The case arose from the reimbursement by the Italian authorities of medicinal products used for an indication for which they are not authorised, in circumstances where there is an alternative authorised product available. Italian law permits the reimbursement of such products “provided that the [unlicensed] indication is known and is in line with research conducted by the national and international medical-scientific community on the basis of economic and suitability considerations”. In these cases the Italian Medicines Agency (AIFA) puts in place monitoring arrangements intended to protect patient safety.
Avastin® (bevacizumab), which is licensed for administration by intravenous infusion for various oncology indications, was added to the Italian reimbursement list in 2014, for intravitreal injection in the eye for the treatment of ophthalmology conditions, on the following conditions:
- To ensure sterility, packaging of bevacizumab in single dose syringes must be carried out solely by hospital pharmacies satisfying defined requirements and following rules to ensure the doses are properly prepared.
- The product can be administered only by highly specialised ophthalmological departments in designated public hospitals.
- Administration may take place only once the patient has signed an informed consent, including the scientific reasons, accompanied by adequate information about the existence of approved alternative therapies at higher cost to the Italian health service.
- A monitoring record must be created with an adverse reactions declaration form.
Novartis Farma challenged the inclusion of Avastin® in the reimbursement list on the basis that this was incompatible with EU pharmaceutical law. In particular: (i) the general use of medicinal products “off-label”, for financial reasons, in circumstances where the suitability of the licensed product for such use has not been tested, breaches the mandatory character of a marketing authorisation (MA) under Art 6 of Directive 2001/83/EC and is incompatible with Directive 89/105/EEC (the Transparency Directive); (ii) by allowing AIFA to establish monitoring mechanisms to safeguard patient safety, Italian law permits AIFA to encroach on the role of the EMA as established by Regulation No 726/2004; and, (iii) the repackaging of Avastin® does not comply with the conditions required for the exemption under Art 3.1 of Directive 2001/83/EC to apply.
The Italian Court referred four questions to the CJEU.
The CJEU repeated the finding made in F. Hoffmann-La Roche and Others, C‑179/16, that EU medicines rules do not prohibit off-label prescription or repackaging for such use, but do require that such activities comply with the conditions laid down in those rules.
The CJEU therefore answered the questions
- Art 3(1) of Directive 2001/83/EC (as amended) must be interpreted as meaning that Avastin® after being repackaged according to the conditions laid down by Italian law falls within the scope of the Directive (i.e. the exemption under Art 3.1 does not apply).
- Art 6 of Directive 2001/83/EC does not preclude national measures such as those established in Italy, which lay down conditions under which Avastin® may be repackaged in order to be used for the treatment of ophthalmological indications not covered by its marketing authorisation.
- In view of the response to the previous question, the Court found that it had no need to consider whether the supply of an unlicensed medicine was contrary to the requirements of Directive 89/105/EEC (the Transparency Directive).
- Arts 3, 25 and 26 of Regulation No 726/2004 must be interpreted as not precluding national measures such as those established in Italy, which authorise AIFA to monitor medicinal products such as Avastin®, the off-label use of which is reimbursed by the national health system and, where relevant, to introduce measures necessary to safeguard patient safety.