The regulatory regimei Classification
Product definitions in the applicable EU legislation provide the starting point for distinguishing between medicines, medical devices and other regulated products. These definitions are supplemented by various borderline principles, specific rules and guidelines. In particular, EU case law has held that, when a product falls under the definition of two product types that are regulated under EU law, it must be classified under the EU rules that provide the higher level of public health protection. Article 2(2) of Directive 2001/83/EC formally incorporates this principle into EU law. It provides that:
In cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a 'medicinal product' and within the definition of a product covered by other Community legislation the provisions of this Directive [i.e., the medicines rules] shall apply.
EU legislation also lays down certain borderline principles. For example, Directive 93/42/EC contains specific principles for devices that are intended to administer medicines; devices and medicines that form single integral products, intended exclusively for use in the given combination and that are not reusable; and devices that incorporate, as an integral part, a substance that, if used separately, may be considered to be a medicine and that is liable to act upon the body with action ancillary to that of the device.
The European Commission also publishes various manuals on the scope of the application of EU legislation. For example, it has published a 'Manual […] on the scope of application of the Cosmetics Regulation (EC) No 1223/2009' and a 'Manual on borderline and classification in the community regulatory framework for medical devices'. The Commission has also published concrete guidance on the borderline between medicines and medical devices in MEDDEV 2.1/3.
National competent authorities, acting under the supervision of the national courts, must determine borderline issues case by case, taking into account all the characteristics of the product.ii Non-clinical studies
Non-clinical studies to demonstrate the health or environmental safety of new chemical or biological substances must be conducted in compliance with the principles of good laboratory practice (GLP). The principles of GLP provide a framework within which laboratory studies, both in vitro and in vivo, are planned, performed, monitored, recorded, reported and archived. Directive 2001/83/EC expressly provides that certain non-clinical (pharmaco-toxicological) studies of medicines must be carried out in conformity with GLP.
All tests on animals conducted in the EEA must be carried out in accordance with Directive 2010/63/EU on the protection of animals used for scientific purposes. Directive 2010/63/EU anchors the principle of the 'three Rs' (to replace, reduce and refine the use of animals) in EU legislation. It also lays down minimum standards for housing and care, and regulates the use of animals through an evaluation requiring an assessment of pain, suffering, distress and lasting harm.iii Clinical trialsMedicines
Clinical trials of medicines for human use are regulated under Directive 2001/20/EC, at least until Clinical Trial Regulation (EU) No. 536/2014 becomes applicable, which is now likely to be in 2020. Clinical trials of medicinal products in human subjects require notification to, or authorisation by, the relevant Member State's competent authority. In addition, a clinical trial of a medicinal product requires a favourable opinion by an ethics committee. The sponsor of a clinical trial, or its legal representative, must be based in the EEA.
Clinical trials must be conducted in accordance with internationally recognised principles of good clinical practice (GCP) and must comply with the Declaration of Helsinki (1996 version). Medicines used in clinical trials must be manufactured in accordance with standards of good manufacturing practice (GMP) and released by the holder of a manufacturer's authorisation in the EEA.
A clinical trial may be undertaken only if provision has been made for, among other things, insurance or indemnity to cover the liability of the investigator and sponsor, and the receipt of informed consent from the trial subjects.
Companies must report all suspected serious unexpected adverse reactions to the competent authorities and to ethics committees within 15 days, and seven days in the event of a fatality, and must submit an annual listing of all suspected serious adverse reactions that occurred during that period.
Although the European Commission has previously consulted on specific rules for 'non-commercial trials', no such rules have been adopted.Medical devices
Clinical investigations of medical devices are governed by Directive 93/42/EEC, Directive 90/385/EEC or Directive 98/79/EC, as applicable. The rules on clinical investigations of devices apply to studies of non-CE-marked devices, and to CE-marked devices if they are not CE-marked for the purpose being investigated. The directives do not recognise the concept of the 'sponsor'; rather, the manufacturer of the device intended for use in the clinical investigation is responsible for ensuring compliance with the relevant requirements. Compliance with certain standards, such as EN ISO 14155:2011 on clinical investigations of devices, raises a presumption that the manufacturer complies with the applicable provisions under the Directives.
