Life Sciences 2021 Comparisons

Last Updated March 22, 2021

Law and Practice

Authors



Studio Legale Vaiano Cataldo is based in Rome, and consists of a team of 15 administrative lawyers headed by Professor Diego Vaiano and by Francesco Cataldo. The firm specialises in the legal field of life sciences, with particular regard to pharmaceutical law and medical devices, in relation to which it provides judicial and extra-judicial advice and assistance to the most important companies worldwide. The firm also provides legal counselling on public procurement, in particular on services and supplies, offering support at every stage of the procedure, from the study of tender deeds to the preparation of any requests for clarification or quotation documents, up to the executive phase. Where necessary, the firm offers assistance before the Regional Administrative Courts, the Council of State and the ordinary civil jurisdiction (Courts, Courts of Appeal and Court of Cassation), too. Other areas of activity where the firm can boast recognised expertise are those of administrative licensing of public goods and services, trade and production activities, environment, construction and urban planning, public competitions, and arbitration.

For medicinal products for human use, the main regulatory reference in Italy is Legislative Decree No 219/2006, issued in implementation of Directive 2001/83/EC (Community code relating to medicinal products for human use).

The matters not directly governed by the aforementioned legislative decree – such as, for example, those relating to the National Health Service's (NHS’s) drug pricing and reimbursement conditions or to the evaluation of the therapeutic equivalence between different active ingredients – find their discipline within an objectively very vast and inhomogeneous series of norms.

With regard to medical devices, the application of the European Regulations 2017/745 (MDR) and 2017/746 (IVDR) is imminent. The application of the first was initially planned to start on 26 May 2020, but was subsequently extended by one year, in consideration of the COVID-19 emergency. The second Regulation, relating to in vitro medical diagnostic devices, will instead be in force starting on 26 May 2022. Until these dates, the previous Community directives (90/385/EEC, 93/42/EEC and 98/79/EC) – and the Legislative Decrees that transpose their provisions at a national level – will continue to apply.

The authorities responsible for the application and verification of compliance with the aforementioned Regulations are:

  • the Ministry of Health, which exercises, among others, the functions of the State with regard to protection of human health, co-ordination of the NHS, veterinary healthcare, as well as supervision and monitoring of the circulation of medical devices;
  • the Italian Medicines Agency (AIFA), a body with legal status under public law, which operates on the basis of the guidelines and supervision of the Ministry of Health and the Ministry of Economy and Finance, and which is assigned the function of ensuring the consistency of the pharmaceutical system, as well as the task of establishing, through negotiations with pharmaceutical companies, the price and reimbursement conditions for medicinal products.

The decisions of the regulatory bodies in pharmaceutical matters are administrative acts or measures. As such, they can be challenged within 60 days of their communication or publication, with an appeal before the Regional Administrative Courts (TARs). Sentences pronounced by the TARs are appealable before the Council of State. Decisions made at appeal level can be challenged before the Supreme Court for reasons relating to jurisdiction only.

As an alternative to the appeal to the TAR, it is possible to file an extraordinary appeal with the President of the Republic within 120 days from the date of publication of the provision.

These remedies are applied identically for the challenge of any other administrative measure and, therefore, also with regard to medical devices.

Pharmaceuticals are classified in different ways, according to their reimbursement and supply status.

For the purposes of reimbursement, the AIFA classifies drugs in the following categories:

  • class A, essential medicines and drugs for the treatment of chronic diseases, the cost of which is borne by the NHS;
  • class H, medicines dispensed in the hospital, or in a similar facility, with costs to be borne by the NHS;
  • class C, medicines not reimbursed by the NHS.

For the purposes of supply, the regimes currently provided for by the legislation are as follows:

  • medicines subject to medical prescription;
  • medicines subject to medical prescription to be renewed from time to time;
  • medicines subject to special medical prescription;
  • medicines subject to restrictive medical prescription, including:
    1. medicines that can be sold to the public subject to prescription by hospital healthcare professionals (HCPs) or specialists;
    2. medicines that can only be used in a hospital (or similar) environment;
    3. medicines that can only be used by specialists;
  • medicines not subject to medical prescription, including:
    1. over-the-counter (OTC) or self-medication drugs;
    2. the remaining non-prescription medicines.

As far as medical devices are concerned, the national legislation follows that of the Community directives. There are, therefore, three categories of products:

  • active implantable medical devices, ie, devices requiring some form of energy to function and meant to be entirely or partially implanted, by surgical or medical intervention, in the human body;
  • medical devices (in general);
  • in vitro medical diagnostic devices, intended for in vitro use for the examination of specimens from the human body, including donated blood and tissue.

The first two categories of medical devices are grouped into different classes, according to their complexity and the potential risk for the patient (class I, IIa, IIb, III).

A different risk classification is instead provided for in vitro diagnostic devices.

Again with reference to medical devices, a further classification exists, for nomenclature purposes, called CND, or national classification of medical devices. This classification was selected by the Medical Device Co-ordination Group of the European Commission as a useful basis for developing the nomenclature for the European database EUDAMED, in consideration of its peculiarities in terms of structure, purpose and usability.

The regulatory framework governing clinical trials of medicinal products for human use, currently in a transition phase, is the result of a progressive stratification of national and community regulations.

Among these are, in particular:

  • Legislative Decree No 211/2003, which implemented Directive 2001/20/EU;
  • Legislative Decree No 200/2007, which implemented the subsequent directive 2005/28/EC;
  • Legislative Decree No 158/2012, which provided for the reorganisation of the Ethics Committees (independent bodies responsible for ensuring the protection of subjects enrolled in clinical trials);
  • Legislative Decree No 52/2019, which provided for the reorganisation of the legislation, introducing co-ordination provisions with (EU) Regulation No 536/2014.

This latest Regulation, which will abrogate the aforementioned Directive 2001/20/EC, aims to harmonise the procedures and requirements applicable to clinical trials in the various member states. The Regulation was published on 27 May 2014, but its application is subject to the activation of the database and the EU portal of clinical trials. The operativeness of these systems, after several extensions, is currently scheduled for December 2021.

