The study, published in Frontiers in Medical Technology by Makiko Mochizuki and Hideki Maeda of Meiji Pharmaceutical University in Tokyo, examined approvals of biopharmaceuticals in device presentations recorded by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) and the U.S. Food and Drug Administration (FDA) between January 2000 and December 2025. The researchers excluded small-molecule drugs, vaccines, biosimilars, and interchangeable products, focusing instead on originator biologics delivered through prefilled syringes, autoinjectors, reusable multidose pen injectors, on-body injectors, and cartridges designed for dedicated administration devices sold separately. After removing products with unclear approval dates, the final dataset comprised 261 products: 167 approved in both countries, 74 approved only in the United States, and 20 approved only in Japan.

The headline number is striking. Among 176 U.S.-approved biologics with device presentations, 16 percent had never been approved in Japan. In an era when drug lag has become a national policy concern in Japan, that figure might suggest a systemic failure to bring device-enabled therapies to Japanese patients. But when the authors dissected the discrepancy, the device itself was rarely the culprit. The overwhelming majority of missing products reflected what the researchers call approval loss by drug: the active substance had simply never been developed for the Japanese market, regardless of which delivery system it used. Once those drug-level losses were excluded, the difference in device presentation approvals between the two countries collapsed to almost nothing. Even for prefilled syringes, which showed the largest raw gap, only six U.S.-approved products lacked Japanese approval when the underlying drug was available.

Statistical testing confirmed the visual impression. A Pearson chi-square test comparing device presentation approvals between Japan and the United States, after excluding products lacking active substance approval in either country, yielded a p-value of 0.961, and Fisher’s exact test, applied because on-body injectors were so rare, produced a nearly identical 0.963. In plain terms, there is no systematic device-specific barrier separating the two markets. Approval loss by device, the analysis concludes, should be understood primarily as a subset of approval loss by drug, with the approval status of the active substance acting as the dominant determinant of what patients can access.

Approval lag told a more nuanced story. Among U.S.-first products, median delays varied numerically across device categories: autoinjectors reached Japan fastest at roughly 10 months, prefilled syringes at about 12 months, on-body injectors at about 14 months, multidose pen injectors at roughly 24 months, and cartridge presentations at roughly 31 months, the longest of all. Yet Kruskal-Wallis tests found no statistically significant differences in lag among device presentations, whether for Japan-first products (p = 0.088) or U.S.-first products (p = 0.299). The numerical spread, the authors argue, reflects historical and strategic factors rather than an intrinsic regulatory penalty attached to any particular device type. Many of the slowest approvals, notably multidose pen injectors and cartridges, clustered between 2006 and 2010, before Japan’s comprehensive drug lag countermeasures took effect and when some products still required parallel approval or certification as medical devices before pharmaceutical marketing authorization could proceed.

A pivotal regulatory shift helps explain why autoinjectors now cross the Pacific so quickly. In 2014, Japan’s health ministry issued a notification on combination products that eliminated dual submission requirements when the primary mode of action is pharmacological and the product falls within the combination product guidance. Integrated pen injectors and autoinjectors could thereafter proceed solely under the pharmaceutical pathway, shortening review times substantially. Autoinjector approvals have risen sharply since 2015, coinciding with both this guidance and Japan’s broader drug lag mitigation efforts. The authors also observed that Japan had roughly twice the U.S. proportion of products approved with autoinjector-only presentations, suggesting that some sponsors now skip the traditional stepwise sequence from vial to prefilled syringe to autoinjector and develop the advanced device directly, potentially accelerating market introduction.

The deeper divergence between the two countries lies not in which devices are approved but in how many are approved at once. In the United States, 77 percent of brands had secured approval for multiple presentations, compared with only 66 percent in Japan. U.S. sponsors frequently submitted a full suite of formulations, vials, prefilled syringes, and autoinjectors together, at initial approval, allowing clinicians to tailor treatment to patient-specific needs, preferences, and financial circumstances. Japan more commonly adopted a stepwise approach, approving basic presentations first and adding device presentations later. The authors attribute this pattern to cautious assessment of return on investment in a market whose global share has fallen from roughly 25 percent in 1998 to 4.4 percent in 2023, established clinical practice norms, challenges in adopting multiple presentations within healthcare institutions, and the administrative burden of maintaining and withdrawing marketing approvals.

Packaging adds a further layer of regulatory friction that is easy to overlook. Nine percent of products showed differences in package components between the two countries, and 4 percent differed in device configuration, with injection devices from different manufacturers carrying distinct designs and form factors. Some component differences were stark: needles were packaged with the product in the United States but not in Japan. The root cause is not corporate whim but divergence in the definitions and regulatory scope of combination products, including the allowable range of components that may be included within a single product submission. Because an identical package often cannot be supplied to both markets, companies must prepare Japan-specific packaging with unique component configurations. This prolongs pre-submission preparation, contributes to approval lag, and after approval increases supply chain complexity, posing risks not only to operational efficiency but to stable product supply, a concern that has grown more acute as device components advance and diversify.

The structural backdrop to drug loss in Japan remains sobering. As of March 2023, 86 products, or 60.1 percent of drugs unapproved in Japan, had already been approved in both the United States and the European Union without entering Japanese development, and 72 of those originated from emerging biopharma companies, orphan drug programs, or pediatric indications. Uncertainties in revenue projections under Japan’s unique drug pricing system, including concerns about price reductions, and the shifting economics of global pharmaceutical development continue to depress the priority assigned to the Japanese market. Against that landscape, the new finding that device presentations themselves face no significant additional barrier is genuinely reassuring, and it reframes the policy conversation: the battle for patient access is won or lost at the level of the molecule, not the injector.

The authors propose three remedies: accelerating compound approval in Japan, promoting simultaneous development of multiple device presentations from the initial submission stage, and enhancing international harmonization of regulatory concepts and scope for combination products, including alignment on component requirements and packaging standards. Such harmonization, they argue, would streamline review, expand user choice, and strengthen supply chain robustness. The study is the first systematic quantitative comparison of Japan-U.S. approval patterns for biologic drug delivery devices, and the authors acknowledge its limitations: small-molecule and vaccine devices were excluded, withdrawn products may not have been fully captured, and some products classified as unapproved may represent future device lag rather than permanent loss. Future research incorporating review documents, company submission strategies, and pre-submission consultation records, they note, will be essential for fully elucidating the drivers of approval lag by device. For now, the message for regulators and developers alike is clear: harmonize the packaging, accelerate the molecule, and the devices will follow.

Subject of Research: Approval lag and loss for biologic-device combination products in Japan and the United States

Article Title: Approval lag and loss for biologic-device combination products in Japan and the United States

Article References: Mochizuki, M., & Maeda, H. (2026). Approval lag and loss for biologic-device combination products in Japan and the United States. Frontiers in Medical Technology, 8, Article 1924169. https://doi.org/10.3389/fmedt.2026.1924169

Image Credits: AI Generated

DOI: 10.3389/fmedt.2026.1924169

Keywords: Approval, loss, biologic-device, combination, products, Japan, United, States, scientific research