The study must be conducted in accordance with the latest version of the Declaration of Helsinki, which includes requirements for the informed consent of study subjects. Prior to conducting a study in the EEA, the manufacturer, or its authorised representative based in the EEA, must seek ethics committee approval and notify the device regulators in the relevant jurisdictions. All serious adverse events must be reported immediately to the competent authorities.
The EU rules do not contain specific requirements for compensation and insurance for injuries to study subjects. There are no special rules for investigator-initiated studies.
Medical Devices Regulation (EU) 2017/745 contains detailed new clinical trial rules for medical devices, modelled on those applicable to clinical trials of medicines, which will apply from 26 May 2020. Among other things, the new rules impose obligations on the sponsor of the investigation, and contain specific requirements for compensation and insurance for injuries to study subjects. The IVD Regulation (EU) 2017/746 contains similar rules for clinical trials of IVDs, and will apply from 26 May 2022.iv Named-patient and compassionate use proceduresMedicines
Generally speaking, no medicinal product may be placed on the market in the European Union without a marketing authorisation. However, this is subject to a number of exemptions, including the 'named-patient' exception. The named-patient exemption covers the provision of unauthorised medicines with assumed benefits in situations where alternative treatment options are either non-existent, unsatisfactory or have been exhausted.
The named-patient exemption applies only where the supply of a medicine is:
- in response to a bona fide unsolicited order;
- formulated in accordance with the specification of a doctor and for use by his or her individual patients on his or her direct personal responsibility; and
- to fulfil a 'special need'. This exception must be construed narrowly, and in accordance with the overarching principle underlying Directive 2001/83/EC that 'the protection of public health must take precedence over economic considerations', and that the precautionary principle should be applied so as to err in favour of protecting public health where there is any doubt about the efficacy or safety of a product.
Article 83 of Regulation (EC) No. 726/2004 also specifies that Member States may make certain medicines available for 'compassionate use'. The Regulation defines 'compassionate use' to cover:
making a medicinal product [...] 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 can not be treated satisfactorily by an authorised medicinal product.
To qualify for compassionate use, the medicine must be either subject to a marketing authorisation application or be undergoing clinical trials. Member States must notify the EMA whenever they make use of the compassionate use procedure outlined in the Regulation.
EU Member States interpret the named-patient and compassionate use regimes differently, and application requirements and administrative procedures vary significantly in each jurisdiction.Medical devices
A medical device must comply with the applicable essential requirements and bear a CE mark before it can be placed on the market in the EEA. There is no EU-wide 'named-patient' or 'compassionate use' exemption for medical devices, although a number of Member States operate similar schemes under national laws for medical devices. However, the EU medical devices directives permit the supply of 'custom-made devices' without a CE marking, provided they meet applicable requirements under the directives. A 'custom-made device' is 'any device specifically made in accordance with a duly qualified medical practitioner's written prescription which gives, under his or her responsibility, specific design characteristics and is intended for the sole use of a particular patient'. The definition excludes mass-produced devices that need to be adapted to meet the specific requirements of the medical practitioner or any other professional user.
The manufacturer of a custom-made device must draw up a statement containing certain information, including:
- the manufacturer's name and address;
- a statement that the device is intended for exclusive use by a particular patient, with the name of the patient;
- the name of the medical practitioner or other authorised person who made out the prescription for the product;
- the specific characteristics of the product as indicated by the prescription; and
- a statement that the device conforms to the essential requirements and, where applicable, indicating which essential requirements have not been fully met, with the grounds.
Manufacturers of medicines must obtain a marketing authorisation before they can place their products on the EEA market. For certain products, including, in general terms, biotechnology products, advanced therapy medicinal products, orphan drugs and new active substances for the treatment of AIDS, cancer, neurodegenerative disorder, diabetes, autoimmune diseases, other immune dysfunctions and viral diseases, the marketing authorisation application must be submitted to the EMA for review through the centralised procedure. The CHMP also has the discretion to permit other products to use the centralised procedure if it considers them sufficiently innovative. Using the resources of selected national medicines agencies, the CHMP considers the application and gives an opinion on the approvability of the product. However, the marketing authorisation itself is granted by the European Commission and this is valid throughout the European Union and, by extension, the EEA.