For medical devices, the legislation on clinical investigations is currently contained in the Legislative Decrees which implement the Community directives in force on the subject. Furthermore, starting from 26 May 2021, these directives will be regulated by the new EU MDR (Articles 62 to 82 and Annex XV).

The authorisation procedure for clinical trials is divided into several phases, within which the foreseeable risks and inconveniences are carefully evaluated with respect to the expected benefit.

The bodies involved in the procedure are the following:

  • the AIFA, for the issue of the authorisation;
  • the Italian National Institute of Health (Istituto Superiore di Sanità), for the advisory opinion on Phase I studies and amendments;
  • the Ethics Committees, for the opinions on the merits in the healthcare facilities where the clinical study is carried out;
  • the General Managers of the healthcare units, for the stipulation of contracts;
  • the EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) network, for the reporting of adverse reactions.

As previously mentioned, the publication of EU Regulation No 536/2014 – which will be fully operational with the activation of the database and the EU portal – started a reform process, leading to the issue of Legislative Decree No 52/2019, of which, however, the implementing decrees (which will concretely redefine the procedures in force) are still pending.

The discipline relating to clinical investigations relating to medical devices is also in a transition phase.

According to the discipline dictated by the new EU MDR, in general and subject to exceptions, clinical investigations are mandatory for implantable and class III medical devices, while for other devices they are necessary only if the clinical data found in other available sources is not sufficient to prove compliance with the general safety and performance requirements.

The procedural process outlined by the new EU MDR involves the submission of an application by the sponsor of the clinical investigation. The member state concerned is required to communicate whether the application is complete within ten days from the date of receipt. At this point, if no additional information is requested and if the application concerns a low-risk device among those mentioned in Article 70, paragraph 7, letter a) of the MDR, the sponsor can start the clinical investigation on the same date as the validation of the application, provided that no negative opinion has been expressed by the competent Ethics Committee.

For the other medical devices, however, the initiation of the investigation requires prior notification of the authorisation by the member state.

Alongside this procedure, the Regulation governs specific procedures for the clinical investigations relating to devices already in possession of the marking (Article 74), for the clinical investigations conducted for purposes other than compliance assessment (Article 82), as well as a co-ordinated assessment procedure for clinical investigations conducted in more than one member state (Article 78). 

These procedures differ, in some respects, from that currently in force at national level, which does not require an actual application, but rather a notification to be sent to the competent ministerial direction which, for medical devices belonging to classes I, IIa and IIB (excluding implantable and long-term invasive devices), allows the relevant sponsor to start the investigation immediately, provided that it has the favourable opinion of the competent Ethics Committee.

As of 21 July 2014, the funders of a study or clinical trial relating to medicinal products for human use are required to publish its results on the European database managed by the European Medicines Agency (EMA). Through this database, it is possible to obtain information on the objectives of the study and the main results achieved.

This obligation is reinforced in the new Regulation (EU) No 536/2014, which – as previously mentioned – is expected to enter into force in December 2021. Indeed, this Regulation expressly establishes that a summary of the results of the clinical trial and an abstract presented in terms understandable to laypersons are to be made available in the EU database, regardless of the outcome of the clinical trial.

Similarly, the new EU MDR, applicable from 26 May 2021, requires the sponsor to submit a report on the investigation, within one year of its conclusion, regardless of its outcome.

The guidelines for the collection of the informed consent to participation in clinical trials – drawn up by the National Co-ordination Centre of Ethics Committees – recommend that the consent collection process also include "telematic” tools, in order to facilitate a full understanding by the participant. The same guidelines clarify that “in selected situations, to be assessed on a case-by-case basis, to facilitate the participation of all potentially interested patients, interactive telematic tools can be used for the patient information process and/or for the collection of their consent”.

Pursuant to the GDPR (General Data Protection Regulation), data resulting from clinical trials falls within the scope of “particular categories of personal data”.

As such, it can be transferred to third parties or affiliates only in compliance with the provisions of the aforementioned Regulation. Depending on the case, it may be necessary for the trial promoter to enter an agreement (possibly autonomous), with these subjects on the processing of personal data.

The creation of a database containing particular categories of personal data should take place in compliance with the technical and organisational measures provided for by the GDPR, in particular in order to guarantee the safety of the processing and the compliance with the principle of data minimisation.

The European legislation, implemented at national level, defines the characteristics that medicines and medical devices should possess to be considered as such.

The main criterion that is used to distinguish a medicine from a medical device is the method by which the product pursues its intended purpose. Unlike medicines, in fact, medical devices must exert their action through methods that are not mainly pharmacological or immunological, nor through metabolic processes.

EU Regulation No 726/2004 requires applicants to use the centralised procedure co-ordinated by the EMA for the authorisation of medicinal products derived from the following biotechnological processes:

  • recombinant DNA technologies;
  • controlled expression of genes carrying codes for biologically active proteins in prokaryotes and eukaryotes, including transformed mammalian cells;
  • hybridoma- and monoclonal antibody-based methods.

In addition, the registration of other biological drugs, not derived from the aforementioned procedures, may be requested through national, decentralised or mutual recognition procedures. In the case of biological or biotechnological originators, the application to be submitted to the AIFA for registration purposes is that based on a complete dossier, pursuant to Article 8 of Legislative Decree No 219/2006.

The same legislation, however, provides that the dossier to be presented in these cases is supplemented by additional information, precisely indicated in the Annex to Legislative Decree No 219/2006, which is justified in consideration of the peculiarities of biological medicines and their sensitivity to changes in raw materials or production processes. These peculiarities are also reflected in the registration requirements of biosimilar medicines, which may be more demanding than those necessary for the “simplified” authorisation of generic medicines (Article 10, paragraph 7, Legislative Decree No 219/2006).

