Writing in the October edition of DIA’s Global Forum magazine, Chief Executive of Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) Yasuhiro Fujiwara outlines how his agency has begun to utilise real-world data (RWD) and real-world evidence (RWE) in its regulatory decision-making processes and how this will evolve moving forward.
Real-world data (RWD) and real-world evidence (RWE) have been actively discussed worldwide in terms of utilisation 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 utilisation of RWD and RWE throughout a medical product’s lifecycle, from pre-approval through development to the post-marketing phase.
In clinical trials, randomisation is critical because it ensures comparability between groups and thereby minimises 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 randomised 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.
However, in cases when a randomised 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 utilisation, 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 utilisation of registries in drug development. With reference to the need for utilising registries, including disease registries and product registries in drug development in cases where traditional randomised clinical trials are not feasible (such as for orphan drugs), the PMDA developed two guidelines about basic principles for utilising 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 utilised 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.