For all other products, the competent authorities of the Member States are responsible for granting marketing authorisations for products that are sold in their markets. Applicants who intend to market such products in more than one Member State may seek marketing authorisations under the mutual recognition procedure or the decentralised procedure. If the product has already been authorised in one Member State, the mutual recognition procedure facilitates mutual recognition of the existing authorisation in another Member State. The decentralised procedure, on the other hand, may be used in cases where the product has not received a marketing authorisation in any Member State. Under this procedure, the applicant submits an identical dossier to each relevant Member State and one, known as the reference Member State, takes the lead in reviewing the application.
The applicant for a marketing authorisation under any of these procedures must be established in the EEA. It must submit sufficient data to demonstrate the quality, safety and effectiveness of the product. The format for the marketing authorisation application form and the underlying dossier is consistent for all medicinal products. Dossiers must follow the International Conference on Harmonisation common technical dossier format, in which quality and manufacturing, preclinical and clinical trial sections are accompanied by associated summary reports.
There is scope for applicants to omit some or all of the preclinical and clinical trial data if the product falls within the definition of a generic of a reference product for which regulatory data exclusivity protection has expired. The marketing authorisation underpinning the reference medicinal product must be based on a complete dossier; a generic application referring to a generic dossier is not possible. Generic applicants may need to submit additional preclinical or clinical data if their product does not fall within the definition of a generic (i.e., where there are differences in active substances, therapeutic indications, strength, pharmaceutical form or route of administration, in relation to the reference medicinal product, or where bioequivalence cannot be demonstrated through standard bioavailability studies). In these cases, bridging data is required to demonstrate that the differences do not affect the product's relative safety and effectiveness inappropriately.
Preclinical and clinical data can be omitted and replaced with references to scientific literature if the product has been in well-established medicinal use in the European Union for at least 10 years. An existing marketing authorisation holder may also give consent for a subsequent applicant to reference the pharmaceutical, preclinical and clinical data on file for the original product.
Specific rules govern biological medicinal products and acknowledge that complex substances, or mixtures of substances, of biological origin are sensitive to changes in source materials and manufacturing processes. The rules therefore focus less on the characterisation of substances themselves from a chemical perspective and more on control of the manufacturing and quality control processes to produce substances or mixtures of comparable quality, safety and effectiveness. This is reflected in special rules for the approval of biological medicinal products that are similar to a reference product. Once the reference product's data exclusivity period has expired, the applicant may file an application equivalent to a generic application but will generally need to submit a body of data demonstrating comparable quality, safety and efficacy.
There is a simplified registration process for traditional herbal medicinal products. A herbal product is only 'traditional' if the applicant can produce bibliographical or expert evidence that the medicinal product in question, or a corresponding product, has been in medicinal use throughout a period of at least 30 years, 15 of which must have been within the European Union.
There is also a simplified procedure for homeopathic medicines. Although the safety and quality of such products has to be demonstrated, the products are not permitted to make medicinal claims. The scheme is restricted to homeopathic products for oral and external use and does not allow indications (the descriptions of diseases or conditions for which the medicine is intended to be used).Medical devices
There is no pre-market government review of medical devices in the European Union unless the device also contains a medicine or a blood derivative. However, all medical devices placed on the market in the EEA must meet the relevant essential requirements set out in Directive 93/42/EEC, Directive 90/385/EEC or Directive 98/79/EC, as applicable, taking account of the intended purpose of the device.
More detailed requirements and technical specifications are set out in voluntary harmonised European standards. Compliance with harmonised standards is not mandatory, provided that the manufacturer demonstrates compliance with the essential requirements. However, compliance with applicable standards raises a presumption of conformity with the essential requirements.
