The Life Sciences Law Review: Italy

Introduction

The life sciences sector covers all aspects concerning research, manufacturing, commercialisation and use of medical and veterinary products, medical devices, special foods, food supplements and cosmetics.

This sector covers a wide range of legal matters, including compliance with national and international ethical codes, good clinical practices (GCP), good manufacturing practices (GMP), good distribution practices (GDP); contract drafting (licences, marketing authorisation (MA) transfers, manufacturing, toll manufacturing, distribution, storage, co-promotion and co-marketing); joint ventures, company transfers and share transfers as well as extraordinary transactions in the relevant fields of industry; participating in public tenders; data protection; advertising, competition and parallel imports issues; relationships with regulatory authorities (Italian Medicines Agency (AIFA), Ministry of Health); clinical trials and observational studies.

Under Italian law, the state and local authority competences in the healthcare sector are:

  1. the Ministry of Health (MoH), which regulates narcotic drugs and psychotropic substances, medical devices, biocides, personal protective equipment, medical-surgical devices, food supplements and other healthcare products. The Ministry is also responsible for ensuring the traceability of medicines throughout the distribution chain;
  2. AIFA, which is responsible for all aspects concerning the investigation (authorisation and monitoring of clinical trials and supervision of observational studies and compassionate use programmes), production and imports (e.g., granting of manufacturing or import authorisations), access to the market of medicinal products (including marketing authorisations, price negotiation and reimbursement procedure), as well as the post-marketing activities (e.g., pharmacovigilance, oversight of shortages and temporary unavailability, recalls); and
  3. regional or local health authorities, which are responsible for granting licences to warehouse keepers, wholesale distributors, pharmacies and other shops where non-prescription medicines may be sold.

The regulatory regime

i Classification

Medicines are defined as all substances or combinations of substances that are presented as having the properties of treating or preventing disease in humans or combinations of substances that can be used in humans, with the intention of restoring, correcting, modifying physiological functions or to make a medical diagnosis by a pharmacological, immunological or metabolic action (Legislative Decree No. 219/2006, the Medicines Code, implementing Directive 2001/83/EC).

Medical devices include various devices, tools, software, materials and substances that should be clearly distinguished from other products such as cosmetics, herbal medicines, food supplements and aesthetic equipment. The new European Regulations, 2017/745 on Medical Devices and Active Implantable Medical Devices (MDR), entered into force on 26 May 2021 and provides two main elements to consider a product as a medical device: the specific medical purpose and the principal intended action. The specific medical purpose is described as diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease or compensation (for injuries) or investigation, replacement or modification of the anatomy while, as of the principal intended action, it is specified that the device must achieve it through a mode of action other than by pharmacological, immunological or metabolic means. These latter can only assist the device function but not represent the main means through which the intended action is achieved.

In general, the new MDR expands the definition of 'Medical Device' (Article 2.1), including, for example, all devices for cleaning, sterilisation or disinfection of other medical devices, devices undergoing reprocessing and devices that do not have a specific medical use (e.g., coloured contact lenses).

Software specifically intended by the manufacturer to be used for one or more of the medical purposes outlined in the definition of medical device is also considered a medical device.

However, some products are called 'borderline' by regulatory authorities because it is not straightforward to determine if they fall within the definition of medical device or within the definitions provided by regulations governing other sectors.

It is up to the manufacturer to decide whether its product falls within the definition of a medical device. In case of doubt, the competent authorities will decide on the placement of borderline products. To this end, the Borderline and Classification Medical Devices Expert Group set up by the European Commission has prepared a 'Manual on borderline and classification in the Community Regulatory Framework for medical devices', which is applied by the Italian Ministry of Health.

In relation to in vitro diagnostic medical devices, which have to be distinguished from medical devices in general, Regulation IVDR (EU) 2017/746 will come into force on 22 May 2022.

This latter Regulation provides for rules and requirements for the placing on the market, making available and putting into service of IVDR.

As defined in Article 2 of Legislative Decree 196/2004, food supplements are 'food products intended to supplement the common diet and which constitute a concentrated source of nutrients, such as vitamins and minerals, or other substances having a nutritional or physiological effect, in particular but not exclusively amino acids, essential fatty acids, fibers and extracts of vegetable origin, both mono-composed and multi-composed, in pre-dosed forms'.

In other words, food supplements are processed foods containing ingredients that aid specific bodily functions in addition to being nutritious. They only have a physiological effect, and no therapeutic effects.

