Points to Consider in Developing Drugs for Pediatric Inflammatory Bowel Disease — PMDA Early Consideration Summary

In Plain Language

This document addresses the limited availability of approved treatment options for children with inflammatory bowel disease (IBD), even though many treatments have been developed and studied in adults. It sets out considerations for planning studies of drugs for pediatric ulcerative colitis (UC) and Crohn’s disease (CD), where patient numbers are small and some assessments, especially endoscopy, can place a greater burden on children. Developers should plan studies that assess efficacy, safety and pharmacokinetics, while considering whether adult study results can contribute to the evidence for children. The document discusses who to enroll, study design, dose selection, endpoints and statistical planning. Its aim is to support development and evaluation that address pediatric patients’ needs and allow appropriate comparison with adult results where relevant.

What This Guidance Covers

The document presents a basic approach to developing drugs for pediatric IBD: specifically, UC and CD. It focuses on clinical studies in pediatric patients, including the selection of participants, study design, efficacy assessment, statistical analysis and safety evaluation. It says that, in principle, clinical studies should investigate a drug’s efficacy, safety and pharmacokinetics in pediatric patients with UC or CD.

The considerations apply to development planning rather than prescribing decisions. They address circumstances where adult IBD development is already underway and adult clinical-study results may contribute to explaining a drug’s efficacy and safety in children. The document does not set out one study design for every product: it says the appropriate design depends on the information available when the pediatric study is planned, and recommends planning individual studies in consultation with PMDA.

The document describes a general challenge for pediatric development: smaller patient populations can make it difficult to design studies that provide sufficient evidence. It also notes a particular burden in IBD because endoscopy is important for diagnosis or assessment of disease activity and can be more burdensome for children than adults. Accordingly, developers need to consider how pediatric symptoms and disease activity will be assessed, rather than simply assuming adult assessment approaches will fit every pediatric study.

Why It Matters

PMDA explains that multiple treatments for IBD have been approved in Japan, but the clinical studies supporting approval for most of them involved adults aged 18 years or older. Pediatric dosage and administration had not been investigated for many of these treatments. As a result, the number of drugs approved for pediatric IBD was lower than the number available for adults, and product information called attention to the absence of pediatric clinical studies.

The document also describes why pediatric studies may need particular planning. Children with IBD may be a relatively small study population, and endoscopic examinations can impose a greater burden than in adults. At the same time, the document states that the pathophysiology and diagnostic criteria for UC and CD, and the overall treatment goals, are similar between pediatric and adult patients. That similarity can make adult evidence relevant in some development programs, but does not remove the need to consider whether responses to a drug could differ by age.

The treatment goals described are short-term improvement or remission of symptoms, followed by long-term maintenance of clinical and endoscopic remission. PMDA’s considerations aim to help developers plan pediatric studies that address these goals while taking account of feasibility, the available adult evidence and the characteristics of the pediatric population.

Key Recommendations

1. Plan to evaluate pediatric efficacy, safety and pharmacokinetics. In principle, clinical studies should be conducted to investigate all three in pediatric patients with UC or CD. The document recognizes that small populations may make it difficult to obtain sufficient evidence in some cases.

2. Use adult evidence thoughtfully, not automatically. Where adult IBD studies are already available, their results may be used in part to explain efficacy and safety in pediatric patients. Developers should consider potential factors that could lead to different drug responses in children and adults, and fully explain why using adult results as part of the pediatric evidence is appropriate. After pediatric study results are available, the developer should explain whether there is any evident difference between pediatric and adult results for efficacy, safety and pharmacokinetics.

3. Make pediatric and adult studies comparable where possible. If adult results are to contribute to the explanation of pediatric efficacy and safety, the severity of enrolled patients, endpoints and assessment timing should be the same as in adult studies as much as possible. The document also calls for similar primary and secondary endpoints and evaluation time points, including induction and maintenance phases, when adult results are being used to support pediatric evaluation.

4. Choose participants to reflect intended pediatric use. The study population should include patients across various ages as much as possible, based on the ages of children likely to receive the drug in clinical practice. The document says it is preferred to include certain older pediatric patients in adult studies to evaluate efficacy and safety together with adults when they are expected to have the same drug exposure as adults, similar dosage and administration are expected, and the same drug is available. It refers to patients aged 10 or 12 years and older in this context.

5. Define diagnosis, severity and treatment history carefully. It is appropriate to enroll patients with a definitive diagnosis of UC or CD, with other diseases ruled out based on endoscopic and biopsy-based histological findings. Disease severity should be selected using appropriate indices and should reflect the drug’s clinical positioning and the patients expected in practice. If adult study results contribute to pediatric evaluation, the pediatric severity should match the severity defined in the adult study. Treatment-history criteria should also reflect intended clinical use and the treatment history of pediatric patients. When previously treated patients are included, it is desirable to determine in advance the proportion enrolled according to prior biological-product treatment. If adult evidence is used, matching the proportions of previously treated and untreated patients is preferred where possible, considering differences in actual use between children and adults.

