Consideration in the development of drugs for pulmonary arterial hypertension — PMDA Early Consideration Summary

In Plain Language

Pulmonary arterial hypertension (PAH) is a serious disease in which changes in the lung blood vessels raise pressure and can lead to right heart failure and death. The document sets out PMDA’s current considerations for developing PAH drugs in Japan, where the small number of patients can make some large trials difficult to conduct. It describes ways to plan confirmatory trials, including the preferred main outcome, alternatives that may be considered, and how to assess treatment effects. It also discusses consistent study design, patient selection, analysis, and longer-term safety data. Because PAH also affects children, the document strongly recommends planning pediatric development alongside development in adults.

What This Guidance Covers

The document concerns clinical development strategies for drugs to treat PAH in Japan. It covers the clinical data package and participation in multi-regional trials; confirmatory-trial design and endpoints; evaluation periods and safety data; statistical analysis; patient eligibility and concomitant PAH treatment; dosage and administration; and development for pediatric patients.

Its recommendations address confirmatory trials and related development planning. The document does not provide a general account of all PAH care, nor does it set out detailed advice on nonclinical studies, manufacturing, or the treatment of other forms of pulmonary hypertension. It refers to PAH and its clinical assessment, including pulmonary vascular resistance, six-minute walk distance, and World Health Organization functional class.

Why It Matters

PAH can cause serious illness, including right heart failure and death. The document notes that Japan has approved several PAH drugs with different mechanisms of action and routes of administration, but medical needs remain for patients whose prognosis is not sufficiently improved by existing treatments. Development of new therapies continues, along with discussion of how to evaluate their effects.

The treatment goal identified in the document is to improve prognosis. Yet PAH is a rare disease, making it difficult to conduct a confirmatory trial in Japan alone with morbidity/mortality events as the primary endpoint. These events, abbreviated as M/M events in the document, combine death and clinical worsening of PAH. The document therefore highlights multi-regional development and explains other possible approaches when an M/M-events trial is not feasible.

Children present a related challenge: the document says the number of pediatric patients with PAH is extremely limited, so a pediatric-only confirmatory trial using M/M events as the primary endpoint would be very challenging. It describes how adult trial results may help explain efficacy in children in certain circumstances, while still calling for pediatric-specific development planning and evaluation.

Key Recommendations

1. Plan the overall clinical data package with the rarity of PAH in mind. Since a Japan-only confirmatory trial with M/M events as the primary endpoint would be difficult, active participation in multi-regional clinical trials should be considered from early development.

   If overseas confirmatory-trial results are available, or such trials are underway but Japan’s participation is difficult, a strategy could include trials comparing efficacy and safety between Japanese and non-Japanese populations. These could be domestic or multi-regional trials involving countries or regions not participating in the referenced overseas trials. The aim would be to evaluate similarity of the results and explain efficacy and safety in Japanese patients with reference to the overseas results.

   A similarity-evaluation trial should align as closely as possible with the referenced overseas trials. If its design differs, the reasons should be explained and it should be demonstrated that similarity can still be evaluated. When an M/M-events primary endpoint is difficult to set, other endpoints that allow comparison with overseas trial results may be acceptable. Consultation with PMDA about specific study designs is strongly recommended.

2. Use an appropriate comparative design for confirmatory trials. In principle, the trial should be randomized, double-blind, and comparative, with an appropriate control group. Placebo may be used while appropriate PAH treatment is maintained. If the aim is to show superiority or non-inferiority to existing PAH drugs, the document says it is appropriate to use existing PAH drugs as the control.

3. Prefer M/M events as the primary endpoint, while defining events carefully. Because the treatment goal is to improve prognosis, M/M events are the most recommended primary endpoint. Nonfatal events should be selected for their relevance to survival and clinical significance; examples include hospitalization due to worsening PAH, lung transplantation, and appropriately defined disease progression. The protocol should define M/M events as specifically as possible. A blinded, independent endpoint adjudication committee should assess events centrally to reduce differences in judgments across sites and regions and support objective assessment.

4. Consider alternatives when M/M events are not feasible. Pulmonary vascular resistance (PVR) is an objective measure that has been reported to correlate with prognosis. If physical differences are expected in the study population, pulmonary vascular resistance index (PVRI), adjusted for body surface area, should be considered. Either change from baseline or rate of change in PVR may be used as the primary endpoint, and both perspectives are important to evaluate.

   Six-minute walk distance (6MWD) has been used as a primary endpoint in many trials of PAH drugs approved in Japan and overseas. However, it can be influenced by factors other than treatment, including age, height, learning effects, and patient motivation, and its relationship to prognosis in PAH has not been established. It is therefore no longer recommended as a primary endpoint in recent confirmatory trials. It may nevertheless be acceptable when PVR evaluation is challenging or when using 6MWD is considered appropriate for comparison with existing trial results.

5. Include other relevant efficacy measures and choose a suitable evaluation period. Secondary or exploratory endpoints may include pulmonary hemodynamic measures such as PVR or mean pulmonary artery pressure; exercise tolerance such as 6MWD; World Health Organization (WHO) functional class; echocardiographic measures such as estimated right ventricular pressure or tricuspid annular plane systolic excursion (TAPSE); and cardiopulmonary exercise test (CPET) measures such as peak oxygen consumption (peak VO2).

   For M/M events, an event-driven design may be appropriate. If the study uses a fixed evaluation period, its duration should account for the time needed to achieve a treatment effect in the target population. When PVR or 6MWD is the primary endpoint, 24 weeks may be considered for evaluation. Since PAH drugs are expected to be used for a long time in clinical settings, safety data for at least 52 weeks of administration is generally required.