Manufacturers must demonstrate that their devices comply with the relevant essential requirements through a conformity assessment procedure. The method for assessing conformity varies depending on the type and class of the product, but normally involves a combination of self-assessment by the manufacturer and a third-party assessment by a notified body, an independent and neutral entity appointed by a country to conduct the conformity assessment. As a general rule, clinical evidence is required to demonstrate that the device functions as intended and that it is safe. The clinical evidence may comprise studies on the device itself and, where appropriate, relevant data on equivalent devices from the peer-reviewed literature. Devices that conform to the essential requirements must bear a CE mark and can then be commercially distributed throughout the EEA.
For IVDs, custom-made devices and Class I devices, where the manufacturer self-declares conformity with the essential requirements, the manufacturer, or its authorised representative in the EEA, must register with the competent authority in the country in which it is established prior to placing any such product on the market.
The general principles for CE marking will remain the same under the new Medical Devices Regulation (EU) 2017/745 and the new IVD Regulation (EU) 2017/746, although there will be additional regulatory authority involvement in the conformity assessment of certain Class III and Class IIb devices, as well as devices incorporating medicinal substances or tissues and cells of human or animal origin.vi Regulatory incentivesMedicines
A supplementary patent certificate, extending the term of a patent with respect to a particular medicinal product, will be granted if, in the EU Member State in which the application is submitted and at the date of the application:
- the product is protected by a basic patent in force;
- a valid marketing authorisation has been granted for the product;
- the product has not already been the subject of a certificate; and
- the marketing authorisation in question is the first marketing authorisation for that product.
The certificate takes effect at the end of the patent term for a period equal to that between the filing date of the basic patent and the date of first marketing authorisation for the product, reduced by five years, provided that the duration of the certificate cannot exceed five years.
Regulatory data exclusivity in Europe is independent of a product's patent position. New chemical entities approved on the basis of a complete, free-standing data package are entitled to eight years' regulatory data exclusivity from the date on which the product is first approved in the EEA. During that period, generic applicants cannot file applications referring to the innovator's safety and efficacy data. At the end of that eight-year period, generic applicants may file and the authorities may review applications. However, the innovator is granted a further two years of 'market exclusivity' before any generic product may launch. This period of market exclusivity can be extended by a further year if a new therapeutic indication that provides a significant clinical benefit is approved during the first eight years of data exclusivity. For applications prior to 20 November 2005 for centralised approvals, authorisation holders were entitled to 10 years' data exclusivity protection. For applications for national approvals prior to 30 October 2005, authorisation holders are entitled to 10 years' exclusivity in Belgium, France, Germany, Italy, Luxembourg, the Netherlands, Sweden and the United Kingdom, but six years in every other EEA jurisdiction.
Regulation (EC) No. 141/2000 contains additional data exclusivity provisions for 'orphan medicinal products'. These are products intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10,000 persons in the EEA; or that without incentives is unlikely to generate sufficient return to justify the necessary investment. An orphan designation can be granted only if there is no satisfactory method of diagnosis, prevention or treatment of the condition authorised in the EEA, or if the product will be of significant benefit.
If a medicine is approved as a designated orphan medicine, the product will benefit from 10 years' market exclusivity during which regulators cannot accept applications for similar medicinal products for the same indication, unless they offer a significant clinical benefit (i.e., in terms of safety or efficacy). Similar medicinal products are those with the same or similar active moieties.
Regulation (EC) No. 1901/2006 also provides specific incentives for the development of products with paediatric indications. If a product is approved on the basis of a dossier that includes paediatric clinical trial data generated in accordance with an approved paediatric investigation plan, the applicant will benefit from one of two periods of exclusivity: (1) if the product is an orphan medicine, it will benefit from an additional two years of orphan drug exclusivity (i.e., a total of 12 years' orphan exclusivity); or (2) if the product is not an orphan medicine and is eligible for patent term extension (referred to as a supplementary protection certificate), the patent term will be extended by six months.Medical devices
The EU medical devices rules do not provide for any form of regulatory exclusivity. These innovations are almost exclusively protected through patent rights and protection of confidential know-how.vii Post-approval controlsMedicines
The marketing authorisation holder for a medicine is ultimately responsible for any product placed on the market under its approval, and must also fulfil several obligations by virtue of its status. While the associated legal responsibility and liability cannot be delegated, the marketing authorisation holder can delegate the performance of related tasks to third parties, provided that this delegation is appropriately documented.
