I OVERVIEW

The Italian pharmaceutical business registered the highest growth rate from 2008 to 2018 and represents the third sector in terms of research and development investments in Italy. Moreover, according to data recently published by a local industry association, Italy is the biggest manufacturer of medicines in the EU.2 This trend has not been significantly affected by the covid-19 crisis.

In a universal healthcare system where essential healthcare treatments are guaranteed free of charge to all the population, the pharmaceutical sector is, on the one hand, driven by control of public expenditure and, on the other, by innovation and quality. As explained in more detail in this chapter, Italy is the country where managed entry agreements with payers (i.e., agreements under which the payment is somehow connected with the benefit that the medicine is able to guarantee to patients) are most developed. This legal instrument enables both pharma companies and payers to share financial risk due to uncertainty surrounding the introduction of new technologies.

In this search for balance, originators and generics whose relationship is often affected by anticompetitive behaviours ultimately aimed at hindering the market entry of generic drugs have found their place. In this respect, over the past few years the Italian Antitrust Authority has been one of the most active authorities at the EU level, also in terms of enforcements.

II LEGISLATIVE AND REGULATORY FRAMEWORK

In the pharmaceutical sector, the applicable Italian legislative and regulatory framework mainly consists of:

  1. Regulation (EC) No. 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency;
  2. Regulation (EC) No. 1394/2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No. 726/2004;
  3. Legislative Decree No. 219/2006 implementing Directive 2001/83/EC;
  4. Legislative Decree No. 50/2016 on Code of Public Contracts;
  5. Legislative Decree No. 30/2005 on Code of Industrial Property;
  6. Law No. 287/1990 on rules for protecting competition and the market;
  7. Article 48 of Decree Law No. 269/2003, converted, with amendments, into Law No. 326/2003, which establishes the procedure for fixing the price of medicinal products reimbursed by the National Health System; and
  8. Resolution No. 3/2001 of the Inter-ministerial Committee for Economic Planning setting forth criteria for the negotiation of prices of medicinal products.

III NEW DRUGS AND BIOLOGICS – APPROVAL, INCENTIVES AND RIGHTS

i Drugs

Approval pathways

As a general rule, under Italian law the approval pathway for new drug applications does not differ from that ordinarily envisaged for all medicines, according to Legislative Decree No. 219/2006 implementing Directive 2001/83/EC (the Pharma Code). That said, schemes for expedited approval and programmes to encourage the development of new drugs are available, as detailed below.

Under Italian law, there are two main routes for authorising medicines: a centralised route, governed by Regulation (EC) No. 726/2004 (i.e., the centralised authorisation procedure), and a national route, regulated by the Pharma Code, which in turn comprises three different authorisation procedures, namely the national procedure, the mutual recognition procedure and the decentralised procedure.

Pursuant to the centralised authorisation procedure, pharmaceutical companies submit a single marketing-authorisation application to the European Medicines Agency (EMA).3 The advantage of this procedure is to allow the marketing-authorisation holder to market the medicine and make it available to patients and healthcare professionals throughout the EU on the basis of a single marketing authorisation. Today, the great majority of new, innovative medicines pass through the centralised authorisation procedure to be marketed in the EU.4

To obtain a marketing authorisation through the national, mutual recognition5 or decentralised procedure,6 the applicant is always requested to submit an application meeting the conditions referred to in article 8 of the Pharma Code, which lists the key information and documents to be assessed by the competent regulatory authority (the Italian Medicine Agency (AIFA)). As better described in subsections ii and iii below, specific rules apply with respect to the assessment of applications for marketing authorisations concerning generic drugs and biosimilars.

Both the EMA and the AIFA charge fees for applications for marketing authorisation. Those due to the AIFA are established by the Decree of the Ministry of Health dated 6 December 2016. Said Decree also provides that, with respect to applications filed through the decentralised procedure where Italy acts as reference Member State, fees are increased by 20 per cent, whereas applications filed through the mutual recognition procedure where Italy acts as reference Member State benefit from a 80 per cent reduction. Fees are adjusted every year for inflation. Fee reductions and incentives are available for micro, small and medium-sized enterprises, designated orphan drugs, multiple applications on usage patent grounds and other classes of application.7

Schemes for expedited approval and programmes to encourage the development of new drugs

Over the past few years, priority regulatory programmes and fast-track procedures for the approval of innovative products have been adopted at the EU level with the purpose of making them quickly available to patients, and promoting research and development investments.