6. Predefine analysis and manage the influence of existing treatment. Survival analysis of time to event is generally appropriate for comparing M/M events. For other endpoints, use analysis methods suited to their characteristics. The analysis plan should define how missing values and intermediate events will be handled. Depending on the components of M/M events, methods that account for the clinical importance of each component may be considered.

   Trials should include patients across the range of pulmonary hypertension symptom severity, classified by WHO functional class, for whom the drug is expected to be used in clinical settings. If patients may continue existing PAH drugs with different mechanisms of action, the study should minimize their impact on evaluation of the study drug. The document gives two measures: include patients who have received stable doses of existing PAH treatments for a certain period before study-drug administration, or prohibit changes to doses of existing PAH treatments during the study.

7. Specify dose-adjustment procedures and plan for pediatric development. If the regimen allows titration, dose reduction, or dose increase after reduction, the protocol should specify the timing and criteria for decisions as specifically as possible. In pediatric trials, the need for titration from a low dose to help ensure patient safety is appropriate to consider.

   It is strongly recommended to formulate a pediatric development plan in parallel with adult development. In children, consider trials to explore dosage and administration and the establishment of pediatric formulations. The document also recommends consulting PMDA on pediatric plans and specific trial designs.

Practical Implications

Interpretation: These considerations make early alignment across the clinical, statistical, operational, and regulatory teams particularly useful. The trial plan needs to connect the treatment goal—improved prognosis—to an endpoint that can be assessed credibly in the intended population and setting. Teams considering a similarity strategy should plan how the Japanese or additional regional trial will relate to the referenced overseas trial, and, if designs differ, how the difference will still allow results to be compared.

For trial operations, detailed endpoint definitions and blinded central adjudication are practical ways to support consistent decisions about whether an event qualifies. Where background PAH therapies continue, eligibility rules or restrictions on dose changes can help limit their influence on the study-drug assessment. Where dose adjustment is planned, clear protocol criteria and timing can make the treatment strategy interpretable across participants.

For statisticians and data teams, the document points to time-to-event analysis for M/M events and asks that missing values and intermediate events be addressed in advance. The different possible endpoint types also mean the analysis method should fit the endpoint rather than be selected generically. Longer-term safety collection matters even when the primary efficacy evaluation is shorter, because treatment is expected to continue over a long period in clinical practice.

For pediatric planning, the document’s approach calls for a parallel development plan rather than waiting until adult development is complete. The study design should allow a certain level of evaluation in each age or weight category, while recognizing that some age categories may not be suitable for the same endpoints used in adults.

Technical Details

The document does not give a formula for PVR or a numerical decision rule for selecting an endpoint. It distinguishes the main endpoint options by their stated properties and limitations:

• M/M events: the most recommended primary endpoint because the treatment goal is improved prognosis. A blinded independent committee should centrally assess events. Time-to-event comparisons are generally suited to survival analysis, and an event-driven design may be appropriate.
• PVR or PVRI: PVR is described as objective and reported to correlate with prognosis. If physical differences are expected, consider PVRI, which is adjusted for body surface area. A primary endpoint may be change from baseline or rate of change; the document says it is important to evaluate from both perspectives.
• 6MWD: potentially acceptable in the specified circumstances, but not recommended as a primary endpoint in recent confirmatory trials because of influences unrelated to the drug intervention and an unestablished relationship with prognosis. It may be considered when PVR evaluation is challenging or when appropriate for comparison with existing trial results.

The document also identifies a practical issue for PVR assessment: right heart catheterization is commonly performed in Japan to assess treatment effects, but performing this invasive test may be ethically challenging in other countries and regions. This is relevant when planning multi-regional studies and choosing measurements that can be applied across participating settings.

For pediatric development, the document describes a possible strategy under stated conditions. Because pediatric PAH is rare and pediatric-only M/M-events trials would be very challenging, adult confirmatory-trial results may be used to explain efficacy in children if PAH pathophysiology, diagnostic criteria, clinical classifications, severity classifications, and treatment algorithms are similar between children and adults, and if there are no significant differences in exposure when recommended doses are administered. In that situation, pediatric trial endpoints should be set based on comparability with adult trial results. The design should allow a certain level of evaluation in each age or weight category, while recognizing that the same endpoint as in adults may be difficult to use in some age categories.

Who Should Read It

This document is relevant to teams developing PAH drugs for Japan, especially those planning confirmatory trials or a multi-regional clinical development program. It may be useful to clinical and biostatistics teams selecting endpoints, defining events, planning analyses, and setting study duration; clinical operations teams addressing central event assessment and background treatment; and regulatory teams considering how Japanese data relate to overseas trial results.

It is also relevant to pediatric-development teams planning studies, dosage exploration, or pediatric formulations alongside adult development. Investigators and other professionals involved in PAH trials may find the sections on patient populations, functional class, invasive assessment, dose adjustment, and endpoint choices useful for understanding the development considerations presented by PMDA.

Official PMDA Source

• Official title: Consideration in the development of drugs for pulmonary arterial hypertension (Early Consideration)
• Issuing body and office: Pharmaceuticals and Medical Devices Agency, Office of New Drug II
• Date on cover: January 7, 2025
• PMDA PDF: Official PMDA document (PDF)
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Consult the official document for the full text; this summary does not replace it. PMDA provides the English version for reference, and the Japanese original prevails if the two differ. PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication, which may change as scientific knowledge develops.

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