This content was co-authored by Ian Dodds-Smith, Jackie Mulryne and Silvia Valverde of Arnold & Porter Kaye Scholer LLP and Alexander Ehlers of Ehlers, Ehlers & Partner.
Health services framework and competent authorities
Describe the bodies and their responsibilities (public and private sector) concerned with the delivery of healthcare and appropriate products for treatment.
Although the primary responsibility for delivering and controlling healthcare services and products is held by the European Union member states, the EU complements national policies harmonising certain aspects of the services, such as the evaluation and authorisation of medicines and medical devices and their placement in the EU or European Economic Area (EEA) market.
The European Commission, supported in particular by the Directorate for Health and Food Safety, proposes healthcare-related legislation, provides financial support and coordinates health-related activities involving both medicinal products and medical devices. All EU legislation in this area is adopted with the involvement of the Council, the European Commission and the European Parliament under the Treaty on the Functioning of the EU.
Competent authorities for authorisation
Identify the competent authorities for approval of the marketing of medicinal products and medical devices. What rules apply to deciding whether a product falls into either category or other regulated categories?
Medicinal products are authorised at EU level by the European Commission, which takes the decision based on the scientific evaluation carried out by the European Medicines Agency (EMA) in Amsterdam. It is in charge of the centralised authorisation procedure and supports coordination between national competent authorities. The EMA has seven scientific committees and a number of working parties and related groups that conduct the scientific work of the Agency. These include, among others, the Committee for Medicinal Products for Human use (CHMP), the Pharmacovigilance Risk Assessment Committee, the Committee for Orphan Medicinal Products, the Paediatric Committee and the Committee for Advanced Therapies.
The Heads of Medicines Agency Coordination Group was set up for the examination of any question relating to the marketing authorisation (MA) of a medicine in two or more member states, and is involved in the coordination of assessment for nationally approved products via the mutual recognition or decentralised procedure.
Medical devices are regulated and authorised differently depending on their classification based on the risk categorisation of the product. Once the applicable class or list has been determined, manufacturers need to follow the appropriate conformity assessment procedure. This may require the manufacturer to have its quality systems and technical documentation reviewed by a Notified Body before it can place its products on the market. A Notified Body is an organisation designated by the competent authorities of an EU country to assess the conformity of certain products before being placed on the market.
There are a number of EU-wide organisations that seek to assist with the coordination between Notified Bodies, and these have been strengthened under the new Medical Devices Regulations, discussed in question 3. For example, the Medical Device Coordination Group (MDCG) provides advice to the Commission and assists the Commission and the member states in ensuring a harmonised implementation of the Medical Devices Regulations. The Competent Authorities for Medical Devices project was established to enhance collaborative working, communication and surveillance of medical devices across Europe.
Sometimes, it may be unclear whether a product is a medicinal product, medical device, cosmetic, biocidal, food or another category of product. In the case of these ‘borderline products’, the decision on a product’s classification is taken on a case-by-case basis. The starting point is the analysis of whether the product falls within the legal definition of any of these categories under EU law. The European Commission has published numerous guidance documents to facilitate the demarcation between these categories of products.
Describe the general legislative and regulatory framework for approval of marketing of medicinal products and medical devices.
The legal framework for the approval of medicinal products for human use is primarily controlled by Directive 2001/83/EC and Regulation (EC) No. 726/2004. This legislation also includes harmonised requirements for the manufacture, distribution, advertising and pharmacovigilance of medicines.
There are four different routes or procedures for obtaining an MA for a medicinal product, three of which are European-level authorisation procedures for which there is coordination between member states (the centralised procedure, the decentralised procedure and the mutual recognition procedure), and the fourth being the national procedure.
Under the centralised procedure, marketing authorisation holders (MAHs) may obtain a single EU centrally authorised MA. The product is assessed on an EU-wide basis and approved by the European Commission. The EMA, with the assistance of its committees, organises the evaluation using scientific expertise from the member states. The centralised procedure is compulsory for some products, optional for others and not available for the rest.
The mutual recognition procedure and the decentralised procedure result in national MAs, although the procedure for assessment is coordinated across the EU. Mutual recognition must be used when a product is already authorised in at least one member state on a national basis and the MAH wishes to obtain an MA for the same product in at least one other member state. The decentralised procedure may be used if the product is not already authorised in any member state, but the MAH is not able or does not want to use the centralised procedure.
Additionally, EU law sets requirements for certain specific areas, such as medicinal products for rare diseases (the Orphan Drugs Regulation (EC) No. 141/2000), medicines for children (the Paediatrics Regulation (EC) No. 1901/2006) and Advanced Therapy Medicinal Products (the ATMP Regulation (EC) No. 1394/2007). All EU legislation for medicinal products for human use may be found in volume 1 of the Rules Governing Medicinal Products in the European Union. The legal framework is complemented by a large number of guidelines of a regulatory and scientific nature, such as the guidance contained in volume 2 of the Rules Governing Medicinal Products in the European Union, known as the Notice to Applicants.
The criteria for assessment are the medicinal product’s safety, quality and efficacy based on its application dossier, and the competent authority determines a positive or negative risk-benefit balance. The Directive requires all MAs to include the approved product information, which is the summary of product characteristics (SmPC), labelling (which is the internal and external packaging of the product) and package leaflet (or patient information leaflet). EU law determines the content, format and layout that applies to these documents. On 31 January 2019, the EMA published a draft statement on the key principles for the development and use of electronic product information for medicines for human use in the EU for public consultation.
The current legislation on medical devices is set out in Directive 93/42/EEC concerning medical devices, Directive 90/385/EEC on active implantable medical devices, and Directive 98/79/EEC on in vitro diagnostic medical devices. These Directives are implemented into the national legislation in each member state.
