Off-label uses of pharmaceuticals: News from Italy

A smiling
Silvia Scalzini ...

As patent law aficionados may know, this Kat is not the ultimate commentator on patent law and life sciences matters. However, she has recently been informed of interesting developments in the regulation of off-label uses of pharmaceuticals in her native land, ie Italy.

Katfriend with a crush on life sciences Silvia Scalzini (PhD candidate, Scuola Superiore Sant'Anna, Pisa, Italy) explains what they are all about: 

"Off-label uses of pharmaceutical drugs are currently at the centre of heated discussion in Italy. Off-label uses are those uses for which drugs have not been officially approved by drug regulators, eg different therapeutic indications, patient age range or dose instructions [this explanation was vital to this Kat to understand what Silvia was talking about]. Off-label uses frequently concern well-known compounds for which “scientific evidence suggests their rational use in clinical situations that have not been approved from a regulatory point of view”.

According to Italian law, off-label uses of pharmaceuticals are permitted but very limited, especially if there are alternative approved drugs available for the same treatments. In essence, off-label uses are only allowed (and their price is covered by the National Health Service - NHS):

·    In the absence of an approved therapeutic alternative;

·    In the event of favourable results from phase II clinical trials; or

·    After inclusion by the Scientific Technical Committee of the Italian Medicines Agency (IMA) in a specific list.

Thus it may happen that some off-label uses of pharmaceuticals, that are effective, safe and cheaper than the alternative approved drugs, are de facto limited (or hindered), with resulting harm to the public interest in terms of access to therapies and high costs for the NHS.

... And a slightly less confident copyright Kat
when she is informed that her car
is actually heading
to a life sciences symposium

This problem has been highlighted in a recent decision by the Italian Competition Authority (ICA) in Case I760 Roche-Novartis/Farmaci Avastin e Lucentis. 

The ICA fined Roche and Novartis for over EUR180m, on grounds that they had created a cartel for the sale of two major ophthalmic drugs, Avastin and Lucentis. According to the ICA, the two companies put in place a “complex collusive strategy” in order to exclude cheaper drug Avastin (approved for treating some forms of cancer and used - off-label - in the ophthalmic field) from the market, so to “channel demand towards the much more expensive drug Lucentis”.

Avastin was developed by Genentech, a subsidiary of Roche, and commercialised by Genentech (in the US) and Roche (outside the US), pursuant to a commercialisation agreement between the two undertakings.

Despite the widespread off-label use of Avastin for ophthalmic purposes, neither Genentech nor Roche have ever applied to register a therapeutic indication in this field. Genentech later developed Lucentis, (which contains “an active substance similar to Avastin’s”), specifically intended for ophthalmic use.

Did you say cartel or Kartell?

By virtue of a license and collaboration agreement, Lucentis is marketed by Genentech (in the US) and by Novartis (outside the US).

Because valid alternative approved drugs for the same treatment exist and evidence was published to challenge the ophthalmological use of Avastin, off-label use of Avastin has been progressively limited.

This happened despite independent comparative studies supported the equivalence of the two drugs in ophthalmic uses.

The ICA found that Roche and Novartis colluded “to create an artificial product differentiation and purport Avastin as more dangerous than Lucentis, in order to influence prescriptions of medical doctors and health services” to maximise their profits. Indeed, while Novartis benefited directly from Lucentis’ sales, Roche also received significant royalties through its subsidiary Genentech.

According to the ICA, this cartel prevented several patients from accessing the treatment and resulted in additional expenses for the NHS.

In the wake of this decision, on 20 March 2014 the Italian Government issued a Law Decree to reform the rules for off-label uses of pharmaceutical drugs, and also improve the overall efficiency of the system.

The decree provides – within certain budgetary constrains – for the possibility of an ex officio registration of therapeutic indications that were not included in the original marketing authorisation for a drug for which, however, there is a “justified public interest” in its use.

According to the decree, where such a “justified public interest" is found, the IMA can inform the marketing authorisation holder (ie the patent holder or his successor in title) that it is possible to choose one of the following options:

·    To assign the rights on such indication to the Ministry of Health for free for the sake of the “ex officio” registration process;

·    To proceed directly at its own expense to the registration of the indication, but defining the terms and mode for the pivotal studies relating to the registration in agreement with IMA;

·    To object the registration of the indication in question.

If the rightholder does object and the objection is not justified, the IMA will give “adequate information” of such objection on its institutional website.

According to Italian Minister of Health Beatrice Lorenzin, these rules are “respectful of phase II clinical trials, designed to protect patients, respectful of the industrial property rights of the companies and effective in allowing IMA temporarily to allow the off-label use of a drug even before the conclusion of the second level of testing".

However, despite the Minister’s efforts to balance different interests, the decree raises some questions that should be clarified when this is transposed into law [this must happen within 60 days from the publication of a law decree into the Gazzetta Ufficiale]:

1.   What does “justified public interest” mean in regard to off-label uses of drugs? What criteria should be adopted for determining it?

2.   In case of an “unjustified” objection to the registration of the therapeutic indication by the rights-holder, what does “adequate information on the institutional website of the IMA” mean? And would this rule have the desired effect of encouraging the rights-holder to proceed (directly or indirectly) to the registration of an off-label indication (for which it previously had no commercial interest)? Would other measures be more effective?

To know how this delicate balance between public and private interests will be managed, we will have to await the outcome of Parliamentary debate on transposition of the decree into law."