These include the 'accelerated assessment procedure', which is available for medicines of a major interest for public health and, in particular, from the viewpoint of therapeutic innovation, and reduces assessment time for marketing authorisation applications to 150 days or less (compared with the standard 210 days),8 and the 'conditional marketing authorisation', which applies to medicinal products for seriously debilitating or life-threatening diseases, including orphan medicines and medicines for emergency situations, and allows the earlier authorisation of drugs for patients with unmet medical needs, on the basis of less complete clinical data.9

In addition, both at the EU and national level, early access programmes allowing a drug to be available on the market before its official launch are also available. The most remarkable example of these instruments are 'compassionate use programmes', which provide for the use of unauthorised medicines that are expected to help patients with life-threatening, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with currently authorised medicines.10 Compassionate use programmes are coordinated and implemented by Member States, which set their own rules and procedures. In Italy, the Decree of the Ministry of Health dated 7 September 2017 allows the compassionate use of medicines for patients suffering from rare or life-threatening diseases, if no other valid therapeutic alternative is available; patients who have already been treated with clinical benefit in a similar clinical trial; or patients who cannot be included in a clinical trial.11

While EU regulatory support instruments focus on the approval process of medicinal products, at the national level, the Italian regulatory framework mainly provides for incentives and fast-track procedures for the pricing and reimbursement of innovative drugs.

In this respect, a first set of rules apply to medicines classified by the AIFA as 'innovative drugs'. Indeed, the designation of a medicinal product as innovative drug allows the access to specific funds established by the Budget Law of 2017. This piece of legislation introduced a fund of €500 million per year for innovative drugs and a fund of €500 million per year for innovative cancer drugs allocated by the Italian government to enable patients to benefit from free-of-charge treatments with these medicines.

Another fund for the reimbursement by the National Health System (NHS) of orphan drugs for the treatment of rare diseases and medicines not yet authorised that may offer the hope of treatment for specific and serious disease is that introduced by Law No. 326/2003. This fund is financed through the 50 per cent of the contribution that pharma companies must pay on a yearly basis and corresponding to the 5 per cent of the annual expenses for promotional activities incurred by the same companies.

In addition, Law No. 648/1996 allows the reimbursement by the NHS of innovative medicinal products marketed in other EU Member States other than Italy; investigational medicinal products not yet authorised; and medicinal products to be used for a therapeutic indication not covered by the relevant MA (i.e., off-label use), when there is not valid treatment alternative.

Other legal instruments supporting manufacturers of innovative drugs are those established by Decree Law No. 158/2012, converted with amendments into Law No. 189/2012, for orphan drugs and medicines having exception therapeutic relevance for which the pricing and reimbursement procedure can be started even before the granting of the relevant marketing authorisation. Said Decree also provides that, once authorised, these products can be immediately placed on the Italian marked pending the conclusion of the relevant pricing and reimbursement procedure, whose duration is also reduced from 180 to 100 days.

In Italy, innovative medicinal products, such as biological drugs, are also the subject of specific agreements (managed entry agreements) aimed at enabling marketing authorisation holders (MAHs) and payers to share the financial risk of the reimbursement of these new medicines due to uncertainty surrounding the introduction of new technologies. Managed entry agreements can be outcome-based, such as payment by results and risk sharing, or financial-based, such as cost-sharing agreements and capping.

Patent protection and exclusivity rights

After the marketing authorisation is granted, it shall have a validity of five years and may be renewed for an additional period of five years, on the basis of a new evaluation of the risk-benefit ratio to be carried out by the AIFA. To this end, the MAH shall submit an updated version of the marketing authorisation dossier covering all aspects relating to the quality, safety and efficacy. Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the AIFA decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

While normal patent protection runs for 20 years from the date when the request for patent protection is submitted, with the relevant holder being able to immediately exploit his or her product from a commercial standpoint, in the pharmaceutical sector manufacturers of medicinal products must first obtain the mentioned marketing authorisation to place their products on the market. Unfortunately, the scientific and technical efforts connected with the obtainment of said authorisation typically leads to delays of up to 12 years from the date of filing the request for patent protection until an authorisation is granted, with the consequence that the actual remaining period for the commercial exploitation of the patented medicinal product is generally reduced to eight years.