The marketing authorisation (MA) has an initial five-year validity period. It can be renewed, at the request of the holder, with an application to be presented at least six months before the expiry date, on the basis of a new assessment of the risk/benefit ratio carried out by the AIFA. In cases in which this assessment gives a positive result, the MA is renewed with unlimited validity, unless the AIFA, for pharmacovigilance-related reasons, decides to proceed with a further five-year renewal. In the event that the risk/benefit assessment is not favourable, the interested party can submit to the AIFA an opposition to the refusal provision, on which the latter decides, within 90 days, after consulting the Italian National Institute of Health. If even this last decision is not favourable, the AIFA notifies the holder and announces with a press release that the medicine can no longer be marketed.

Once the MA has been issued, it can be revoked, suspended or modified in the cases established by Article 141 of Legislative Decree No 219/2006 (eg, when the medicine is harmful, it does not allow the effect for which it is authorised to be obtained, the risk/benefit ratio is not favourable and in the other cases indicated by the law).

In addition to the above, any MA issued loses its validity if it is not followed by the effective marketing of the medicinal product on the national territory within the following three years, or if an authorised medicinal product already present on the market is no longer effectively marketed for three consecutive years. However, these provisions can be derogated from by the AIFA for public health reasons.

For medical devices, the EC certification and the underlying compliance assessment issued by the notified bodies have a maximum validity of five years (renewable). The MDR, the application of which is expected to take effect from 26 May 2021, confirmed these validity periods, and regulated a transitional regime for the marketing of certified products in compliance with the Directives currently in force.

For medicinal products, the authorisation procedures are divided into:

  • a centralised procedure, aimed at obtaining an MA valid in all EU countries, which is co-ordinated by the EMA and its Committee for Medicinal Products for Human Use (CHMP), and ends with the issuing of a decision by the European Commission;
  • a mutual recognition procedure, which allows the extension to one or more EEA countries of an MA already granted by a member state;
  • a decentralised procedure, which allows an MA to be obtained that is simultaneously valid in two or more EEA countries on the basis of identical documentation;
  • a national procedure, which allows a valid MA to be obtained within the Italian state only.

In order to initiate the procedure, the applicant is required to submit an application for authorisation to the competent authority, attaching a dossier containing the information required by Annex I to Directive 2001/83/EC.

Once the application is received, the competent authorities analyse its compliance and verify the existence of the conditions for issuing the MA. The legislation provides for a maximum term of 210 days, starting from the date of presentation of the valid application, for the conclusion of centralised, decentralised and national procedures. The mutual recognition procedure, however, provides for a term of 180 days.

The procedures for changing the terms of an MA are governed by EU Regulation 1234/2008. These procedures are different, depending on the variation requested.

Type IA variations, which have little or no impact on the quality, safety and effectiveness of the medicinal product, can be implemented even before being notified to the competent authorities (these include, for example, administrative changes relating to the identity or address of the MA-holder or the manufacturer).

For the implementation of the other variations, however, it is necessary to wait for the completion of the silent consent (type Ib variations), or the express authorisation from the competent authorities (type II variations, relating for example to the addition of an indication, to the production process, etc).

With regard to medical devices, the marking procedures differ according to the relative risk class.

For the lowest risk class (class I), it is generally possible to mark the device on the basis of a declaration of compliance with the essential requirements provided for by the legislation, a declaration that can be made by the manufacturer themselves.

For the other classes of devices, and for sterile devices or devices with a measuring function, also in class I, the assessment procedure provides instead for the involvement of a notified body, from which the manufacturer is required to request the issue of a certificate of compliance.

In general, any variations to the approved device require a new approval by the notified body that issued the EU technical documentation assessment certificate, if they may affect the safety and performance of the device or the conditions of use prescribed for that device.

When certain conditions are met, the national legislation allows free access to a drug therapy that has not yet received the AIFA’s authorisation.

According to Law No 648/1996, this possibility is provided for, provided that there is no valid therapeutic alternative:

  • for innovative medicines authorised in other States, but not in Italy;
  • for medicinal products not yet authorised, but undergoing clinical trials;
  • for medicinal products to be used for a therapeutic indication other than that authorised.

Medicines that can be used pursuant to the aforementioned Law No 648/1996 are included in a special list of the AIFA, and can be prescribed at the total expense of the NHS for all the subjects who, in the national territory, are affected by the condition identified in the provision.

Early access to the drug is also allowed under “compassionate-use” programmes, for drugs still undergoing clinical trials, in patients suffering from serious or rare diseases or whose lives are in danger, when, in the physician’s judgement, there are no further valid therapeutic alternatives. Access to the investigational drug requires a favourable opinion from the Ethics Committee, subject to confirmation of the pharmaceutical company’s availability to supply the drug for free.

Subject to the authorisation of the Ministry of Health and the favourable opinion of the Ethics Committee, the possibility of resorting to compassionate use is also provided for 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.

After the granting of the MA, the holder takes into account any scientific and technical progress, and introduces the changes necessary for the medicine to be produced and controlled according to generally accepted methods.

In addition, pursuant to Legislative Decree No 219/2006, the same holder is obliged to inform AIFA immediately of any prohibitions or restrictions imposed by the competent authorities of any country in which the medicine is marketed, as well as any other new data that may affect the risk-benefit assessment of the same.

In terms of pharmacovigilance, the legislation requires the MAH to record suspected adverse reactions in detail, and to notify with the utmost urgency those characterised as serious.

This information must be collected and submitted by the MAH in the form of PSURs (Periodic Safety Update Reports).

Similarly, vigilance obligations are envisaged for medical device manufacturers or their authorised representatives, starting with the immediate communication to the competent authority of all the incidents of which they have become aware and of all the corrective actions that have been undertaken to avoid or reduce the risks associated with the use of a medical device.

The AIFA has adopted a regulation for the access to documents created or held permanently by itself. The regulation provides that the Administration may limit access to a document, obscuring some of its contents, when this is necessary to protect the confidentiality of persons, groups or companies. The same regulation excludes, in principle, from the right of access the documentation concerning the production methods and the know-how on the manufacture of pharmaceutical products. In principle, the jurisprudence denies the right of third parties to access any information relating to any confidential discounts granted by pharmaceutical companies to NHS bodies in the context of pricing and reimbursement contracts stipulated with the AIFA.