Furthermore, cosmetics are regulated by EU Regulation 1223/2009, which entered into force on 11 July 2013. Pursuant to that Regulation, a cosmetic product is defined as 'any substance or mixture intended to be applied to the external surfaces of the human body (epidermis, hair system and hair, nails, lips, external genital organs) or to the teeth and mucous membranes of the mouth for the sole or main purpose of cleaning them, perfuming them, changing their appearance, protecting them, keeping them in good condition or correcting body odors'.

ii Non-clinical studies

Pre-clinical studies are scientific research activities aimed at testing a medicine or another medical treatment in animals. The aim of a preclinical study is to collect data in support of the safety of the new treatment. These studies should discover any potential harmful effects of the medicine on the body because of its pharmacological action, such as: (1) toxic effects; for example, on the reproductive system; (2) the possibility that the drug causes genetic modifications; and (3) in the case of some substances, the possibility that they cause a carcinogenic growth. Preclinical studies are required before clinical trials in humans take place.

The use of animals to conduct pre-clinical studies requires authorisation by the Ministry of Health, which shall assess the scientific research project, as well as the adoption of a series of measures for animal protection provided for by the Legislative Decree No. 26/2014, implementing the Directive 2010/63/EU.

iii Clinical trials

Medicines

The distinction between clinical trials and other clinical studies ('observational studies') drawn by Regulation (EU) No. 536/2014 also applies in Italy.

Observational studies are conducted on medicines for which a marketing authorisation has been granted. They are aimed at assessing the safety of a medicine under normal conditions of use and on large numbers of patients, at collecting additional information on the efficacy of the medicine in clinical practice, and at evaluating the prescriptive appropriateness and pharmaco-economic aspects.

According to the AIFA's guidelines, these studies must meet the following requirements: (1) the medicine must be prescribed in accordance with the indications for use contained in its marketing authorisation; (2) the prescription of the medicine is in line with ordinary clinical practice; (3) the decision to prescribe the medicine to a patient does not depend on, and is not influenced by, that of including the patient in the study; and (4) the diagnostic and evaluation procedures correspond to current clinical practice.

Due to their characteristics, observational studies do not entail higher risks to patients, and therefore they are not subject to the requirements laid down in the legislation on clinical trials. In particular, these studies do not require the AIFA's authorisation, but a notification to, or the approval by, the competent ethics committees.

The following bodies are responsible for medicine clinical trails: (1) AIFA is responsible for the authorisation of the clinical trial and of the amendments to each phase; (2) the National Institute of Health (ISS) may give opinions on clinical trials and amendments to Phase I; (3) the ethics committees within the clinical sites where the clinical study is carried out issue opinions on the research protocol and other documents (including the informed consent form and the data protection policy and consent form); (4) the Directorates General of the clinical sites take care of the contractual agreements for the conduction of the trial; and (5) the Eudravigilance network is responsible for the reporting of serious and unexpected adverse reactions during the trials.

Moreover, the National Coordination Centre of Local Ethics Committees for clinical trials on medicinal products for human use and medical devices coordinates and oversees the assessment by the local ethics committees of ethical aspects relating to clinical trials on medicines, to ensure the coherence among the activities carried out at local level and the respect of the deadlines.

AIFA has the power to conduct trial site inspections, to verify the compliance of the clinical trial activities with the GCPs and, in case of serious infringements of these standards, it may revoke the clinical trial authorisation.

The sponsor of a clinical trial is defined as a person, company, institution or body that takes the responsibility of promoting, managing and eventually financing a clinical trial.

Clinical trials for industrial or commercial purposes are promoted by pharmaceutical companies or other profit-making entities (except for private scientific care institutions), whose results can be used in the industrial development of a medicine or for regulatory or commercial purposes.

The sponsor must be established in the EU or have a local representative in the EU.

The trial sponsor must submit to the competent ethics committees together with the clinical trial protocol and other required documents, an insurance policy meeting the requirements laid down in the Ministry of Health's Decree of 14 July 2009. The insurance policy must ensure the compensation for damages caused to trial subjects by the activities carried out in the course of the clinical trials, so to cover the civil liability of the investigator and the sponsor, including those damages involuntarily caused as a result of an accidental event or because of negligence, imprudence or inexperience.

To enroll a patient in a clinical trial, it is necessary to collect his or her informed consent. Clinical trial subjects must be provided with complete and clear information about the trial to assess the risks and benefits of their participation and freely decide to participate or not to participate in the trial. Such information includes: (1) the benefits and risks of the treatment; (2) how the patient's confidentiality and privacy will be protected; (3) how his or her biological samples will be used, stored and destroyed; (4) the insurance coverage; and (5) his or her right to revoke the consent to the participation in the trial at any time and the consequences of such withdrawal.