The marketing authorisation holder must establish and maintain a pharmacovigilance system and must have permanently and continuously at its disposal within the EEA a qualified person for pharmacovigilance, who is responsible for oversight of the pharmacovigilance system, documented in a pharmacovigilance system master file. Key requirements include expedited reporting of suspected serious adverse reactions within 15 days, reporting of suspected non-serious adverse reactions within 90 days and submission of periodic safety update reports (PSURs). The marketing authorisation holder must comply with good pharmacovigilance practice guidelines adopted by the EMA.
The marketing authorisation holder must have a 'scientific service' responsible for disseminating scientific and medical information on its medicinal products, predominantly to healthcare professionals, but also to regulators and patients.
Since July 2012, all new marketing authorisation applications must include a risk management plan (RMP) describing the risk management system that the marketing authorisation holder will put in place. Previously, an RMP was only required 'where appropriate', such as for biological products or products containing a new active substance. The RMP must identify or characterise the safety profile of the product, document measures to prevent or minimise the risks associated with the product, and document post-authorisation obligations that have been imposed as a condition of the marketing authorisation. Such risk-minimisation measures or post-authorisation obligations may include additional safety monitoring, more frequent submission of PSURs or the conduct of additional clinical trials or post-authorisation safety studies.
A new marketing authorisation is valid for five years. Upon renewal, the authorisation will become valid indefinitely, unless the competent authority concludes that safety grounds merit a further five-year fixed term.
Variation applications must be submitted to the competent authorities to make any amendments to marketing authorisations, the summary of product characteristics or package leaflet for the product, or the underlying dossiers. Variations are classified as Type IA, which should be implemented and then notified to the competent authorities, Type IB, which should be notified to the competent authorities in advance and may be implemented if the authorities have not objected within 30 days, and Type II, which require prior approval from the competent authority.
Transfers of marketing authorisation require the prior approval of the competent authority. The procedure and timing varies depending on the marketing authorisation approval procedure and the country, but in all cases an application will need to be submitted to the competent authority, with documentation provided by both the transferor and the transferee. There will usually be an agreed transition period of three to six months before the transfer is completed. Generally speaking, the competent authorities discourage transfer applications while renewal or variation procedures for the marketing authorisation are in train.
The competent authorities shall suspend, revoke or vary a marketing authorisation if the view is taken that the medicinal product is harmful or lacks therapeutic efficacy, that the risk-benefit balance is not favourable or that its qualitative and quantitative composition is not as declared. Marketing authorisations may also be suspended, revoked or varied if incorrect information was submitted in the marketing authorisation application, the marketing authorisation has not been updated appropriately, or conditions of the marketing authorisation, such as commitments to perform post-authorisation safety studies, have not been satisfied.
Once a product has been launched in a jurisdiction, there is an obligation on marketing authorisation holders and their distributors to meet demand in that jurisdiction. EU law includes sunset clauses for marketed medicines. These provide that a marketing authorisation shall cease to be valid if the product is not placed on the market within three years of the marketing authorisation being granted, or if a previously marketed product is no longer actually present on the market for a period of three consecutive years. For centrally approved products, the sunset provisions would not be triggered provided the product was marketed in at least one EEA jurisdiction.Medical devices
Device manufacturers are required to put in place and maintain a systematic procedure for review of post-market experience, including reporting of incidents to competent authorities when required, and to implement any necessary corrective actions.
A device manufacturer must maintain a copy of the technical documentation underpinning its CE marking and make this available for inspection by national device regulators on request. The dossier should be kept up to date. If the applicable conformity assessment procedure has involved a notified body, any significant changes to the dossier or the manufacturer's quality system should be submitted to the notified body for approval and may require an update or reissue of any certificates of conformity issued by the notified body.
Notified body certificates of conformity are valid for a fixed duration. Throughout the term of the certificate, the manufacturer will be subject to periodic surveillance audits to verify continued compliance with the applicable requirements. In particular, there will be a new audit by the notified body before it will renew any certificate.