The situation is different for the authorisation procedures for generic medicines. In such cases, in fact, the jurisprudence has recognised the right of access to Marketing Authorisation Applications and bio-equivalence tests by the companies that market the reference medicine, noting that the latter have an interest worthy of protection in verifying the actual equivalence between their patented medicinal products and the generic ones that are the subject of the MA Application.

For medical devices, the provisions of the general legislation on the right of access apply (Article 22 et seq, Law No 241/1990).

Directive 2011/62/EU and delegated Regulation 2016/161 have integrated the regulatory system, providing for specific provisions to oppose the inclusion of counterfeit medicines into supply chains.

In order to counteract these phenomena, it was decided, in particular, to equip the packaging of the medicines with a unique identifier and an anti-tampering device.

The application of a Unique Device Identifier (UDI), including a product and production identifier, is also required for medical devices under Article 27 of the new EU MDR, the applicability of which in the member states, as previously mentioned, is currently scheduled from 26 May 2021. Article 94 of the same regulation requires the competent authorities of the member states to draw up annual market surveillance activity plans and to allocate sufficient resources to carry out such activities.

A national anti-forgery Task Force is active in Italy. The main institutions involved in this Task Force and in the drug counterfeiting issue are the AIFA, the Ministry of Health, the Istituto Superiore di Sanità (National Institute of Health) (ISS), the Illegal Traffic of Medicines (Nuclei Antisofisticazioni e Sanità) (NAS) (Carabinieri), the Ministry of Economic Development (Ministero dello Sviluppo Economico) (MISE) and the Customs and Monopoly Agency.

Part of the control activity carried out concerns the management of reports relating to the discovery of suspicious products at customs. Specifically, this activity takes the form of a series of checks which have the purpose of ascertaining the origin of the products and their relative composition through laboratory analyses.

For medical devices, customs surveillance is mainly carried out by the Maritime, Area and Border Health Offices of the Ministry of Health. The surveillance activity is carried out through three levels of verification (documentary, identity, material), to ascertain the compliance of medical goods with the requirements and prescriptions provided for by national and community regulations.

Pursuant to Legislative Decree No 219/2006, the production of medicines and medical devices require the authorisation of the AIFA and the Ministry of Health, respectively. The authorisation, which does not expire, is issued after an inspection aimed at ascertaining that the applicant has qualified personnel and technical-industrial means compliant with the regulations.

The wholesale distribution of medicines is subject to authorisation by the Regions, and requires the availability of suitable premises and adequately trained personnel (Legislative Decree No 219/2006).

The legislation on medical devices does not regulate the wholesale market.

For the classification of medicines for supply and reimbursement purposes, see 1.3 Different Categories of Pharmaceuticals and Medical Devices.

On the basis of these classifications and the relative conditions of use, medicines can be assigned to the following distribution channels:

  • hospital distribution, for medicines used in hospital. The distribution regime applicable in these cases requires hospital pharmacies to dispense medicines to hospitalised patients, subject to direct purchase from pharmaceutical companies following the outcome of public tenders;
  • territorial distribution, for chronic medicines or even short-term therapies and for clinical situations that do not require hospitalisation. The distribution regime applicable in these cases provides that the medicine is purchased by the wholesaler, dispensed by local pharmacies and, where included in reimbursement class A, reimbursed to the subjects in question by the NHS according to the relative amounts due provided for by law;
  • direct distribution, for medicines which, although not intended for hospitalised patients, meet the criteria of differential diagnostics, of therapeutic criticality, and of periodic control by the specialist structure. These medicines are purchased and dispensed by health facilities according to the scheme illustrated above for the hospital distribution, and are delivered to patients by hospital pharmacies. However, in some regions, there are agreements entered into with the pharmacist trade associations, based on which patients can collect these drugs at some affiliated pharmacies that are authorised to supply them. These cases fall within the “distribution on behalf of the health facility”.

The import and export of medicines are governed by Legislative Decree No 219/2006.

For medical devices, it is necessary to refer to the European directives, the national implementing legislation and, starting from 26 May 2021, the new EU MDR. Articles 13 and 60 of that regulation are specifically dedicated to import and export activities.

The competent authorities for implementing the regulation are the AIFA and the Ministry of Health.

In general, the compliance with authorisation requirements and obligations similar to those envisaged for the production activity is required for subjects importing medicines.

For the parallel import of medicines registered in a member state, for which a similar medicine exists in the Italian market, the importer must have the regional authorisation for wholesale distribution. Moreover, for each workshop that carries out the re-labelling or repackaging of the product, a production authorisation is required.

There is no specific authorisation for subjects importing medical devices. However, they are responsible for the compliance of the product marketed in the Union.

Starting from 26 May 2021, with the full operation of the MDR, importers of medical devices will be required to comply with the obligations set out in Article 13 of the MDR itself (eg, obligation to verify CE marking, EU declaration of compliance, labelling, etc).

Imports of medicines must be previously authorised by the AIFA.

Notwithstanding this general rule, the importation for personal use of medicines duly authorised in a foreign country is allowed in the following cases:

  • medicines for which a valid therapeutic alternative does not exist or is not accessible in Italy, upon request and under the responsibility of the attending physician;
  • medicines personally imported by the traveller upon entering the national territory, provided they are intended for personal use for a treatment not exceeding 30 days.

The import of medical devices is subject to supervision by the Maritime, Air and Border Health Offices of the Ministry of Health. The surveillance activity ends with the final issue of an import-authorisation measure, or with a non-importation measure in the case of failure to pass the controls.

The import of goods into the EU is regulated by a standardised classification system, which identifies products on the basis of a tariff code. The classification is based on the harmonised system managed by the WHO (HTS, first six digits of the code), on the further subdivisions applied by the Union Combined Nomenclature (CN) and, finally, on the Community Customs Tariff (TARIC). The TARIC code, consisting of ten digits, identifies the applicable rates, any preferential duties and a whole series of other measures (temporary suspensions, quotas, ceilings, etc) specifically applicable to the product being imported.

