may be marketed anywhere in the European Union or EEA, provided that it complies with applicable requirements. A parallel importer would not need a specific authorisation from a regulatory perspective.