6. Consider randomized controlled studies first, with feasibility in view. In principle, the conduct of randomized controlled studies should be considered. If a domestic randomized controlled study in Japan is difficult because of participant numbers, a global randomized controlled study may be possible; conducting or participating in one should be considered. A single-arm study may be an option if an appropriate feasibility survey indicates that a randomized controlled study is extremely infeasible. The document gives accumulated experience of use in pediatric patients and inability to expect enrollment in a placebo-controlled randomized study as examples of circumstances in which a single-arm study may be selected.

7. Plan for long-term assessment when the drug is intended for maintenance. For drugs expected to be used long-term to maintain remission, the study period should be at least 1 year to assess long-term efficacy and safety. Dose selection should refer to adult dose/exposure-response data when available. If it is uncertain whether a similar dose/exposure-response relationship applies in pediatric patients, additional information is needed; pediatric pharmacokinetic data from other diseases may, for example, help determine a dose for pediatric UC or CD.

8. Set sample size to balance evidence and feasibility. For a global study, participation from Japan should be considered. The Japanese sample size is recommended to take account of feasibility, balance with planned enrollment in other countries, and evaluation of consistency between results in the overall population and the Japanese population. For a domestic Japanese study, the target sample size should ensure sufficient power while taking feasibility into account. If adult or overseas results contribute to efficacy and safety data, the sample size should be defined to obtain results comparable with those studies. In either global or domestic studies, age groups should be represented as appropriately as possible to evaluate efficacy and safety by age group.

9. Evaluate induction and maintenance efficacy appropriately. For drugs expected to be used in both phases, efficacy should be evaluated in both. If the primary endpoint addresses only induction or only maintenance, the other phase should be evaluated as a secondary endpoint; maintenance is prioritized as the primary endpoint in that situation. The primary endpoint should also be selected with the potential effect on the marketing-approval indication in mind.

10. Plan statistical analyses before the study begins. The analysis plan should be specified in advance and documented in the protocol and/or statistical analysis plan, according to the role of each analysis. For a single-arm study, it is preferred to specify the primary and key secondary analyses before the first participant is enrolled. The primary analysis of the primary endpoint should generally use statistical hypothesis testing or a similar approach. Even when feasibility limits the power that can be expected, criteria for study success based on statistical considerations should be defined in advance. For a single-arm study, the primary endpoint should demonstrate efficacy exceeding a prespecified threshold; statistical hypothesis testing is recommended. If sufficient power cannot be ensured, success criteria based on comparison with a statistically considered threshold should still be specified in advance, using estimation-based methods or similar approaches as appropriate.

11. Address the estimand, interim events and missing data prospectively. The estimand—including the study population and primary endpoint—should be clarified in advance. The primary estimand should be clearly defined in the protocol in line with the study’s primary objective. The definition and handling of interim events, such as stopping the investigational drug, should be considered before appropriate sensitivity analyses are predetermined. How missing data will be handled should also be specified in advance.

12. Assess growth and longer-term safety. Because growth failure is a consideration in pediatric IBD treatment, the use of corticosteroids that cause growth failure should be kept as short as possible. In pediatric studies, it is preferred, if possible, to assess indicators of growth such as secondary sexual characteristics and bone age, in addition to height and body weight. For drugs expected to be used long-term to maintain remission, long-term safety should be evaluated using clinical-study results from a treatment period of at least 1 year.

Practical Implications

Interpretation: The document’s emphasis on planning makes early alignment between clinical, statistical, pharmacology and regulatory teams important. Teams can use the intended pediatric population and likely clinical use to shape eligibility criteria, age-group representation, endpoints and the evidence needed to support dose selection. These choices are connected: for example, using adult results as part of the pediatric evidence increases the importance of explaining potential age-related response differences and aligning study severity, endpoints and assessment timing where possible.

Interpretation: Feasibility is not presented as a reason to skip statistical planning. Even if the expected sample size cannot provide sufficient power, the document calls for advance criteria for study success based on statistical considerations. A possible single-arm design also brings a specific planning issue: the study should have a prespecified threshold against which the primary endpoint can show that efficacy exceeds that threshold. Teams will need to justify the threshold and set out the analysis approach before enrollment.

Interpretation: For clinical operations, the document points to the practical tension between obtaining endoscopic information and limiting examination burden in children. It says that total colonoscopy is desirable wherever possible for UC assessment, while also saying that the burden of the examination for pediatric patients needs consideration. For study teams, this means the planned assessments should be considered alongside feasibility and the need to make pediatric results interpretable in relation to adult studies.