The EU manages trade relations with third countries in the form of trade agreements designed to create better trade opportunities and to overcome trade barriers. Among the other agreements worth of mention here are the CETA (EU-Canada) and the JEFTA (EU-Japan); the latter entered into force on 1 February 2019, with a negotiated free trade area of more than 635 million people. The agreement includes, among others, the pharmaceutical sector, to the regulation of which a specific chapter is dedicated.

The price of medicines not reimbursed by the NHS is established by the MA-holders, and can only be changed upwards in January of each odd year.

The price of the medicines reimbursed by the NHS is defined through negotiation between the companies and the AIFA.

The criteria with which the AIFA must comply during the negotiation are established by the Decree of the Ministry of Health of 2 August 2019, published on 24 July 2020. It should be noted, however, that the legitimacy of this ministerial decree is currently sub iudice.

The discipline dictated by the decree in question provides that the negotiation is initiated by the pharmaceutical company by submitting a specific request, accompanied by the documentation listed in Article 2, paragraph 2 of the same decree.

For the conclusion of the procedure, a term of 180 days is provided for, the suspension of which is allowed for a period not exceeding 90 days.

In the case of lack of agreement, the procedure ends negatively, with the classification of the medicine in class C. In the case of a positive outcome, the procedure is finalised by an agreement between the AIFA and the pharmaceutical company defining the price and reimbursement conditions applicable to the medicine.

The negotiated price is valid for a period of 24 months, unless otherwise agreed by the parties, but the AIFA can still restart the negotiation before the deadline in the event of particular “market changes”, in the case of “new evidence” on the positioning in therapy or on the estimated benefits, or if a shortage of the medicine on the Italian market occurs.

The negotiated price represents the maximum price for the sale of the drug to the NHS bodies, on which further discounts can be negotiated during the tender. In addition to this price, in the market segment of territorial distribution, VAT and the profit margins envisaged by the law in favour of pharmacists and wholesalers are added. The sum of these components thus determines the retail price of the medicine (ie, the price reimbursed to the pharmacist by the NHS), which is divided among the players in the supply chain on the basis of the following quotas: 66.65% for the manufacturing pharmaceutical companies, 6.65% for wholesalers and 26.7% for pharmacists. For the transfer of equivalent medicines referred to in Article 7, paragraph 1, of Legislative Decree No 347/2001, not originally covered by a patent or licences deriving from that patent and assigned to the territorial distribution circuit, the quota attributable to the pharmaceutical company is reduced from 66.65% to 58.65% and the corresponding percentage of 8 points that is released is divided between pharmacists and wholesalers, according to market rules.

For medical devices, there are no price-negotiation procedures similar to those for medicines. Prices are set by the producers and, for the supplies to NHS bodies, they are negotiated upon the outcome of public tenders between the supplying companies and the regional purchasing centres.

The prices of medicines and medical devices marketed in Italy are not strictly bound to those quoted, for the same products, in other European countries and in the rest of the world. Nonetheless, Ministerial Decree of 2 August 2019 provides that the information on the “marketing, consumption and reimbursement in other countries” must be communicated by pharmaceutical companies during the negotiation of the price and reimbursement conditions of medicines, and are taken into consideration by the AIFA during the negotiation process.

A reference price system is instead envisaged in the public contracts sector, to contain the variability of the regional award prices of certain products having a high impact in terms of cost for the NHS. Following this system, Legislative Decree No 95/2012 introduced the institution of “renegotiation” of existing contracts, which NHS bodies are required to exercise in the event of a deviation of more than 20% of the award price compared to the price of reference. In the case of failure of a renegotiation agreement, the NHS bodies have the right to withdraw from the contract without any charge. This system, however, has not so far found concrete application in the pharmaceutical sector, but in exceptional cases.

Additional control systems of award prices, starting prices and the renegotiation of existing contracts have been provided for, for medical devices, by Law No 296/2006 and by Legislative Decree No 78/2015.

Medicines are eligible for reimbursement by the NHS if they are deemed by the AIFA to be indispensable for the treatment of chronic or serious diseases, after negotiating the relative price and reimbursement conditions with the company holding the MA.

For the government of pharmaceutical expenditure, the State makes use of various instruments, among which the most incisive is certainly the setting of an overall expenditure ceiling, equal to 14.85% of the National Health Fund, divided into a ceiling for the pharmaceutical expenditure under agreement and a ceiling for pharmaceutical expenditure for direct purchases (drugs purchased directly from the NHS bodies). The current legislation provides, in fact, that pharmaceutical companies must participate in the settlement of the overspending of the aforementioned ceilings to varying degrees, depending on the ceiling that has been overrun. For the direct purchases ceiling, in particular, pharmaceutical companies must participate in the settlement for an amount equal to 50% of the relative overrun (so-called pharmaceutical pay-back).

While the ceiling for the pharmaceutical spending under agreement has always proved to be capacious, the one intended for direct purchases has proved to be seriously underestimated over the years, recording, starting from 2013, overspends for increasingly greater amounts, exceeding one billion euros per year. The requests for pharmaceutical pay-back have been the subject of extensive litigations, which for some years are still pending before the administrative justice bodies.

With the latest in a long series of regulatory interventions, the legislator provided that, starting from 2021, “without prejudice to the overall value of 14.85%” of the national healthcare fund (FSN, Fondo Sanitario Nazionale), the expenditure ceilings are re-calculated to a level equal to 7% for the expenditure under agreement and 7.85% for the direct purchases expenditure, with an increase of the latter of about one percentage point compared to in the past.

The legislation also provides for a ceiling and a settlement mechanism for the expenditure on medical devices. The percentage of the deficit borne by the supplying companies was set at 40% of the overspending in 2015, 45% in 2016 and 50% starting from 2017. Each company contributes to the settlement in a measure equal to the percentage incidence of its turnover on the total expenditure for the purchase of medical devices to be paid by the NHS, as established by an agreement during the State-Regions Conference. However, this system has not yet found any application.

The cost-benefit analysis and the “added therapeutic value” of a medicine in relation to the therapeutic alternatives available are the evaluation criteria adopted by the AIFA when negotiating the price conditions of the medicines reimbursed by the NHS.

