Europe Searches for Better Collaboration Across Regulators

Closer alignment of evidence for drug registration and evidence for reimbursement has become an ambition expressed with increasing frequency and vehemence in European discussions of medicines policy, and a respected Belgian research center made some audacious recommendations as to how the gap might be narrowed in a report published as 2021 came to an end.

KCE’s report, “Evidence gaps for drugs and medical devices at market entry in Europe and potential solutions,” emerges at a timely moment, with 2022 a crucial year in Europe for medicines regulation. The groundwork will begin this month for Europe’s emerging joint health technology assessment for drugs, and before the end of the year, the EU will propose a rewrite of its 20-year-old pharmaceutical legislation. With so much of the European drug evaluation system in the melting pot over the coming months, the opportunity for change has never been so apparent.

The disconnect between drug registration and pricing is notorious in Europe. Separate systems govern the two processes—with the European Medicines Agency (EMA) adjudicating on the terms of the marketing authorization, and national or regional health technology assessment (HTA) and pricing bodies deciding on reimbursement. Inevitably, this leads to duplications—and still more problematic, to inconsistencies—in demands for evidence. As KCE puts it, “the regulatory and payer processes frequently fail to generate the comparative evidence required for informed decision making.”

After review of the situation in Europe, the study concludes that action must be taken to bring the two processes more closely together. “The pre-market clinical trials generated for medicinal products should meet not only the regulatory requirements but also clearly answer the comparative effectiveness questions of relevance for patients, clinicians, and healthcare payers,” it says.

There is an attractive logic in combining the two, and it is easy to see why it is an attractive goal. But saying it is one thing. Getting it done is another. KCE approaches the question by recommending a tightening-up of the expectations for data generation by clinical trials. “The regulators will actively support the generation of the necessary comparative data that patients, clinicians, HTA bodies, and payers need in order to choose the best treatment,” it says.

The methodology outlined is for a pre-market comparative randomized clinical trial to be initiated and completed early, in representative patients, so that HTA bodies can assess the comparative evidence. The trial should compare the innovation with the standard of care in relevant patients, using patient-relevant outcomes as trial endpoints. “A placebo-only arm, or sometimes a sham-only arm, can be added if scientifically and ethically justified,” according to KCE’s recommendations. The outcomes should include quality of life, and the use of non-validated surrogate endpoints should be avoided. When the information for the regulator is available before the comparative evidence, EMA should issue a novel type of temporary marketing authorization that requires further follow-up and the completion of comparative trials. Where the clinical questions and evidence requirements of both the regulatory and the HTA processes cannot be answered using the same trial, a separate pre-market randomized trial is needed that meets the comparative evidence requirements of HTA bodies.

KCE has spelled out its recommendations to regulators and HTA bodies at great length. But it is rather shorter on its vision for how regulators and HTA bodies are to be empowered to make the prescribed shifts in their roles and responsibilities. “This aim can be achieved by adapting the EU legal framework, with the support of the member states’ governments and the European Commission,” it says blandly. But herein will lie challenges every bit as demanding as the technical and managerial tasks it counsels.

Any talk of adapting legal frameworks in Europe is a step into intensely political territory—and the EU legal framework is an intensely political construct, with every dot and comma the outcome of extensive and hard-fought negotiations. The three-year confrontation that preceded the adoption of the HTA regulation late in 2021 demonstrates the point. And the fact that the regulation adopted is, after all that, still a weak compromise—necessary to avoid outright rejection of the more ambitious initial proposal—serves to reinforce the point.

Reflector is Pharmaceutical Executive’s correspondent in Brussels