There is no set process for transferring ownership of notified body certificates of conformity. The transferor and transferee should contact the relevant notified body and agree on the process. If the transferee will be operating the same manufacturing process at the same facility, a new or updated certificate of conformity can be issued in a matter of days. If, however, the transferee will be manufacturing the device at a different facility, the notified body may need to conduct a new conformity assessment prior to issuing a certificate of conformity in the name of the transferee.viii Manufacturing controlsMedicines
Manufacturers of both marketed and investigational medicinal products must have a manufacturing authorisation from the competent authority in the EU Member State in which they are established. The manufacturing authorisation will be limited to the premises and the medicinal products specified in the manufacturer's application. Importers of medicinal products from outside the EEA may also require a manufacturing authorisation.
Medicinal products must be manufactured in accordance with the principles of GMP, set out in Directive 2003/94/EC and the European Commission's guidelines in Volume 4 of the Rules governing medicinal products in the European Union.
Manufacturers must have at least one qualified person permanently and continuously at their disposal. The qualified person is ultimately responsible for certifying that each batch of finished product released onto the market has been manufactured in accordance with GMP and the specifications set out in the marketing authorisation or investigational medicinal product dossier. For medicinal products that are imported from outside the EEA (irrespective of where the product was actually manufactured), the qualified person must ensure that each batch of product has undergone full quality control testing in an EEA Member State prior to release onto the market.
The procedure for transfers of manufacturing authorisations is a matter of national law, but the EU rules require manufacturers to notify the competent authority of any changes to the particulars in the manufacturing authorisation application, including in particular any change in the identity of the qualified person.
Active substances intended for use in the manufacture of medicinal products must have been manufactured in accordance with GMP. Importers, manufacturers and distributors of active substances must register with the competent authority in the EU Member State in which they are established and may be subject to an inspection. The registration application must identify the active substances and the premises concerned. The applicant must update the registration annually, and must notify the competent authority immediately of any changes that may have an impact on the quality or safety of the active substances.Medical devices
There are no EU rules requiring approval of manufacturing facilities for medical devices. However, the conformity assessment procedures may involve a notified body assessment of the manufacturer's quality system. The manufacturer can demonstrate conformity with the requirements for the quality system by complying with the applicable harmonised standards, including ISO 13485:2012 on Standards for Quality Management System on Medical Devices. Any changes to the assessed quality system must be submitted to the notified body for approval.ix Advertising and promotionMedicines
Medicines advertising is defined broadly to include any form of door-to-door information, canvassing activity or inducement designed to promote the prescription, supply, sale or consumption of medicinal products. It includes visits by sales representatives, the supply of samples, provision of gifts and hospitality, and sponsorship of meetings. Certain activities are specifically exempted from the medicines advertising rules, including responses to specific questions about a medicinal product and the dissemination of factual, informative announcements and reference material. These are only exempted if they are non-promotional in nature.
All medicines advertising must be consistent with the product's approved summary of product characteristics, factual, accurate, balanced and not misleading. Advertising of medicines pre-approval or off-label is prohibited. Advertisements to healthcare professionals must also be presented in a certain format, for example, indicating the brand and generic name of the relevant product with suitable prominence, and must contain certain minimum information about the product. Direct-to-consumer advertising of prescription medicines is prohibited, and there are strict rules governing the content of direct-to-consumer advertising of non-prescription medicines.
No gifts or other benefits may be given to healthcare professionals unless they are inexpensive and relevant to the practice of medicine. Any hospitality provided in conjunction with an event must be limited to the main purpose of the event and given only to healthcare professionals. There are also specific rules on the provision of samples to healthcare professionals.
Medicines advertising enforcement is largely on the basis of self-regulation. The European Federation of Pharmaceutical Industry Associations (EFPIA) has adopted a code of practice on interactions with healthcare professionals, a code of practice on interactions with patient organisations and a code of practice on the disclosure of transfers of value. Most national pharmaceutical industry associations have adopted their own codes of conduct based on the EFPIA codes.Medical devices
Unlike the medicines rules, there are no harmonised European level rules governing the advertising and promotion of medical devices, resulting in Member States adopting somewhat divergent approaches to the regulation of medical device advertising. However, the general advertising rules requiring that advertisements are substantiated, factual, balanced and not misleading apply to medical device advertising.
