Out-Law Analysis 5 min. read

Recent ruling in France and EU study highlight tensions around 'off-label' use of drugs, says expert

ANALYSIS: A recent ruling in France and the publication of a new EU study highlight the tensions that exist around the 'off-label' use of drugs.

'Off-label' use of drugs refers to the prescription of medicines by doctors for different treatments than those they were originally intended for. Within the EU, only France, Italy and Denmark specifically govern off-label use of drugs in national law, although off-label use of drugs is prevalent in other parts of the trading bloc.

The European Commission recently published a study into the off-label use of medicinal products in the EU (193-page / 1.99MB PDF). According to the study, off-label use of drugs across the EU varies in prevalence, but that doctors often turn to off-label prescriptions to treat a variety of conditions in children and adults where there is "unmet medical needs", including orphan diseases, cancer and arthritis.

The study highlighted that a main advantage of off-label use of drugs is that it can provide patients with access to innovative treatments, often at lower cost than other drugs licensed for treating the conditions patients are experiencing.

However, legitimate concerns about patient safety and the potential liability of doctors, health bodies and drugs manufacturers stemming from off-label use of medicines were also flagged in the study.

One of the most prominent disputes that has arisen over the use of drugs off-label concerns how Roche's anticancer drug Avastin has been prescribed to help treat the eye disease 'wet age-related macular degeneration' (AMD). The case was specifically referred to in the EU study, which was published just a few days after a French ruling was issued on the legitimacy of the use of Avastin to treat AMD.

The Avastin case in France

In 2015, the agence nationale de securité du médicament et des produits de santé (ANSM), the body responsible for assessing the risks of medical products, issued a 'temporary use recommendation' (RTU) to allow doctors to prescribe Avastin to treat AMD.

The French Code of Public Health authorises off-label use provided that certain conditions are met.

Off-label use is permitted under the code so long as there is no other product with the same active substance, same dosage and pharmaceutical form benefitting from a marketing authorisation or an RTU in existence in France, provided that an RTU for the off-label use has been issued by the ANSM and that the doctors consider that the use of said product is necessary to improve or stabilise the patient's conditions.

The ANSM decision on off-label use of Avastin was taken after Roche had been given authorisation to market Avastin to help in the treatment of cancer and despite the fact that other licensed drugs existed on the market designed to treat AMD.

One of the alternative licensed drugs is Lucentis 10mg/ml, which is manufactured by Novartis. Novartis owns a stake in Roche.

Novartis and Roche have claimed that the risk of infection is greater in the use of Avastin to treat AMD as a result of the repackaging of Avastin vials into syringes to treat AMD. However, off-label use of Avastin to treat AMD has reported cost benefits for the French government when compared to the cost of prescribing Lucentis to treat AMD.

Novartis and Roche challenged the decision by the ANSM to issue an RTU for Avastin to be used in the treatment of AMD before the French State Council. It claimed misuse of authority by the ANSM in the hope of both revoking the RTU and taking the case before the Court of Justice of the EU (CJEU) for a determination of whether the RTU issued complied with EU law, specifically an EU directive containing rules on medicinal products for human use, and an EU regulation on procedures for the authorisation and supervision of those medicinal products.

However, on 24 February the French State Council upheld the ANSM's decision to award the RTU for Avastin.

The French State Council's ruling

With its decision, the French State Council confirmed a number of points that relate to the issuing procedure of an RTU, the legality of the provisions on which the RTU is based, and also highlighted steps doctors must take if seeking to use drugs off-label.

Among its findings, the Council said that French law does not require marketing authorisation holders to be consulted before an RTU for one of their products is issued. It said, however, that Novartis Pharma and Novartis Europharm had been notified of the prospective RTU and that relevant commissions and work groups within the ANSM had been properly consulted and provided their assessment on the benefits and the risks of the use of Avastin for the treatment of AMD. The Council further confirmed that every necessary step to be taken to ensure the safe use of drugs does not need to be run past the European Medicines Agency (EMA).

The Council said that the European Commission had been properly notified of the technical rules related to the use of a drug within an RTU in the Avastin off-label case, in line with the requirements of EU law.

The Council also confirmed that the conditions in the French Code of Public Health that need to be satisfied before an off-label RTU can be issued are in line with EU law.

The Council considered the fact that Novartis had been granted marketing authorisation for Lucentis as proprietary medicine in 2014 which prevented the commercialisation of a generic drug equivalent for at least 10 years. However, it said that that fact did not prevent the extension of the therapeutic indication of Avastin which already benefited from marketing authorisation, even though the extension would put Avastin into competition with Lucentis.  

In its ruling, the Council said that the issuing of an RTU does not exempt doctors from having to demonstrate that the off-label prescription of Avastin is essential for the improvement and stabilisation of a patient with AMD.

The Council said RTUs must be targeted at the specific needs of patients and are not designed to encourage drugs to be prescribed outside of the scope of their marketing authorisation in general cases.

The issue of reimbursement was also considered by the Council, as Avastin is subject to reimbursement in France and is available at a lower price than Lucentis. It stressed, however, that economic factors are irrelevant in determining whether an RTU for off-label use should be issued. The prescription of Avastin for AMD, it said, is subject to the specific therapeutic conditions of the patient.

The Council also said that RTU in dispute before it is in place for three years from the time it was issued and can only be renewed after evaluation of updated data concerning the effectiveness and presumed security of off-label use of the Avastin.

Could off-label drug use be governed differently in future?

The European Commission's study explored the potential measures that could be introduced to change the way off-label use of drugs is governed in future.

One option considered was whether the evidence that can be relied upon to inform the marketing authorisation of off-label indications could be expanded beyond industry-based 'randomised controlled trials'.

EU-wide guidance on off-label use could also be developed, it said, to inform how each EU country addresses off-label use within their own national frameworks. It also said new incentives could be introduced to encourage drugs manufacturers to broaden the scope for which their own drugs could be used, after determining that there is little reason why pharmaceutical businesses would do that currently.

Other options looked at measures which could be introduced at healthcare system level or doctor-patient level. They included requiring doctors to obtain permission from a health authority to prescribe drugs off-label, where the authority would "evaluate the evidence on efficacy and safety". In addition, the study suggested the information available to patients about off-label use of drugs could be improved.

Virginia de Freitas and Emmanuel Gougé are experts in life sciences at Pinsent Masons, the law firm behind Out-Law.com.

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