Thus, with the introduction of the supplementary protection certificate (SPC), a new system of supplementary patent protection was introduced for pharmaceutical products and compounds that are capable of being the object of protection (for more information on SPCs, see Section IV).12

Other exclusivity rights granted to the MAH of the originator drug are those provided for by data protection rules laid down in Article 10 of the Pharma Code. This Article establishes the principle that an applicant for a marketing authorisation shall not be required to provide the results of preclinical tests and of clinical trials if he or she can demonstrate that the concerned product is a generic of a reference medicinal product that is or has been authorised under Article 6 of the Pharma Code for not less than eight years in Italy or in the EU. A generic medicinal product so authorised shall not, however, be placed on the market until 10 years have elapsed from the initial authorisation of the reference product (market exclusivity); a clear reference to such a prohibition is included in the provision granting the relevant marketing authorisation.

This 10-year period can be extended to a maximum of 11 years if, during the first eight years of those 10 years, the MAH obtains an authorisation for one or more new therapeutic indications, which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies.

The Italian regulatory framework thus ensures a protection of the MAH's exclusivity right, which is parallel to, and does not necessarily coincide with, that granted by the patent regime, according to a mutual independence approach that excludes the patent linkage (as better described in Section IV).13

ii Generic and follow-on pharmaceuticals

Pursuant to the Pharma Code, a generic medicinal product is a medicinal product that has the same qualitative and quantitative composition in active principles and the same pharmaceutical form of the reference medicinal product, and whose bioequivalence with the latter has been demonstrated by appropriate bioavailability tests.

In other words, generic drugs are those medicinal products that, on the basis of predetermined, objective and measurable scientific and methodological criteria, can be regarded as equivalent, in terms of quality, safety and efficacy, to reference originator drugs developed and authorised following clinical studies that confirmed the relevant prerogatives. For this reason, Article 10 of the Pharma Code provides that generic drugs can be authorised through the simplified procedure described in subsection i above. As said, generic drugs so authorised cannot be placed on the market until 10 years have elapsed from the initial authorisation of the reference product, with possibility of extending said 10-year period up to a maximum of 11 years.

In this respect, under Italian law, the applicant for a marketing authorisation for a generic drug may carry out tests necessary for submitting the file before the end of the exclusivity period of the originator without this being regarded as an infringement of the rules on the protection of industrial and commercial property. Notwithstanding the foregoing, Article 11(1) bis, of Law Decree No. 158/2012, converted into Law No. 189/2012, provides that generic drugs shall not be reimbursed by the NHS before the expiration of the patent or supplementary protection of the originator.

Generic drugs do not benefit from exclusivity rights.

iii Biologics and biosimilars

A biological medicine is a medicine that contains one or more active substances made by or derived from a biological source. Some of them may be already present in the human body and examples include proteins such as insulin, growth hormones and erythropoietins. The active substances of biological medicines are larger and more complex than those of non-biological medicines. Only living organisms are able to reproduce such complexity.14

Biological medicines also include biotechnology-derived medicines whose active substances are developed by means of recombinant DNA technology, the controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes, including transformed mammalian cells and hybridoma, and monoclonal antibody methods15.

A biosimilar is biological medicine highly similar to another already approved biological medicine in the EU, for which marketing exclusivity rights have expired. Developers of biosimilars are required to demonstrate through comprehensive comparability studies with the reference biological medicine that:

  1. their biological medicine is highly similar to the reference medicine, notwithstanding natural variability inherent to all biological medicines; and
  2. there are no clinically meaningful differences between the biosimilar and the reference medicine in terms of safety, quality and efficacy.

Biosimilar development relies heavily on comparability studies to establish similarity to the reference product. This involves a comprehensive head-to-head comparison of the biosimilar and the reference medicine.16

In the EU, marketing authorisation applications for biotechnology-derived medicinal products, including biosimilars, are by law reviewed centrally by the EMA. The European Commission issues the decisions concerning the authorisation of these medicinal products on the basis of the scientific opinions from the EMA. The resulting marketing authorisation is valid in all EU Member States.17 Other biological medicinal products can also be authorised through the national, mutual recognition or decentralised procedure on the basis of the same scientific and regulatory standards required under the centralised procedure before the EMA.

Rights granted to biological medicines are those described in subsection i above.

IV PATENT LINKAGE

The expression 'patent linkage' generally refers to the practice of subordinating the marketing of generic drugs to the assessment, by the competent regulatory authority, that the product for which a marketing authorisation is sought does not infringe the intellectual property rights of any third party (patent or supplementary protection certificate).

