The regulatory regimei Classification
Pursuant to the Royal Legislative Decree 1/2015, a medicinal product is any substance or combination of substances presented for treating or preventing diseases in human beings or animals, and that may be administered with a view to restoring, correcting or modifying physiological functions or to making a medical diagnosis.
Medical devices are defined as any instrument, apparatus, appliance, computer programme, material or other article, whether used alone or in combination, intended by the manufacturer to be used for human beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease, injury or handicap, investigation, replacement or modification of the anatomy or of a physiological process or control of conception, and that does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but that may be assisted in its function by such means.
The distinction between medical devices and medicines is not always clear, but if a product could be included within the definition of a medicinal product, the Royal Legislative Decree 1/2015 shall be applicable, although the product could also be subject to other regulations. The AEMPS is also competent to determine whether a product can be considered a medicine, a medical device or any other product (e.g., personal care or cosmetic products). To assess these cases, which would be settled on grounds of the actual health or medical utility of the product, specific European guidelines are applicable.ii Non-clinical studies
Non-clinical studies shall be performed in facilities that have obtained a certificate of compliance with good laboratory practices (GLP). The AEMPS is the competent authority regarding the adoption of the applicable GLP, determined by specific guidelines. It would also perform the necessary inspection before issuance of the corresponding certificate of compliance.
Non-clinical studies on animals shall comply with the requirements of Royal Decree 53/2013, of 1 February, on the basic rules on the protection of animals used in investigations, regarding their treatment, transport, registry or housing and care during the study.iii Clinical trials
All clinical trials performed in Spain are subject to Royal Decree 1090/2015 of 4 December on Clinical Trials and Ethic Committees on Medicines Research and the Spanish Clinical Trials Registry (Royal Decree 1090/2015), which implements Regulation (EU) 536/2014. The document 'Instructions of the Spanish Agency of Medicines and Medical Devices (AEMPS) to conduct clinical trials in Spain', of 20 December 2018, is of particular interest, providing for a practical approach on the current regulation.
Pursuant to Royal Decree 1090/2015, three requirements must be met to perform clinical trials in Spain:
- single, binding and favourable decision of an ethics committee;
- resolution of authorisation issued by the competent authority (AEMPS); and
- conformity of the site where the clinical trial is going to be performed, by means of a Clinical Trial Agreement.
To conduct a clinical trial in Spain, the sponsor or its legal representative shall be established in the European Union and shall subscribe an insurance or financial guarantee that covers the damages that could arise for the trial subject, as well as any liability that might be incurred by the sponsor, principal investigator and members of the investigator team, except for cases of 'low-intervention clinical trial'. Sponsors shall also assure that all the subjects taking part in the clinical trial (or their legal representative, in the case of minors or mentally disabled people) have given their written, informed consent, which may be revoked at any time.
While performing a clinical trial in Spain, the sponsor and the investigator shall ensure that it complies with the protocol and with the principles of good clinical practice. They shall also take into account the quality standards and guidelines of the International Conference on Harmonisation on good clinical practice. The sponsor is responsible for the continuous assessment of the benefit-risk balance of the clinical trials and, thus, it must report to the AEMPS any information substantially affecting these aspects. Royal Decree 1090/2015 also imposes on the sponsor the obligation to report unexpected serious adverse reactions associated with investigational medicinal products of which it becomes aware, whether occurring in Spain or in other countries.
Royal Decree 1090/2015 also applies to clinical trials conducted by investigators without the engagement of pharmaceutical or medical devices industry (i.e., non-commercial clinical research), containing special regulations regarding insurance requirements and applicable fees.iv Named-patient and compassionate use procedures
Under exceptional circumstances, the AEMPS can authorise the use of investigational medicines before they have obtained a marketing authorisation or have been the subject of a marketing authorisation application, pursuant to the requirements in Royal Decree 1015/2009, of 19 June, on the availability of medicines in special situations (as set out in Royal Decree 1015/2009), providing that the patients receiving them:
- do not have access to a satisfactory therapeutic alternative available in the market;
- are not taking part in a clinical trial; and
- have an urgent medical need and therefore cannot wait until the investigation is over or alternative medicines are authorised.
