Approval Timelines for Advanced Therapeutics in Inflammatory Bowel Disease: A Comparison Between the European Medicines Agency and the Food and Drug Administration

Regulatory agencies approve new therapies based on evidence of efficacy and safety. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) are the 2 largest global regulators setting standards, and their guidance is often followed by other regulatory agencies. The decisions of the 2 agencies are often compared: broadly speaking, the outcomes of review processes are highly concordant,1 although the process usually takes longer with the EMA than with the FDA.2 A recent analysis showed that the difference in review times was mainly driven by drugs for cancer and hematologic disease.2 Approval timings for drugs for inflammatory bowel disease (IBD) in adults have not been previously compared for the 2 regulatory agencies, although they are potentially significant and may lead to disparities in the care of patients with IBD. We investigated the approval timelines for advanced therapeutics in IBD, comparing submission dates, review times, and approval timings relative to the publication of pivotal studies supporting authorization by the FDA and EMA. We identified advanced therapeutics (monoclonal antibodies and small molecules), both originator and biosimilar, approved by the FDA or EMA from January 1, 1998, to March 31, 2023, for Crohn’s disease (CD) or ulcerative colitis (UC). We extracted submission and approval dates from the respective regulatory databases (https://www.ema.europa.eu/en/medicines, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm). For European approvals, the date of the positive opinion of the Committee for Medicinal Products for Human Use was used, in line with previous analyses. Dates of results publication were extracted from ClinicalTrials.gov and dates of online journal publication were extracted from the respective journal websites. We calculated descriptive statistics for the median difference between FDA and EMA approval dates, the time of review by each regulatory agency, and the timing of approval relative to the full publication of the registration study in a clinical trials registration repository, and in a peer-reviewed journal. Approval timings were compared between monoclonal antibodies and small molecules and between originators and biosimilars. Comparisons between the 2 regulators were only made for drugs approved by both agencies. A total of 30 drugs were identified with market authorization in the United States or Europe for CD or UC; 25 were indicated for CD and 27 were indicated for UC; and 22 were indicated for both diseases. In total, there were 13 drugs approved by both the FDA and EMA for CD and 16 approved for UC. Among originators, 2 (certolizumab, natalizumab) were approved for CD by the FDA, but not by the EMA, and 2 (filgotinib, mirikizumab) were approved for UC by the EMA but not by the FDA. Subcutaneous formulations of vedolizumab and infliximab were also only approved by the EMA. Certolizumab and natalizumab were judged by the EMA to offer insufficient therapeutic benefit. Filgotinib was not submitted for approval in the United States, while mirikizumab was not yet granted FDA approval for UC due to reservations about the manufacturing process. Among drugs approved by both regulatory agencies, 59% (n = 17 of 29) of applications were first submitted to the EMA and 52% (n = 15 of 29) of drugs were first approved by the EMA (Figure 1). The review time by the EMA was longer by a median of 32 days across CD drugs (median review times: 379 days vs 364 days) and longer by a median of 34.5 days across UC drugs compared with the FDA (372.5 days vs 349 days) (Table 1). Review times were similar between originators and biosimilars; in a small sample of 3 drugs, median review times were shorter for small molecules than for monoclonal antibodies. Median review times, median times from approval to publication in a clinical trial repository, and median times from approval to publication in a peer-reviewed journal for advanced therapeutics for inflammatory bowel disease by the EMA and FDA. Values are median (interquartile range). The difference was calculated as FDA duration minus EMA duration. Comparisons were restricted to drugs approved by both agencies. Biosimilars are approved for both Crohn’s disease and ulcerative colitis in the same review procedure. Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration. Median review times, median times from approval to publication in a clinical trial repository, and median times from approval to publication in a peer-reviewed journal for advanced therapeutics for inflammatory bowel disease by the EMA and FDA. Values are median (interquartile range). The difference was calculated as FDA duration minus EMA duration. Comparisons were restricted to drugs approved by both agencies. Biosimilars are approved for both Crohn’s disease and ulcerative colitis in the same review procedure. Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration. Timing of approvals by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA), publications in clinical trial (CT) registries, and journal publications of advanced therapeutics (monoclonal antibodies and small molecules) for Crohn’s disease (A) and ulcerative colitis (B). Biosimilars are denoted by an asterisk. In general, results were published to a clinical trial registry before approval, with publications occurring closer in time to regulatory approval with the EMA (Table 1) and from approval to publication of a peer-reviewed journal (Table 1). The median duration to publish pivotal trial results in a peer-reviewed journal was about 1 year prior to FDA approval for CD drugs and about 6 months for UC drugs, while in both cases publication occurred closer in time to EMA approval (Table 1). Among drugs approved by both agencies, the FDA approved 23% (n = 3 of 13) drugs for CD and 38% (n = 6 of 16) drugs for UC before publication of registration trial results, while the EMA approved 46% (n = 6 of 13) drugs for CD and 44% (n = 7 of 16) drugs for UC before publication of registration trial results. In this cross-sectional study, we found the approval timings of advanced therapeutics for the treatment of IBD to be similar between the FDA and the EMA, although review times were approximately 1 month longer by the EMA. There were no substantial differences in review times between originator monoclonal antibodies, biosimilar monoclonal antibodies, and