In 2017, the EU adopted new medical devices regulations, the Medical Devices Regulation (EU) 2017/745 (the MDR) and the In-vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) (collectively, the new MDRs) with the aim to improve the clinical safety of devices on the market and to create fairer market access for manufacturers. These Regulations, unlike the existing three Medical Devices Directives that they will replace, do not need to be transposed into national law to be applicable, thus, limiting the discrepancies in interpretation across the EU.
The current Medical Devices Directives and the future MDR and IVDR regulate the activities of all stakeholders involved in the testing, manufacturing, approval, supply and distribution of medical devices. The MDR and IVDR entered into force on 25 May 2017 and will progressively replace the existing Directives. The MDR will be fully applicable in May 2020 and the IVDR in May 2022.
The steps for a manufacturer of a medical device to obtain a CE marking necessary to be able to place the device on the market are similar to those for other consumer products that need CE marking. The overall process has not changed under the new MDRs. First, manufacturers must identify the correct classification and provisions applicable to their devices, and in particular, the essential requirements that the devices have to fulfil (now known as the general safety and performance requirements). Second, manufacturers must ensure that the product meets all the harmonised standards that exist for the device in question. Then, they must demonstrate that their medical devices meet the requirements in the legislation by carrying out a conformity assessment. EU member states can designate accredited Notified Bodies to conduct conformity assessments, where this is necessary due to the risk classification of the device. The conformity assessment usually involves an audit of the manufacturer’s quality system and, depending on the type of device, a review of technical documentation from the manufacturer on the safety and performance of the device. Alternatively, for some devices, the device can be self-certified without the involvement of a Notified Body. Manufacturers can place a CE mark on a medical device once it has passed a conformity assessment. The identification number of the Notified Body should also be affixed to it (where relevant). Manufacturers must draft and sign an EU declaration of conformity stating that the product meets all legal requirements.
Although the current Medical Devices Directives already provide numerous requirements regarding the labelling and packaging of medical devices, the new MDRs will implement a large number of changes with further requirements for the instructions for use, new unique device identification requirements, more serial and lot numbers, highlighting of the identity of the authorised representative, warnings and precautions on the label, medical device symbols and electronic information for use, among others.
What legislation controls and which rules apply to ethics committee approval and performance of clinical trials in your territory for medicinal products and medical devices?
Clinical trials for medicinal products are currently governed by the Clinical Trials Directive 2001/20/EC. This Directive will be replaced by the Clinical Trials Regulation (EU) No. 536/2014, which aims to ensure a greater level of harmonisation in the EU. Although the Clinical Trials Regulation entered into force in 2014, the timing of its application depends on the development of a fully functional EU portal and database by the EMA, European Commission and member states. The clinical trials EU portal is expected to be finalised in 2020.
Under the Clinical Trials Directive, the sponsor of a clinical trial must obtain an authorisation from the competent authorities in the member states where the trial is being conducted to carry out the trial, together with a positive opinion from the relevant ethics committee.
Both the current Medical Devices Directives and the new MDRs require the manufacturer or person responsible for placing the medical device on the EEA market to produce and maintain a clinical evaluation report for each device. The clinical evaluation involves the assessment and analysis of clinical data relating to a medical device in order to verify its safety and performance. This may include the need to conduct clinical investigations, but this not a requirement of the current Directives. Any clinical investigations that are carried out must be conducted in accordance with Annex X of the Medical Devices Directive (or the equivalent Annex for other types of devices). As part of this process, the competent authority will consider the application to conduct the clinical investigation, and the ethics committee will provide an opinion on the investigation.
The European Commission has issued detailed guidance on clinical evaluations of medical devices to expand on the provisions in Annex X of the current Directive, which is now consolidated in the latest version of MEDDEV 2.7/1, revision 4.
The new MDRs place more focus on clinical evaluations, and the requirements for clinical investigations. At present, the MEDDEV guidance has not been updated in line with the new legislative requirements.
What requirements exist for reporting the commencement of a trial and its results to the competent authorities or the public?
In line with the requirements of the Clinical Trials Directive, the EU Clinical Trials Register was launched to provide the public with some of the information held in the EudraCT database, which is the database used by the competent authorities to collect information on clinical trials.
Before commencing a clinical trial and before submitting an application to the national competent authority, the applicant must obtain a unique EudraCT number, which identifies the protocol for the trial. The applicant is then able to submit the clinical trial application to the national competent authority. However, it is the responsibility of the national competent authorities to update the information in the EudraCT system regarding the approval of the clinical trial application form, substantial amendments and end of the trial.
Certain of this information is made public, and is searchable via the Register website. The data on the results of these trials are entered into the EudraCT database by the sponsors themselves and are published in this Register once the sponsors have validated the data.
To support these provisions, the Commission has developed guidance on posting and publication of information on clinical trials and result-related information on clinical trials (2012/C 302/03) to expand on the transparency obligations of the Clinical Trials Directive. In relation to results, the guidance states that for all trials (paediatric and non-paediatric), result-related information should be supplied and made public within 12 months of the completion of the trial (not only after grant of the MA), including a summary of the results and conclusions.
Under the Clinical Trials Regulations, the transparency obligations have been given a legislative setting, with more obligations being placed on sponsors of clinical trials to make information about the trials they conduct public.
Currently, there is a European central repository for information about medical devices. This is the Eudamed2, which is a secure web-based portal managed by the European Commission. However, Eudamed2 is restricted to national competent authorities. It is not publicly accessible. In any event, there are no obligations in relation to disclosure of information on clinical investigations. However, the Medical Devices Directives contain a general provision that clinical investigations should be conducted in line with the Declaration of Helsinki, including in relation to publication of results of investigations.
The new MDRs provide for a much larger Eudamed database, which is expected to be available to the public in 2020. Some information on clinical evaluations will be included on this database for certain devices. However, this does not include an obligation to routinely disclose information on clinical investigations for devices.
Consent and insurance
Are there mandatory rules for obtaining trial subjects’ consent to participate? Must sponsors arrange personal injury insurance to a particular limit?
