Consideration in the Development of Drugs for Pulmonary Arterial Hypertension in Japan

1. Background and Purpose

Pulmonary arterial hypertension (PAH) is a serious, progressive vascular disease that leads to increased pulmonary arterial pressure and vascular resistance, potentially resulting in right heart failure and death. In Japan, PAH is designated as an intractable disease, with thousands of patients requiring targeted therapeutic options. Although several treatments with different mechanisms and routes of administration have been approved, unmet medical needs remain for patients whose prognosis is not sufficiently improved by existing therapies. To aid planning of future PAH drug development, the PMDA issued an Early Consideration document outlining key clinical development considerations. ([turn0view0]

2. Strategic Clinical Development Considerations

2.1 Multi-regional vs. Domestic Trials

Because PAH is a rare disease, conducting confirmatory trials in Japan alone with morbidity/mortality (M/M) events as primary endpoints is challenging. Therefore, early participation in multi-regional clinical trials (MRCTs) is recommended to strengthen the evidence package. If overseas confirmatory trials exist, sponsors may conduct comparative trials to evaluate efficacy and safety between Japanese and non-Japanese populations, aligning trial designs closely with referenced overseas studies where possible. ([turn0view0]

2.2 Primary Endpoints

The most scientifically rigorous primary endpoint for PAH confirmatory trials is a composite of M/M events (including clinical worsening and death), defined clearly in the study protocol. When event-driven designs are not feasible, alternatives such as pulmonary vascular resistance (PVR) or 6-minute walk distance (6MWD) may be acceptable, though 6MWD has limitations related to variability and clinical relevance. The choice of endpoints should reflect the goal of improving prognosis. ([turn0view0]

2.3 Secondary / Exploratory Endpoints

Secondary endpoints can include hemodynamic parameters (e.g., mean pulmonary arterial pressure, PVR), functional measures (e.g., exercise tolerance, WHO functional class), and other exploratory outcomes like echocardiographic parameters. These should be prespecified and justified in the protocol. ([turn0view0]

3. Study Design and Patient Considerations

3.1 Control Groups and Comparators

Confirmatory trials should generally be randomized, double-blind, comparative studies. Use of placebo with background therapy is acceptable, or active comparators (approved PAH drugs) may be used when demonstrating superiority or non-inferiority to existing therapies. ([turn0view0]

3.2 Target Patient Population

Study populations should include patients across the spectrum of PAH severity where the investigational drug is intended to be used. When concomitant use of existing PAH therapies is allowed, measures must be taken to minimize confounding effects on efficacy evaluation, such as requiring stable doses before study entry. ([turn0view0]

4. Dosage, Administration, and Safety

Careful specification of dosage and administration strategies is essential to allow dose adjustment, such as titration or dose reduction. Trial designs should also address safety monitoring over adequate durations, as PAH drugs are typically used long-term. Generally, safety data for at least 52 weeks of administration is expected. ([turn0view0]

5. Pediatric Development

PAH also affects pediatric patients, and PMDA strongly recommends planning pediatric development in parallel with adult trials. Given the limited number of pediatric patients with PAH and the difficulty of standalone confirmatory trials, strategies may include leveraging adult trial data to support pediatric efficacy, with primary endpoints and study designs adapted according to age and weight categories. Consultation with PMDA on pediatric planning and trial design is advised. ([turn0view0]

6. Early Engagement with PMDA

Consistent with Early Consideration principles, the document underscores the importance of consulting PMDA early in development planning to discuss proposed trial designs, endpoints, and overall strategy to ensure alignment with regulatory expectations and reduce potential delays during review. ([turn0view0]

References

• PMDA Early Consideration: Consideration in the development of drugs for pulmonary arterial hypertension (Office of New Drug II, Jan 7, 2025), Provisional Translation. ([turn0view0]