Interpretation: For global programs, Japanese participation and Japanese sample size are planning questions, not simply enrollment targets considered in isolation. The document ties the Japanese sample-size recommendation to overall study balance, feasibility and the evaluation of consistency between results for the full study population and Japanese participants. Likewise, age-group sample sizes matter because the document encourages evaluation across age groups as much as possible.

Technical Details

The document names several activity indices but does not provide scoring cutoffs or a complete measurement manual. It describes the indices as composite scores made from specified components. These summaries help clarify what the document means by selecting an “appropriate index”; the index should suit the disease and study purpose.

• For UC: Mayo Score (MS) combines stool frequency, rectal bleeding, endoscopy and physician’s global assessment. The modified Mayo Score (mMS) consists of the four MS subscores except physician’s global assessment.
• For CD: Crohn’s Disease Activity Index (CDAI) combines stool frequency, abdominal pain, global health status, extraintestinal complications, use of antidiarrheal medications, abdominal mass, hematocrit and weight.
• For pediatric CD: Pediatric Crohn’s Disease Activity Index (PCDAI) combines abdominal pain, patient function and global health status, stool frequency and form, hematocrit, erythrocyte sedimentation, albumin, weight, height, abdominal pain and abdominal mass, perirectal lesion, and extraintestinal complications.
• For endoscopic CD assessment: Simple Endoscopic Score for Crohn’s Disease (SES-CD) combines size of ulcer, area of ulcer, area of lesion and presence or absence of stenosis.

The efficacy endpoint recommendations differ by disease. For UC, clinical remission based on indices such as MS and mMS is recommended as the primary endpoint. The document recommends evaluating clinical improvement, steroid-free remission, endoscopic improvement, endoscopic remission and maintenance of clinical remission as secondary endpoints. Total colonoscopy is desirable wherever possible, with the examination burden for children taken into account.

For CD, the document recommends considering co-primary endpoints, taking feasibility into account: (1) clinical remission based on indices such as CDAI and PCDAI, and (2) endoscopic remission or endoscopic improvement based on indices such as SES-CD. The purpose is to demonstrate efficacy for both endpoints. Recommended secondary endpoints include clinical improvement, steroid-free remission, the endoscopic outcome not selected as primary, and maintenance of clinical remission.

In single-arm studies, the document calls for a prespecified threshold for the primary endpoint, so that the analysis can assess whether the study drug’s efficacy exceeds it. Possible sources for setting a threshold include the placebo group in randomized clinical studies of the drug in adults, and a meta-analysis of placebo groups in randomized controlled studies of other drugs in pediatric or adult patients with the same severity and treatment history as the planned pediatric study. These are potential reference sources described in the document, not a fixed formula or universal threshold.

The estimand is another advance-planning concept in the document. It should identify the population and primary endpoint and correspond to the study’s primary objective. The protocol should also clarify how interim events—such as discontinuation of the investigational drug—are defined and handled, and specify appropriate sensitivity analyses and missing-data handling in advance. The document emphasizes comprehensive interpretation of results: primary and secondary endpoints matter, especially where feasibility limits power, and pediatric results should be checked for evident differences from adult results when adult evidence contributes to the pediatric efficacy explanation.

Who Should Read It

This document is relevant to sponsors and development teams planning clinical studies of drugs for pediatric UC or CD, particularly when adult clinical-study results are available or a global study is being considered. It may also be useful to clinical and medical teams selecting pediatric eligibility criteria and disease-activity assessments; statisticians drafting sample-size assumptions, estimands and analysis plans; clinical operations staff assessing enrollment and examination feasibility; and regulatory teams preparing the rationale for pediatric dose, efficacy and safety evaluation. Investigators and other professionals involved in pediatric IBD studies may find its discussion of age groups, treatment history, remission phases and growth monitoring useful when considering study plans.

Official PMDA Source

• Official title: “Points to Consider in Developing Drugs for Pediatric Inflammatory Bowel Disease (Early Consideration)”
• Issuing body: Pharmaceuticals and Medical Devices Agency, Office of New Drug I
• Date on the document: March 24, 2025
• PMDA PDF: Official PMDA 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 provides the English version for reference, and the Japanese original prevails if the two versions differ. PMDA describes Early Consideration documents as reference information reflecting its views at the time of publication; those views may change as scientific knowledge develops.

Related Clinical Biostats Resources

• All Clinical Biostats tutorials — Browse other educational tutorials on clinical research and statistics.
• Statistical Calculators — Access calculators that may assist with statistical planning and analysis.