Linkage mechanisms tend to be supported by those countries (mainly developing countries) where there are not early resolution mechanisms and an efficient judicial system. However, while patent linkage may be useful to prevent litigation between originators and generic drugs manufacturers, it is often used by the former as a defensive tool to delay the market entry of the latter and keep prices for their patented drugs higher for longer.

The EU does not support patent linkage mechanisms, mainly on the grounds that they are in contrast with the EU regulatory system and, in particular, with the scope of the EU Bolar exemption (European Directive 2001/83/EC, Article 10) according to which clinical trials for generics and biosimilar are exempt from infringement.

Italy does not recognise the patent linkage concept, although until 2012, the Italian Code of Industrial Property (CIP) included a specific provision preventing generic drugs manufacturers from starting the registration process for the relevant products before the last year of validity of the patent or supplementary protection.18

This provision was repealed by Law No. 27/2012, following the start by the European Commission, on 14 March 2011, of an infringement procedure for violation of the EU legislation on medicinal products. Since then, Italian legislation no longer prevents the manufacturer of a generic drug from starting the approval process and obtaining a marketing authorisation for the relevant drug pending the patent or SPC for the originator's product or active ingredient. On the contrary, Article 68 of the CIP expressly exempts from infringement studies and experiments (e.g., preclinical studies and clinical trials) and the subsequent practical activities, aimed at obtaining, also abroad, a drug marketing authorisation, whenever the relevant activity takes place.

In other words, as long as the generic or biosimilar drug manufacturer does not offer for sale or put on the market the generic product, or both, it is allowed to conduct any type of activity in preparation of the future commercialisation of the same, once the patent or SPC expires (the above-mentioned Bolar exemption).19

The rights of generics and biosimilar manufacturers have been further broadened by Regulation (EU) 2019/93320 (in force since 1 July 2019), which has introduced new exemptions to the exclusive right of an SPC holder (the SPC manufacturing waiver). Pharma companies established in the EU are now allowed to manufacture a generic or biosimilar version of a medicinal product protected by an SPC, provided that it is exclusively intended for export to a non-EU market where the patent protection has been expired or never existed, or storing medicinal products for a period of six months preceding the SPC expiry (including any related act that is strictly necessary for said making or storing), or both.

These new rules represent a significant revolution in the market for generic and biosimilar medicinal products as they offer a real opportunity for their manufacturers to increase the volume of their exports to third countries and be ready to enter the European market immediately after the certificate expires.

At the same time, Regulation (EU) 2019/933 provides also for clear safeguards to ensure transparency and avoid the possible illicit diversion onto the EU market of generics and biosimilars produced for export, including:

  1. notification requirement: companies intending to start manufacturing SPC-protected medicines for export shall notify the competent national patent authorities and SPC holders no later than three months before the start of the making in the Member State or no later than three months before the first related act, prior to that making;
  2. due diligence requirement: manufacturers shall inform their supply chain that the products in question are only for exporting or storing, or both, with a view to EU day-one entry on the market of a Member State upon expiry of the corresponding certificate; and
  3. labelling obligation: any export of SPC-protected products outside the EU will be subject to compliance with specific labelling requirements.

Finally, the SPC manufacturing waiver does not apply to those certificates that have already taken effect at the time the Regulation has entered into force, whereas it applies to those SPCs that were already applied for before the entry into force of the Regulation, but have not yet taken effect before that date, for which a transitional regime is provided.21

In conclusion, while makers of generics and biosimilars can still be sued by originators under Article 66 of the CIP22 if they offer for sale or undertake any preparatory sale act outside the scope of the Regulation (EU) 933/2019, the measure of the SPC manufacturing waiver should be energetically applauded by all the European generic and biosimilar industries for all the positive effects it is expected to generate, potentially increasing their competitiveness with manufacturers established in non-EU countries, not to mention the fact that it may also facilitate a faster availability of a wider choice of medicines at lower prices within the EU borders as soon as the relevant patent or supplementary protection expires.