Under Royal Decree 1015/2009, the healthcare professional responsible for the treatment can also authorise the use of medicines for different uses than those included in its marketing authorisation, provided the patient has been duly informed and no therapeutic alternative is available.v Pre-market clearanceMedicines
For medicinal products to be distributed within Spain, a marketing authorisation must be obtained first and the products must be registered with the medicines registry hosted by the AEMPS.
The marketing authorisation can be obtained through a centralised procedure before the European Medicines Agency (only applicable to certain products) and permits marketing throughout the European Union. A marketing authorisation to place the product wholly within Spain can also be obtained. Royal Decree 1345/2007 of 11 October on the authorisation procedure, registration and dispensation conditions of industrial medicinal products for human use in Spain (Royal Decree 1345/2007) provides for the requirements to follow a national, decentralised or mutual recognition procedure before the AEMPS.
The authorisation procedure requires the submission of an application containing all the relevant aspects of the medicinal product, including: name, composition and therapeutic conditions, safety measures, pharmacovigilance system, pharmacological tests, and preclinical and clinical trial results. These results are not required if the application is made with the consent of a marketing authorisation holder (MAH) or if it is referred to an active ingredient that has a clearly established use within the European Union or to a generic medicinal product that has been authorised for a minimum of eight years within the European Union (simplified procedure). The AEMPS would assess the positive therapeutic effects of the medicinal product on the grounds of its safety, quality and efficacy, under a benefit-risk balance approach.
Royal Decree 1345/2007 also contains special requirements applicable to the marketing of certain medicinal products, including vaccines (each batch shall be authorised by the AEMPS prior to its release), herbal medicines (only registration is needed) and homeopathic products (which requires a simplified procedure of authorisation when certain conditions are met).Medical devices
Medical devices can only be placed on the market or put into service when they comply with certain requirements ensuring their safety. Medical devices can be categorised as diagnostic in vitro and active implantable, and are subdivided into Classes I, IIa, IIb and III, depending on their risk. Pursuant to Royal Decree 1591/2009, anyone who wants to place medical devices of Classes IIa, IIb or III on the Spanish market for the first time shall report it to the AEMPS, which must keep an up-to-date register of all communications. Manufacturers of Class I or custom-made medical devices that are responsible for their first commercialisation shall be included in a register organised by the AEMPS.
Further to these requirements, with the exception of custom-made devices and devices intended for clinical investigation, medical devices need to obtain the CE mark, which can only be placed by the manufacturer when the devices fulfil the legal requirements, according to the evaluation accomplished by the competent notified bodies, which shall be authorised by the MoH.vi Regulatory incentives
Royal Legislative Decree 1/2015 includes the European criteria regarding the protection of innovation and investigation, while ensuring competition in the Spanish market. An applicant for a generic medical product can submit its application for marketing authorisation after at least eight years have expired since the medicine of reference obtained a marketing authorisation in any of the EU Member States. This allows the evaluation procedure to move forward, although the generic medicine cannot be effectively placed on the market until the period of data exclusivity protection has elapsed (10 years after approval of the medicine of reference or 11 years if new indications have been authorised for the medicine during the first eight years).
This protection regime is completed with the inclusion of the Bolar exception into Article 61.1(c) of Law 24/2015, of 24 July, on patents, which implies that the patent's scope of protection shall not be extended to studies and trials performed for the authorisation of a generic medicine in Spain or abroad, and the subsequent practical requirements, including the preparation, production and use of the active ingredients for those purposes.
Regulation (EC) 469/2009 allows for an extension of the patent term for medicinal products by means of a supplementary protection certificate (SPC), which shall be granted by the Spanish Patent and Trademark Office. This SPC can be extended by up to six months if the application for a marketing authorisation is accompanied by studies conducted in compliance with an agreed paediatric investigation plan, pursuant to Regulation (EC) 1901/2006.vii Post-approval controls
Pursuant to Royal Decree 1345/2007, the MAH shall observe the conditions of the marketing authorisation as well as any modification adopted after it has been granted, introducing any changes that may be required regarding the manufacturing or control system of the product. The MAH must also respect the principle of continuity in the provision of the service and keep the product dossier up to date. Furthermore, the MAH must (1) have comprehensive knowledge of the medicinal product, promoting its rational use; (2) participate with the control programmes, informing the AEMPS of the product's withdrawal from the market; and (3) guarantee the collection of any medicinal waste from the product.
