Off-Label Use: It's Complicated!

No way of cutting through the Gordian knot of off-label prescribing in Europe, according to a study just out in Brussels. "It's complex," concluded the researchers who have been studying the issue for years now on a European Union grant.

They have conducted a systematic review of scientific literature and other less formal literature, a legal analysis, interviews with stakeholders and an expert meeting. And out of that they have distilled information on the prevalence and incidence of off-label use and its drivers, as well as a description of the national regulatory and ethical frameworks governing off-label use across the EU.

They also offer a factual analysis of how authorities have addressed the issue, and how patients, healthcare professionals and industry have reacted to this.

But after all that, the report does not provide any recommendations. (And, intriguingly, it has suddenly and inexplicably been removed from the EU website).

Does it matter? You bet it does! Apart from any issues of patient safety or drug availability, two major drug firms have just lost a legal action intended to prevent authorities resorting to off-label use to save money. That case was a spearhead for an EU-wide industry fight back against the practice, driven by fears of losing a big chunk of revenues (although the industry case focuses - understandably - more on patient safety and regulatory coherence than on the economic aspects).

It is Roche's Avastin that has prompted the current controversy. In France and in Italy the authorities have allowed – even favored - the use of this anti-cancer drug as a cheap alternative to Novartis' Lucentis in treating wet age-related macular degeneration. In late February, after two years of arguments, France’s top court threw out a company appeal against the French authorities' behavior.
 
This isn't a promising precedent for the wider industry campaign to keep prescribing within the limits of a product's indications. The big pharma club in Europe, EFPIA, raised the issue formally with the EU legal authorities two years ago, in a bid to head off what it portrays as an administrative abuse and a lapse in standards of drug authorization. Two years down the line, the EU legal authorities have not yet given any clear indication of what they plan to do. The study published at the end of February is the only response so far – and it doesn't help much.
 
And of course the subject is indeed complex. How far should clinicians be constrained by the approved indications for a medicine when there is empirical evidence that it can also help patients with other conditions? Why should healthcare systems pay more for a treatment that is approved when they can get the same result for less money by urging a cheaper alternative that is considered to be equally effective? Is it not in the nature of drug use that new potential uses emerge through clinical practice? And why should authorities protect drug firms against substitution with off-label medicines when the drug industry itself has frequently connived at, if not frankly promoted, off-label use of its products.

At the same time, however, official endorsement - and even encouragement - of off-label use carries a certain degree of inconsistency, since elaborate rules have been put in place in Europe and elsewhere over the last fifty years to ensure that medicines are thoroughly tested for specific uses before they can be prescribed. To abandon that official line can be seen as threatening a Pandora's box of inappropriate prescribing.

EFPIA and two other related organizations, Eucope and EuropaBio, greeted the publication of the report with a cautionary statement: "Whilst we accept that off-label medicines can be prescribed by physicians to address a patient’s concrete medical needs with his or her consent, we strictly oppose the promotion of off-label use for economic reasons which contradicts the EU principle that the protection of public health must unquestionably take precedence over economic considerations."

The Gordian knot is likely to remain in place as long as EU rules are limited only to the authorization of medicines, and remain aloof from questions of prescribing. And given the determination of doctors to retain their own prized professional autonomy, that is likely to remain the case for a long time to come.

Peter O’Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.