V COMPETITION ENFORCERS

The Italian Antitrust Authority (IAA), which was established by Law No. 287/1990, is the competent authority to ensure the protection of competition and the market, through the supervision and repression of abuses of dominant position and agreements restricting fair competition. The IAA is endowed with powers to conduct specific investigations of alleged violations of competition law and general investigations also in the pharmaceutical sector. In the case of detected violations, the IAA can order interim measures to warn against the elimination of the violation and can impose fines of up to 10 per cent of the turnover of the sanctioned company. In addition, the IAA controls concentration operations, which for their relevance are subject to reporting obligations to the IAA, and may order their suspension or require specific conditions for their authorisation. Finally, the IAA may take legal action against public administration measures that infringe competition law.

Among the enforcement priorities in the pharmaceutical sector, the IAA focuses on co-marketing agreements, which are common to promote the sale and marketing of medicines. According to such agreements, two pharmaceutical companies agree to sell, concurrently and autonomously, the same product with different trademarks. However, said agreements may generate antitrust concerns if their effective use is a means of exchanging commercially sensitive information, fixing prices or achieving market sharing.

Furthermore, the IAA control focuses on the abuse of dominant position risk, which might occur if a company holding the patent unlawfully seeks to expand the scope of the right by preventing competitors from entering the market. To ensure the potentially pro-competitive function of the patent protection, the IAA intervenes against abusive uses of patents; for instance, if there is a misuse of the patent right with respect to the function for which it was granted to the detriment of competition.

The interplay between innovative companies and manufacturers of generic drugs constitutes another issue of greater interest for competition law in the pharmaceutical sector, also because of its implications on public expenditure. To mediate between the protection of industrial property rights and the competitive and efficient guarantee of right to health, the IAA must ensure that the transition from patent protection to the generic drugs' market entry is carried out in accordance with competitive principles. The first priority in this respect for the IAA is to ensure that there are no private agreements between originators and manufacturers of generics aimed at delaying full competition in the market and at gaining market share from the patent holder when the patent expires.23

Under this approach, according to the report of the European Commission on competition enforcement in the pharma sector published on 28 January 2019, the IAA resulted the most active authority within the EU in the period 2009–2017, having issued pecuniary sanctions to pharma companies totalling €198.5 million.24

VI MERGER CONTROL

The IAA is the competent authority to merger control assessing whether the concentrations, which for their relevance must be notified to the IAA itself pursuant to Article 16 of Law No. 287/90, lead to the constitution or strengthening of a dominant position endangering in a substantial and durable way competition in the national market.

In the Italian economical context, the IAA must balance the need, on the one hand, to avoid the operations of concentration leading to a structure in which high market shares concentrate in the hands of a few operators, and, on the other hand, the interest to promote growth of the many small and micro-sized enterprises. In light of this, the IAA tends to limit as much as possible its own interventions with regard to concentrations by imposing conditions or prohibiting operations only in cases where it is essential to protect competition in the relevant market.25

In the period 2007–2017, the IAA authorised with remedies 24 concentrations out of a total number of transactions requiring further investigation amounting to 46,100. In total, the IAA ordered the adoption of 147 measures in the 24 operations covered by its ex post assessment, with an average of about six measures per decision. Taking into consideration the relevant industries, the IAA imposed the higher number of remedies for concentrations in the retail distribution, insurance and banking sectors. Conversely, there were no relevant decisions concerning the pharmaceutical sector, whose merger operations normally have a transnational dimension and involve the European Commission.26

VII ANTICOMPETITIVE BEHAVIOUR

The two main drivers of competition in the pharmaceutical sector are product innovation through R&D and price. For this reason, the most important competitive dynamics entail the relationship between originators and manufacturers of generic drugs, which is often affected by anticompetitive behaviours ultimately aimed at hindering the market entry of generic drugs. In this respect, with the most recent landmark decisions, the IAA focused on abusive conducts and anticompetitive agreements.

In January 2012, the IAA sanctioned with a €10.6 million fine for abuse of dominant position holding that the dominant company (Pfizer) had abused patent protection for a certain medicine to achieve an undue extension of the exclusivity regime, delaying the entry into the market of generic medicines, which cost significantly less than the originators.27

In 2014, in the Lucentis Avastin case,28 the IAA sanctioned Hoffmann-La Roche and Novartis with a pecuniary fine amounting respectively to €90.6 million and €92 million, as they entered into an anticompetitive agreement aimed at discouraging and limit off-label use of Hoffmann-La Roche's oncology medicine for treatment of age-related macular degeneration. According to the IAA, the arrangement was intended to disseminate information raising concerns about the safety of Avastin used in ophthalmology to shift demand towards the more expensive Lucentis. The decision of the IAA was confirmed by the Council of State with its decision No. 4990 dated 15 July 2019.29

