Marketing, Manufacturing, Packaging & Labeling, Advertising
All about marketing, manufacturing, packaging & labeling, advertising in Spain. Prepared in association with Faus & Moliner Abogados, a leading law firm in Spain, this is an extract from The Pharma Legal Handbook: Spain, available to purchase here for USD 99.
1. What is the authorization process for the marketing of new drugs, biologics, medical devices, over-the-counter medications, and other medicinal products?
The AEMPS is the authority in charge of granting marketing authorizations in Spain, whether they result from a national procedure or from a mutual-recognition or decentralized procedure. Marketing authorizations granted by the AEMPS are regulated by Royal Decree 1345/2007. Some provisions of such Royal Decree also affect medicines authorized by the European Commission pursuant to the centralized procedure.
The AEMPS shall grant an authorization if the product:
- fulfils the established quality requirements;
- is safe under normal conditions of use;
- is effective in the therapeutic indications;
- is correctly identified; and
- provides the patient with the necessary information.
The positive therapeutic effects of the medicinal product shall be assessed in relation to any risk for the patient’s health or public health, viewed under a risk-benefit perspective.
The key stages of the procedure are the following:
- submission of the application to the AEMPS;
- validation and acceptance of the submission;
- issuance of the evaluation report; and
- resolution of the application, and issuance, where appropriate, of the marketing authorization of the product.
The maximum period to notify to the applicant the resolution of the authorization procedure is 210 calendar days.
As regards marketing of medical devices, except for custom-made devices, all medical devices must bear a CE marking of conformity when they are placed in the market in Spain (please refer to Chapter 1, Question 3). Likewise, for class IIa, IIb and III devices, a communication must be made to the AEMPS the first time that a person places a medical device for distribution or use in the Spanish market.
2. What is the authorization process for the marketing of generic versions of these products?
As regards the authorization process for the marketing of generic versions of drugs, such process is a bit more simple because the applicant for a marketing authorization may not be obliged to provide the results of pre-clinical and clinical trials if it can demonstrate that the medicinal product is a generic medicinal product of a reference medicinal product, which is or has been authorized for not less than eight years in a Member State of the European Union.
The applicant may also replace the pre-clinical and clinical trial results with appropriate documentation of scientific references, provided the active substances of the product have had a well-established medical use over at least ten years within the European Union and are of recognized efficacy and of an acceptable standard of safety.
Finally, where the medicinal product is of the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form as another medicinal product that has already been authorized, the applicant may rely on the pre-clinical and clinical documentation of the authorized medicinal product, with the permission of the holder thereof.
In the case of biological medicinal products similar to a reference biological medicinal product which fall outside the definition of a generic medicinal product, appropriate pre-clinical and clinical trial results must be provided in respect of such conditions.
3. What are the typical fees for marketing approval?
Please refer to Question 4 on Regulatory, Pricing and Reimbursement Overview.
4. What is the period of authorization and the renewal process?
Please refer to Question 5 on Regulatory, Pricing and Reimbursement Overview.
5. What are the requirements, if any, for post-approval pharmacovigilance?
Royal Decree 577/2013 imposes the following post-approval pharmacovigilance obligations to the marketing authorization holder:
- respecting the Good Practices on Pharmacovigilance for the pharmaceutical industry published by the AEMPS;
- having an adequate pharmacovigilance system, including a master file of the system and undertake periodic audits;
- having a suitably qualified person responsible for pharmacovigilance in the European Union;
- having a contact person for pharmacovigilance in Spain;
- submitting periodic safety reports to the European Medicines Agency;
- having a risk management system for each medicinal product;
- notifying and recording in the Eudravigilance database suspected adverse reactions to the medicinal product;
- monitoring worldwide scientific literature related to the medicinal product;
- carrying out post-authorization studies of efficacy and/or safety required by the competent authorities; and
- performing a continuous evaluation of the benefit-risk parameters of the medicinal product.
Furthermore, products subject to additional monitoring requirements must include a black inverted triangle in their package leaflet and data sheet, accompanied by the phrase “this medicine is subject to additional monitoring”.
6. Are foreign marketing authorizations recognized?
Under Royal Decree 1015/2009, the recognition of a medicinal product that has a foreign marketing authorization requires prior approval from the AEMPS. Approval is subject to the following requirements:
- there is no other adequate medicinal product authorized in Spain;
- a physician must justify in writing the prescription; and
- the patient must consent in writing to the prescription, after having been duly informed.
