Orphan drug regulation: a global comparison of the United States Food and Drug Administration, European Medicines Agency, and Japanese pharmaceuticals and medical devices agency approaches.

The pharmaceutical industry is vital for healthcare advancement through innovative medications, improving lives. A substantial challenge is "Drug lag," hindering patient access and increasing disease adjusted life years burdens. We aim to examine drug lag for Iran Food and Drug Administration (IFDA) approved drugs versus US Food & Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) over 2001 to 2021. We reviewed new molecular entities within this period, using descriptive statistics in Excel 2019. Drug lag is assessed from relative and absolute perspectives, considering approval gaps and annual rates. Among 710 FDA-approved drugs, 410 received EMA approval, 344 from PMDA, and 148 from IFDA. For 148 IFDA and FDA-approved drugs, the maximum drug lag was 237 months. The mean relative drug lag was 65.18 ± 61.56 months. Compared to EMA (112 drugs), the maximum lag was 257 months, with a mean relative lag of 70.29 ± 53.67 months. With PMDA (127 drugs), the maximum lag was 253 months, with a mean relative lag of 38.23 ± 60.57 months. Iran faces significant drug lag compared to developed countries' regulatory bodies, limiting patient access to innovative treatments. Addressing this issue is crucial for timely drug access, reducing disease burdens. Further research and policy interventions are needed to mitigate drug lag's impact on Iran healthcare landscape.

Endpoints of Clinical Trials for Marketing Authorization of Drugs for Hematologic Malignancy in Japan, the US and the EU

IntroductionOncology drugs often receive their first expedited approval in the United States, yet the degree of alignment with subsequent regulatory decisions in other jurisdictions remains uncertain. We examined concordance in evidentiary evaluation and review timelines between the US Food and Drug Administration (FDA)-first expedited oncology approvals and subsequent decisions by the European Medicines Agency (EMA), Therapeutic Goods Administration (TGA), and Pharmaceuticals and Medical Devices Agency (PMDA).MethodsThis study included all oncology drugs that received their first expedited approval from the FDA in 2019–2023. Subsequent EMA, TGA, and PMDA decisions were evaluated in pairwise comparison with the FDA. Concordance with the FDA was assessed for expedited pathway use, pivotal trial selection, and three analytical components (primary endpoint, target population, and data cut-off date (DCO)). Submission interval and review duration relative to the FDA were compared using Wilcoxon rank-sum tests.ResultsAmong 36 FDA expedited oncology approvals, EMA (n = 28), TGA (n = 18), and PMDA (n = 15) granted subsequent authorizations through expedited or standard pathways. TGA showed the highest concordance with the FDA, retaining expedited pathways in 72% of cases and closely mirroring the FDA’s analytical interpretations in the same pivotal trials. EMA maintained a similar rate of expedited use (71%) but often broadened target populations or used later DCOs (median +136 days). PMDA, in contrast, relied mainly on standard approvals (93%) with Japan-specific population analyses. Across all agencies, primary endpoint choice remained concordant with the FDA. EMA had the shortest submission lag (median 27 days), whereas TGA cases exceeded 600 days. All agencies had longer review duration than the FDA.DiscussionThese findings highlight the need for international harmonization of regulatory frameworks and evidentiary thresholds to promote consistency in approval decisions and accelerate global access to innovative cancer therapies.

The Comparison of Review Processes of Hematological Malignancy Drugs Between the Pmda and the FDA

Bispecific antibodies (BsAbs) that bind two distinct antigenic epitopes represent a new therapeutic paradigm. However, their clinical benefits and global regulatory status remain uncertain. In this cross-sectional analysis, BsAbs data from the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Chinese National Medical Products Administration (NMPA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) were identified up to December 31, 2025. BsAb indications, supporting trials (pivotal and confirmatory), and regulatory approval statuses were analyzed. Clinical benefits based on improved efficacy endpoints, and approval time lags among agencies, were compared. Twenty BsAbs and 33 BsAb indications were identified. Of 33 indications, 27 were oncology and six were non-oncology. Among oncology indications, only six (6/27, 22.2%) demonstrated benefits with improvements in overall survival (OS) and/or quality of life (QoL). The remaining 21 (21/27, 77.8%) oncology BsAb indications showed benefits based on surrogate endpoints. All six non-oncology indications showed benefits based on true endpoints without surrogacy. Among the 38 supporting trials for oncology indications, the majority (36/38, 94.7%) were pivotal trials, while only two (2/38, 5.3%) were confirmatory trials. Most of these trials (32/38, 84.2%) recruited relapsed/refractory patients. Of 20 BsAbs, 12 received initial approval from the FDA, five from EMA, two from NMPA, and one from PMDA. FDA-approved BsAbs obtained EMA approvals with a median lag of 82.5 days, whereas approvals in China and Japan were delayed by a median of 602 and 455 days, respectively. Most oncology BsAb indications remain without OS or QoL benefits. The FDA approved the largest number of BsAbs. Regulatory approval time lags in NMPA and PMDA are substantially longer than those in EMA.

