Considerations for the Clinical Evaluation of Blood Coagulation Factor VIII and Factor IX Products for Pediatric Congenital Hemophilia — PMDA Early Consideration Summary

In Plain Language

This document discusses how to evaluate blood coagulation factor VIII (FVIII) and factor IX (FIX) products being developed for children with congenital hemophilia. It addresses how pediatric participants may be included in clinical evaluations alongside adults, and when evidence from children outside Japan may help support evaluation in Japanese children. The document considers children aged 12 years and older separately from children younger than 12, while noting that individual development plans may need different approaches. Its reasoning includes the similarities in disease, treatment aims and efficacy measures across age groups and between Japan and other countries described in the document. It also highlights gathering information about children during development and, where relevant, shortly after a product launches.

What This Guidance Covers

The document sets out considerations for clinical evaluation of FVIII and FIX products for congenital hemophilia in pediatric patients. It addresses two groups: children aged 12 years and older who may be evaluated together with adults, and children younger than 12 years who are not evaluated together with adults. It discusses the possible use of clinical trial evidence from non-Japanese children younger than 12 to evaluate efficacy and safety in Japanese children of that age, subject to conditions described in the document.

The scope is not limited to a single product formulation or dosing schedule. The document describes factor products broadly, including plasma-derived and recombinant products, and notes that recombinant products include standard half-life and extended half-life products. It also says the principles may be applicable to non-factor products, but recommends using scientific consultations with PMDA to consider individual clinical trial plans early in development. The document presents a development approach, does not deny other development strategies, and cautions that its principles may not apply in individual cases or may change as new findings emerge.

Why It Matters

The background is concern about “drug loss”: medicines approved in the European Union and the United States that are not developed in Japan. The document says that this concern also applies to medicines for children. PMDA describes efforts during consultations on adult drug development to check development status in Japan and elsewhere for medicines that may be used in children, and to encourage pediatric development in Japan.

For congenital hemophilia, products have often been evaluated in children aged 12 years and older together with adults. The document notes that, because the disease is rare, some products have been approved for use in children younger than 12 despite no clinical trial results in Japanese children being available at the time of approval. In these cases, the applications were supported by results in non-Japanese children and global clinical trial results that included Japanese participants aged 12 years and older. The document therefore describes how evidence across age groups and populations may be considered, and how pediatric information can be collected after launch when younger Japanese children were not studied in trials.

As context, the document describes congenital hemophilia as a condition caused by deficiency or dysfunction of FVIII or FIX. It states that the basic pathological condition, treatment policy and efficacy endpoints are similar in adults and children. That similarity informs the possibility of evaluating older children with adults, while the document retains conditions and case-by-case judgment rather than treating the approach as universal.

Key Recommendations

1. Children aged 12 years and older may appropriately be evaluated with adults. The document considers this appropriate for congenital hemophilia because the disease’s etiology and pathology, treatment policy and efficacy endpoints are similar in adults and children, and international co-development commonly uses 12 years as an age cutoff. The document refers to the general condition that the pediatric dosage regimen is expected to be the same as the adult regimen or within its range, and that the adult formulation can also be used for children.
2. Including children younger than 12 with adults may be possible, but it needs justification. If a development plan takes this approach, the document says it is necessary to justify the evaluation in terms of dosage regimen, evaluation method and other relevant considerations. It does not present younger-than-12 inclusion as the default approach.
3. Obtain pediatric information when children are evaluated with adults. The document says it is beneficial and worth implementing to obtain information on children, including blood pharmacokinetics (how the product behaves in the blood over time). It also says a subgroup analysis is worth performing when a sufficient number of pediatric participants is obtained.
4. Consider product-specific information collection after marketing. For children evaluated together with adults, the document says appropriate as-needed information collection should be considered for each product.
5. For younger-than-12 children, consider non-Japanese pediatric evidence under stated conditions. The document says that efficacy and safety data in non-Japanese children younger than 12 may be used to evaluate efficacy and safety in Japanese children younger than 12, and an application may be submitted without clinical study results in Japanese children of that age, provided the conditions in the document are met. These include availability of trial results that include Japanese patients aged 12 years and older and absence of clinically significant differences in efficacy, safety and other information between non-Japanese and Japanese patients aged 12 years and older.
6. Collect and communicate information after launch when trial data in younger Japanese children are unavailable. In that situation, the document says patient information should be collected shortly after product launch with emphasis on the target pediatric population, and the early post-marketing information obtained should be provided to healthcare professionals.
7. Participate in multi-regional clinical trials where possible. In its section on children younger than 12 who are not evaluated together with adults, the document says that, for multi-regional clinical trials, it is important for Japan to participate whenever possible, even if the number of Japanese participants is very small.