For medical devices, the 2016 Stability Law assigned to a “Control Room” the task of carrying out a multi-dimensional technical assessment of medical devices, based on the criteria of relevance, safety, effectiveness, economic impact and organisational impact of the devices themselves, consistent with the relevant European guidelines (EUnetHTA). The rules provide that the individual NHS bodies can no longer carry out this activity autonomously, but must resort to evaluating structures established at a regional or national level, which must in any case operate under the co-ordination and on the basis of the priorities identified by the Control Room.

For the government of pharmaceutical expenditure, the AIFA makes use of additional instruments related to the expenditure ceilings, that specifically affect the phases of prescription, dispensing and reimbursement of the medicines whose costs are borne by the NHS.

Among these, the so-called “AIFA Notes” are particularly important: they are a regulatory tool aimed at limiting the scope of reimbursement of certain medicines by defining the indications and/or limitations that every physician should comply with in order to be able to prescribe the drug with costs borne by the NHS. At the time of the prescription, the doctor records the number of the Note on the prescription itself, thus certifying that the conditions provided for by that Note are met for the prescription of the medicine with costs borne by the NHS. The Notes are periodically reviewed in order to update the indications and limitations provided therein according to the new evidence available in the scientific literature.

Further regulatory instruments concern the prescription and dispensing of originator medicines and their equivalent counterparts included in the “transparency list” referred to in Article 7 of Legislative Decree No 347/2001. The following mechanisms apply to the medicines included in the list in question:

  • limitation of the maximum reimbursement price by the NHS, which is reduced to the price of the cheaper equivalent drug based on the same active ingredient included in the transparency list;
  • automatic replacement of prescriptions, by virtue of which the pharmacist is obliged to dispense to the patient the aforementioned drug included in the transparency list with the lowest price, unless the treating physician has expressly added the "No Replaceability" clause to the prescription, or unless the patient has insisted in any case on obtaining the dispensing of the most expensive drug, in both cases personally paying the price difference.

Finally, there is a regional practice which tends to orient/encourage/discourage doctors’ prescribing choices on the basis of measures that presume an evaluation of the therapeutic equivalence between medicines containing different active ingredients. This is the case, for example, of the decisions concerning:

  • the promotion of the prescription of certain active ingredients, less expensive, in place of others;
  • the creation of tenders for the competing purchase of medicinal products based on different active ingredients.

Over the years, a practice has emerged that has seen the regions adopt decisions of this type with a certain frequency, and in no particular order, with the consequent creation of inequalities of treatment among the patients in accessing pharmaceutical care services included in the essential levels of care. To sort the matter and ensure uniformity in the access to services, the legislator has therefore intervened on the regulatory level, establishing that the aforementioned decisions, which require an evaluation of the therapeutic equivalence between medicines containing different active ingredients, can be adopted by the regions only “on the basis of the justified and documented assessments expressed by the Italian Medicines Agency” (Article 15, paragraph 11-ter, Legislative Decree No 95/2012).

In implementing the aforementioned Article 15, paragraph 11-ter, the AIFA adopted the guidelines that should have identified the criteria for establishing, in practice, the therapeutic equivalence between medicines based on different active ingredients. The aforementioned document, however, was also contested by the entire pharmaceutical industry, which strongly opposed it, denouncing its many criticalities, starting from the failure to identify, basically, the criteria for evaluating therapeutic equivalence, in the absence of which those made by the AIFA essentially assume the characteristics of arbitrary and unquestionable decisions. The legitimacy issues raised are currently pending before the administrative justice bodies.

In October 2019, the European Commission’s Medical Devices Coordination Group published a guideline on the qualification and classification of software as medical devices. The document reaffirms the general principle according to which the purpose given by the manufacturer to the software is the main criterion that must be used for the purposes of its qualification and classification as a medical device. Consequently, it must be considered that software used solely for research or information retrieval activities cannot be classified as medical devices. Conversely, software intended for the analysis and processing of health information for medical purposes can be qualified as medical devices, and classified in risk class IIa, or in higher classes, if the decisions to be made on the basis of the software itself can seriously impact the health status of the user.

On 17 December 2020, the State-Regions Conference approved a document containing “national guidelines for the provision of telemedicine services”. The guidelines govern, in detail, the telemedicine activities that can be included in the essential levels of care (in particular, tele-visits, medical tele-consultation, medical health tele-consultation, tele-assistance by healthcare professionals, tele-reporting), and their limits and possibilities of use, as well as the applicable rules in terms of tariffs, accountability and necessary technological standards.

Advertising to the public is allowed, subject to authorisation by the Ministry of Health, for medical devices and Standard Operating Procedure (SOP)/OTC medicines. Advertising can also be carried out via the internet, but in this case it must comply with the rules established in the guidelines specifically issued by the Ministry of Health. Precisely these guidelines, however, almost absolutely prohibit the possibility of advertising medicines via social networks, with an exception only for Facebook desktop (right column) and YouTube.

The outbreak of the COVID-19 pandemic has given a particular impulse to the process of dematerialisation of prescriptions.

The Ordinance of the Head of Civil Protection of 19 March 2020 introduced, for the emergency phase, alternative methods to the paper prescription, in order to reduce travel and the number of accesses to the NHS GPs’ offices.

Lastly, the inter-ministerial decrees of 25 March 2020 and 30 December 2020 extended the use of electronic medical prescriptions to other types of medicines, including those not reimbursed by the NHS, while disciplining the dematerialisation of prescriptions and also the relative reminders for the post-emergency phase.

The online sale of medicines is governed by Legislative Decree No 17/2014 and is thereby permitted only for SOP/OTC drugs, and only in the online shops of pharmacies and parapharmacies, subject to authorisation by the region of competence and registration in the list of authorised subjects, kept by the Ministry of Health.

For medical devices, online sales are permitted under Article 6 of the new EU MDR.

The Italian electronic health record (FSE, Fascicolo Sanitario Elettronico) is managed by the regions in compliance with the general rules established by Article 12 of Legislative Decree No 179/2012 and by the current legislation on the protection of personal data. The FSE (or EHR) collects all the health and social health data and digital documents generated by clinical events concerning the patient. The consultation of the data present in the FSE can be carried out only with the consent of the patient, and always in compliance with professional secrecy.

