The recent ruling (21 November 2018) of the European Court of Justice puts an end to the dispute over the off-label use of bevacizumab for age-related macular degeneration.
Below is a short summary which reconstructs the facts regarding the use of two monoclonal antibodies against vascular endothelial growth factor (bevacizumab and ranibizumab) in treating the disease.
Bevacizumab is produced by Roche and has been authorised for oncological treatment for some types of tumour, although it is also used off-label for retinal macular degeneration, after being removed from the original vial and dispensed into single-use syringes for intravitreal injection.
Ranibizumab has been authorised as indicated both for oncological and for ophthalmic use and is available in packs that are adapted for use. It is produced by Novartis, which also owns a portion of Roche's shares. In 2014 the Italian Competition (Antitrust) Authority established an agreement between the two companies to encourage the use of ranibizumab (which is 30 times more expensive than bevacizumab) and hit the two companies with a penalty of 180 million euros.
There is a large amount of data in the literature that clearly documents the equivalence of bevacizumab to ranibizumab (e.g. the CATT, IVAN, MANTA, GEFAL, LUCAS, BRAMD, VIBERA studies), although Roche has never asked for bevacizumab to be indicated for macular degeneration. In Italy, law 648/96 allows the off-label use and redeemability of drugs that have valid evidence of efficacy and safety. Hundreds of drugs are prescribed on the basis of this law, and even bevacizumab was included in these lists. In September 2012, when many data on the efficacy and safety of bevacizumab were already known, AIFA (the Italian Medicines Agency) excluded bevacizumab from 648. This measure appears to be in contrast with the WHO attitude, which in 2013 included bevacizumab as the only drug for intravitreal indications in the 18th list of essential drugs, and also contrasts with the position of the European Medicines Agency (EMA), which in August 2012 stated that “... the CHMP agreed that detailed safety information provided from the CATT and IVAN studies is reassuring and no evidence can be provided that bevacizumab is systematically more unsafe than ranibizumab and vice-versa”.
Following the dispute arising from requests for the intravitreal use of bevacizumab, the 648 rule was further specified. Thus, it is now possible to prescribe an off-label drug, even where there is a therapeutic alternative with an approved indication: “Even if there is another therapeutic alternative in the field of authorised medicines, after evaluation by AIFA, medicines that can be used for a therapeutic indication other than the authorised one are included in the list (of Law 648/1996), with consequent expenditure by the Italian Health Service, provided that such indication is known and conforms to research conducted within the national and international medical-scientific community, according to parameters of economy and appropriateness” (Article 3 Law 79/2014).
Thus, in 2014, AIFA included bevacizumab for the treatment of senile macular degeneration in the list of drugs provided by the Italian National Health Service and approved its packaging to authorised pharmacies. But this is not the whole picture. Novartis considered that this act of AIFA favoured the use of Avastin® not in line with the marketing authorisation (AIC) and filed a lawsuit against the regional authorities, against AIFA, and (sic!) against Roche.
The Council of State addressed the European Court of Justice to settle the matter.
The European Court of Justice stated in the ruling that competence for the organisation and management of health services, in setting the prices of medicines and taking over the financial burden of national health systems is the responsibility of the Member States and that the taking over by the National Health Service of a medicine used off-label does not contravene the law of the European Union. It also stated that European Union law does not prohibit the prescription of a drug for off-label use nor its repackaging for such use, in fact authorising the repackaging of Avastin®, which is less expensive.
However, it has subordinated the packaging and the ophthalmic use of Avastin® to some conditions: individual prescription, dispensing and packaging by an authorised pharmacy in view of hospital administration, in order to ensure that no chemical changes are caused affecting the physical properties of the drug.
Finally, the Court pointed out that the pharmacovigilance system also extends to any off-label use and that, being a biotechnological drug, pharmacovigilance is exercised by the competent national authorities (AIFA for Italy) and by the EMA. Beyond the judicial litigation, the important thing regarding this issue is that the fundamental issue on the basis of which measures must be adopted, even the regulatory ones on off-label uses, is that of scientific evidence, in the exclusive interest of patients.