The Life Sciences Law Review: Italy
The life sciences sector covers all aspects concerning research, manufacturing, commercialisation and use of medical and veterinary products, medical devices, special foods 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, 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; clinical trials and observational studies.
Under Italian law, the state and local authority competences in the healthcare sector are:
- the Ministry of Health, which regulates narcotic drugs and psychotropic substances, medical devices, biocides, personal protective equipment, medical-surgical devices, and other healthcare products. The Ministry is also responsible for ensuring the traceability of medicines throughout the distribution chain;
- the Italian Medicines Agency (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
- regional 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
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).
On the other hand, medical devices include various devices, tools, software, materials and substances that can be used for the prevention, monitoring, diagnosis and treatment of a disease without having a pharmacological, metabolic or even immunological action.
In principle, the intended use of the medical device, which has always a medical purpose (Legislative Decree No. 46/1997, implementing the Directive 93/42/EEC) should clearly distinguish it from products that do not have such purpose, such as cosmetics, herbal medicines, food supplements and aesthetic equipment. 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.
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.
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; (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.
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.
iii Clinical trials
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 European Union 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; (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.
The Ministry of Health is competent to assess clinical investigations on (1) non-CE marked (a mark of conformity within the European Economic Area) medical devices; (2) CE-marked medical devices that are used according to an indication of use other than the certified one; and (3) CE-marked medical devices whose structure has been modified.
Those clinical investigations are promoted by the manufacturers of the medical devices (or their 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 device (pre-marketing investigations). The results of these investigations will be submitted to a notified body for the purpose of obtaining the CE certification of the device (or of a new use of the device).
As a rule, the clinical investigations on medical devices must be notified to the Ministry of Health and submitted to the ethics committees of the health facilities where the investigations will be conducted.
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 clinical investigations performed by health or scientific institutions for not-for-profit purposes on CE-marked medical devices that have not been modified and are used for the same intended use covered by the CE marking assessment procedure and according to the instructions for use provided by the manufacturer ('post-marketing investigations') only require the favourable opinion of the competent ethics committee.
The Ministerial Decree of 2 August 2005, which regulates the procedures for submitting the notification of clinical investigations, specifies that the manufacturer of a medical device must arrange an appropriate personal injury insurance.
iv Named-patient and compassionate use procedures
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.
Such request must be made for a patient who is not participating in a clinical trial on a named-patient basis (without a protocol) or in an expanded access programme (in accordance with a protocol).
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 his or her 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 National Health System (NHS) of the costs of the off-label use of medicines by inserting them into the '649 List' (i.e., the list of medicines dispensed under Law No. 648/1996). This is possible:
- 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
- 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.
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.
To obtain authorisation for compassionate use, the Ministry of Health and the ethics committee must be provided by the doctor with information on the medical device, the clinical conditions of the patient to be treated and the rationale for using the device for compassionate use, as well as the confirmation of the manufacturer's availability to supply the device for free for the duration of the compassionate use.
v Pre-market clearance
The marketing authorisation procedures provided for in European legislation are:
- the national procedure;
- the mutual recognition procedure and decentralised procedure;
- the centralised procedure; and
- 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.
The fees for submitting a request for a marketing authorisation for a medicine are indicated in Ministerial Decree of 6 December 2016, and, as of 1 April 2020, they are automatically updated on the basis of the Italian National Statistical Institute (ISTAT) index of the cost of living referred to December 2019.
At European level, there specific rules for approval (including rewards or incentives) of orphan drugs, medicines for paediatric use and advanced therapy medicinal products (ATMPs).
Under Italian law, a simplified marketing authorisation procedure applies to herbal and homeopathic products, in both cases under certain conditions.
Medical devices can be marketed as long as they are CE marked.
Any medical device to bear the CE marking must correspond to the 'essential requirements' set out in Annex I of Legislative Decree 46/97, implementing the Directive 93/42/EEC. These are safety and efficacy requirements that both the devices and their manufacturing process must meet.
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 must submit to the notified body a request for the approval of its production facilities or its medical device.
The CE certification granted by a notified body is valid for up to five years. It can be extended for subsequent periods of five years each, upon request submitted within the deadline indicated by the contract entered into between the manufacturer and the notified body. The CE marking and the placing on the market of in vitro diagnostic medical devices (IVD) are governed by the Legislative Decree No. 332/2000 (implementing the Directive 98/79/EC). The CE marking and the placing on the market of active implantable devices (with the exception of custom-made devices) are governed by Legislative Decree No. 507/1992 (implementing the Directive 90/385/EEC). The involvement of the notified body is required for the assessment of the technical documents prepared by the manufacturer.
vi Regulatory incentives
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 European Union (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. Since 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 authorities 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.
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
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.
Clinical investigations with CE-marked medical devices and used according to the intended use provided for by the CE conformity assessment ('post-marketing clinical investigations'), subject to approval by the relevant ethics committee, can be directly conducted, with the sole requirement to notify the Ministry of Health of the commencement of the clinical investigation. It is up to the competent ethics committee to express a favourable opinion on such investigations.
