Europe: Putting Off Off-label Decisions

When in doubt, commission a study. This well-known tactic has come to the rescue of the European Union once again in the face of renewed controversy over off-label prescribing of medicines. EU officials are now pondering who they should nominate to provide a study on the subject, and a decision is expected shortly. The envisaged starting date for the study is the first quarter of 2015 and it is anticipated that the study will be finalized in 2015. All of which provides the EU with a perfect excuse for doing nothing in the interim about off-label prescribing.

That isn't going to satisfy the research-based industry. Companies with innovative products have been fulminating for years about the risks - risks to public health, they like to say, although they also add, sotto voce, risks to profits. They went on the offensive early this year with a joint demand to the European Commission for urgent action against Italy, where voce has not been at all sotto in an epic clash that has developed over health ministry recommendations that a cheap cancer drug should be used instead of an expensive eye drug. The product at the centre of the complaint is Roche’s cancer medicine Avastin, which the Italian health ministry has been reimbursing since last summer for use as an eye treatment, in preference to the more expensive Lucentis from Novartis. Italy is ignoring EU medicines rules and its action “undermines key elements of the EU pharmaceutical regime, in particular the marketing authorization system”, says the complaint, which has been put together by the European Federation of Pharmaceutical Industries and Associations, EuropaBio representing biopharmaceuticals, and Eucope - the European Confederation of Pharmaceutical Entrepreneurs, which represents a number of mid-sized innovative pharmaceutical companies.

They argue that the Italian measures, introduced just over a year ago, “are based on budgetary considerations that should never overrule the protection of public health”. They point to a procedure for listing certain off-label uses of medicines that can then be reimbursed, based on, amongst other criteria, cost control considerations. And they cite a judgement by the European Union's highest court that prohibits member states from reverting to off-label use as a cost-containment measure in cases where approved alternatives exist. But the Italian courts have taken a different view: just over a year ago, they fined the two companies more than $200 million for collusion in seeking to protect profits from Lucentis by opposing off-label prescribing of Avastin. The Italian approach is strongly defended by European consumers, who instigated the Italian court case: national health authorities should intervene to protect overriding public health interests, they insist - including protecting the public purse.

The industry call for action has wider implications than merely putting a stop to leaks in Italy's application of EU drug rules. "Similar practices occur more and more in other member states, through therapeutic recommendations or by setting budgets for specific medical procedures at levels that de facto impose off-label use of medicines or the use of unapproved medicines instead of authorized products," says the complaint. If this is allowed to go on unchecked, research and development of new medicines will be discouraged. EFPIA already publicly criticized an announcement by the French government that it intended to enlarge the use of-off label drugs for economic reasons. Last July the industry association said the plan was in effect creating "secondary national marketing authorizations" and "could potentially put patients at risk". And only weeks ago, a Spanish official proudly displayed to European colleagues in the latest EU committee on drugs, known as STAMP, the rules in Spain that allow off-label use.

This is just some of the background to the impending study on off-label use. But the confrontation is not just between a couple of rogue member states (backed by consumers) and the industry. There is hardly any agreement at all among European regulators on the subject. Or indeed between EU institutions. More than a year ago, the European Parliament adopted a resolution on patient safety that called for specific action regarding the off-label use of medicines. It urged the European Medicines Agency to "draw up a list of off-label medicines which are used in spite of there being an approved alternative", and said it should "develop guidelines on the off-label use of medicines, on the basis of medical need and taking account of patient protection".

The European Commission, which is responsible for seeing that EU laws are complied with (and for proposing new laws where they are needed), responded to the Parliament with caution: "Although EU legislation regulates marketing authorizations of medicinal products, it does not specifically regulate the off-label use of medicinal products," it pointed out. So "the issue of off-label use of medicinal products is complex and deserves consideration" - and while it grudgingly acknowledged that EMA "could be an important player", it warned that an EMA list of medicines used off-label might not be representative. "Not all member states have the same approved medicinal products on their market", the Commission remarked, and some countries have already developed their own recommendations and guidelines for off-label use. Consequently, the call for action by EMA "would be premature”.

So a study is a much better idea. It solves nothing, but it satisfactorily puts off any obligation to act until well after the study has delivered its findings. For a Commission that is hesitant to provoke further resistance in the health arena from member states (who have already shot down two recent Commission proposals - one on information to patients, and the other on drug pricing and reimbursement mechanisms), a study is a very respectable solution. All the more so since it will have a wide scope.

It will look from the scientific perspective at public health aspects, and in particular patient safety. But it will also look at the legal questions relating to the regulatory framework. It will gather information - eminently safe as an initiative. The study should "systematically consult the members state authorities and stakeholders (patients, healthcare professionals and industry)" on current practices, the drivers for off-label use (essentially, the availability of duly authorized products, and their cost), and measures in place to ensure patient safety. And the information collected will serve "to identify if there is a need for coordination at EU level and, if so, possibly, to what extent", according to a summary of the preparatory reflections among senior EU officials. As a double safety-catch on having to take action, the preparations explicitly noted that "We do not intend to be conclusive at this stage regarding the definition of off-label use", and the consultant chosen will be expected to extend or modify the working definition. That should all keep everyone busy until the end of this year - obviating any stress among officials over the ongoing controversy.

The current Commission position is comfortably hands-off on the question. EU legislation on medicines does not regulate off-label use. "It is the marketing authorization that defines the approved indications", say Commission officials. "Any departure from those terms will remain, in most member states, the responsibility of the prescribing physician". In other words, don't come to us. If you've got a problem, talk to the member states. And if member states have a problem, then they will have to talk to doctors. But leave us alone. We've started a study. What else do you want?