In case of minors or incapacitated persons, consent must be given by their authorised representative.

Clinical trials that have no industrial or commercial purposes must comply with the specific requirements laid down in the Ministry of Health's Decree of 17 December 2004. The sponsor of these trials may be a public body or institution or not for profit research or health foundation or association or a scientific research society or one of the Scientific Institutions for Hospitalisation and Care or an employee of one of these entities. The sponsor must not be the owner of the patent for the medicine that will be investigated. Moreover, the clinical trial and its results must not have any for profit purpose.

The sponsor must ensure that they notify to the competent regulatory authority and to the ethics committee all adverse events that have a reasonable chance of having a causal link with an investigational medicine and are serious and unexpected.

Medical devices

Medical devices are currently undergoing changes to their legislative framework.

The Law of 22 April 2021, No. 53, in force since 8 May 2021, laid the foundations for the adaptation of the Italian legislation, with the aim of complying with the provisions of the European Regulations, while maintaining some national provisions already consolidated and not in contrast with the new European provisions.

With regard to clinical investigations, starting from 26 May 2021, European Regulation 2017/745 applies, in accordance with the Ministry of Health Circular dated 25 May 2021, pending the establishment of Eudamed and the Italian adaptation regulations.

According to the MDR, clinical investigations on Class I to III medical devices are not mandatory, as long as all safety requirements set out in the Regulation are met. In relation to other classes of medical devices, clinical investigations have to be carried out before commercialisation.

The clinical investigations are promoted by the sponsor in accordance with the provisions of Chapter VI of the new European Regulation (or its legal representatives or delegated persons) and are mostly aimed at obtaining the clinical data that are necessary to prove the safety and efficacy of the medical devices or implantable devices (pre-marketing investigations). The role of the sponsor assuming responsibility for the clinical investigation should be able to be performed by either the manufacturer or another individual or entity. The results of these investigations will be submitted to a notified body for the purpose of obtaining the EU conformity (CE) certification of the device (or of a new use of the device). Such notified bodies are appointed by each Member State.

As a rule, in Italy the clinical investigations on medical devices must be notified to the Ministry of Health and submitted to the ethics committees (Ministerial Decree 8 February 2013) of the health facilities where the investigations will be conducted. Clinical investigations of medical devices can be carried out in all public and private health facilities of the Italian National Healthcare Service (NHS). The medical devices legislation sets out the ethics principles and the GCPs that must be complied with when conducting clinical investigations on medical devices. In particular, any activity that may have an impact on human beings must be carried out in accordance with the Helsinki Declaration. The application for clinical investigation must include a proof of insurance cover or indemnification of subjects in case of injury, duly approved by the competent ethic committee (pursuant to Article 69 and the corresponding national law).

iv Named-patient and compassionate use procedures

Medicines

Under the Ministry of Health's Decree of 7 September 2017, 'compassionate use' consists in the free supply by a pharmaceutical company of medicines not yet authorised under investigation in Phase III or, for patients in life-threatening illness conditions, in concluded Phase II clinical trials, provided that they are manufactured or imported from abroad in accordance with the legal requirements laid down in Italian legislation.

The doctor may request the supply of an investigational medicinal product for the treatment of patients suffering from serious diseases, rare diseases, rare cancers or in conditions of illness that put them in danger of life, for whom no valid therapeutic alternatives are available or who cannot be enrolled in a clinical trial.

The doctor is responsible for the compassionate use and must obtain the informed consent from the patient, as well as a favourable opinion from the competent ethics committee, which must notify AIFA of the activated nominal use or compassionate use programme.

The doctor is required to report to the person responsible for the pharmacovigilance at their health facility or directly to the National Pharmacovigilance Network through the AIFA's online platform and to the competent ethics committee any suspected adverse reactions, specifying that the medicine is given to the patient for compassionate use.

The medicine given to the patient for compassionate use must be supplied for free by the manufacturer for the entire duration of such use.

Under certain circumstances, upon request of patients' associations, scientific societies, health facilities, universities or clinicians, AIFA may authorise the reimbursement by the NHS of the costs of the off-label use of medicines by inserting them into the '648 List' (i.e., the list of medicines dispensed under Law No. 648/1996). This is possible:

  1. if there is no valid therapeutic alternative for:
    • innovative medicines authorised in other countries, but not in Italy, or for investigational medicines;
    • medicinal products to be used for a therapeutic indication other than that authorised; or
  2. if there is a valid therapeutic alternative for medicines to be used for a therapeutic indication other than the authorised one, provided that this indication is known and is in accordance with the research conducted within the national and international medical-scientific community, according to economy and appropriateness parameters.