In the same year, the IAA investigated on the alleged conclusion of an anticompetitive agreement by Novartis and Italfarmaco that had been coordinating their activities for a three-year period in relation to tender procedures for the supply of a drug with a long-acting octreotide active ingredient. Although the IAA closed the case finding no infringement, the same had suspected that the two competitor companies had implemented bid-rigging practices to influence the outcome of tender procedures, in particular to fix prices and share the market between them. During the investigations, the IAA had focused on the effects of the co-marketing arrangement Novartis and Italfarmaco had entered into with the suspect it was a mean for a pervasive exchange of sensitive information between the two companies.30

In the Aspen case in September 2016,31 the IAA imposed a €5.2 million fine on Aspen for abusing its dominant position by setting unfair prices for important off-patent medicines used to treat cancer. The IAA found that Aspen abused its dominant position in Italy by threatening to initiate supply termination, imposing price increases of between 300 and 1,500 per cent and by applying particularly aggressive tactics towards the AIFA in negotiating these prices. The IAA decision was upheld by the Administrative Court of the Lazio Region.32 An appeal against this judgment is pending before the Italian Council of State.

Recently, in the covid-19 emergency, the IAA has intervened several times in relation to anticompetitive conducts of pharmaceutical companies. Specifically, on 17 March 2020, the IAA suspended the marketing of an antiviral drug sold for more than €600 and ordered the blackout of the related website.33

VIII OUTLOOK AND CONCLUSIONS

In its search for balance between innovation and quality, on the one hand, and control on public expenditure, on the other, the Italian legislator has put in place a complex legislative and regulatory framework that, while still protecting patent and exclusivity rights of developers of new drugs with the purposes of prompting investments in research and development, is also characterised by universal access to medicines and expenditure savings, connected with the availability of biosimilar and generic drugs. In this respect, the pharma business short and medium-term outlook seems encouraging, notwithstanding the impact of the covid-19 contingencies.

To make sure that all marketing opportunities offered by the Italian pharmaceutical sector are properly exploited and that patents and exclusivity rights are duly protected, both developers of originators and generics should take into account the IAA's incisive supervisory and enforcement activity aimed at detecting and repressing anticompetitive behaviours in this sector.


Footnotes

1 Roberto Cursano is a partner, Lorenza Mosna and Riccardo Ovidi are associates, and Irene Carlet is a legal trainee at Studio Professionale Associato a Baker & McKenzie.

2 Italian Association of Pharmaceutical Companies, Report on the pharmaceutical industry in Italy, 2019, www.farmindustria.it/documenticategory/i-numeri-dellindustria-farmaceutica-in-italia/.

3 The centralised procedure is compulsory, among others, for: (1) human medicines containing a new active substance to treat HIV, AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases; (2) medicines derived from biotechnology processes, such as genetic engineering; (3) advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines; and (4) orphan drugs (medicines for rare diseases). It is optional for other medicinal products: (1) containing new active substances for indications other than those stated above; (2) that are a significant therapeutic, scientific or technical innovation; and (3) whose authorisation would be in the interest of public health at EU level.

4 Pursuant to the centralised procedure, the EMA's Committee for Medicinal products for Human Use carries out a scientific assessment of the application and gives a recommendation on whether the medicine should be marketed. However, the EMA has no authority to actually authorise marketing in the different EU countries since, under EU law, the authorising body for all centrally authorised product is the European Commission, which takes a legally binding decision based on the EMA's recommendation. Once granted by the European Commission, the centralised marketing authorisation is valid in all EU Member States as well as in the European Economic Area countries Iceland, Liechtenstein and Norway. Commission decisions are published in the Community Register of medicinal products for human use.

5 The mutual recognition procedure, which is applicable to the majority of conventional medicinal products, is based on the recognition of a pre-existing national marketing authorisation by one or more EU countries. To be eligible for the mutual recognition procedure, a medicinal product must have already received a marketing authorisation in one EU country. An application for mutual recognition may be addressed to one or more EU countries. The applications submitted must be identical, and all EU countries notified. The country charged with evaluating the application or reference Member State notifies the other concerned Member States. The reference Member State is then charged with deciding on the product. This evaluation process may take up to 210 days, and ends with the granting of a marketing authorisation in that EU country. The concerned Member States then have 90 days to recognise the decision of the reference Member State, and the summary of product characteristics (SPCs), labelling and packaging. National marketing authorisations are granted within 30 days.