149 Background: New anticancer therapies have led to substantial improvements in prognosis across many cancers. Commercial access to a drug is not possible until the drug has received regional regulatory authority market authorization. In prior work (1), we found that European Medicines Agency (EMA) drug approvals frequently lagged US Food and Drug Administration (FDA) approvals from 2010-2019. Here, we expand the analytic time period to 2004-2023 and include two additional regulatory agencies – Health Canada (HC) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Methods: Drugs with an anticancer indication and first global approval from 2004-2023 were preliminarily identified. Only drugs with an approval by all 4 regulators were included. For each drug, the first and last regulator’s initial approval dates were determined, and the interval between first and last approval was calculated. For drugs approved by all 4 regulators within 1 year (y), it was further determined whether they were considered first-in-class. Results: 209 drugs met the preliminary criteria, and 98 (47%) had approvals by all 4 regulators. The FDA was most commonly the first to approve (84 drugs), followed by PMDA (9 drugs), then EMA (5 drugs); HC was never first to approve. 43 of the FDA-first approvals (51%) were by the accelerated approval (AA) pathway; none of the EMA-first approvals were on the conditional marketing pathway. PMDA was most commonly the last to approve (62 drugs), followed by HC (21 drugs), the EMA (14 drugs), then the FDA (1 drug). The median (IQR) time between first and last regulator’s first approval was 2.4 y (1.3-3.5 y). Some drugs had >5 y between first and last regulator’s approval (Table 1). Conversely, only 16 drugs were approved by all regulators within 1 y, and only 1 drug (isatuximab) was approved by all within 6 months. Of the 16 drugs approved within 1 y by all regulators, 6 (37.5%) were first-in-class: asciminib, elotuzumab, idecabtagene vicleucel, inotuzumab ozogamicin, sotorasib, and trastuzumab emtansine. Conclusions: This study shows that patients with cancer in the US usually have access to new cancer drugs earlier than those in Europe, Japan, and Canada, at least in part due to AA pathways. Less than 8% of newly approved cancer therapies are approved by all 4 regulatory agencies within 1 y of first approval, with a lengthy median first-to-last delay that could exceed the life expectancy of many patients with advanced cancer. Greater global regulatory collaboration in the approval of new anticancer drugs is essential to ensure patients have aligned and coordinated access. (1) Lythgoe et al. JAMA Network Open 2022.[Table: see text]

Are Regulators Talking to Each Other Across Borders?

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The first biosimilar was approved in April 2006 in the EU, June 2009 in Japan, and March 2015 in the USA. However, a detailed comparison and trend analysis of the biosimilar approvals by the three agencies has not been reported. It is important to understand current biosimilar approval status, biosimilar drug lag, and drug loss (i.e., biosimilar void) for considering this impact and avoiding the biosimilar lag and loss as much as possible in the future. We surveyed the biosimilar approval information from the websites of Japan's Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) regarding the reference product, nonproprietary name, brand name, type of biologics, and approval date. Furthermore, we calculated the differences in timing of biosimilar approval among the three agencies (biosimilar lag) and surveyed the publicly available data based on the ClinicalTrials.gov for the consideration of reference products not subject to biosimilar development (biosimilar loss). The Ministry of Health, Labour and Welfare/PMDA, the US FDA, and the EMA have approved 38, 69, and 125 biosimilars until March 2025, respectively. The biosimilar lag increased among Japan, the USA, and the EU, and recently expanded in Japan in comparison with the USA and the EU. Moreover, our survey indicated 29 candidates for biosimilar loss and 16 active drug substances being orphan drugs. Biosimilar development has been expanding in Japan, the USA, and the EU. Our findings reveal a clear expansion of the biosimilar lag for the delay in Japan and may also explain the biosimilar loss for some potential biosimilars.