Practical Implications

Interpretation: For sponsors planning a global development program, the document makes the age grouping and the basis for combining evidence important planning questions. A plan that includes children aged 12 years and older with adults can draw on the similarities the document identifies, while still benefiting from pediatric-specific information. For younger children, a plan to rely on non-Japanese pediatric data needs to address the stated conditions rather than assume that evidence can be transferred without assessment.

Interpretation: Protocol and analysis planning can anticipate the information the document highlights. For example, sponsors may consider how pediatric blood pharmacokinetic information will be obtained and whether enough children may be enrolled to support a subgroup analysis. The document does not specify a minimum number for such an analysis; it says to perform one when a sufficient number of participants is obtained.

Interpretation: Regulatory and clinical teams may need to plan for evidence generation across development and after launch. If there are no trial data in Japanese children younger than 12, the document points to early post-marketing collection focused on the target pediatric population and sharing that information with healthcare professionals. It also states that collection should be considered as appropriate for each product, so the approach is product-specific rather than described as a single fixed plan.

These practical points explain how the document’s considerations may affect planning; they are not additional PMDA requirements beyond the document’s own wording.

Technical Details

Disease and treatment context. Congenital hemophilia is described as an X-linked recessive inherited bleeding disorder caused by deficiency or dysfunction of FVIII (hemophilia A) or FIX (hemophilia B). Severity is classified by the activity level of the relevant coagulation factor: severe is <1%, moderate is ≥1% to <5%, and mild is ≥5% to <40%. The document says clinical symptoms are similar in hemophilia A and B despite the different deficient factors.

The treatment principle described is replacement of deficient coagulation factors, including administration in the early stage of bleeding. The document identifies on-demand replacement therapy, preliminary replacement therapy and prophylactic therapy. It distinguishes plasma-derived factor products from recombinant products; recombinant products are further divided into standard half-life and extended half-life products. Because individual extended half-life products have different half-lives, the document says their dose and dosing frequency are to be determined with reference to the package insert.

Repeated factor replacement therapy may lead to neutralizing antibodies, called inhibitors. The document reports this in 20% to 30% of patients with hemophilia A and 3% to 5% of patients with hemophilia B. It describes bypassing hemostatic therapy and inhibitor-neutralizing therapy as approaches to hemostatic management in patients with inhibitors, and also describes immune tolerance induction therapy. Non-factor products are discussed as options for periodic prophylactic treatment, but the document notes that they are not intended for hemostasis at the time of bleeding; separate hemostatic control using factor products is required at bleeding and invasive treatment.

Efficacy measure. The therapeutic goal is bleeding control. The document identifies the annualized bleeding rate (ABR) as the measure generally used for clinical evaluation of efficacy in both adults and children. This shared endpoint is part of the rationale for evaluating children with adults when appropriate.

Age-group evaluation. For children aged 12 years and older, the document’s approach is consistent with the practice it describes in pivotal trials and with the similarity of disease and treatment between adults and children. For younger children, evaluation together with adults may be possible, but the dosage regimen, evaluation method and other aspects need justification. In either case, the document describes evaluation strategies as considerations, not a principle that applies in every individual case.

Evidence for Japanese children younger than 12. The document’s proposed use of non-Japanese pediatric efficacy and safety data is conditional. It assumes clinical trial results that include Japanese patients aged 12 years and older and no clinically significant differences between Japanese and non-Japanese patients aged 12 years and older in efficacy, safety and other information. Its supporting rationale is that the epidemiological profile, disease pathology, and concepts of on-demand treatment and prophylaxis are similar in Japan and overseas; intrinsic and extrinsic ethnic factors are not considered to have a significant impact on efficacy and safety of coagulation factor products; and doses are usually specified based on body weight, which is not expected to have an apparent impact. The document’s conclusion is that, on this basis, an application may be submitted without trial results in Japanese children younger than 12. It does not say that the conditions can be omitted.

Who Should Read It

This document is relevant to sponsors and clinical development teams planning FVIII or FIX product studies for congenital hemophilia, particularly teams deciding whether to evaluate children with adults or how to support development in children younger than 12. Biostatisticians and clinical pharmacology teams may find its discussion of pediatric subgroup analyses and blood pharmacokinetic information useful. Regulatory affairs and medical writing teams may use it to understand the rationale and conditions described for considering non-Japanese pediatric evidence. Clinical operations and investigators involved in pediatric trials or post-marketing information collection may also find its age-group and pediatric follow-up considerations relevant.

Official PMDA Source

• Official title: Considerations for the Clinical Evaluation of Blood Coagulation Factor VIII and Factor IX Products for Pediatric Congenital Hemophilia (Early Consideration)
• Issuing body: Office of Vaccines and Blood Products, Pharmaceuticals and Medical Devices Agency
• Date on the cover: May 22, 2026
• 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; this summary does not replace it. PMDA describes Early Consideration documents as reference information reflecting its views at the time of publication, which may change as scientific knowledge develops. The English version is provided for reference purposes, and the Japanese original prevails if the two differ.

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