Both the Clinical Trials Directive and the Clinical Trials Regulation require informed consent for trial subjects to take part in a clinical trial. The consent must be written, dated and signed. It must be given freely after the subject has been duly informed of the trial’s purpose, significance, implications and risks, and appropriately documented by any person capable of giving consent or, where the person is not capable, by his or her legal representative. If the person concerned is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation.
With regard to personal injury insurance, the Clinical Trials Directive obliges the sponsor to make provision for insurance or indemnity to cover the liability of the investigator and sponsor, without specifying a particular limit at EU level.
Annex X to the Medical Devices Directive states that clinical investigations with medical devices are expected to be designed, conducted and reported in accordance with international standards and the Declaration of Helsinki. The requirements regarding the collection of consent from trial subjects are, therefore, similar to those required for medicine-related trial subjects. Informed consent is required in all cases and it must be given freely, written, dated and signed. There are no specific provisions on insurance, although many ethics committees will require such provision to be put in place.
The new MDRs contain specific provisions on informed consent of subjects involved in clinical investigations, which are broadly in line with the requirements for medicinal products. In addition, the new MDRs set out requirements for a ‘system of compensation’ to be put in place to compensate subjects for damages suffered as a result of participation in a clinical investigation. This system will be put in place on a national basis, and no details are yet available.
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?
With regard to MAs under the EU centralised procedure, the assessment of an application for a new medicine takes up to 210 ‘active days’. This time is interrupted by one or two ‘clock-stops’. Overall, the assessment of a new medicine usually lasts around one year. MAs granted by the EU have an initial period of validity of five years. Once renewed, the MA is valid for an unlimited period of time (see question 17). The EMA charges fees for applications for MAs and for variations and other changes to MAs, as well as annual fees for authorised medicines. The EMA basic fee for an MA application for a human medicine starts at €291,800.
Under the mutual recognition procedure and the decentralised procedure, the reference member state coordinates the evaluation of the product and has primary responsibility for preparing the assessment report on the application. The evaluation process may take up to 210 days after the submission of a valid application. Once all of the member states involved in the procedure agree with the assessment, the procedure closes, and each member state must grant a national MA.
The authorisation procedure timelines, periods of validity and fees for MAs may vary as these follow the national rules.
It generally takes 12 to 16 weeks to get a CE marking for a medical device where this process requires the involvement of a Notified Body. Most Notified Bodies offer options for expedited reviews or dedicated on-site review of design dossiers and technical files. The EC Declaration of Conformity and CE mark are valid as long as the product meets the applicable legal requirements and no significant changes are made to the device.
Protecting research data
What protection 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?
Data submitted by originators is protected for a period of eight years from the initial authorisation of the reference product, by a ‘data exclusivity’ period, after which valid applications for generic products can be submitted that cross-refer to the preclinical and clinical data submitted to support the authorisation of the reference product, so the generic company does not need to generate its own data. In addition, there is a two-year period of ‘market protection’, after which authorised generic products can be placed on the market. This 10 year-period shall be extended to a maximum of 11 years if, during the first eight years, the MAH obtains an authorisation for one or more new therapeutic indications, which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies.
Where a change of classification of a medicinal product has been authorised on the basis of significant preclinical tests or clinical trials, the competent authority shall not refer to the results of those tests or trials when examining another application by another applicant, or holder of an MA, for a change of classification of the same substance for one year after the initial change was authorised.
Where an application is made for a new indication for a well-established substance, a non-cumulative period of one year of data exclusivity 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. Medical device manufacturers may use a device that is already on the market to demonstrate equivalence of their own device. 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 current Medical Devices Directives and the corresponding MEDDEV guidance, Notified Bodies are expected to challenge the manufacturer’s access to credible information to substantiate a claim of equivalence. Under the new MDRs, 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?
To implement Regulation (EC) No. 1049/2001, the EMA’s policy on access to documents, revised in October 2018, allows citizens of the EU and natural or legal persons residing or having their registered office in an EU member state to access EMA documents. This includes documents received by EMA or in its possession, such as research data submitted by applicants for MAs. The EMA’s policy also provides that it will ensure protection of commercial interests in accordance with the notion of commercially confidential information (CCI). As there is no legal definition of CCI, the EMA policy defines it as ‘any information which is not in the public domain or publicly available and where disclosure may undermine the economic interest or competitive position of the owner of the information’.
This is the same notion that the EMA uses in its separate policy for the proactive publication of clinical trial data for medicines once the decision-making process on an application is complete. Although the EMA policy sets out that the majority of data in clinical reports is not CCI, it provides that any information contained in the clinical reports submitted to the EMA that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interests of the applicant, would be considered as CCI. In recent General Court cases on access to EMA documents, the Court states that exceptions from the principle of widest possible public access to documents must be interpreted and applied strictly and that the mere fact that a document concerns an interest protected by an exception is not sufficient to justify application of that exception. These judgments have been appealed to the Court of Justice of the European Union (CJEU).
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 access the technical information relating to an application for CE marking held by the Notified Bodies.
Regulation of specific medicinal products
Are there specific rules for approval, and rewards or incentives for approval, of particular types of medicinal products, such as traditional herbal and homeopathic products, biologicals and biosimilars, controlled drugs, orphan drugs and those for paediatric use?
Medicines that have been granted an orphan designation by the EU benefit from protocol assistance, a form of specific scientific advice by the EMA, at a reduced charge; access to the centralised authorisation procedure; and 10 years of market exclusivity protecting the product from market competition from similar medicines with similar indications once they are approved. Companies applying for designated orphan medicines pay reduced fees for regulatory activities. Companies classified as micro, small and medium-sized businesses (SMEs) benefit from further incentives when developing medicines with orphan designation. These include administrative and procedural assistance from the EMA’s SME office and fee reductions. Separately, the European Commission offers research grants for sponsors of orphan medicines.
