PMDA Set Out Points to Consider for Externally Controlled Trials in March 2025

The Pharmaceuticals and Medical Devices Agency (PMDA) published Points to consider for externally controlled trials as an Early Consideration dated 24 March 2025, issued through its Center for Product Evaluation. An English provisional translation was made available as of May 2025; the Japanese original is the authoritative version. Early Considerations set out the agency’s current thinking on emerging topics and are not formal binding requirements.

The document addresses trials in which a single-arm study is compared with an external control. Such trials are generally open-label and non-randomised, and the document identifies the inability to control for bias as one of their main limitations. It notes that various data sources, such as other clinical trials and real-world data (RWD), may be considered for use as external controls, and that the points to consider apply differently depending on the data source.

The PMDA does not present external controls as a substitute for randomisation in general. The document states that randomised controlled trials should be conducted as the clinical trials providing the main evidence of efficacy and safety for applications, with externally controlled designs considered where such trials are not feasible, for example in some rare diseases.

The Early Consideration explicitly does not address the reliability of RWD used as an external control. Instead it refers readers to related notifications, in particular the Ministry of Health, Labour and Welfare (MHLW) notification Points to Consider for Ensuring the Reliability in Utilization of Registry Data for Applications, dated 23 March 2021 (PSEHB/PED and PSEHB/MDED Notification No. 0323-2).

The 2021 notification applies where registry data are used as clinical data in applications, including for marketing approval. PMDA materials summarise four general areas it covers: personal information and consent, the reliability of registry data, the appropriateness of registry data for the intended use, and early consultation with the registry holder. Applicants are not required to meet every item, and PMDA materials note that the level of reliability required may vary with the purpose for which the data are used.

An earlier MHLW notification, Points to Consider for Ensuring the Reliability of Post-marketing Database Study (PSEHB/PED Notification No. 0221-1, dated 21 February 2018), covers the use of medical information databases for marketing approval, re-examination or re-evaluation data. A question-and-answer document issued in September 2022 extended guidance on these topics to registries and medical information databases. Japan’s MID-NET database, operated by the PMDA, has been in full operation since April 2018 under its own rules and Good Post-marketing Study Practice.

The PMDA offers consultations on registry use and on the reliability of registry data for marketing approval and post-marketing applications, including for medical devices. Its accumulated experience from these consultations informed the 2021 notification. Sponsors intending to use registry data as an external control should therefore consider both a consultation on trial design and a consultation on data reliability.

Conference material describes the Early Consideration as a summary of the PMDA’s current thinking on externally controlled trials, and cites the use of an externally controlled design drawing on data from previous clinical trials in a Japanese approval of vutrisiran. Secondary summaries of the document, including vendor white papers, state that they are not official translations and should be read with that in mind.

Sponsors planning an externally controlled trial for a Japanese application should first document why a randomised trial is not feasible or appropriate. The choice of external control source should be justified by its comparability with the trial population in terms of eligibility, prognostic factors, outcome definitions and timing, and the analysis should address the bias inherent in non-randomised comparison.

Where the external control comes from a registry or medical information database, the reliability expectations in the 2018 and 2021 MHLW notifications apply in addition to the Early Consideration. Early engagement with the registry holder, and with the PMDA through its consultation services, is the most direct way to confirm that the data and design will be acceptable.

For medical writers, the main task is to present the external control comparison transparently. Clinical study reports and application summaries should describe the source of the external control, the criteria used to select patients, how key variables were defined and aligned with the trial, how missing data were handled and which sensitivity analyses were performed. Where the same development programme is also being submitted in the United States or Europe, teams should check that the description of the external control is consistent across regions while meeting any Japan-specific expectations, including the reliability documentation required under the MHLW notifications.