Medical devices

In exceptional cases of necessity and urgency, in the interest of protecting the health of an individual patient and in the absence of valid therapeutic alternatives, a medical device without the CE mark for the proposed indication can be used, even outside of a clinical investigation, subject to authorisation by the Ministry of Health and the favourable opinion of the competent ethics committee.

Article 59 of the MDR confirms the possibility of derogating the procedure to affix the CE mark on the device whose use is in the interest of public health or safety or health of patients. The Member State making use of this option shall inform the Commission and the Member States where the use of the device in question is granted for more than one patient.

v Pre-market clearance

Medicines

The marketing authorisation procedures provided for in European legislation are:

  1. the national procedure;
  2. the mutual recognition procedure and decentralised procedure;
  3. the centralised procedure; and
  4. the parallel import procedure.

In order to obtain marketing authorisation for a medicine, the applicant is obliged to submit to the competent regulatory authority an application consisting of a dossier containing information on chemical-pharmaceutical, preclinical and clinical aspects, structured according to a standardised format (Common Technical Document). The data and studies submitted to support the application shall comply with guidelines defined at European level.

As a rule, the marketing authorisation is valid for a five-year term and is renewable for a further five years or indefinitely.

As to the national marketing authorisation procedure, AIFA, with the support of its Technical Scientific Commission (CTS) and the ISS, makes a thorough assessment of the data presented by pharmaceutical companies regarding the chemical-pharmaceutical, biological, pharmaco-toxicological and clinical characteristics of each drug intended to be placed on the Italian market, to ensure its safety and efficacy requirements.

Once the marketing authorisation has been granted, AIFA continues to conduct such evaluations for the entire life cycle of the medicine and for any subsequent modification of its marketing authorisation.

The mutual recognition and decentralised procedures are regulated by the Italian Medicines Code in accordance with the EU law.

AIFA carries out the administrative and technical-scientific evaluation of the documentation presented in support of the marketing authorisation application (or of a variation or renewal application) both when it is the Reference Member State and when it is a Concerned Member State.

Medical devices

Medical devices can be marketed as long as they are CE marked.

Article 52 of MDR states that the procedure for assessing the conformity of a medical device begins with an assessment made by its manufacturer. The procedure differs according to the class to which the device under investigation belongs (I, IIa, IIb, III).

Class I medical devices may be CE marked and placed on the market once the manufacturer has released a declaration of CE conformity of the device with the essential requirements. Although the declaration of CE conformity is released by the manufacturer of the medical device, without the involvement of a notified body, the manufacturer must have the technical documentation that demonstrates the safety of its device.

For Class IIb, IIc and III medical devices, the manufacturer is required to prepare a summary of safety and clinical performance that is clear to the user and, where appropriate, to the patient. The summary must be submitted to the notified body chosen by the manufacturer for conformity assessment and should be made public on Eudamed.

The purpose of the harmonised evaluation procedure is to avoid jeopardising the principle of free movement of goods by implementing different procedures for each Member State.

vi Regulatory incentives

Medicines

Applications for Italian pharmaceutical patents must be filed at the Italian Patent and Trademark Office, while applications for European pharmaceutical patents must be filed at the European Patent Office. The rights conferred by a patent for industrial inventions are territorially defined and consist of the exclusive right to work the invention and earn profit therefrom in the territory of the Italian state or of the EU.

Patent protection lasts for 20 years from the filing date. Protection for a medicinal product that is the subject of a marketing authorisation can be extended by supplementary protection certificates (SPCs) under the SPC Regulation (EC) No. 469/2009.

An SPC can last for up to five years after expiry of the patent, or 15 years from the date of the first marketing authorisation in the EU, whichever is earlier.

An SPC for a pharmaceutical can be extended for up to a further six months where there is an agreed paediatric investigation plan (PIP) and compliance with the other requirements of Regulation (EC) 1901/2006 on medicinal products for paediatric use. Because the manufacturer of a new medicine needs to obtain a marketing authorisation for commercialising its medicine, and, to this end, it needs to submit to the regulatory authority's efficacy, safety and quality data on the medicine. The production of such data requires significant investments by conducting clinical trials. To remunerate these investments, the manufacturer is granted with a data and market exclusivity by EU and Italian law.

