Another Battleground Takes Shape in Europe: Real-World Evidence

It’s been coming for years, but now it’s starting to bite. The medicines development community is struggling to find consensus on how to generate real-world evidence and how to use it, and here in Europe the policy tensions are influencing the scientific exchanges. It’s the latest in a string of hot-button issues, and is keeping the Brussels bubble bubbling, even as those beachside cocktail parties and poolside loungers beckon. Discussions on pediatric medicine incentives, health technology assessment (HTA), or Europe’s beating cancer plan had all been ticked off from the “do before the holidays” list, and safely deferred to the traditional (hard-pressed and overworked US readers may wish to look away now) September return to work in this part of the world.

However, the European Medicines Agency (EMA) and a phalanx of international regulatory colleagues casually tossed a stone into the placid waters of late July with a call for international collaboration to integrate real-world evidence (RWE) into regulatory decision-making. For many researchers, this could be an interesting move. But not for many critics of what they like to depict as a headlong and ill-considered rush into new methods. And those critics include a lot of physicians, HTA agencies, patient groups, and, yes, regulators too. In other words, the stage is set for yet another round of sharp words over the immediate and longer-term future of drug development.

EMA and colleagues in the International Coalition of Medicines Regulatory Authorities (ICMRA) have agreed in a joint statement that notes the rapid increase and evolution in the use of real-world data (RWD) and RWE in developing, authorizing, and monitoring medicines. And right from the start, they address the tough questions. Yes, RWE can help bridge knowledge gaps, they recognize. But “there are still challenges that need to be addressed”—and these include heterogeneous data sources across the globe, different levels of data quality, and the wide range of issues linked to data sharing and access.

The challenges need to be met, these regulators agree, and they now foresee a range of collaborative measures to seek solutions. They plan to start with harmonization of RWD and RWE terminologies, by generating common operational definitions that are clear over their scope and level of granularity—relating to randomized clinical trials and observational studies. Existing international activities touching on RWD at the level of the International Conference on Harmonization can play a role here, too, they suggest. Guidance and best practice need aligning early on, as well, with common principles for RWD quality, metadata to enable characterization and discoverability of RWD; establishing the scenarios where RWE may be suitable in regulatory decision-making; and standardized templates for study protocols and reports that would be accepted in regulators in different parts of the world.

“Readiness”—which has become something of a motto in light of the demonstrated “unreadiness” of the COVID-19 response—also gets top attention from these regulators. They envision strengthening joint work on RWE through specially created expert groups on specific topics, notably including the challenges of “emerging health threats” and how studies based on RWD from different countries could address such public health challenges. They also want to see transparency brought to the entire debate. This means defining common principles and practices for systematically registering prespecified study protocols and study results in publicly available registries—with the additional proviso that they should include details of feasibility assessments. It will also require publication of study results in open-source, peer-reviewed journals, and regulators should exert their influence to promote this, they believe.

None of this is going to be as easy as just making a list of what has to be done. But there is new momentum behind the objective: more than 40 countries, representing medicines regulatory authorities globally, as well as representatives from the World Health Organization have contributed to this initiative, with EMA, FDA, and Health Canada in the lead. And for all the regrets that continue to be expressed about the lack of readiness of health authorities to respond to the COVID pandemic, one evident positive outcome is that international medicines regulators and researchers did learn to work together in new and ultimately productive ways—including in relation to RWE.

As a flavor, however, of the potential conflicts ahead, just take a quick look at some of these recent observations from influential and important organizations that take differing views about the future—drawn from the major EU consultation on its upcoming review of pharmaceutical legislation. For every Takeda urging “greater predictability in terms of the uptake of RWE” or Johnson & Johnson identifying the enabling of optimal RWE use as “a key objective,” there isthe European doctors’ association warning that RWE “should only be considered as complementary to randomized clinical trials and should under no circumstances be promoted as a replacement,” or the influential Prescrire journal enjoining European and national regulators “not to weaken marketing authorization requirements by shifting the provision of real and strong evidence before authorization to hypothetical and biased real-world data after marketing authorization.” The summer is already unseasonably hot. The arguments this will generate will do nothing to cool it down.