According to Royal Decree 577/2013, of 26 July, on pharmacovigilance of medicinal products, a MAH must maintain a pharmacovigilance system that allows it to control the safety of the marketed medicinal products and to identify any change regarding the risk–benefit ratio. This regulation also includes further obligations to report and record any suspected adverse reactions, periodic safety update reports or the qualified person responsible for pharmacovigilance.
Manufacturers and authorised representatives, distributors or importers of medical devices are also required to notify the AEMPS of any defective operation or alteration within the characteristics of the devices or their labelling, as well as any technical or health-related circumstances that have led to the adoption of any systematic measure on the devices, according to Royal Decree 1591/2009.
Marketing authorisations are granted for a period of five years, although they can be renewed after such period, prior to the re-evaluation of the risk–benefit ratio. This renewed authorisation shall be valid indefinitely, provided there are no pharmacovigilance reasons that justify the submission of another renewal procedure. The marketing authorisation can be revoked or suspended because of a lack of quality, safety or efficacy, according to Royal Decree 1345/2007. It can also expire if the MAH does not market the medicinal product within three years or, if it is not available for three years, once it has been duly placed on the market. Any amendment, transfer, suspension or revocation of the marketing authorisation shall be authorised by the AEMPS and included in the medicines registry in order to produce its effects.viii Manufacturing controls
The manufacturing of medicines in Spain is subject to the granting of a manufacturing authorisation by the AEMPS, pursuant to Royal Decree 824/2010, of 25 July, on pharmaceutical laboratories, manufacturers of active substances and external trade of medicines and investigational medicines. To obtain the manufacturing authorisation, the applicant shall identify the specific medicines and pharmaceutical forms that it intends to manufacture. The applicant must be in possession of appropriate facilities and technical and safety measures to develop the activity, and it must designate, at the very least, a technical director and a responsible production manager. The applicant is also obliged to comply with the good manufacturing practices adopted by the AEMPS according to European requirements. The AEMPS must keep a registry of the authorised manufacturing laboratories, and every amendment, transmission or expiry of the authorisation has itself to be authorised and further registered to be effective.
The MAH that provides its own facilities to store its medicinal products in Spain must obtain authorisation as an MAH laboratory from the AEMPS – a manufacturing authorisation would facilitate this.
Manufacturing of medical devices is subject to a prior activity licence for the facilities, issued by the competent authorities pursuant to the requirements of Royal Decree 1591/2009.ix Advertising and promotionMedicinal products
The main principles concerning the advertising of medicinal products in Spain are laid down in Royal Legislative Decree 1/2015 and in Royal Decree 1416/1994, of 25 July, on advertising of medicinal products for human use. The autonomous regions have also adopted guidance interpreting the principles in the legislation and regulations setting their own proceedings for compliance. In addition, self-regulation has an important role in advertising: Farmaindustria (a private association of pharmaceutical companies) has adopted the 'Spanish Code of Good Practice for the Pharmaceutical Industry' and the Personal Healthcare Association (ANEFP) has released a 'Spanish code of good practices for the promotion and advertising of non-prescription medicinal products'. Both texts extend the legal obligations for advertising and make them more demanding, but the texts are only applicable to members of Farmaindustria or ANEFP, or those who choose to abide by them.
As a general principle, only medicines that have complied with all the steps needed to obtain a marketing authorisation in Spain can be advertised, provided that the advertising encourages rational use of the medicine by presenting it objectively, without being misleading and not exaggerating its properties.
Advertising to consumers is only allowed for medicines not included in the public reimbursement system, which are not prescription medicines and that do not contain narcotic or psychotropic substances. Advertising does not require prior authorisation, although it shall be subject to regulatory supervision and certain restrictions are applicable regarding its content (i.e., recommendations by healthcare professionals related to the virtues of the product are prohibited).
Advertising aimed at persons qualified to prescribe or supply medicinal products shall be in line with the technical and scientific information of the medicine duly authorised by the AEMPS, and must be objective, well-founded, thorough and not misleading. When performed in written form, the advertising is subject to prior communication with the healthcare authorities of the autonomous regions. The supply of samples is exceptionally allowed when geared towards persons qualified to prescribe medicinal products under certain circumstances. Royal Decree 1416/1994 also contains provisions for other means of publicity aimed at healthcare professionals, which is further explained in Section V.Medical devices
The main aspects of regulation regarding advertising of medical devices are laid down under Royal Legislative Decree 1/2015 and Royal Decree 1591/2009; the Code of Conduct of the Spanish Federation of Healthcare Technology Companies (FENIN) shall also be taken into account for members of the federation.
