Study: Regulators often diverge from FDA on expedited oncology approvals
Among oncology drugs first approved by the US Food and Drug Administration, other regulatory authorities varied in how they approved the same products, both in terms of the regulatory frameworks and the evidentiary thresholds used as the basis for the approvals, according to recent research published in Frontiers in Pharmacology.
Regulatory authorities such as the European Medicines Agency (EMA) were more likely to approve the same products but based on a higher evidentiary threshold, while the Therapeutic Goods Administration (TGA) was more likely to agree with FDA analyses of pivotal trials but on a longer timeline, researchers said.
“Our findings highlight persistent divergence in regulatory frameworks and evidentiary thresholds across agencies, reflected in differences in data maturity requirements, approval pathways, and review timing that contribute to fragmented regulatory outcomes and unequal patient access,” Yeh Hyun Kim, of the college of pharmacy at Ewha Womans University in Seoul, and colleagues wrote in their study.
Kim and colleagues conducted a review of 36 oncology drug-indication pairs granted expedited approval through FDA between 2019 and 2023, and were subsequently reviewed by EMA, TGA, and Pharmaceuticals and Medical Devices Agency (PMDA). The researchers compared decisions by EMA, TGA, and PMDA with concordance to FDA decisions based on use of an expedited pathway, and selection of pivotal trials as well as whether each agency considered the same primary endpoint, target population, and data cut-off date as FDA.
Overall, EMA authorized 28 drug-indication pairs, TGA authorized 18 drug-indication pairs, and PMDA authorized 15 drug-indication pairs across expedited or standard pathways. Of these, EMA authorized 20 drug-indication pairs through expedited pathways and 8 pairs through standard pathways, TGA authorized 15 drug-indication pairs through expedited and 5 pairs through standard pathways, and PDMA authorized 14 drug-indication pairs through standard pathways and 1 pair through an expedited pathway. A majority of pivotal trials analyzed across FDA, EMA, TGA, and PDMA had a single-arm with evidence from early-phase trials that had small patient populations with 200 participants or less, but nearly all agencies analyzed the same primary endpoint across pivotal trials.
The researchers found TGA used an expedited pathway most often compared to FDA (72%) and used similar analytical interpretations to the agency for the same pivotal trials compared to the agency. While EMA used expedited pathways at a similar rate (71%) for the same group of drug-indication pairs, their target populations tended to be broader, and EMA also had later data cut-off dates compared to FDA.
“In expedited contexts, where pivotal trials analyze 200 or fewer patients, these observed features—namely the use of later data cut-offs and broader population definitions—may reflect the EMA’s regulatory emphasis on ensuring sufficient evidence maturity and population characterization within the constraints of conditional approval,” the researchers said.
In terms of the PMDA, standard approval was primarily used, and the focus was on Japan-specific population analyses, Kim and colleagues said, which “aligns with critiques that Japan’s conditional approval functions more like a full approval, limiting regulatory flexibility,” and the differences between PMDA and FDA may be due to eligibility criteria structural differences.
When comparing submission lag times to FDA, EMA had shorter submission lags for drug-indication pairs where concordance with FDA was greater (median 27 days), but more lag time for pairs where low concordance with FDA was observed (median 521 days). TGA showed longer submission lag times for both high concordance (median 324 days) and low concordance (median 626 days) drug-indication pairs, while PDMA mainly had longer submission lag times for drug-indication pairs with low concordance with FDA (median 367 days).
“[T]he longer submission gaps observed for the TGA may be associated with a sequential submission strategy by design rather than regulatory inefficiency: sponsors await FDA authorization before initiating TGA submission, after which the TGA conducts a targeted assessment leveraging the existing FDA review,” Kim and colleagues explained.
The researchers said divergence between various regulators on acceptable evidence for expedited approval may be at odds with societal expectations for evidentiary certainty over faster access to products.
“Greater transparency, aligned evidentiary standards, and strengthened international collaboration will be critical to realizing the full potential of expedited programs and promoting global regulatory harmonization,” the researchers concluded.