Medicines authorised in the EU that include reference to the results of studies from a paediatric investigation plan included in the product information are eligible for an extension of their supplementary protection certificate (SPC) by six months, even when the studies’ results are negative. If the product is an orphan product, the 10-year period of market exclusivity is increased to 12 years. 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 an SPC are eligible for a paediatric-use MA (PUMA). If a PUMA is granted, the new data submitted to support authorisation of the product will benefit from 10 years of market protection.
Priority medicines, or medicines that target an unmet need, are supported by the EMA via the PRIME scheme, where the EMA offers proactive support to medicine developers and enables accelerated assessment of medicines’ applications.
Developers of advanced therapy medicinal products (ATMPs) can obtain reductions in the fees payable to EMA for scientific advice and for the certification procedure.
The EMA’s dedicated SME office provides regulatory, financial and administrative assistance to SMEs. It also provides fee exemptions and reductions for regulatory procedures, assistance with translations, inclusion on an online SME register for networking and workshops, and training sessions. The European Commission publishes three separate inventories consolidating the incentives available in EU member states for orphan drugs, paediatric medicines development and SMEs at national level.
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?
The EU legal framework of pharmacovigilance for medicinal products for human use is provided for in Directive 2001/83/EC for all medicinal products authorised under EU pharmaceutical law, and Regulation (EC) No. 726/2004 for centrally authorised products. The legislation was amended by Regulation (EU) No. 1235/2010 and Directive 2010/84/EU. The changes introduced by the latter Directive must be transposed into national law, while Regulation (EU) No. 1235/2010 is directly applicable in all EU member states.
The new pharmacovigilance legislative package has applied since July 2012 across all EEA countries. The regulatory tools made available under the revised legislation include risk management plans, post-authorisation studies, signal detection and management at EU level, periodic safety update reports, and assessment and reviews of medicines through referrals. The legislation creates a Pharmacovigilance Risk Assessment Committee, which is responsible for assessing and monitoring safety issues for human medicines. Under the new legislative package, MAHs 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 (ADRs) has been centralised through electronic submissions to the EudraVigilance database. Previously, reports were made via the individual national competent authority. Since September 2013, it has been mandatory to display a black inverted triangle on the product information of medicines that are being monitored particularly closely by regulatory authorities. With this measure, the European Commission aims to improve the safety of medicines and to highlight to patients the importance of reporting suspected ADRs.
Post-marketing obligations is an important part of both the currently applicable Medical Devices Directives and the new MDRs, although the provisions under the new MDRs have been greatly increased, with detail from the existing guidance being placed on a legislative footing. Under the current Directives, and accompanying MEDDEV guidance, manufacturers of medical devices are required to implement and maintain a post-market surveillance system that monitors the clinical performance and clinical safety of the device as part of their quality management system. There are also obligations on vigilance, whereby the manufacturer must collect and evaluate incidents and implement corrective action as required. The relevant competent authorities will work with the manufacturer to identify any corrective action considered necessary, and information is disseminated to other member states in the form of a National Competent Authority Report. Where appropriate, manufacturers should also notify their authorised representative and any other agents (eg, distributors) involved in the supply of the device to ensure a coordinated response to any identified risks.
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?
Manufacturers and importers (for medicines coming from third countries) located in the EEA must hold a manufacturing or import authorisation issued by the national competent authority of the member state where they carry out these activities. They must comply with EU Good Manufacturing Practice (GMP) guidelines, which describe the minimum standard that a medicine manufacturer must meet in their production process. Importers are responsible for ensuring that the third-country manufacturers they are importing from comply with GMP. MA applicants must ensure that the proposed manufacturing sites included in the MA application comply with GMP.
To obtain a manufacturing or import authorisation, the applicant must specify the medicines that are to be manufactured or imported and the place where they are to be manufactured or controlled; have at his or her disposal suitable premises and control facilities and 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 national level.
Possession of a manufacturing authorisation includes authorisation to distribute by wholesale the medicines covered by such authorisation, however, possession of an authorisation to wholesale distribute does not allow one to manufacture medicines.
Manufacturers or their authorised representative should be based in the EU or EEA to place medical devices on the EU or EEA market. Importers of medical devices from outside the EU or EEA are not required to obtain an import authorisation, but can become legally responsible under the medical devices legislation for those devices. They may choose either to sell the device under the name of the manufacturer as its authorised representative in the EU, or to sell under their own name (own brander), but will then require an agreement with the manufacturer to ensure the importer has access to the technical documentation relating to the CE marking of the device, as they must ensure that the products that they place on the market comply with the applicable requirements. In this case, the importer needs to engage a Notified Body to obtain a CE mark under its own name. No authorisation is required to distribute medical devices that have been lawfully placed on the EU market.
The new MDRs introduce clearer obligations for importers and distributors of medical devices, which include various obligations to verify the compliance of the device with the legislation. However, the position mentioned above in relation to authorisations, and the requirements of the importer, are maintained. In addition, both importers and distributors must provide competent authorities, upon request, with all the information and documentation that is at their disposal and is necessary to demonstrate the conformity of the device.
What civil, administrative or criminal sanctions can authorities impose on entities or their directors and officers for breach of the requirements concerning controlled activities?
The enforcement of the provisions of the pharmaceutical legislation is mainly carried out at national level. At EU level, Regulation (EC) No. 726/2004 and Regulation (EC) No. 658/2007 (the Penalties Regulation) have established an EU financial penalties regime, according to which the EMA may investigate and report on alleged breaches of the EU pharmaceutical rules by holders of an MA 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 MAHs.
