Around the Globe

Regulatory Utilization of Real-World Data and Real-World Evidence in Japan
Pharmaceuticals and Medical Devices Agency (PMDA) Chief Executive Perspective
Yasuhiro Fujiwara
PMDA Chief Executive

eal-world data (RWD) and real-world evidence (RWE) have been actively discussed worldwide in terms of utilization for regulatory decision-making on the benefit-risk assessment of drugs. In Japan, the Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have worked to promote the utilization of RWD and RWE throughout a medical product’s lifecycle, from pre-approval through development to the post-marketing phase.

In clinical trials, randomization is critical because it ensures comparability between groups and thereby minimizes potential bias in the allocation of test treatments. For this reason, a pivotal study supporting the efficacy and safety for marketing approval should be conducted in a randomized controlled manner, as long as such a study is feasible for the target disease or investigational intervention, as the basic foundation of generating quality evidence.
Yashuhiro Fujiwara against a blue background
PMDA Chief Executive
Yasuhiro Fujiwara
However, in cases when a randomized controlled trial cannot be conducted because of the limited patient population for rare diseases or other reasons, the PMDA has been making good use of RWD/RWE for regulatory decision-making.

For example, PMDA has implemented the following practices to obtain the pivotal justification for efficacy and safety: a comparison between the data from an uncontrolled study and the data from an observational study on the natural history as an external control, using objective endpoints such as survival rate; and a comparison between the data from an uncontrolled study and the data in patients who met the inclusion criteria at the site participating in the concerned study but did not receive the test treatment.

Nevertheless, there are diseases with unmet medical needs for which drugs, medical devices, and regenerative medical products have still not been developed owing in part to their extremely limited patient population. In response, the MHLW and the PMDA have endeavored to further promote RWD utilization, especially for early patient access to orphan products, for marketing applications or applications based on results of post-marketing re-examination/use evaluations or re-evaluations of drugs, medical devices, and regenerative medical products.

For example, the PMDA published guidelines for conducting pharmaco-epidemiological studies with medical information databases in drug safety assessments in 2014 and developed points to consider for ensuring the reliability of post-marketing database studies for drugs in 2018.

Moreover, the revised “Japan Revitalization Strategy” in 2015 adopted by the Cabinet (Cabinet decision on June 30, 2015) promoted the use of novel clinical development methodologies, more specifically by creating the clinical innovation network project to establish an infrastructure for clinical development based on the disease registry information. Since then, the PMDA has worked to promote the clinical innovation network project in collaboration with academia, the MHLW, and the Japan Agency for Medical Research and Development for the further utilization of registries in drug development. With reference to the need for utilizing registries, including disease registries and product registries in drug development in cases where traditional randomized clinical trials are not feasible (such as for orphan drugs), the PMDA developed two guidelines about basic principles for utilizing registries for applications and points to consider for ensuring the reliability of registry data for applications in March 2021.

These two guidelines apply to cases where registry data are mainly utilized in clinical study documents included in the application or notification (approval application, applications for re-examination/interim evaluation inspection/use-results evaluation, application for re-evaluation, application after conditional and time-limited approval, revision of package insert) for drugs, medical devices, and regenerative medical products submitted in accordance with the Pharmaceuticals and Medical Devices Act.

Registry data are expected to promote development of medical products when used as an external control in clinical trials or as data alternatives to clinical study results for a marketing application or utilized for the application of post-marketing re-examination/use-results evaluation or re-evaluation.

Reliability of collected data should be ensured in line with the purpose for utilizing these data. When considering registry data to be used in line with such purpose, a good understanding of data characteristics and management is important to avoid use of the registry data that could lead to wrong interpretations or conclusions relative to the development of medical products.

If the applicant (or sponsor/sponsor-investigator) considers using registry data for the marketing approval or other application related to a product, the applicant is expected to investigate potential registries and consult the registry owners at an early stage about identifying issues to address and potential actions to take for such usage. Applicants and registry holders should particularly consider personal data protection, including the appropriate procedures for obtaining informed consent from patients.

Moreover, since 2017, PMDA has provided new consultation services about use of RWD/RWE, such as pharmaco-epidemiological consultations on designing and planning post-marketing studies including a study utilizing RWD. In more recent years (2019 and 2020), PMDA also initiated consultations targeting the registry data and database-based studies not only for pharmacovigilance but also for new drug applications. These consultation services will offer opportunities for mutual understanding and problem solving between the PMDA and stakeholders, including industry, investigators, and registry holders, regarding studies for generating appropriate RWD and RWE.

Discussions regarding the acceptability of RWD and RWE for regulatory submissions in the review of approval applications and scientific consultations have continued to increase.

Based on all these experiences, PMDA has recognized two important premises that support use of RWD/RWE for regulatory decision-making. The first premise is the reliability and quality of the RWD in terms of accuracy, consistency, and completeness. RWD should be appropriately managed to provide data adequate for the study of regulatory submissions. The second is the appropriateness of the analytical methods used in a study. This should be based on the latest scientific knowledge and consider the characteristics of the RWD in consideration.

Practically, the required range and level of data reliability differ depending on the purpose of their utilization in evaluation or assessment in the regulatory setting; e.g., post-marketing surveillance, external control of clinical trials, or complement in addition to clinical study data. To avoid incorrect interpretations or erroneous conclusions about the benefit-risk of a product based on RWD, RWD should be utilized with a good understanding of the circumstances surrounding that data, such as its characteristics and management, to ensure that it fits with the study purpose.

Industry, registry or database owners, and related stakeholders are encouraged to have advance discussions about their utilization strategy with the PMDA through consultation services, especially in cases where RWD are to be used as the major evidence of the efficacy and safety of a product in applications for approval or post-marketing re-examination.

More experience about RWD utilization through the review of marketing approval applications and scientific consultations is expected to facilitate mutual understanding of important characteristics of RWD, leading to better RWD utilization in the regulatory setting and identification of practical solutions to challenges in this setting.

Moving forward, use of RWD in the regulatory setting will become more diversified in utilization purposes and data types; for example, utilization of RWD for evaluating product efficacy in addition to product safety, and various types of RWD, including registries, electronic health records, and other health-related information databases, are expected to increase. Development of more guidelines on RWD/RWE in Japan, such as general principles and data reliability standards for medical database utilization for marketing approval applications, will soon be needed. Updating existing guidelines will also be necessary in timely response to scientific advances based on accumulated experiences.

In April 2021, the PMDA established the RWD working group (RWD WG), which comprises multidisciplinary PMDA experts from various offices such as the office of new drug review, pharmacovigilance, nonclinical and clinical compliance, medical informatics, and epidemiology. The RWD WG discusses all regulatory issues relating to RWD/RWE, such as data reliability standards and methodological approaches, and promotes utilization of RWD in the Japanese regulatory framework. This group also plays an active role in sharing knowledge and experiences not only within MHLW/PMDA, but also with stakeholders, academia, and foreign regulatory authorities.

The PMDA will continue to make efforts to promote the appropriate utilization of RWD/RWE in the regulatory setting. We look forward to more discussions, international collaborations, and further accumulation of regulatory experiences aimed at facilitating appropriate RWE-based benefit-risk assessments of drugs, medical devices, and regenerative medical products.