IntroductionGlobally, 7,000 rare diseases affect 300 million people, which poses challenges for developing treatments in these discrete patient populations. Developing medicines for rare diseases requires innovation, but despite regulatory incentives challenges persist for health technology assessment (HTA) and payers. Understanding the current regulatory and HTA decision-making landscape for orphan products is essential for all stakeholders.MethodsData on new active substances (NAS) approvals (2013 to 2022) by the European Medicines Agency, the United States Food and Drug Administration (FDA), the Pharmaceuticals and Medical Devices Agency (PMDA), Swissmedic, and the Therapeutic Goods Administration were collected to analyze the timing, approval pathways, and global rollout trends for orphan and non-orphan products. Data were collected from HTA agencies in Australia, England, France, Germany, the Netherlands, Poland, Scotland, and Sweden to explore synchronization in decision timing and first HTA decision. Comparative analysis encompassed decision frameworks and funding mechanisms for orphan products among HTA agencies.ResultsOrphan drug approvals increased in the past decade, with the FDA having the highest designation rate (55% for 2018 to 2022). Flexible pathways, mostly used by the FDA (92%) and the PMDA (100%), expedited orphan drug reviews. However, international submissions for orphan drugs experienced longer gaps than non-orphan drugs across the jurisdictions. Divergence in rollout timing to HTA and recommendation resulted from varied submission strategies and review processes. Only the Scottish Medicines Consortium had a dedicated orphan pathway. In England, the National Institute for Health and Care Excellence patient access and managed access agreements (84% of orphan recommendations) and cancer drug fund (45% of orphan recommendations) facilitated patient access.ConclusionsThe study shows a decade long rise in global orphan drug approvals, underpinned by regulatory flexibility, particularly by the FDA and the PMDA. Identified divergences in decision frameworks among regulatory and HTA agencies, as well as HTA agencies themselves, call for increased stakeholder alignment. This necessitates synchronizing evidence generation during development and improving decision frameworks for streamlined review and reimbursement processes.

ObjectivesTo understand the regulatory landscape in the UK and globally before the introduction of the Medicines and Healthcare Products Regulatory Agency’s (MHRA) International Recognition Procedure (IRP). This paper aims to inform on the IRP’s potential impact on access to innovative medicines, by comparing medicines approval in the UK with other international regulatory agencies.MethodsA retrospective analysis of 154 technologies (medicine(s) + studied indication(s)) was conducted based on the National Institute for Health and Care Research Innovation Observatory technology briefings submitted to the National Institute for Health and Care Excellence (NICE) in 2020. These briefings serve as the trigger for the NICE Technology Assessment process. Data on the medicines’ submission and approval dates were extracted across five IRP reference regulators, which are the regulators from the US (Food and Drug Administration (FDA)), European Union (EU) (European Medicines Agency (EMA)), Japan (Pharmaceuticals and Medical Devices Agency (PMDA)), Australia (Therapeutic Goods Administration (TGA)) and Singapore (Health Science Authority (HSA)). The dates were compared with data from the UK (MHRA).Results95 (62%) medicines were approved by at least one regulatory agency, while 59 (38%) medicines were not approved by any regulatory agency. The number of medicines approved by the following regulatory agencies is FDA (n=84, 55%), EMA (n=80, 52%), MHRA (n=71, 46%), TGA (n=51, 33%), HSA (n=41, 27%) and PMDA (n=38, 25%). The first submissions were primarily to the FDA (n=64) or the EMA (n=24). The FDA had the highest number of first approvals (n=70), followed by the EMA (n=17), PMDA (n=5) and the MHRA (n=1). The FDA used more expedited pathways than other regulators (n=61). Compared with the MHRA, FDA approvals were on average 360 days faster and EMA approvals 86 days faster.ConclusionThere were significant differences in market access timelines across the five reference regulators, with the FDA and EMA having the highest number of approved medicines, first submissions and first approvals. IRP applications with the FDA or EMA as reference regulators may expedite access to innovative medicines in the UK by reducing the approval dates gap between the FDA/EMA and the MHRA. This understanding of the regulatory landscape will help inform future planning to accommodate the disruption that the IRP may cause.