To the authors’ knowledge, there has only been one infringement procedure against a pharmaceutical company, and the Commission closed the procedure on 15 December 2017 without a financial penalty being imposed. During that procedure, it became apparent that there were a number of legal and procedural issues that rendered the Penalties Regulation regime problematic. Recent changes to the EU financial penalties regime aim to address these issues. Based on new provisions in Regulation (EC) No. 726/2004, the European Commission will adopt a new delegated act containing the procedure that can lead to a fine. The new rules will contain provisions on initiation of the procedure, measures of inquiry, rights of defence, access to file, and confidentiality. It has been discussed that these rules could reduce the role of the EMA in the investigation of possible infringements and leave more responsibilities to the Commission. Prior to the new delegated act, the existing procedure under the Penalties Regulation remains applicable.
The current rules on medical devices are enforced at national level. National competent authorities have a range of investigatory and enforcement powers to ensure the safety and quality of the device. 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. Prosecution may carry a penalty of fines, in some jurisdictions or imprisonment, or both.
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. These are:
- medicinal products prepared in a pharmacy in accordance with a medical prescription for an individual patient (or magistral formula);
- medicines prepared in a pharmacy in accordance with a pharmacopoeia intended to be supplied directly to the patients served by the pharmacy (or officinal formula);
- intermediate products intended for further processing;
- radionuclides in the form of sealed sources;
- whole human blood or plasma;
- ATMPs prepared on a non-routine basis (custom-made ATMP) and used in a hospital for an individual patient;
- industrially produced medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised healthcare professional (HCP) and for use by an individual patient under the HCP’s direct personal responsibility to fulfil special needs; and
- member states may temporarily authorise the distribution of unauthorised medicines in response to the suspected or confirmed spread of pathogenic agents and other chemical or toxic agents that could cause harm.
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?
Medicines authorised in both the EU member state of origin and the EU member state of destination may be parallel imported, provided the imported product has the same composition of active substances and there are no therapeutic difference from the corresponding product authorised in the member state of destination. Parallel importers must submit a notification of intention to parallel distribute to the EMA (for centrally authorised products) or an application to the national competent authority for a parallel import authorisation prior to any importation. They must also hold a wholesale distribution authorisation covering importing, storage and sale of the relevant products. Any relabelling or repackaging activities will likely require a manufacturing authorisation. EU law does not restrict individuals importing medicines into an EU member state from another provided they are strictly for use by that person or a member of their immediate family.
A medical device that has been marketed in an EU or EEA country may, in principle, be placed on the market in another EU or EEA country by a parallel importer. Once a medical device has been CE marked, it may be marketed anywhere in the EU or EEA, as long as the requirements set out in the currently applicable Medical Devices Directives are met. A parallel importer would not normally be regarded as the manufacturer of the device, unless that person repackaged the product and rebranded it so that the product is placed on the market under that person’s name; or changes were made such that the device is no longer covered by the original CE mark; for example, if the parallel importer modifies the device in some way. If the parallel importer becomes the manufacturer, the device would need to go through a new conformity assessment procedure before it may be CE marked and placed on the EU market. The parallel importer is obliged to ensure that the device meets the essential requirements of the relevant Medical Devices Directive and that its packaging and instructions for use are properly CE marked and accompanied by the relevant Notified Body number.
What are the main requirements relating to variation of authorisations for medicinal products and medical devices?
Variations to the terms of MAs are regulated under Commission Regulation (EC) No. 1234/2008 (the Variations Regulation) and the corresponding Commission Variation Guidelines. The procedure and requirements differ depending on the type of variation in question, which include type IA for minor variations, type II for major variations and type IB for those variations that are neither type IA, type II nor an extension. An extension of an MA is a change that falls within the categories set out in Annex I of the Variations Regulation, mainly: changes to the active substances and changes to strength, pharmaceutical form or route of administration.
If a manufacturer makes changes to a medical device that would potentially affect its performance or safety characteristics, it would need to liaise with the relevant Notified Body and submit the necessary documentation to determine if the CE mark remains valid. For self-certified devices, this assessment is done by the manufacturer.
What are the main requirements relating to renewal of authorisations for medicinal products and medical devices?
Centrally authorised MAs are renewable after five years upon application by the MAH to the EMA. Once renewed, the MA will be valid for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance, to mandate one additional five-year renewal period. MAs granted under exceptional circumstances are also valid for five years. However, conditional MAs must be renewed annually. The MAH must apply for a renewal no later than nine months before the expiry date of the MA. Fees are payable except for the renewal of a conditional MA.
The EC Declaration of Conformity and CE mark are valid as long as the product meets the applicable legal requirements and no significant changes are made to the device.
How easy is it to transfer the existing approvals or rights to market medicines and medical devices? How long does this take in general?
An MAH may transfer the MA to a new MAH. MA transfer applications for centrally authorised products, including mock-ups of the product information, must be submitted for each product (Regulation (EC) No. 2141/96). Changes of name or address of an MAH is not a transfer but a type IA variation. Since 1 January 2010, the electronic common technical document is the only acceptable electronic format for all applications and submissions for the centralised procedure, and this includes transfers. A transfer application follows a 30-day procedure following the receipt of the application. When transferring the MA of a designated orphan medicinal product, the MAH must also transfer the orphan designation of the product, although these two transfers are handled under different procedures. The EMA’s European Product Assessment Report of the medicine will be revised to implement the change in the MAH.
A change of the manufacturer of a medical device will transfer all the obligations and requirements relating to the medical device in question to the new manufacturer, which would need to liaise with the corresponding Notified Body to update the technical documentation of the device, as well as the product information and instructions for use, as needed.
Defective and unsafe products
What are the normal requirements for handling cases of defective or possibly unsafe products, including approvals required for recall and communication with health professionals?
The EMA coordinates the assessment of reports of product quality defects of centrally authorised products. MAHs and manufacturing authorisation holders are obliged to report to the EMA any product quality defect, including a suspected defect of a centrally authorised medicine, that could result in a recall or abnormal restriction on supply. This includes any new information that may influence the evaluation of the product risk-benefit or any restriction imposed by the competent authority of any country. In addition, MAHs must notify the national competent authorities of the country (EU or third country) where the suspected defective product is distributed. If the nature of a product quality defect presents a serious risk to public health, national competent authorities inform each other through the rapid alert system and a recall mechanism may be activated.