Every advertising message included in the general media (newspapers, radio, television, web pages, etc.) that is directly targeted at the general public must first be authorised by the competent healthcare authorities of the autonomous region.
When aimed at consumers, it is forbidden to advertise medical devices financed through the National Healthcare System (NHS) or that are intended to be used exclusively by healthcare professionals.x Distributors and wholesalers
Royal Decree 782/2013, of 11 October, on distribution of medicinal products of human use, contains obligations, restrictions and requirements applicable to the distribution entities allowed in Spain.
This Decree applies to wholesalers, pharmaceutical companies that perform distribution functions by themselves, third parties that assume distribution activities on behalf of wholesalers, and medicines warehouses subject to custom vigilance. The Decree also regulates the brokering activities that relate to those who carry out the distribution obligation but have no physical contact with the medical products.
To supply pharmacies and hospitals, wholesale distributors and third parties acting on their behalf shall obtain an authorisation granted by the healthcare authorities of the autonomous region where the business is located. If the wholesale distributors and third parties carry out distribution activities in the territory of another autonomous region, these activities shall also be notified to the competent authorities of that region. The AEMPS directly authorises any medicines warehouse subject to customs vigilance, and brokers are only compelled to notify their activity to the AEMPS, which keeps an updated registry.xi Classification of products
Pursuant to Royal Decree 1345/2007, medicinal products can be categorised as:
- non-prescription medicines (over-the-counter); and
- prescription medicines, which can also be classified as:
- medicines subject to renewable prescription;
- medicines subject to special prescription (i.e., containing narcotic or psychotropic substances); and
- medicines subject to restricted prescription (medicines for hospital use, medicines for hospital diagnosis to be prescribed by a specialist and medicines under special medical supervision).
This classification has important legal consequences: non-prescription medicines can be purchased online, while prescription medicines are the only types of medicines that can be included in public funding procedures.xii Imports and exports
Regarding medicinal products, only those duly authorised and registered in the AEMPS registry can be imported into Spain. Companies willing to import medicinal products shall obtain an authorisation as a manufacturing laboratory by the AEMPS, and are subject to all the obligations contained in Royal Decree 824/2010. Exportation is allowed to laboratories and distribution entities that fulfil the legal requirements, and shall be notified to the AEMPS.
Laboratories that intend to import medical devices shall also obtain an activity licence for the facilities. Medical devices due to be exported to third countries must have this fact included in the labelling.xiii Controlled substances
The regulatory competence regarding the importation, exportation and commercial sale of certain narcotics and psychotropic substances is attributed to the AEMPS, which must authorise the manufacture of such substances when they are intended to be marketed in other countries. The importation and exportation of narcotics and psychotropic substances are also subject to prior authorisation by the AEMPS, which would assume the control of said activities, and the further distribution and dispensation of such substances. The AEMPS also assumes administrative management regarding the control of the aforementioned substances, such as the production and distribution of official receipt templates or the issuing of certificates and permits for carriage by travellers for the purpose of medical treatment.xiv Enforcement
The AEMPS and the healthcare authorities of the autonomous regions, according to their respective competence, may perform inspections to verify the fulfilment of the obligation imposed under the applicable regulation, such as compliance with the quality standards on good clinical practice, the pharmacovigilance duties imposed on the MAH, or good manufacturing practices. Issues regarding distribution, prescription, dispensation and advertising are mainly attributed to the autonomous regions. The infringement of legal obligations can be sanctioned with economic fines ranging from €6,000 to €6 million, depending on the nature of the infringement. With regard to medicines, infringements can be also penalised by confiscation by the Public Treasury of the profits obtained as a consequence of the infringement, as established in Royal Legislative Decree 1/2015.
Farmaindustria, FENIN and ANEFP also regulate the special mechanism to ensure the compliance of the obligations stipulated by their codes of conduct, which are only applicable to their members and those who choose to abide by them.