The 8+2+1-year data and market exclusivity period works as follows: data submitted by originators is protected for an eight-year period from the initial authorisation of the reference product, after which who applies for the marketing authorisation for a generic product may refer to the results of the preclinical and clinical trials already filed by the originator of the reference product. In addition, the generic product cannot be put on the market unless a 10-year period has elapsed from the initial authorisation of the reference product; this 10-year period can be extended to a maximum of 11 years under specific circumstances.

Medicinal devices

Patent protection applies to medical devices in the same way as for medicines. On the other hand, there is no data and market exclusivity for medical devices.

vii Post-approval controls

Medicines

Many of the risks associated with the medicine will be discovered after authorisation based on data from various sources: reports of suspected adverse reactions, post-authorisation clinical safety studies (PASS), drug use studies (DUS), scientific literature and periodic safety update report (PSUR) sent by the pharmaceutical companies to the competent regulatory authority through the online platform.

The holder of the marketing authorisation for a medicine granted by the AIFA (MAH) is required to record in detail all suspected adverse reactions to the medicine observed in Italy, in the EU or in a third country. The MAH is also required to register and notify AIFA with the utmost urgency, and in any case within 15 days from when it was informed, of any suspected serious adverse reaction to the medicine reported to it by healthcare professionals (HCPs) or health facilities, as well as any other suspected serious adverse reaction to medicine of which it has become aware.

The MAH must have, on a permanent basis, a person responsible for the pharmacovigilance within its organisation who meets the professional requirements laid down in the law.

The MAH is required to provide AIFA with information on suspected adverse reactions in the form of PSURs.

The MAH must put in place a system that ensures the prompt examination of any safety claim and the efficient and quick recall of defective or unsafe medicines from the market.

The MAH must inform AIFA of all defects that can require the recall of its medicines.

The recall of a medicine because of safety reasons can also be ordered by AIFA in the performance of its post-marketing supervision. In this case, AIFA must inform the European Medicines Agency (EMA) and the competent authorities of other Member States of its decision.

Medical devices

The MDR has introduced a more stringent post-marketing surveillance and vigilance system. Manufacturers will be required to collect and analyse post-marketing clinical data as part of the ongoing evaluation of the safety and efficacy profile, and make available a surveillance report (for Class I devices) or periodic safety report (for Class IIa, IIb, and III devices), according to Articles 83–90.

viii Manufacturing controls

Medicines

In order to produce medicines on the national territory, even for export purposes, an authorisation by AIFA is required.

The manufacturing authorisation may be granted within a 90-day term, after an inspection of the applicant's facilities aimed at verifying the presence of qualified personnel and the required technical and industrial means.

The manufacturer must comply with the GMPs. Companies holding a manufacturing authorisation may also sell the medicines to wholesale distributors or directly to hospitals and health facilities. In such a case, they must also comply with the GDPs.

Medicinal devices

The manufacturers of medical devices must produce them in accordance with the technical documents prepared for the purposes of CE marking and submitted to the notified bodies.

The manufacturers of medical devices that are based in a non-EU country need to appoint an authorised representative in the EU, according to Article 11 of MDR that can be contacted by the competent authorities and notified bodies based in the EU.

ix Advertising and promotion

Medicines

Medicines advertising is defined as any information, customer search or exhortation action intended to promote the prescription, supply, sale or consumption of medicines. The legal definition of medicines advertising is broadly interpreted by both the health authorities (AIFA and the Ministry of Health) and the courts.

Advertising of unauthorised medicines (or unauthorised therapeutic indications) is always prohibited.

Pharmaceutical advertising addressed to HCPs must be filed with AIFA before starting the advertising campaign, and it can be used by the pharmaceutical company if, within 10 days from the filing date, AIFA has not raised any objections.

Advertising to the general public of prescription-only medicines or medicines containing substances defined as psychotropic or narcotic is also forbidden.

Advertising to the general public of non-prescription medicines requires the prior authorisation by the Ministry of Health. The latter has adopted specific guidelines on the online advertising of non-prescription medicines.

Medical devices

Advertising of medical devices which, according to the indications of the Ministry of Health, may be dispensed only upon a doctor's prescription or may only be used with the doctor's assistance is forbidden.

Advertising of other medical devices requires prior authorisation by the Ministry of Health. With regard to the medical devices for which advertising to the public is permitted, the Ministry of Health can indicate the cases in which the authorisation is not required.

Article 7 of the MDR explicitly addresses the issue of advertising of medical devices (MDs) by prohibiting the use of text, names, trademarks, images and figurative or other signs that could mislead the user or patient, but without making any reference to procedural aspects or authorisation regimes involving competent authorities.