Post-marketing obligations are overseen by the national competent authorities in the member states, although the European Commission can undertake a coordination role where a product is withdrawn from the market. As set out in question 11, corrective action may need to address any incident identified with a device, and this may include the recall or withdrawal of a device to reduce the risk of death or serious injury. The manufacturer of the device must assess the need for the recall and works with the competent authorities to ensure appropriate information is provided to HCPs.
These measures will be strengthened under the new MDRs, which provide for a more active role by all the stakeholders involved in post-marketing surveillance and vigilance in a manner proportionate to the risk class.
Summarise the rules relating to advertising and promotion of medicinal products and medical devices, explaining when the provision of information will be treated as promotional. Do special rules apply to online advertising?
The promotion of medicinal products in the EU is controlled by a combination of legislation, contained in Title VIII of Directive 2001/83/EC and self-regulation by reference to industry codes of conduct, mainly the European Federation of the Pharmaceutical Industry Association (EFPIA) Code of Practice 2019 (the EFPIA Code), which covers the promotion of medicines to HCPs and the interactions with such HCPs, healthcare organisations (HCOs) and patient organisations (POs). The EFPIA Code is designed to be implemented by its national member associations. In June 2019, EFPIA consolidated its three codes of conduct for HCPs, POs and disclosure of transfers of value (ToV) into a single Code of Practice, which must be implemented by 31 December 2020.
EU law provides different rules for advertising of medicines to the public and advertising aimed at HCPs. Advertising to the public is permitted for medicines legally classified as non-prescription, while advertising for prescription-only medicines may only be targeted at persons qualified to prescribe or supply medicines. Advertising of unauthorised medicines or indications is not permitted. All medicine advertising must be consistent with the approved SmPC.
Under the Directive, advertising is defined as ‘any form of door-to-door information, canvassing activity or inducement designed to promote the prescription, supply, sale or consumption of medicinal products’. Therefore, corporate or financial information describing a company’s area of business and progress in research will likely fall outside of the definition, provided it is not presented in a promotional style and includes no claims in relation to medicinal products or medical treatments and does not encourage patients to ask their doctors to prescribe a particular product.
Online advertising is regulated under the same provisions and controls as traditional advertising, although the various industry codes of practice have been updated periodically in the recent years to add provisions specifically designed for the particularities created by the use of the internet by the industry, including the use of online platforms and social media.
The EU laws governing the promotion and advertising of medical devices are less detailed than those established for medicines. The new MDRs introduce a new requirement concerning promotional claims. The new provision expressly prohibits the making of claims, when promoting a medical device, that may mislead the user or the patient with regard to the device’s intended purpose, safety or performance by:
- ascribing functions and properties to the device that the device does not have;
- creating a false impression regarding treatment or diagnosis, functions or properties that the device does not have;
- failing to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; or
- suggesting uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out.
This new provision will apply in addition to the existing EU general consumer legislation on misleading advertising.
From a self-regulation perspective, at EU level, the largest medical device manufacturer’s industry association, MedTech Europe, issues a Code of Business Practice (the MedTech Code), which is obligatory for its member associations and member companies, and regulates their interactions with the medical community and other stakeholders. The MedTech Code became binding on corporate members in January 2017. Its Q&A section was amended in June 2019.
What regulations exist to discourage the provision of inducements to healthcare professionals to prescribe, sell, supply or recommend use of a particular medicinal product or medical device?
Directive 2001/83/EC clearly prohibits the supply, offer or promise of gifts, pecuniary advantages or benefits in kind to persons qualified to prescribe or supply medicines where medicines are being promoted, unless they are inexpensive and relevant to the practice of medicine or pharmacy. This prohibition is required to be reflected in the national laws of all member states. Hospitality extended to HCPs is considered acceptable in the context of promotional events, provided it is limited to the main purpose of the event and offered to HCPs only.
The EFPIA Code reflects these restrictions, prohibiting gifts for the personal benefit of HCPs, HCOs’ members and POs’ representatives (either directly or indirectly), such as social courtesy gifts or sporting or entertainment tickets. Providing cash or offering cash, cash equivalents, promotional aids (non-monetary items given for promotional purposes) or personal services is also prohibited. Personal services are any type of service unrelated to the profession and that confer a personal benefit to the recipient. Donations and grants to HCOs and POs are allowed under strict conditions, but donations and grants to individuals are not permitted.
Given the private nature of Notified Bodies, both the Medical Device Directives and the new MDRs require Notified Bodies to carry out their assessments and verifications with the highest degree of professional integrity and free from all pressures and inducements, particularly financial, which might influence their judgement, especially from persons with an interest in the results of the verifications.
From a self-regulation perspective, and in line with general anti-bribery legislation applicable in many countries, the MedTech Code sets out the principles that interactions with HCPs should be transparent, and must not be misused to influence purchasing decisions, through undue or improper advantage, nor should such interactions be contingent upon sales transactions or use or recommendation of a particular product. More specifically, the MedTech Code prevents member companies from offering and providing educational grants to individual HCPs with certain exceptions, as explained in more detail in question 22, and has phased out the provision of financial or in-kind support directly to individual HCPs to cover costs for their attendance at third-party organised educational events (with the exception of procedure training). It also sets out clearer transparency obligations with regards to all interactions with HCPs, in terms of notification to the HCP’s superiors or relevant health institutions before the interaction may take place, disclosure of payments (made as educational grants) and a centralised platform for the approval of conferences and other events (the Conference Vetting System).
Reporting transfers of value
What requirements apply to recording and publishing details of transfers of value to healthcare professionals and organisations by companies marketing medicinal products or medical devices?