The main regulatory reference on the subject is the industrial property code (CPI, Codice Proprietà Industriale). There are specific regulations which integrate the CPI for the pharmaceutical sector and which concern, among others, the release of Supplementary Protection Certificates for medicines (SPCs, EC Regulation No 469/2009) and the legal protection of biotechnological inventions (Directive 98/44/EC).

The possibility of obtaining patents for second medical use is generally recognised, provided that the patentability requirements are met and it is therefore possible to demonstrate the innovative nature of the new use compared to the previous one.

The patent coverage of the new use inevitably expires after the initial one. Consequently, in the period between the first and second deadlines, a somewhat hybrid situation arises, during which generic medicines can be marketed, but not for the second use, which is protected by the patent issued subsequently. This particular dynamic meant that also in Italy, as in many other countries, second- and subsequent-use pharmaceutical patents have been the subject of litigation.

Pharmaceutical companies can apply for an SPC, which allows them to extend the duration of the basic patent. These certificates are governed by Regulation No 469/2009/EC and have a duration equal to the time elapsed between the filing of the patent application and the granting of the first European MA, minus five years. In any case, the certificate can never have a duration exceeding five years from the expiry of the basic patent.

On 1 July 2019, Regulation (EU) No 2019/933 entered into force, which amended Regulation (EC) No 469/2009, providing for some exceptions to the protection provided by the Supplementary Protection Certificate. In particular, it has been possible to produce a generic – or biosimilar – version of a medicine protected by a certificate, during its period of validity, in the following cases:

  • for the purpose of exporting to a non-EU market where the protection conferred by the certificate has expired or never existed;
  • for the purpose of creating, in the six months preceding the expiry of the certificate, a stock intended to be marketed in the EU immediately after the expiry of the certificate.

The conducts subject to violation are identified, mainly, in the production, use, marketing, sale, import of the protected product/procedure, without the consent of the relative owner. The supply – or the offer to supply – to subjects other than the right-holders the means relating to an indispensable element of the invention, necessary for its implementation, also constitutes a patent infringement.

The owner of an industrial property right can request that the injunction be ordered for any imminent violation of their right and the continuation or repetition of the violations in progress and, in particular, can request the prohibition of manufacture, marketing and use of the things constituting a violation of the law, and the order to withdraw these activities from the market.

For the coverage offered by supplementary protection certificates (SPCs) and for the exemptions provided for by Regulation No 2019/933, see 9.3 Patent Term Extension for Pharmaceuticals.

The main defensive exceptions that can be raised in the pharmaceutical and medical devices sector are based on the classification of the contested acts as:

  • acts carried out in the private sphere and for non-commercial purposes;
  • acts performed on an experimental basis relating to the subject of the patented invention;
  • studies and trials aimed at obtaining, even in foreign countries, a Marketing Authorisation for a drug and the consequent practical requirements, including the preparation and use of the pharmacologically active raw materials strictly necessary for this purpose;
  • extemporaneous, and per unit, preparation of medicines in pharmacies upon medical prescription, and the medicines thus prepared, provided that industrially manufactured active ingredients are not used.

The legal system envisages the possibility of requesting compulsory licences for the non-exclusive use of the invention, but the conditions provided for the granting of such licences are extremely restrictive and stringent (eg, in the case of failed implementation of the invention, for dependent patents, for health emergencies according to the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement)).

The actions that can be carried out by the owner of the right or its exclusive licensee include, among others: actions to ascertain a counterfeiting, paternity and claim action, condemning actions upon the cessation of counterfeiting and compensation for damages, typical precautionary actions governed by the CPI (eg, injunction, description, seizure, etc), other precautionary actions contemplated by the CPC and, finally, executive actions.

For its part, the other party, in addition to explaining defences and exceptions, can challenge the validity of the patent by counterclaiming.

For the purposes of the marketing of generic medicines, no preventive judicial or extra-judicial actions are required. However, generic companies have the right to promote such actions to request, for example, the assessment of the invalidity of the title, or its forfeiture.

Without prejudice to data exclusivity (see 10.4 Data Exclusivity for Pharmaceuticals and Medical Devices), according to the Italian legislation an application for an MA for a generic medicine cannot be rejected or deferred by the AIFA for reasons relating to patent coverage. Furthermore, the authorised equivalent medicinal product cannot be classified as a drug dispensed with costs borne by the NHS with effect prior to the expiry date of the patent or the Certificato Complementare di Protezion (Complementary Protection Certificate) (CCP), published by the Ministry of Economic Development.

Counterfeiting gives rise to criminal – as well as civil – liability, integrating the criminal offences envisaged by Article 473 of the Italian Criminal Code, punished with imprisonment from six months to four years and with a fine from EUR2,500 to EUR35,000.

The verification of the commercial name of a medicinal product falls within the competence of regulatory agencies only to the extent that its use could cause a safety or public health risk.

As regards the parallel import of medicines, the principles affirmed by EU and national jurisprudence provide that the medicine imported from abroad normally retains the trade name registered in the country of origin. The latter can be changed with a name coinciding with that with which the same drug is marketed in the country of destination only in the event that:

  • there are regulations or practices in the country of destination that prevent the marketing of the product with the trade mark used in the country of origin;
  • the use of the designation of origin can create a confounding risk for public health.

Conversely, the change of destination is not permitted if the replacement of the trade mark is exclusively due to the desire, on the part of the parallel importer, to achieve a commercial advantage.

Article 7 of the new EU MDR also regulates the aspects in question for medical devices, prohibiting the use of texts, names, trade marks and signs that could mislead the user with regard to the destination, safety and performance of the device.

IP Protection is potentially applicable to the graphic layout or design of pharmaceutical products to the extent that they meet the requirements of the legislation for the granting of such protection (eg, novelty, lawfulness, etc).