The open question, therefore, is whether the implementation of the regulation implies a tacit abrogation of Article 21 of legislative decree 46/1997, stating that advertisement to public has to be authorised by the MoH.

Despite the fact that a national authorisation procedure affects the principle of free movement of goods that the regulation strongly aims to protect, the MoH has unofficially stated that the obligation to submit to the competent authority the authorisation request for the advertising of MDs shall be deemed still in force. An official position from the MoH is awaited.

x Distributors and wholesalers

Medicines

Medicines may be supplied to hospitals or pharmacies by the manufacturer or its warehouse keepers, the importer and the wholesale distributors. Each of these operators need to hold a manufacturing or import licence or a wholesale licence.

If a company holds a manufacturing authorisation, it does not need to also have a wholesale licence, provided that it is referred to the same medicines.

The warehouse keepers (i.e., companies that hold, for their subsequent distribution, medicines on the basis of 'storage' agreements entered into with the MAHs of the medicines (or with their local representatives)) need to hold a wholesale licence.

In order to ensure the medicines' traceability, each actor of the distribution chain must have a unique code assigned by the Ministry of Health to its plant or warehouse and register in the MAH's database all relevant information about the medicines that go in or out of the warehouse.

The MAH may appoint a distributor that, on the basis of a specific agreement with the MAH, is responsible for the commercialisation of its medicine in Italy.

Medical devices

With the implementation of MDR, all economic operators involved in the MD supply chain (manufacturer, authorised representative, importer and distributor) have specific obligations and responsibilities defined in Articles 10–14. The distribution of medical devices does not require any specific licence by a health authority.

xi Classification of products

Medicines

Medicines can be classified according to their nature or for reimbursement purpose.

In relation to their nature, medicines can be:

  1. ethical, if they can be dispensed only with a prescription;
  2. medicines that do not require a prescription (SOP, in Italian), if they can be sold without a medical prescription, but with the advice of the pharmacist;
  3. over-the-counter (OTC) medicines, if they can be freely sold to the public.

For reimbursement purposes, medicines are classified into three different categories:

  1. class A medicines , fully reimbursed by the NHS and supplied through local pharmacies or public health facilities;
  2. class H medicines, fully reimbursed by NHS and that can be used only in hospitals or in health facilities; and
  3. class C medicines, fully at the patients' expenses.

Medical devices

Medical devices are grouped, according to their complexity and potential risk for the patient, into four classes: I, IIa, IIb, III.

With the implementation of the MDR, the same classes of MDs are maintained, but with additional specifications regarding classification criteria (Annex VIII of the MDR).

xii Imports and exports

Medicines

Under the Italian Medicines Code, the same rules governing the manufacturing of medicines apply to imports of medicines from other EU Member States. If medicines are imported from third countries, which according to international agreements ensure the respect of standards equivalent to the European GMPs, then the importer is not required to meet requirements that are similar to those applicable to manufacturers, provided that it can prove that adequate controls have been conducted by the third country's authorities.

Companies holding a wholesale distribution licence may also export medicines abroad.

As to parallel imports, that is imports into Italy of medicinal products authorised in another EU Member State by companies that are different from the MAHs of these medicines, these require the AIFA's parallel import authorisation. To this end, the applicant must demonstrate the identity between the medicinal products authorised in Italy and those that will be imported from another EU Member State in accordance with the Ministerial Decree of 29 August 1997 and the EU Commission's Communication COM(2003) 839.

Imported medicines bear, on the outer package and on the leaflet, the data of the company that has repackaged the product and of the importer.

Medical devices

Medical devices that have been placed on the European market can be imported into the Italian market or exported abroad by the manufacturers or other companies without the need of specific authorisations.

xiii Controlled substances

The Ministry of Health (Drugs Central Office) can authorise the import or export of narcotic or psychotropic substances and medicines containing narcotic or psychotropic substances.

Companies holding a manufacturing or wholesale distribution authorisation for narcotic or psychotropic substances may also apply for an authorisation to import or export these substances.

xiv Enforcement

Infringements of regulatory requirements for medicines and medical devices may be sanctioned, respectively by AIFA and the Ministry of Health.

AIFA may decide the suspension, modification or the withdrawal of the marketing authorisation for a medicine or it can ban the sale or order the recall of medicines from the market.

The violation of the requirements for the manufacturing, distribution, sale and promotion of medicines may lead to the application of criminal or administrative sanctions.