Small-molecule inhibitors have transformed oncology in recent years. This study compared regulatory approvals of these agents across the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), focusing on timelines, dosing recommendations, and pediatric labelling. A review of regulatory databases was conducted to identify small-molecule inhibitors approved for adult malignancies. Drug labels were compared to determine dosing concordance (Fully, Partially, or Non-Concordant), approval dates, and pediatric indications. Data extraction involved two independent reviewers. Fifty-five inhibitors were approved by all three agencies. Adult dosing was Fully Concordant in 49 (89%), partially in 4 (7%), and Non-Concordant in 2 (4%). The median approval gap was 25months (range: 1-88). FDA granted first approval for 85.5% of agents, followed by PMDA (12.7%) and EMA (1.8%). Among these 55 drugs, only 15 had pediatric indications (27%), 7 of them (46.7%) approved across all three regions. No complete divergence in pediatric dosing was observed, although minimum age thresholds varied. Despite strong alignment in adult dosing, regulatory disparities in approval timelines and pediatric labelling persist, risking delays in therapy availability. More harmonized multinational trials and regulatory alignment could facilitate timely approvals while allowing for population-specific considerations in dosing and safety.

Pharmaceutical regulation of genetically modified organisms (GMOs) is one of the critical issues for developing viral vector-based medicines. In this perspective, we introduce the recent improvement of regulatory operations in GMOs like viral vector-based products in Japan by comparing those in the United States and the European Union. The recent advancements in genetic modification and editing techniques have accelerated the development of advanced-therapy medicinal products using genetically modified viral vectors and cells.1 Despite the increase in use of GMOs/living modified organisms (LMOs) in medicine, the potential risk of GMOs/LMOs on the environment is a concern. To address internationally the environmental issues related to biological diversity, including the usage of GMOs/LMOs, 196 nations as of 2021 have concluded or signed the Convention on Biological Diversity (CBD), which is the first global agreement to cover all aspects of biological diversity. The Cartagena Protocol based on CBD aims to ensure the safe handling, transport, and use of GMOs/LMOs, produced by modern biotechnology, which may have an impact on biological diversity. The Cartagena Protocol was entered into force on September 11, 2003. The Cartagena Protocol requires the parties to consider the necessity of the standard of handling of GMOs/LMOs and, if necessary, to establish the standard. The EU countries had already established domestic laws based on Directive 2001/18/EC that addressed the handling of GMOs/LMOs for medical use before the establishment of the Cartagena Protocol. Therefore, the EU countries did not have to take any additional actions to regulate the handling of GMOs/LMOs for pharmaceuticals. In 2003, the Japanese government established the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms,2 known as the Cartagena Act, for the handling of the GMOs/LMOs. This Act is similar to Directive 2001/18/EC and the domestic laws established in the EU countries. In contrast to the European Union and Japan, the United States is one of the few countries that have not signed the CBD and the Cartagena Protocol. The United States enacted one specific environmental law named the National Environmental Policy Act of 1969 (NEPA) that regulates all kinds of environmental assessments. For initiating clinical trials, developers should submit appropriate clinical trial-related applications (investigational new drug (IND) application in the United States, clinical trial application (CTA) in the European Union, and clinical trial notification (CTN) in Japan) to each regulatory agency. In the European Union and Japan, approval of the usage of the GMOs/LMOs in the clinical trials is also mandatory before starting clinical trials (Figure 1). The objective of the EU domestic laws is to protect humans and the environment when carrying out deliberate release of GMOs/LMOs into the environment. Thus, developers (academia and/or industry) planning clinical trials in the EU countries should submit an environmental risk assessment (ERA) of each GMO to each country where the clinical trial will be conducted. In Japan, the Cartagena Act has two types of GMO/LMO regulations, the deliberate release, with GMO/LMO-specific rules for usage (Type-1 Use Regulation (T-1R)) and containment use for closed production sites and laboratories (Type-2 Use Regulation (T-2R)). Clinical trials are within the scope of T-1R, therefore developers planning to conduct clinical trials in Japan should submit an ERA and the T-1R application for GMOs/LMOs. In the United States, the submission of an ERA is not required for IND applications. However, when GMOs/LMOs may affect the quality of the environment, the US Food and Drug Administration (FDA) will request an ERA during the review process of the IND (the Title 21 of the Code of Federal Regulations (CFR) 