EU law does not set out requirements regarding the recording or publishing of the details of ToVs to HCPs by pharmaceutical companies. Requirements are, however, imposed by the national legislation of some European countries, such as France and Portugal, and by the self-regulatory codes.
The EFPIA Code provides for disclosures of ToV to HCPs and HCOs, whether directly or indirectly. When deciding how a ToV must be disclosed, member companies, must, wherever possible, identify and publish relevant information at the individual HCP level (rather than the HCO level) as long as this can be achieved with accuracy and consistency and in compliance with applicable laws and regulations. The items to be disclosed are those ToVs relating to donations and grants (to HCOs), contribution to costs related to events and fees for service and consultancy. Where certain information cannot reasonably be allocated to one of the categories above or cannot be disclosed on an individual basis for legal reasons, member companies must disclose the attributable amounts to those ToVs in each reporting period on an aggregate basis. Research and development ToVs must also be disclosed on an aggregate basis. Disclosures must be made pursuant to the national code of the country where the recipient has its professional address and on the company’s website or on a central platform, depending on national requirements.
With regard to POs, each EFPIA member company must disclose a list of POs to which it provides financial support or significant indirect or non-financial support or with whom it has engaged to provide contracted services for that member company. The information to be disclosed is the name of the PO, the monetary value of the financial support, the non-monetary benefit that the PO receives and the total amount paid per PO for contracted services over the reporting period. The information must be disclosed on the member company website at national or European level.
As with medicinal products, there are no legal provisions at EU level requiring medical technology or medical device companies to disclose payments to HCP, HCOs or POs. However, there are requirements to disclose certain ToVs under the national laws of some member states and under the MedTech Code.
Under the MedTech Code, member companies are obliged to maintain appropriate transparency by requiring prior written notification to the hospital administration, the HCP’s superior or other locally designated competent authority, fully disclosing the purpose and scope of the interaction.
In addition, member companies must document and publicly disclose all educational grants in accordance with the Code’s disclosure guidelines. Educational grants include support for third-party organised educational events, grants for public awareness campaigns and scholarships and fellowships. Each member company must disclose all payments related to their educational grants to HCOs based in Europe without limitation of value. Amounts paid to each recipient HCO will be aggregated on a category-by-category basis, but will need to be itemised upon request from the competent authorities. The disclosure may be made on the MedTech Europe website or on the national platform, if one is set up under national rules.
Enforcement of advertising rules
Describe the bodies involved in monitoring and ensuring compliance with advertising controls for medicinal products and medical devices, distinguishing between any self-regulatory framework and control by the authorities.
Traditionally, the enforcement of the EU provisions regarding advertising of medicinal products and medical devices is undertaken at national level by the national competent authorities. The provisions of the EU Directives mentioned above are implemented under national law and thus, enforcement falls within the remit of the national competent authorities.
With regard to medicines, the Penalties Regulation, mentioned in question 13, is designed to apply to breaches of the Regulation relating to centrally authorised medicinal products.
From a self-regulation perspective, the enforcement of the advertising requirements, including the requirements on the disclosure of ToV set out under the EFPIA Code for medicines and under the MedTech Code for medical devices, is carried out by the national associations under their respective enforcement rules.
What are the possible financial or other sanctions for breach of advertising and promotional controls for medicinal products or medical devices?
Sanctions for breaches of national legal provisions on advertising vary from fines to imprisonment of responsible individuals under a criminal law framework to administrative fines in certain jurisdictions. Sanctions may escalate if the breach of the advertising provisions is linked to an illegal inducement of an HCP and the matter falls within the remit of the national anti-bribery law or there has been a breach of the anti-trust rules. Under the self-regulatory systems, sanctions for breaches of the national codes provisions include fines, publication of cases, issuance of corrective notices to HCPs, audits and ultimately suspension or cancellation of the company’s membership to the relevant national industry association and potentially of corresponding European industry associations, such as EFPIA and MedTech.
Pricing and reimbursement
What are the controls imposed on pricing of medicines and medical devices and reimbursement by national social security systems that are applicable to manufacturers, distributors and pharmacists?
The controls on pricing of medicines and medical devices and the decisions regarding reimbursement of these products by national social security systems applicable to manufacturers, distributors and pharmacists are carried out exclusively at national level.
Off-label use and unlicensed products
May health professionals prescribe or use products for ‘off-label’ indications? May pharmaceutical companies draw health professionals’ attention to potential off-label uses?
EU legislation does not prevent HCPs from prescribing or using products off-label on their own responsibility, but national controls may exist. However, the EU advertising rules described in question 20 prevent pharmaceutical companies drawing the attention of HCPs to potential off-label uses or promoting their medicines in a manner that is not consistent with the SmPC.
Pharmaceutical companies may, however, discuss such issues with HCPs in a reactive manner, as a response to specific unprompted questions from HCPs or in an strictly non-promotional context, as part of a legitimate exchange of scientific information. The CJEU has stated that it is prohibited to include in advertising claims information that conflicts with the SmPC. However, not all of the information contained in an advertisement needs to be identical to that in the SmPC, provided the claims are consistent with the information in the SmPC. Advertisements may, therefore, include additional claims, provided that these confirm or clarify, and are compatible with, the information set out in the SmPC. Any such additional information must also meet the various other requirements of Directive 2001/83/EC, such as being presented objectively, faithfully and in such a way as to allow independent verification, and not being exaggerated, misleading or inaccurate.
It is considered to be off-label use if the HCP or patient uses a medical device differently to how the manufacturer has instructed. This includes changing a medical device to suit new needs, or using the device for a purpose that is not in line with the intended purpose and CE marking. As is the case for medicinal products, EU law does not prevent HCPs from using medical devices off-label. The use of the device off-label will be at the risk of the HCP.
