Bringing Evidence Back into Fashion in European Drug Rules

At a recent major European meeting on health technology assessment (HTA), the head of the French drug agency HAS said she was very much in favor of comparative evidence in drug evaluation. It was an observation that might have passed unremarked in other circumstances, since it is what would normally be a statement of the obvious from the head of a prestigious body whose work is based on evidence. But it was remarked, and it was remarkable. Because invocations of “evidence” have recently acquired a new resonance in Europe among those who are suspicious of what they see as a headlong rush to shortcuts in drug approvals. And the observation was all the more conspicuous because it came from a distinguished European figure who had just chaired the first meeting of the committee of 27 EU member states who will play a decisive role in the operation of the new European HTA system.

The following day, at a Brussels seminar on treatment optimization, the head of European Social Insurance Platform (ESIP), one of Europe’s biggest health insurance organizations said: “We need strong evidence for informed and timely decisions. It is important to strengthen cooperation on data requirements among decision-makers.” That remark came on the heels of ESIP’s publication of its proposals for the upcoming review of European drug rules, which emphasized the healthcare payer’s interest in ensuring “robust and timely evidence-generation” enshrined in the new legislation. ESIP considers “the gold standard” to be randomized controlled trials with an active comparator using clinically meaningful endpoints, and warns against the trend to shifting the assessment of safety, quality, and efficacy from pre- to post-marketing authorization. Conditional approval pathways should be limited, it says, and standards of quality and study design enforced, with increased transparency over their methodology.

The background to that seminar, according to AIM, another major grouping of healthcare payers, and one of the meeting’s co-organizers, is that “many therapies enter the market without sufficient evidence on their clinical benefit for patients,” creating “a challenge of ensuring sustainable access to efficient therapies.”

Such comments highlight a shift in attitude to innovation among many key healthcare constituencies in Europe. The heady days of a decade ago, when the likes of Hans-Georg Eichler—then the senior medic at the European Medicines Agency (EMA)—were advocating exploration of adaptive approvals, have given way to a more cautious approach. Many national health authorities in Europe harbor concerns that faster approvals on limited data are more of an industry-promoted Trojan horse for cutting corners on the way to the marketplace, rather than a rational method of exploiting new science and new data. The dilemma sits at the heart of the EU’s own thinking on how to update its pharmaceutical legislation. “The main source of evidence for the authorization of innovative medicines should remain robust clinical trials with suitable comparators reflecting the standard of care in the EU,” said the European Commission in its 2020 “pharmaceutical strategy” that launched the legislative process—despite its avowed aim “to revise the pharmaceutical legislation to adapt to cutting-edge products, scientific developments (e.g., genomics or personalized medicine) and technological transformation (e.g., data analytics and digital tools) and provide tailored incentives for innovation.”

Europe still has plenty of vigorous advocates of innovative approaches. The main drug industry lobby in Europe, The European Federation of Pharmaceutical Industries and Associations (EFPIA), told the EU in the latest consultation on the plans for legislation that it “must put in place a framework to accommodate tomorrow’s innovation, with the regulatory flexibility to adapt as and when the technology does.” The European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), a European grouping of drug firms with a heavy involvement in advanced therapy products, says adequate policy focus on drug development “has so far been prevented by unfavorable regulatory conditions.” And addressing specifically the prospects for the new EU HTA system, it says that “evidence generated outside of the strict randomized controlled trial design must be accepted such as real-world evidence (RWE), while post-launch evidence-generation should be routinely implemented.”

EUCOPE points out that orphan drugs and advanced therapies in particular, due to their smaller patient populations, rely on less conventional methodological approaches. The HTA discussions chaired by Dominique Le Guludec, the French official quoted above as a champion of comparative trials, provoked an instant response from supporters of a more liberal approach to evidence-generation. RWE4Decisions, a consortium of organizations with an interest in exploring the potential of RWE more extensively, publicly queried what guidance will emerge for the use of RWE in the upcoming joint HTA system in Europe, “since oncology and advanced therapies are priority areas, and often come with little evidence insofar as randomized controlled trials are not always possible.”

Over the next three years, as the EU puts its HTA system fully into place, and revises its pharmaceutical legislation, some of the current battle lines over acceptable or obligatory evidence may be softened by clearer definitions. But, at the same time, the discussion will become more confused because of the growing overlaps and distinctions between evidence for EU marketing authorizations and evidence for national decisions on pricing and reimbursement—a subject which deserves a separate article.