Medical devices and IVDs may be displayed at trade shows and exhibitions before they are CE-marked and placed on the market, provided that they are not used for their intended medical or diagnostic purpose and that a sign makes clear that the devices cannot be marketed or put into service until they have been made to comply with the relevant rules.x Distributors and wholesalersMedicines
Any company engaged in wholesale distribution of medicinal products in the European Union must have an authorisation to engage in the activity, and the licence must state the premises for which it is valid. Manufacturing authorisations include the right to engage in wholesale distribution. Wholesale distribution is defined as all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public.
Traditionally, most Member States have taken the view that wholesale distribution only takes place where the products are handled physically; mere paper transactions have not been regarded as wholesaling. In some Member States, however, the authorities interpret the terms 'procuring' and 'supplying' to cover the act of buying and selling medicines (i.e., the transfer of legal title), even if the company never physically handles the product. This interpretation is becoming more prevalent, following references in Directive 2011/62/EU to 'wholesale distributors, whether or not they physically handle the medicinal products'.
Wholesalers may only obtain their supplies from authorised manufacturers or wholesalers, and may only supply medicinal products to other wholesalers or to persons entitled to supply medicinal products to the general public. The holder of a wholesale dealer licence is subject to various record-keeping obligations, to demonstrate that product is supplied only to those entitled to receive it and to allow for an effective recall of product if necessary. The licence holder must also have at its continuous disposal the services of an appropriately qualified person, who is responsible for ensuring that a quality management system is implemented and that the company complies with the principles of good distribution practice (GDP).
Directive 2011/62/EU introduced the concept of brokering, defined as all activities in relation to the sale or purchase of medicinal products, except for wholesale distribution, that do not include physical handling and that consist of negotiating independently and on behalf of another legal or natural person.
Brokers must have a permanent address and contact details in the European Union, so as to ensure accurate identification, location, communication and supervision of their activities by competent authorities. They must register with the competent authorities in which they have their permanent address. Brokers must comply with the principles of GDP and are subject to the same record-keeping obligations that apply to wholesale distributors.Medical devices
There are currently no EU-harmonised rules that govern the distribution of medical devices, although some Member States do regulate the activity.xi Classification of productsMedicines
Competent authorities must classify medicines as prescription-only or non-prescription but are entitled to further subdivide this classification. For example, competent authorities can, if they wish, classify prescription-only medicines as being subject to 'special medical prescription' (e.g., controlled substances under the UN Conventions and other substances with a risk of abuse or dependency) or 'restricted prescription' (e.g., products that can only be used in a certain setting or by certain specialists). Some Member States also subdivide the classification of non-prescription medicines to allow for products that can only be supplied under the supervision of a pharmacist, over-the-counter products and products for general retail sale.
Medicinal products must be classified as prescription-only if they:
- are likely to present a danger either directly or indirectly if utilised without medical supervision;
- are frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health;
- contain substances or preparations, the activity or adverse reactions of which require further investigation; or
- are normally prescribed by a doctor to be administered parenterally.
The applicant for a marketing authorisation has to identify in the initial application a proposed classification of the product. However, the classification is ultimately decided by the competent authorities when they grant the marketing authorisation.
The marketing authorisation holder can apply to have the product reclassified in light of new information (such as significant post-marketing experience with the product). If the change of classification has been authorised on the basis of significant preclinical tests or clinical trials, the competent authorities may not refer to the results of those tests for one year when examining reclassification applications by other marketing authorisation holders.Medical devices
Medical devices are classified as Class I, IIa, IIb or III, but this is for the purposes of determining the appropriate conformity assessment procedure. Other than the differentiation between active implantable medical devices, in vitro diagnostic devices and other medical devices, there are no EU-harmonised rules that govern the classification of medical devices for the purposes of prescription or sale. Manufacturers often choose to classify devices as being for professional use only.xii Imports and exportsMedicines
An entity importing medicinal products, including bulk product, from countries outside the EEA must hold a manufacturing authorisation. The holder of a manufacturing authorisation must retain the services of a qualified person, who will be responsible for ensuring that any imported product has undergone appropriate quality control testing prior to batch release onto the EEA market.