Similarly, the Ministry of Health can apply criminal or administrative sanctions to companies that fail to comply with the regulatory requirements for medical devices.

The decisions adopted by the Ministry of Health and by AIFA may be challenged by their addressees before the administrative courts.

The Ministry of Economic Development is responsible for the market surveillance of product safety issues and, if necessary, it is assisted by the Italian police authorities.

Pricing and reimbursement

i Medicines

The prices of medicines reimbursed by the NHS must be negotiated and agreed upon with AIFA according to the price and reimbursement (P&R) procedure that is regulated by the Ministry of Health's decree of 2 August 2019. The Decree defines the procedure to be followed to obtain AIFA's price and reimbursement decision on a given product.

A pharmaceutical company applying for P&R negotiation must follow the AIFA's guidelines, issued in accordance with the abovementioned Decree, on how to prepare the P&R dossier supporting the P&R application, which are effective from 1 March 2021.

In order to speed up the access to the market of medicines authorised by the EMA, a legal provision was introduced in 2012 under which centrally approved medicines, within 60 days from the date of the publication of their MA in the EU Official Journal, must be automatically placed in a new class of medicines called C-nn (medicines whose price has not been negotiated with AIFA yet). Therefore, these medicines may be commercialised before the completion of their P&R negotiation with AIFA. The negotiation of the P&R can take place later, provided that the pharmaceutical company decides to apply for the reimbursement of the price from the NHS. This, in effect, ensures the faster availability of new medicines on the market. However, as long as an agreement with AIFA has not been reached, the cost of C-nn medicines is fully borne by the patients or by the hospital where the latter deems it can bear the cost.

If a pharmaceutical company does not apply for P&R negotiation within 30 days from the release of the MA at EU level, AIFA urges the company to file this application within the following 30 days. If the company does not do so, its medicine is no longer under the C-nn class, and thus it can no longer be marketed in Italy, unless the competent authorities allow its use because of relevant public health interests.

AIFA must give priority to the assessment of the applications for P&R concerning orphan drugs, medicines whose exceptional therapeutic and social importance has been acknowledged by AIFA and must make a decision within 100 days from the application date. The negotiated prices of reimbursed innovative medicines are usually associated with some form of conditional reimbursement agreement entered into by AIFA and pharmaceutical companies (managed entry agreements, MEAs) whose aim is to ensure access to new medicines for all patients, at the same time avoiding unnecessary expenses for the NHS.

MEAs can be either 'financial-based' (i.e., aimed at managing budget impact) or 'performance-based' (aimed at managing the use in real life or at providing evidence regarding uncertain decisions).

On the other hand, the price of non-reimbursable medicines is freely decided by their MAHs.

ii Medical devices

The price of medical devices is freely decided by their manufacturers.

Administrative and judicial remedies

Companies may challenge the decisions of competent authorities before the administrative courts (i.e., territorial administrative tribunals and the State's Council).

Legal actions against pharmaceutical companies or medical devices manufacturers may be brought by their customers or competitors before the civil courts.

There are specialised courts for patent litigation ('enterprises tribunals').

The decisions of the Italian competition authority (AGCM) may be challenged before the administrative courts.

Financial relationships with prescribers and payers

Pharmaceutical companies and manufacturers of medical devices must comply with the general anticorruption rules (Legislative Decree No. 231/2001).

Healthcare professionals who work for public hospitals, health facilities and universities must comply with the Ethics Code for the employees of public administrations (Presidential Decree No. 62/2013), which, inter alia, provides that the employees shall not accept, for themselves or for others, gifts or other benefits, except those of insignificant value that are given occasionally in the context of ordinary courtesy relations. Gifts or other benefits shall be deemed of insignificant value if their economic value does not exceed €150.

Moreover, healthcare professionals who are public employees cannot carry out activities that are remunerated that have not been previously authorised by the administration to which they belong. For authorisation purposes, the administration must ascertain the absence of situations of (even potential) conflict of interests (Legislative Decree No. 165/2001).

Under the Medicines Code, in the context of the promotion of medicinal products to healthcare professionals, it is prohibited to grant, offer or promise prizes, pecuniary or in-kind benefits, unless they are of negligible value and are in any case related to the activity carried out by the doctor or the pharmacist. The negligible value of free promotional products for healthcare professionals was determined for each region: broadly it should not exceed €20, but there are some exceptions (e.g., five regions refer to the code article that impose the prohibition without specifying the value).