6 The decentralised procedure applies to situations where the application for marketing authorisation is submitted simultaneously in several EU countries and allows its common assessment. It can be used for medicinal products that do not need to be authorised via the centralised procedure and have not already been authorised in any Member State. Pursuant to this procedure, one of the Member States takes the lead in evaluating the application as reference Member State. Within 120 days of the receipt of a valid application, the latter develops a draft assessment report, SPCs, labelling and package leaflet and forwards the same to the other (concerned) Member States who then have 90 days to express their approval. At the end of the procedure, each Member State who approved the documentation developed by the reference Member State shall issue a marketing authorisation. The advantage of this procedure is that the applicant may obtain the requested marketing authorisation simultaneously in several Member States without having to hold a prior marketing authorisation granted by another Member State.

9 Conditional marketing authorisations are valid for one year and can be renewed annually. The marketing authorisation holder is required to fulfil specific obligations (ongoing or new studies, and in some cases additional activities) with a view to providing comprehensive data confirming that the benefit-risk balance is positive. Once comprehensive data on the product have been obtained, the marketing authorisation may be converted into a 'standard marketing authorisation', which is initially valid for five years and can be renewed for unlimited validity. Medicines for human use are eligible if they are aimed at treating, preventing or diagnosing seriously debilitating or life-threatening diseases.

10 The medicine must be undergoing clinical trials or have entered the marketing-authorisation application process and while early studies will generally have been completed, its safety profile and dosage guidelines may not be fully established.

11 Pursuant to the Decree of the Ministry of Health dated 7 September 2017, a request for compassionate use can be filed by the responsible physician provided that: a phase III clinical trial on the investigational medicine is undergoing (in exceptional cases it is allowed to provide medicines for which a phase II or phase I trial has been completed); the requested medicine is already authorised for indications other than those required by the patient (off-label use); and the medicine, although duly licensed, is not yet available in Italy. Compassionate use programmes must be notified to the AIFA and expire as soon as the medicine is placed on the market. The Italian Council of State, with its Opinion No. 2356/2016, stated that, even though the relevant medicine has already been placed on the market, patients can benefit from free-of-charge compassionate use until the reimbursement agreement has been approved.

12 Giuseppe Franci Ferrari, Fausto Massimino 'Diritto del Farmaco. Medicinali, diritto alla salute, politiche sanitarie', Cacucci Editore.

13 Giuseppe Franci Ferrari, Fausto Massimino 'Diritto del Farmaco. Medicinali, diritto alla salute, politiche sanitarie', Cacucci Editore.

18 Article 68.1 bis CIP: 'companies intending to manufacture medicinal products outside patent protection may start the registration procedure for the product containing the active ingredient one year prior to the date of expiration of the supplementary protection or, in the absence, of the patent protection of the active ingredient, having regard to any possible extension'.

19 Italian case law dealing with cases where originators tried to enforce their rights at the stage of obtaining marketing authorisations by generic companies (mostly issued before the repealing of Article 68.1 bis CIP) is quite well-developed. Since the famous Roche Products Inc v. Bolar Pharmaceutical Co decision, Italian courts (with few exceptions) have agreed that preclinical tests and clinical trials aimed at obtaining the marketing authorisation for generic drugs are permitted under the Bolar clause, regardless of the prohibition set forth by (the now repealed) Article 68 Paragraph 1 bis CIP. In particular, the Court of Milan, on 11 June 2009 in Eli Lilly and Company Ltd and Eli Lilly Italia Spa v. Sandoz International and others, following the interpretation of Article 68 CIP adopted in other decisions by the same court, stated that the mere filing of a request for marketing authorisation for a generic drug, lacking any actual proof of the commercial exploitation of the same, is not sufficient per se to ground a patent infringement claim. In fact, the filing of a request for (and even the subsequent obtainment of) the marketing authorisation does not necessarily indicate a certain time for market entry. According to the court, the principle set forth by Article 68.1 CPI (the Bolar exemption) overcomes the (one-year) limit imposed by Article 68.1 bis CIP. In this respect, the court clarified that only the actual undertaking of specific preparatory activities for the manufacturing and commercialisation of a generic product – such as the purchasing or production of the active ingredient, the storage of the product, the set up of an actual distribution network on the territory or the launch of a promotional campaign – may amount to patent infringement. In the Sanofi v. Teva Pharma case, the same Court of Milan uphold the originator's request for a preliminary injunction against a generic product that had already obtained market approval. The decision was issued after the repealing of Article 68.1 bis CPI. The Court of Milan found that the activities carried out by the defendant in addition to the registration process for the generic product – namely the publication on the Official Gazette of the price of the generic drugs, the communication to the database service provider ADF Service of the intention to start selling the generic drugs, for the purpose of including the product into the Pharma database, and the inclusion of the drug into the transparency list held by the Italian Medicine Agency – clearly represented infringing preparatory activities suitable to cause a prejudice to the originator, both in terms of customers distraction and economic damages due to the reduction of the reimbursement allowed by the NHS.