According to Article 10 of Legislative Decree No 219/2006, the simplified application for the registration of a generic medicinal product cannot be submitted before eight years have elapsed from the issue of the first Marketing Authorisation in Europe of the reference medicinal product (“data exclusivity”). Furthermore, the generic medicine thus authorised cannot be marketed before ten years have elapsed, again starting from the first MA of the reference medicine (“market protection”). If, in the first eight years, the reference medicine has obtained an extension of its therapeutic indications, the market protection period is increased by one year.

These protection regimes are calculated independently of patent protection, and can be opposed to the marketing and registration applications of generic, biosimilar and hybrid medicines, which are similarly based on the identification of a reference medicine and on the use of the (protected) data which supported its marketing authorisation.

The same protection regimes can also be benefited by the holders of Marketing Authorisations relating to medicinal products containing a fixed-dose combination.

There are no similar protection regimes for medical devices.

The emergency legislation has provided for numerous measures aimed at addressing the extraordinary needs deriving from the COVID-19 pandemic. Among these, for the purposes that are relevant here, the following are worth mentioning:

  • VAT exemption until the end of 2020 and a reduced rate of 5% starting from 2021 for a series of instruments and products used for the containment of the COVID-19 pandemic (eg, masks, lung ventilators for intensive care, etc);
  • the possibility of administering vaccines in pharmacies open to the public, under the supervision of doctors and with the assistance – if necessary – of nurses or other trained healthcare personnel;
  • provisions to ensure the local availability of medical devices for oxygen therapy, also on an experimental basis, through the network of service pharmacies.

In order to improve the ability to co-ordinate and analyse the available scientific evidence, the emergency legislation authorised the AIFA to access all the data from experimental and observational clinical studies and from compassionate therapeutic-use programmes activated for COVID-19 patients.

Furthermore, for the same purposes, the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani was identified as the single national body in charge of the evaluation of clinical trials, observational studies and programmes of compassionate therapeutic use of medicines for COVID-19 patients.

Finally, the AIFA was entrusted with the task of publishing a simplified procedure for the acquisition of clinical trial applications and for the modalities of enrolment in the studies.

Article 15 of Legislative Decree No 18/2020 provides for an exceptional authorisation procedure for the production of surgical masks and PPE. Based on this procedure, manufacturers who intend to make use of this derogation send the surgical masks and PPE to the ISS and the Istituto nazionale Assicurazione Infortuni sul Lavoro (INAIL), respectively, self-certifying that they comply with the safety requirements established by current legislation. Within three days the ISS and the INAIL release their decision, based on the self-certification and the technical documentation received from the manufacturer.

As regards the approval of medicinal products, the applicable legislation already provided for the possibility of granting MAs subject to specific obligations in exceptional circumstances (“conditional MA”). This procedure was actually followed by the EMA for the purpose of issuing the MAs of the currently available COVID-19 vaccines.

In order to reduce travel and access to GPs’ offices, the legislation adopted for the emergency period has extended the terms of validity of the restrictive prescriptions of class A drugs. In addition, the duration of the therapeutic plans that include the provision of aids, disposable devices and other prosthetic devices and that expire during the state of emergency was automatically extended.

In order to address any shortage of medicines, the AIFA authorised the import of foreign packs of medicines for the supplies to the NHS structures.

Furthermore, Article 66-bis of Legislative Decree No 34/2020 introduced provisions on the simplification of the procedures for the import and validation of surgical masks and PPE.

See 8.2 Rules for Telemedicine.

The Italian government has never referred to the possibility of submitting mandatory licence applications for the use of patent-protected anti-COVID-19 drugs or vaccines, on the basis of the TRIPS agreement.

Instead, the imminent equity participation of the State in the shares of Reithera (currently engaged in testing an anti-COVID-19 vaccine), an initiative aimed at supporting the expansion of the pharmaceutical company’s production capacity, in implementation of the provisions of Article 34 of Legislative Decree No 34/2020, was announced.

At a national level, no particular liability exemptions have been introduced with regard to anti-COVID-19 drugs, treatments or vaccines.

Article 5 of Legislative Decree No 18/2020 assigned to the extraordinary Commissioner for the management of the emergency the task of providing incentives (also non-repayable) for EUR50 million in order to support projects for the expansion or conversion of activities aimed at the production of medical devices and PPE.

The subsequent Article 6 of Legislative Decree No 18/2020 attributed to the Head of the Civil Protection Department the power to dispose, with his or her own decree, the requisition in use or ownership, from any public or private entity, of health and medical-surgical facilities, as well as movable property of any kind, necessary to deal with the aforementioned health emergency. For the owners of the assets acquired, the law provided for the recognition of a requisition indemnity calculated according to the market value of the assets as of 31 December 2019.

The emergency regulation authorised the extraordinary Commissioner to purchase PPE and other medical devices in derogation from the procurement code, also through advance payments of the entire supply.

Furthermore, with the Law Decree No 76/2020, a series of provisions of a temporary nature were introduced, aimed at achieving – pending the emergency – a simplification of the procedures regarding public contracts.

Studio Legale Vaiano Cataldo

Lungotevere Marzio, n. 3
00186
Roma
Italy

+39 06 68 74 772

+39 06 68 74 870

studiolegale@vaianocataldo.it www.vaianocataldo.it
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Law and Practice in Italy

Authors



Studio Legale Vaiano Cataldo is based in Rome, and consists of a team of 15 administrative lawyers headed by Professor Diego Vaiano and by Francesco Cataldo. The firm specialises in the legal field of life sciences, with particular regard to pharmaceutical law and medical devices, in relation to which it provides judicial and extra-judicial advice and assistance to the most important companies worldwide. The firm also provides legal counselling on public procurement, in particular on services and supplies, offering support at every stage of the procedure, from the study of tender deeds to the preparation of any requests for clarification or quotation documents, up to the executive phase. Where necessary, the firm offers assistance before the Regional Administrative Courts, the Council of State and the ordinary civil jurisdiction (Courts, Courts of Appeal and Court of Cassation), too. Other areas of activity where the firm can boast recognised expertise are those of administrative licensing of public goods and services, trade and production activities, environment, construction and urban planning, public competitions, and arbitration.