7. Are parallel imports of medicines or devices allowed?
According to Royal Decree 1785/2000, parallel imports are allowed in Spain, but the following requirements must be met:
- the medicinal product in question needs to have a marketing authorization both in the country of origin as well as in Spain;
- the company responsible for the parallel import must obtain the prior authorization from the AEMPS;
- the labelling and leaflet of the product must comply with the provisions of Royal Decree 1345/2007; and
- the parallel importer must have an authorization as manufacturer of medicinal products in Spain if it carries out in Spain any repackaging and relabeling of the imported product (otherwise, the importer must have an authorization in Spain to perform the activities of a wholesaler).
Intellectual property rights cannot be used to oppose parallel imports. However, before beginning the marketing of a product that has been introduced in Spain through parallel import, the importer must notify the marketing authorization holder of the medicinal product in Spain of its intention to carry out such marketing in Spain (providing, if requested, a sample of the reconditioned product to be marketed by the importer).
8. What are the restrictions on marketing practices such as gifts, sponsorships, consultancy agreements, travel and entertainment, or other incentives for healthcare organizations and individual medical practitioners?
Under the Code of Farmaindustria (Farmaindustria is the Spanish innovative medicinal products industry association) providing gifts to healthcare organizations is subject to the certain restrictions the most relevant of which are: the gift must not be offered as an inducement to prescribe, recommend or use any particular product; the gift must be for the internal use of the institution in general, and not for the use of an individual (portable electronic devices are expressly excluded); and the gift must be properly documented by the company.
As regards gifts to healthcare professionals (‘HCP’), the following restrictions contained in Royal Decree 1416/1994 apply: the gift must be relevant for the practice of medicine or pharmacy and the cost of the gift must be insignificant. Moreover, according to the Code of Farmaindustria gifts to HCP are subject -among others- to the following general restrictions:
- the gift must have stationary or professional use,
- it must not be related to a prescription-only medicinal product, and
- its market price must not exceed EUR 10.
Educational materials and items of medical utility can be given to HCP as a gift subject to certain restrictions:
- such materials must be relevant to the practice of medicine or pharmacy,
- they must benefit patient care,
- they must not affect the routine practice of the HCP, and
- their market price must not exceed EUR 60.
In addition, the Code of Farmaindustria prohibits the offering or provision of gifts for stationery or professional use within the framework of (i) medical visits mainly related to prescription only medicines, and (ii) scientific and professional meetings organized by a third party, where promotion mainly pertains to prescription-only medicines, with the exception of pens or pads included in the congress bag, that shall not include any kind of corporate/institutional advertising or product advertising. Within the framework of scientific and professional meetings organized by a company, only pens and pads may be offered or provided; as long as that they are not related to a prescription-only medicine and their market price does not exceed EUR 10 (tax included).
Sponsorship of scientific meetings or congresses for HCP, as well as organizing informative, professional and/or scientific meetings is allowed but subject to restrictions. Such sponsorship must be stated in all documents related to the event, as well as in any published derivative work.
It is also possible to pay for the necessary travel, accommodation and enrolment costs to HCP attending such congresses or meetings. According to Royal Decree 1416/1994, such hospitality must be reasonable, meaning that it must not exceed what recipients would normally be prepared to pay for themselves, and such hospitality must remain secondary to the main scientific objective of the event. There are additional restrictions contained in the Code of Farmaindustria, for example: hospitality cannot be extended to accompanying persons, hospitality may be granted only for the duration of the event and one additional day, scientific activities must cover at least 60% of an eight-hour working day, there is a limit of EUR 60 Euros per meal per guest, etc.
As regards entertainment, the hospitality offered to HCP cannot include the organization of social, entertaining or cultural events, except for reasonable welcome cocktails, working meals and gala dinners.
9. How is the manufacturing of medicines and devices regulated and by which agencies?
Performing the industrial manufacturing of medicinal products in Spain requires obtaining an authorization from the AEMPS. The application shall normally be electronically submitted directly to the AEMPS and must be at least in Spanish (although scientific-technical documentation may be submitted in another language). However, non-industrial preparation of compounded medicinal products at hospital and community pharmacies do not require the authorization of the AEMPS.
The key stages in the process to obtain a manufacturing authorization are:
- compilation of the documentation to be submitted to the AEMPS;
- receipt and review of the documentation by the AEMPS;
- compilation and submission of additional information requested by the AEMPS;
- inspection of the manufacturing sites by the AEMPS;
- submission of allegations and additional information as regards objections raised by the AEMPS as a result of the inspection of the manufacturing premises; and
- issuance by the AEMPS of a resolution granting or denying the authorization.