20 Regulation (EU) 2019/933 of the European Parliament and of the Council of 20 May 2019, amending Regulation (EC) No 469/2009 concerning the supplementary protection certificate for medicinal products.

21 According to the Whereas (26) of the Regulation 'it is justified that this Regulation also cover, over a certain period of time, a certificate that was applied for before the date of entry into force of this Regulation, but has not yet taken effect before that date, irrespective of whether or not that certificate was granted before that date. The exception should apply, therefore, from 2 July 2022 to a certificate that takes effect from the date of entry into force of this Regulation. The concept of 'certain period of time' for each individual certificate that takes effect after the date of entry into force of this Regulation should ensure that the exception is applied, on a progressive basis, to such a certificate, depending on the date on which it takes effect and on its duration. Such application of the exception would allow the holder of a certificate that has been granted, but that has not yet taken effect by the date of the entry into force of this Regulation, a reasonable period of transition to adapt to the changed legal context, while at the same time ensuring that makers of generics and biosimilars can benefit effectively, without excessive delay, from the exception'.

22 According to Article 66 CPI, the acts of producing, using, placing on the market, selling the product that is the subject matter of a patent or importing such a product for the aforementioned purposes; and using a process that is the subject-matter of the patent or offering, placing on the market, selling a product that is produced directly by a process that is the subject-matter of the patent, or importing such a product for the aforementioned purposes, are reserved to the right holder.

23 F. Massimino, G. F. Ferrari, Diritto del Farmaco. Medicinali, Diritto alla Salute, Politiche Sanitarie, Cacucci ed., Bari, 2015, 347-354; C. Rabitti Bedogni in the Minutes of the I Italian Antitrust Association Convention, I principali sviluppi nel diritto della concorrenza comunitario e nazionale, Sorrento, 20-21 May 2011; Commission Communication, of 8 July 2008, Executive Summary of the Pharmaceutical Sector Inquiry Report, available at http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/communication_en.pdf.

24 EU Commission, Report on Competition Enforcement in the Pharmaceutical Sector (2009-2017), available at https://ec.europa.eu/competition/sectors/pharmaceuticals/report2019/report_en.pdf.

25 IAA, Annual Report, published on 31 March 31 2019, p. 45, available at https://www.agcm.it/dotcmsdoc/relazioni-annuali/relazioneannuale2018/Relazione_annuale_2019.pdf.

26 IAA, Annual Report, published on 31 March 31 2019, p. 45, available at www.agcm.it/dotcmsdoc/relazioni-annuali/relazioneannuale2018/Relazione_annuale_2019.pdf.

27 The IAA Decision of 11 January 2012; www.agcm.it/media/comunicati-stampa/2012/1/alias-5857.

28 The IAA Decision of 27 February 2014; the relevant press release of the IAA is available at www.agcm.it/media/comunicati-stampa/2014/3/alias-6801.

29 Judgment No. 4990 of the Council of State of 15 July 2019.

30 The relevant press release of the IAA is available at www.agcm.it/media/comunicati-stampa/2014/2/alias-6744.

31 The IAA Decision of 29 September 2016; the EU Commission Report on Competition Enforcement in the Pharmaceutical Sector (2009-2017) makes reference to this case as well, available at https://ec.europa.eu/competition/sectors/pharmaceuticals/report2019/report_en.pdf.

32 Judgment of the Regional Administrative Court of the Lazio Region of 26 July 2017.

33 The relevant press release of the IAA is available at https://en.agcm.it/en/media/press-releases/2020/3/PS11723.