Medical or educational materials not specifically related to a medicinal product may be given free of charge only to public healthcare organisations, unless they have a negligible value (€25 according to Farmindustria Code of Ethics), which in any case must be purchased by the hospital centrally .

In addition, any person who promises or gives an amount of money or any other benefit to a doctor or a pharmacist to encourage them to prescribe or dispense a medicinal product is punishable with imprisonment and a pecuniary sanction (Royal Decree No. 1265/1934). If this is done by a pharmaceutical company then the Ministry of Health may decide the closure of the company's activity.

Special liability or compensation systems

Manufacturers of medicines and devices may face all the types of liability provided for by Italian law: criminal liability, contractual liability (arising from breach of contract) and tort liability depending on the specific violation committed by them.

Moreover, in accordance with the European General Product Liability Directive (85/374/EEC), the Italian Consumer Code (Legislative Decree No. 206/2005) provides for a specific type of tort liability that entitles consumers to compensation with regard to manufacturers for damages suffered because of defective products (product liability).

The Consumer Code also provides for the 'product safety' liability, in accordance with the European General Product Safety Directive (95/2001/EC).

When it comes to risks that manufacturers incur by selling the medicines and medical devices they produce, product liability is the most relevant. A product is defective where it does not offer the safety level that a person is reasonably entitled to expect, taking into account all circumstances, such as:

  1. the way in which the product was distributed;
  2. the product's packaging and evident features, and the instructions and warnings provided;
  3. the product's reasonably expected use and life cycle; and
  4. the date on which the product was placed on the market (Article 117 of the Consumer Code).

In order to escape product liability, the manufacturer must prove either that the defect, damage or the link between the defect and damage does not exist or any of the following circumstances:

  1. the manufacturer did not place the product on the market;
  2. the product defect did not exist at the time the product was placed on market;
  3. based on the scientific state of the art at the time the product was placed on market, it was not possible to establish that the product was defective (Article 118 of the Consumer Code).

Transactional and competition issues

i Competition law

Italian competition law stems from, and is consistent with, EU law. The AGCM is responsible for investigating and monitoring compliance with competition law across all sectors, including pharmaceutical.

In light of practice and case law, the aspects of the life sciences regulatory regime that are most relevant to the application of competition law to pharmaceutical companies are:

  1. the rules concerning the off-label use of medicines (e.g., Avastin v. Lucentis case);
  2. the rules on data and market exclusivity which have an impact on the entry into the market of generic products (e.g., the Lundbeck case concerning a 'pay-for-delay' scheme in a co-marketing agreement; Pfizer's abuse of dominant position case through the application of a complex strategy designed to obstruct the entry of generic drugs into that market); and
  3. the rules governing the pricing and reimbursement of medicines (e.g., the Aspen case concerning the excessive price increase of Aspen's medicines).

The AGCM cooperates with AIFA in the assessment of the compliance of pharmaceutical companies with competition rules, besides coordinating its action with other EU Member States' competition authorities and the EU Commission.

ii Transactional issues

Due to the significant costs of investments (especially in research and development) borne by the manufacturers of medicines and medical devices, licensing and strategic collaborations, joint ventures and mergers and acquisitions are considerably important.

Moreover, in the life sciences industry, companies often enter into co-promotion and co-marketing agreements.

All those types of agreements must also be scrutinised from an antitrust perspective, considering the wide market definition for pharmaceuticals in EU and national merger and antitrust decisions.

Current developments

To cope with the economic crisis caused by the covid-19 pandemic, the EU has issued funds with the aim of boosting the economy. In Italy a plan has been implemented that aims to rationalise the allocation of European resources. This plan, the PNRR, includes some provisions regarding the life sciences field. For instance, €4.05 billion has been earmarked for the modernisation of hospital technology and digital equipment. In a perspective view, this provision could significantly boost the medical device market and supply for hospitals and healthcare organisations.

Interesting insights can be found in the competition bill, currently under consideration in parliament.

As far as orphan drugs, drugs of exceptional therapeutic and social importance and drugs that can only be used in hospitals are concerned, it is intended to provide that in the event of non-submission of the application for classification in the C-nn class of reimbursement within the deadline indicated by law, the price would fixed according to the lowest price within the World Health Organization's classification system at anatomical therapeutic chemical (ATC) level 4.

Eliminating patent linkage is also planned, consequently permitting generic companies to apply for MAs and for pricing and reimbursement procedures before the patent expiry date, thus obtaining an earlier access to the market.

Footnotes

1 Francesco Setti is a senior partner and Francesca Libanori is a partner at Avvocati Associati Franzosi Dal Negro Setti.

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