25.21 and 25.31). In both the European Union and the United States, applicants should submit an ERA result of GMOs/LMOs when applying for marketing authorization, and the FDA or European Medicines Agency (EMA) reviews the appropriateness of the usage of drugs in clinical practice based on the ERA result (Figure 1). In Japan, the resubmission of an ERA is not mandatory when applying for marketing authorization. If developers obtain new data that indicates the environmental risk is lower than expected, resubmission is acceptable at any time to relax the T-1R. Some clinical researchers in Japan recently commented that the Cartagena Act delays the development of medicines containing GMOs/LMOs when compared to that of the medicines regulated by the similar laws in the European Union and the United States.3 But the regulatory framework of Japan is not significantly different from that of at least the European Union (Figure 1). The Pharmaceuticals and Medical Devices Agency (PMDA) is the Japanese regulatory agency responsible for a scientific review of new drug applications and Cartagena Act-related applications. The PMDA believed that such opinions came from the differences between the scheme of the Cartagena Act implementation and the procedure of actual development of drugs, and a lack of information on the Cartagena Act applications among academia. To solve these problems, since 2019, the Ministry of Health, Labor, and Welfare and the PMDA have started to improve the implementation of the Cartagena Act to ensure faster development of drugs (Table 1). The first improvement made in 2019 was the establishment of the PMDA official consultations to address specific measures of the Cartagena Act. The consultations for the Cartagena Act were the first established at the PMDA for the environmental law, and the developers can officially discuss the Cartagena Act-related matters with the PMDA since the establishment. It takes < 3 months to complete the official consultations and for official minutes to be published. The applicant can then submit the T-1R application as soon as the issues pointed out in the consultations are resolved. The administrative processing time after the submission is officially < 6 months, and the median actual administrative processing time and total processing time in 2021 were ~ 2.7 months and < 5 months, respectively. Section 42 of the German Drug law indicates that the evaluation period of CTA for trials dealing with GMOs/LMOs is 90 days after receiving the application conforming to the regulations. Thus, the actual administrative processing time before starting clinical trials is similar between Japan and the European Union. Since 2021, the parallel application of CTN and T-1R is acceptable. Now, developers should receive the approval of the T-1R application before at least the first patient enrollment of the clinical trial in Japan. In the European Union, several countries, such as France, accept the parallel application of CTA and ERA, but some countries, such as Poland, demand the approval of usage of the GMOs in the clinical trials before submitting a CTA.4 The PMDA has published a considerable number of instructions, such as the specific descriptions of ERA for adeno-associated virus (AAV) vectors,5 to provide information about the Cartagena Act to future applicants. The specific ERA for AAV vectors includes the general information and prior knowledge about AAVs and the general principles of risk assessment for AAV vectors. The European Commission has also published specific ERA for AAV in June 2022.6 These instructions and specific descriptions will significantly reduce the burden on applicants and regulators in Japan. Because the ERA submission is not mandatory when applying for marketing authorization, the regulation of the development of gene therapy products in Japan is not more time-consuming than that in the European Union and the United States. No funding was received for this work. The authors declared no competing interests for this work.

This article describes recent developments in licensing and reimbursement policies in the EU, US, and Japan, examines causes of changes and compares differences and projects trends. With respect to licensing, the European Medicines Agency (EMA), US Food and Drug Administration (FDA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) are committed to rigorous evaluation of pharmaceuticals in advance of market access with feedback from postmarket experience. The EMA is exploring integrated adaptive pathways for licensing, with formal pilot tests to provide a practical proof of concept. The FDA is augmenting traditional licensing procedures through reforms including Breakthrough Product Designation. The PMDA is implementing reforms to foster innovation and earlier patient access through its Sakigake strategy and licensing reforms on regenerative medicines. With respect to reimbursement, several generalizations emerge. Relative to US counterparts, EU payers typically set higher standards for evidence of effectiveness as a condition of reimbursement, impose tougher limits on reimbursement by indication, and drive harder deals in negotiations over prices.

A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018