Although the law foresees a period of 90 days for the issuance of the decision regarding the grant of the manufacturing authorization, in practice such decision is issued by the AEMPS around 180 to 270 days after the submission of the application.
Besides, the manufacturing of medical devices, as well as the premises where such activity is performed, requires a prior authorization granted the AEMPS (for custom-made devices an authorization may also be required from the competent regional authorities).
10. Are local manufacturing requirements compatible with Good Manufacturing Practices (GMPs) as defined by the U.S. Food & Drug Administration and/or the European Medicines Agency?
The local manufacturing practices are in accordance with the guidelines issued by the European Medicines Agency.
11. What is the inspection regime for manufacturing facilities?
The health administrations, whenever deemed necessary, are entitled to undertake periodic inspections to the manufacturing facilities. The AEMPS may also inspect the manufacturing facilities whenever it deems necessary, by itself or through the health departments of the relevant Autonomous Regions.
12. Are manufacturing facilities open for inspection by foreign inspectors or third-party inspectors as authorized by the FDA/EMA?
No. The inspections shall be conducted by the AEMPS and any other Spanish competent health administrations. However, there may be inspections undertaken at the request of other agencies, including EMA and FDA.
13. What are the requirements for storage, packaging, and handling of medicines and devices and their constituent components?
The storage, packaging and handling of medicinal products shall comply with the provisions set forth in Royal Decree 824/2010, Royal Decree 782/2013 and the EU Good Distribution Practices of medicinal products for human use.
The storage, packaging and handling of medical devices shall comply with the provisions set forth in Royal Decree 1591/2009.
14. What information must be included in medicine and device labeling?
According to Royal Decree 1345/2007, the labelling of medicinal products must contain the following information:
- name of the medicinal product including the dosage and the pharmaceutical form. Where appropriate, the mention of baby, children or adults. When the product contains up to three active ingredients, the Spanish Official Denomination (DOE) shall be included, otherwise, the International Common Denomination (ICD) or, in its absence, its common name;
- name of the medicinal product in Braille alphabet, considering the particularities of each medicinal product;
- active substances expressed qualitative and quantitative per dosage unit or according to the form of administration for a given volume or weight, using the Spanish DOEs or the ICDs, or, failing that, their common or scientific names;
- list of those excipients known to have a recognized action or effect whose knowledge is necessary for the use of the product and if the product is injectable, or a topical or eye preparation, all excipients must be stated;
- the pharmaceutical form and the contents by weight, volume or number of doses of the product;
- the method and the route of administration;
- a special warning that the medicinal product must be stored out of reach of children;
- any special warning, when the medicinal product requires so;
- In the case of medicinal products containing radionuclides, the dangerous goods transport conditions must be included;
- in case of medicinal gases, the technical specifications they must comply with, the conditions of supply and transport, and, where appropriate, the corresponding symbols must be included;
- expiry date including month and year. In addition, in case of medicinal products with reduced stability after reconstitution, dilution or opening, the shelf life of the reconstituted preparation, diluted or after opening shall be included and they shall also include a box for consignment by users. In case of medicinal products containing radionuclides, the day/ month/year shall be included, and, where appropriate, time: minutes and country of the time reference will be expressed;
- special storage precautions, if any;
- special precautions for disposal of unused medicinal products or waste materials from medicinal products, if appropriate; and if applicable, the symbols authorized by the AEMPS, in order to facilitate the application and development of medicinal products collection systems and to favor the protection of the environment;
- the name and address of the holder of the marketing authorization and, where appropriate, the name of the local representative designated by the holder;
- the National Code of the Medicinal Product;
- the manufacturer’s batch number;
- the number of the authorization for placing the medicinal product on the market;
- in case of medicinal products not subject to medical prescription, the indication of use;
- prescription and dispensation conditions;
- box or blank space to indicate the dosage, duration of treatment and frequency of use or intakes, except in those cases determined by the AEMPS, taking into account the particularities of each medication;
- symbols, acronyms and legends described in Annex IV to Royal Decree 1345/2007; and
- seal of the Health Care System, when applicable.
According to Royal Decree 1591/2009, the labelling of medical devices shall contain the following information:
- the name or business name and address of the manufacturer. In case of products imported into the EU territory and intended to be distributed in the EU, the label, the name and address of the authorized representative must be included, where the manufacturer does not have a registered office in the EU;
- the information strictly necessary for the user to be able to identify the device and contents of the packaging;
- if applicable, the expression “sterile”;
- if applicable, the batch number;
- if applicable, the deadline for safe use of the device, expressed in the year and month;
- if applicable, indication that the device is for single use;
- if applicable, the expression “custom made device”;
- for devices intended for clinical investigations, the expression “exclusively for clinical investigation”;
- special storage or handling conditions;
- instructions for use;
- any warning and cautions;
- manufacturing year; and
- if applicable, sterilization process.