Any promotion of a device should be limited to the intended purpose and CE mark. The legislation and MedTech Code do not contain provisions on providing information about off-label uses. However, all information about a device should be accurate, balanced, fair, objective and unambiguous. As noted in question 20, the new MDRs expressly prohibit the making of claims, when promoting a medical device, that may mislead the user or the patient with regard to the device’s intended purpose, safety or performance by suggesting uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out.
What rules apply to the manufacture and importation and supply to healthcare providers of unlicensed medicines or medical devices?
The manufacture, importation and supply of unauthorised medicines is controlled at national level. Directive 2001/83/EC expressly allows member states to exclude from their provisions industrially manufactured products that have no marketing authorisation where these products are required to meet ‘special needs’. There is, therefore, no harmonisation of the rules controlling ‘special needs’ supply at EU level, and national provisions and guidance vary from country to country.
Member states may temporarily authorise the distribution of unauthorised medicines in response to suspected or confirmed spread of pathogenic agents, toxins chemical agents or nuclear radiation. Unauthorised products may also be manufactured, imported and supplied in the context of medical research under the provisions of the Clinical Trials Regulation or as part of compassionate use programmes for unlicensed medicinal products, described in question 28.
HCPs are advised to use medical devices with a CE mark as this shows that the device has met the legal requirements for safety, quality and performance if it is used as the manufacturer instructs. Medical devices that are custom made for individual patients or used for clinical trials do not need a CE mark.
A device should not be promoted in the EU if it is not CE marked. However, it is possible that if a device is not placed on the market, information can be provided about it, if it is clear that it is not officially launched and does not have a CE mark. The Medical Devices Directives also allow devices to be ‘shown’ at trade fairs, exhibitions, demonstrations, etc, when they do not have a CE mark. This is provided that a visible sign clearly indicates that the device cannot be marketed until it does comply. Similar provisions are included in the new MDRs.
What rules apply to the establishment of compassionate use programmes for unlicensed products?
Regulation (EC) No. 726/2004 allows member states to make certain medicines regulated under the Regulation available for compassionate use. This means making such medicines available for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorised medicinal product.
The medicinal product concerned must either be the subject of an application for an MA in accordance with the Regulation or must be undergoing clinical trials. The CHMP of the EMA may adopt opinions (non-binding on national authorities) on the conditions for use, distribution and the patients targeted after consulting the manufacturer or the applicant. The applicant in respect of the compassionate use programme is obliged to ensure that the patients taking part also have access to the new medicine during the period between authorisation and placing on the market.
There are no provisions covering medical device compassionate use programmes under EU law. Compassionate use programmes are, however, not prohibited. The European Commission recognises in its MEDDEV guidance that, in exceptional cases, major benefits may justify relatively high levels of uncertainty, and access to the market may be granted on the basis of limited clinical evidence, such as experience available from compassionate use programmes. Medical device compassionate use programmes may, therefore, be coordinated and implemented by EU member states according to national legislation and guidance.
Sale and supply
Are there special rules governing the dispensing or sale of particular types of medicinal products or medical devices?
When an MA for a medicinal product is granted at EU or at national level, the conditions and restrictions under which the medicinal product should be made available to patients (the ‘legal status’ of the medicine) must be included as part of the authorisation. The legal status of a medicine may be amended if new facts are brought to the attention of the competent authorities justifying the change.
The Directive sets out levels of categories in relation to the legal status. On the first level, the medicine is classified either as subject to medical prescription or not. For products subject to medical prescription, where applicable, there is a second level: medicines subject to special medical prescription, medicines subject to restricted medical prescription and medicines subject to renewable or non-renewable delivery.
In addition, wherever appropriate, the SmPC of the product will include an explanation on how the medicine should be supplied to patients (ie, to be administered in a hospital setting or prescribed by specialists only), or on the specific type of care required during the treatment of a chronic disease.
The dispensing, sale and use of medical devices is set out in the device’s labelling and instructions for use, which will specify, for example, if the device should be used by an HCP.
What laws and guidelines govern online dispensing, sale and supply of medicinal products and medical devices?
EU law does not prevent the dispensing, sale and supply of medicines online. However, patients are encouraged to only buy medicines from online retailers registered with the national competent authorities in the EU member states, to reduce the risk of buying sub-standard or falsified medicines and medical devices.
The EU first introduced a common logo for legally operating online pharmacies in EU countries as one of the measures to fight against falsified medicines and medical devices. The logo vouches for the authenticity of the websites and guarantees the safety of the products. On 24 June 2014, the European Commission adopted the new common logo through implementing Regulation (EU) No. 699/2014 obliging all online pharmacies and retailers operating in the EU to display the logo. The logo links to the website of the national competent authority listing all legally operating online pharmacies. By clicking the logo, the purchaser may check whether the website is legitimate and whether the retailer is registered.
Update and trends
Forthcoming legislation and regulation
Is there any current or foreseeable draft legislation or other rules that will affect the regulation of pharmaceuticals and medical devices? What is likely to change, and what steps need to be taken in preparation?
Forthcoming legislation and regulation31 Is there any current or foreseeable draft legislation or other rules that will affect the regulation of pharmaceuticals and medical devices? What is likely to change, and what steps need to be taken in preparation?Medicinal products
While the Clinical Trials Regulation was adopted in April 2014, it will not come into operation until six months after the clinical trials portal and database have been set up and independently audited, and notification of the successful audit has been published by the European Commission. The operation of this database has been delayed a number of times, as the development of a system to cover so many aspects of the new Regulation is taking longer than expected.
The MDR will be applicable in May 2020 and the IVDR in May 2022. Despite the amount of detail in the new MDRs, there are many aspects that need to be put in place before they are fully operational. The European Commission and MDCG are busy preparing the guidance documents and implementing legislation to ensure the new MDRs can function. Notified Bodies are also going through the designation procedure to ensure they can accept applications under the new MDRs and that products can be placed on the market under these, although currently, there are only four Notified Bodies that have been designated under the new MDRs.