For much of the last twenty years, the direction of travel seemed clear. Regulators in US and EU have worked to harmonize requirements for market approval and thereby reduce unnecessary duplication of information. Companies have designed global development programs with the expectation that a single evidence package could support approvals in both US and EU.
Will this be true also in the future? If anything, evidence points at divergence?
On a high level, both FDA and EMA remain committed to rigorous evidence. But during recent years, FDA has issued new guidance to communicate their current view on what can be accepted as clinical evidence.
The “two replicate adequate and well controlled pivotal trial” paradigm has been the norm for many years, as defined in the 1998 FDA guidance “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products”. With the scientific development within the rare disease space, this paradigm was challenged. Two replicate pivotal studies were just not doable given the small patient population and the unmet medical need in these patient populations. EMA already in 2001 adopted a “point to consider paper” discussing the concept of one pivotal trial, albeit requiring very high evidentiary standard since there would be no independent replicate finding.
So, what has changed now? FDA has published a series of guidelines during the last couple of years reflecting their view on clinical evidence. In 2019 came the first draft update of the 1998 guidance, emphasizing strength of evidence rather than simply the number of trials.
The most significant concept is that FDA opens for one highly persuasive trial plus more limited confirmatory evidence. For a trial to be persuasive it must be robust and show strong consistency among endpoints and subgroups. FDA continues to recognize the traditional approach of two studies but reasons that two identical replicate studies are not necessarily the best approach. Instead, two non-identical studies with different endpoints could provide complementary evidence. In the end, the strength of the total evidence package determines whether substantial evidence exists.
Are FDA and EMA drifting apart? FDA has clearly taken the leader position moving away from the default two-pivotal trial paradigm. However, EMA is not closing the door as shown by their 2001 position paper. The EU system operates within a fundamentally different environment, balancing the input of multiple Member States. As a result, regulatory change often occurs through a more deliberate and consensus-driven process. In contrast, the relationship between political leadership and the FDA is considerably more direct, potentially enabling faster shifts in regulatory policy and priorities.
EU may soon face a strategic dilemma. Can Europe afford to demand a higher level of pre-approval certainty than the United States? If sponsors can secure FDA approval through faster and more streamlined development programme, will they still be willing to invest in generating the additional evidence that EMA may require?
Ultimately, regulatory standards are not merely a scientific question. They can influence where companies choose to invest, launch products, and seek market access. A widening divergence between FDA and EMA expectations could therefore have implications not only for drug development strategies, but also for the speed at which European patients gain access to innovative treatments.
The bottom line is that a single development program targeting US and EU is still an option as long as the evidence generation is carefully planned and the claims can be scientifically justified on both sides of the Atlantic.