15. What additional information may be included in labeling and packaging?
Please refer to Questions 14.
16. What items may not be included in labeling and packaging?
Any items that may lead to an irrational use of the medicinal products or medical devices.
17. What are the restrictions and requirements for the marketing and advertising of medicines and devices?
Advertising of prescription medicinal products or publicly financed medicinal products directed to the general public is strictly prohibited under Royal Decree 1416/1994 and the Code of Farmaindustria. Also, according to Royal Decree 1416/1994, advertising of medicinal products to the general public for any of the following therapeutic indications is prohibited: sexually transmitted diseases, other serious infectious diseases, cancer, chronic insomnia, diabetes or other metabolic illnesses.
The advertising of non-financed OTC medicinal products must comply with the following requirements: (i) it must clearly indicate that it is an advertisement and that the product advertised is a medicinal product; (ii) it must provide certain information (e.g. the complete name of the product, an invitation to read the instructions of the leaflet and to consult a pharmacist, etc.); and (iii) it must not contain claims or statements that are prohibited (e.g. those directed exclusively or mainly to children, those promising a cure, exaggerated testimonies on the virtues of the product or recommendations of scientists, HCP or celebrities, those suggesting that a medical consultation or surgical procedure is unnecessary, etc.).
According to Royal Decree 1416/1994, advertising of prescription medicinal products is allowed only to HCP. Among the requirements to be complied with, certain information must be provided to the HCP, such as: the dosages and pharmaceutical forms in which the product is available, the prescription and dispensation regime, the retail price and conditions under which the product is publicly financed, the estimated cost of treatment (if possible), etc.
As regards the advertising of medical devices to the public, the prior authorization from the Spanish regional authorities must be previously obtained. On the restrictions, Spanish Law on Medicinal Products expressly prohibits to advertise to the public medical devices which are publicly financed and/or medical devices which are intended to be used or applied exclusively by HCP. Also, according to Royal Decree 1591/2009, it is prohibited to advertise to the public (i) medical devices for self-diagnosis (except for fertility, pregnancy or HIV diagnosis devices), and/or (ii) genetic diagnosis devices.
18. Where can medicines and devices be sold or delivered? Can medicines and devices be sold or delivered via post?
Medicinal products must be sold and delivered by pharmacies only. Medical devices may also be sold and delivered by pharmacies. However, there are non-prescription medical devices which may also be sold and delivered to consumers in other stores, such as supermarkets or cosmetic shops.
As regards the sell at a distance to the public (e.g. via post) of medicinal products and medical devices, there are certain restrictions. According to article 3.5 of Spanish Law on Medicinal Products, it is strictly prohibited to sell at a distance medicinal products and medical devices which are subject to prescription.
Selling non-prescription medicinal products and medical devices at a distance to the public, is not entirely regulated in Spain. There is one specific regulation issued in this regard as regards medicinal products for human use. We refer to Royal Decree 870/2013 regulating the sale at a distance of non-prescription medicinal products to the public. According to the conditions contained therein, brick and mortar pharmacies are entitled to have their own official website to sell OTC medicinal products at a distance to the public.
19. What are the restrictions and requirements for electronic marketing and advertising via email, by Internet, social media, and other channels?
The same restrictions and requirements applicable for non-electronic marketing and advertising apply (please refer to Question 17).
20. May medicines and devices be advertised or sold directly to consumers?
Only non-prescription medicinal products and medical devices, which are not publicly financed, may be advertised and sold directly to consumers. There are additional requirements to be complied with, as referred to Question 17.
21. How is compliance monitored?
Compliance monitorization is exercised by the Spanish regional authorities via prior authorization and/or control ex-post.
Advertising of medical devices to the public is monitored via prior authorization. On the other hand, since there is no authorization needed for the advertising of medical devices to HCP or for advertising of medicinal products to the public or to HCP, compliance monitorization in these cases is exercised ex-post by the authorities. Monitorization ex-post means that the authorities can inspect and review the advertising activities carried out by the company to ensure compliance with the applicable legal requirements. In case of advertising materials addressed to HCPs, the company must send a copy of such materials to the competent authority of the Autonomous Region where said company is located at the time of their distribution in order to facilitate monitoring tasks to these authorities.
22. What are the potential penalties for noncompliance?
Please refer to Question 9 on Regulatory, Pricing and Reimbursement Overview.