EU rules on the import of active pharmaceutical ingredients (APIs) require that APIs imported into the EEA must be manufactured in compliance with standards equivalent to EU GMP. Since July 2013, the competent authority of the exporting country has been required to confirm this compliance in writing. The written confirmation must accompany the imported APIs.
The definition of 'wholesale distribution' in Directive 2001/83/EC includes the export of medicinal products. An entity exporting medicinal products out of the EEA must therefore hold a wholesale distribution authorisation or manufacturing authorisation. As part of their import requirements, certain countries require medicinal products to be accompanied by an export certificate. These certificates confirm that the product or manufacturer to which the certificate relates has met statutory requirements in the country of export. Export certificates can take one of several forms, including a certificate of a pharmaceutical product, or a certificate of manufacturing status. The exact procedure for obtaining these certificates differs according to the laws of the country of export.Medical devices
There are currently no EU-harmonised rules that govern the import or export of medical devices. When effective, Regulation (EU) 2017/745 and Regulation (EU) 2017/746 will introduce new obligations for entities importing medical devices from countries outside the EU, including verifying any device they place on the market is in conformity with the standards of the applicable regulations.xiii Controlled substances
The United Nations (UN) Single Convention on Narcotic Drugs (1961) and the UN Convention on Psychotropic Substances (1971) codify internationally applicable control measures to ensure the availability of narcotic drugs and psychotropic substances for medical and scientific purposes. The individual Member States of the EU are all signatories to these UN Conventions. All signatories have a dual obligation to ensure that these substances are available for medical purposes and to protect populations against abuse and dependence.
The UN Conventions require signatories to require all persons manufacturing, trading (including exporting and importing) or distributing controlled substances to obtain a licence from the relevant authority. Each individual export or import of a controlled substance must also be subject to an authorisation. Before the relevant authority can issue an export authorisation for a particular shipment, the exporter must provide the authority with a copy of the import authorisation issued by the relevant authority of the importing country.xiv EnforcementMedicines
The EMA is responsible for coordinating inspections to verify compliance with GCP, GMP, GLP and pharmacovigilance requirements for all centrally approved products. The EMA does not have any inspectors itself, but instead relies on inspectors from the national competent authorities to conduct inspections on its behalf. If an inspection identifies any non-compliance, typically corrective actions would be agreed with the marketing authorisation holder or other company inspected and, provided these were implemented, no further action would be taken. If the non-compliance gives rise to safety concerns about a particular product, the EMA could recommend to the European Commission that the authorisation be suspended or revoked.
In serious cases of non-compliance for centrally approved products, the European Commission could impose sanctions under the EU Penalties Regulation. The European Commission can fine the marketing authorisation holder up to 5 per cent of the holder's EU turnover in the preceding business year. If the infringement continues, the European Commission may impose further daily fines of up to 2.5 per cent of the holder's average daily EU turnover in the preceding business year, until the infringement ceases. Non-cooperation with the European Commission's investigation of the infringement attracts an additional fine of 0.5 per cent of the holder's Community turnover in the preceding business year.
The national competent authorities are responsible for conducting inspections for products that are not centrally approved and in relation to manufacturing and distribution authorisations. The sanctions for non-compliance are determined by national laws.Medical devices
Manufacturers of medical devices are not subject to regular inspections by competent authorities, although notified bodies will conduct surveillance audits as part of the ongoing conformity assessment procedures for many devices. National competent authorities are responsible for enforcing the medical device rules in their jurisdiction and sanctions are determined by national laws. Safeguard measures in the medical devices directives also allow Member States to restrict or prohibit the marketing of medical devices or to withdraw devices from the market where a device, although correctly marketed and used, may compromise the health and safety of patients, users or others.