The Ministry of Health and the Ministry of Economic Development, within the scope of their respective competences, are responsible for the post-marketing surveillance on medical devices, and may exercise their powers either directly or through authorised bodies in the commercialisation and utilisation stages.
The inspections can be conducted at the premises of the manufacturer or its warehouse keepers, or of the wholesale distributors, importers, sellers or users.
The Ministry of Health can order the recall from the market of medical devices for which safety incidents have been reported. In such a case, the Ministry of Health must inform the European Commission of its decision.
viii Manufacturing controls
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.
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 a legal representative in the EU that can be contacted by the competent authorities and notified bodies based in the EU.
ix Advertising and promotion
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.
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.
x Distributors and wholesalers
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/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.
The distribution of medical devices does not require any specific licence by a health authority.
xi Classification of products
For reimbursement purposes, medicines are classified into three different categories:
- class A medicines are essential medicines and medicines for chronic diseases, fully reimbursed by the NHS and are supplied through local pharmacies or public health facilities;
- class H medicines can be used only in hospitals or in health facilities; and
- class C medicines must be paid entirely by the patient and include both prescription and non-prescription medicines.
When granting the marketing authorisation for a prescription medicine, AIFA may set forth specific supply requirements or restrictions (such as the possibility for medical specialists to prescribe them).
Only non-prescription medicines may be promoted to the general public.
Over-the-counter medicines may be sold not only by pharmacies, but also by parapharmacies and authorised stores.
Medical devices are grouped, according to their complexity and potential risk for the patient, into four classes: I, IIa, IIb, III.
Medical devices that may be used by the patients without the prescription or the assistance of a healthcare professional may be promoted to the general public.
The costs of medical devices are not reimbursed by the NHS, unless they are only used by the patients in a hospital setting.
xii Imports and exports
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 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.
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. The competent authorities are granted with investigative and enforcement powers, such as the powers:
- to inspect production plants, warehouses and retailers;
- to request information;
- to take and test samples and impose controls on the sale or distribution of products pending the outcome of the testing process;
- to seize and destroy unsafe products; and
- to order the recall of the products where the measures implemented by manufacturers and distributors are considered ineffective or inadequate to address the safety risk.
Pricing and reimbursement
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 2020.
A pharmaceutical company applying for P&R negotiation must follow the AIFA's guidelines on how to prepare the P&R dossier supporting the P&R application. The guidelines drafted by AIFA in accordance with the new Decree have undergone a public consultation process, but their final version is not yet available.
The P&R negotiation must end within 180 days from the application date. This term may be interrupted only once, if AIFA requests additional information, documents or data that are necessary for making a decision.
In order to speed up the access to the market of medicines authorised by EMA, a legal provision was introduced in 2012 under which centrally approved medicines, within 60 days from the date of the publication of their marketing authoriisation (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 payors
Pharmaceutical companies and manufacturers of medical devices must comply with the general anticorruption rules (Legislative Decree No. 231/2001).
Because many healthcare professionals in Italy work for public hospitals, health facilities and universities, they must comply with the Ethics Code for the employees of public administrations (Presidential Decree No. 62/2013), which, inter alia, provides that the employee shall not accept, for himself or herself 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 value is negligible if it does not exceed €20 per year for each doctor or pharmacist.
Medical or educational materials not specifically related to a medicinal product may be given free of charge only to healthcare organisations (not to individual doctors).
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:
- the way in which the product was distributed;
- the product's packaging and evident features, and the instructions and warnings provided;
- the product's reasonably expected use and life cycle; and
- the date on which the product was placed on the market (Article 117 of the Consumer Code).
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:
- the manufacturer did not place the product on the market;
- the product defect did not exist at the time the product was placed on market;
- 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:
- the rules concerning the off-label use of medicines (e.g., Avastin v. Lucentis case);
- 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
- 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 has conducted two industry-wide inquiries into the pharmaceutical sector, respectively, in 1997 and 2016. The most recent sectoral inquiry was aimed at assessing whether the market for human vaccines required antitrust intervention. The AGCM concluded that the market for the manufacture of vaccines is oligopolistic and argued that such problem should be addressed by introducing mandatory negotiation of prices with AIFA for essential human vaccines and also by increasing transparency in the technical assessment of the vaccines' necessity and on the entry of generics.
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.
As a result of the covid-19 pandemic, some exceptional rules and procedures have been introduced in Italian legislation, as well as by health authorities' guidelines.
Those new rules concern a wide range of activities in the life sciences sector, such as clinical trials and observational studies, marketing authorisation procedures, products' imports, the manufacturing and marketing of medical devices, sponsorship of scientific congresses for healthcare professionals, and the public procurement in the healthcare sector. Most of them apply only to products that are useful to cope with the pandemic and will remain in force as long as they are necessary to achieve this goal.
At the same time, because of the pandemic, other regulatory developments have been delayed. For instance, certain aspects of the reform of the legislation on clinical trials and on pricing and reimbursement of pharmaceuticals have not been completed yet.
1 Francesco Setti is a senior partner and Marta Moretti is a senior associate at Avvocati Associati Franzosi Dal Negro Setti.