small molecules. The percentage of drugs approved prior to publication of pivotal clinical trial results in a peer-reviewed journal was slightly higher for the EMA compared with the FDA. Decisions of both agencies were mostly concordant, with differences arising from drugs not being submitted for regulatory approval at all (eg, filgotinib for UC in the United States) or being judged to conger insufficient therapeutic benefit (certolizumab and natalizumab in Europe). Regulatory practices differ, however, in the approach to hybrid medicines. A hybrid medicine is a medicine similar to an authorized medicine containing the same active substance but in which there are differences in the indication or pharmaceutical form. Authorization of these drugs depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.3 This situation arose with the development of the subcutaneous formulation of the infliximab biosimilar CT-P13, in which the originator medicine was only approved for intravenous use. The EMA reasoned that the efficacy, safety, and biosimilarity of intravenous CT-P13 to originator infliximab had already been established and that only pharmacokinetic comparability remained to be established, resulting in its approval after conducting a study in 167 patients with rheumatoid arthritis4 and 131 patients with IBD.5 The FDA, on the other hand, mandated the conduct of separate placebo-controlled trials for CD6 and UC,7 enrolling 396 and 548 patients, respectively. After demonstrating superiority to placebo, a biologics license application was submitted to the FDA in January 2023 and is currently under review. Another area of discordance between the 2 regulatory agencies is the subcutaneous formulation of vedolizumab, which was approved by the EMA in 2020 but was rejected by the FDA in December 2019. The contents of Complete Response Letters by the FDA are not made public, but reservations regarding the design and labelling of the subcutaneous injection device were cited by the sponsor.8 Regulatory agencies have the responsibility to ensure patient safety, balanced with timely access to new medication. As in previous analyses, both overall and focused on specific indications,2,9 median review times were longer with the EMA than with the FDA, although the distribution of first approvals was balanced between the 2 regulatory agencies (53% vs 47%). Review times between the 2 agencies vary by therapeutic area: they are almost identical for cardiovascular drugs, substantially shorter for anti-infective agents (by 113 days) and hemato-oncologic drugs (by 173 days) with the FDA, and slightly shorter for all other therapeutic areas (by 30 days).2 This reflects the use of the accelerated approval process by the FDA, originally used for HIV drugs, and recently predominantly for hemato-oncologic drugs.10 Drugs for serious conditions fulfilling an unmet therapeutic need are eligible for this approach and receive approval based on pivotal trials with surrogate endpoints regarded to predict clinical benefit with reasonable likelihood and require postmarketing studies to confirm therapeutic benefit. Except for infliximab, none of the drugs approved for the treatment of IBD underwent accelerated review by the FDA. Review duration was longer for biosimilars than for originators with both agencies and a longer review time with the EMA of a similar magnitude than observed for originators. This reflects the high degree of agreement in guidelines on biosimilars of both agencies, with the existing differences (eg, interchangeability, naming conventions) not impacting the duration of review and ultimate approval. Approval prior to publication of pivotal trial results may lead to uncertainty among clinicians, as only incomplete information on the overall efficacy and safety is available. Limitations of our study should be acknowledged. We could only examine approved applications, as information on unapproved applications is not publicly available. Only official review times were considered, as presubmission inquiries are confidential and not available in the public domain. Finally, regulatory approval is only the first necessary, but not sufficient, step in ensuring that patients have access to new drugs—our study did not capture the postapproval process, which differs substantially between countries. Nonetheless, our study provides background information about the drug approval process to practicing clinicians and explains the differences in access to drugs between the United States and Europe. There is considerable overlap between approvals of advanced IBD therapeutics by the EMA and FDA, with minimally longer review times by the European regulator, which has limited impact on the timing of ultimate approval. The EMA approved subcutaneous formulations of existing biologics before the FDA. The results of this review may help to inform sponsors in their regulatory submission plans. Guarantors of the article: V.J. Development of study concept and design: V.J. Acquisition, analysis, and interpretation of the data: J.H., T.D., L.A., L.G., V.J. Statistical analysis: L.G. Drafting of the manuscript: J.H., V.J. Critical revision of the manuscript for important intellectual content: J.H., C.M., T.D., L.A., L.G., E.C., S.S., V.J. All authors approved the final version of the manuscript including the authorship list. This manuscript, including related data, figures and tables has not been previously published and is not under consideration elsewhere. None declared. J.H. has received speaker fees from AbbVie, Janssen, and Takeda; and consulting fees from Alimentiv Inc. C.M. has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc, Roche, Sanofi, Takeda, and Tillotts Pharma; speaker fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, and Takeda; royalties from Springer Publishing; and research support from Ferring and Pfizer. E.C. has received speaker fees from AbbVie, Janssen, and Pfizer; educational grant support from AbbVie and Pfizer; and consulting fees from Alimentiv and Sanofi. S.S. has received personal fees from Pfizer for ad hoc grant review; and research funding from Pfizer and AbbVie. V.J. has received consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, TopiVert, Ventyx, and Vividion; and speaker fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Shire, Takeda, and Fresenius Kabi. The data underlying this article will be shared on reasonable request to the corresponding author.

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