Points to consider for the discussion with PMDA using the ICH S1B (R1) guideline and in the approval application — PMDA Early Consideration Summary

In Plain Language

The document explains how drug developers can use a weight-of-evidence (WoE) evaluation to consider whether a two-year rat carcinogenicity study would add useful information about human carcinogenicity risk. Rather than deciding from one test alone, the assessment brings together information about the drug and its target, findings from animal studies, and relevant published information. The document describes how developers can discuss a proposed exemption from the rat study with PMDA, including when to consult and what material to prepare. It also addresses situations where developers decide to conduct the two-year study, or where new information emerges after a consultation. These considerations are intended to support evaluation of risk while avoiding studies of low value for human safety and reflecting the 3Rs: replacement, reduction and refinement in animal use.

What This Guidance Covers

This Early Consideration document concerns discussions with PMDA using the ICH S1B (R1) guideline and the presentation of carcinogenicity assessment information in an approval application. Its central issue is whether a two-year rat carcinogenicity study adds value when the drug’s carcinogenicity is assessed through a comprehensive WoE evaluation. The document addresses the PMDA consultation process, materials for the pre-consultation meeting and S1B (R1) consultation, study timing and design considerations, responses to new information, and approval-application documentation.

The introduction describes the WoE approach as considering information obtained from nonclinical studies of drugs under development and publicly available information. Factors include biological properties of the drug target and primary pharmacological effects of the parent compound and its major human metabolites; secondary pharmacological effects of the parent compound and its major human metabolites; and histopathological data from a 26-week repeated-dose toxicity study in rats, including exposure margins, hormonal fluctuations, genotoxicity and immune regulation.

The document does not say that every drug is exempt from carcinogenicity studies. It says that developers should review the relevant WoE elements and select a development strategy: seek to waive the rat study based on the WoE evaluation, or perform the two conventional carcinogenicity studies in rats and mice, taking account of the timing of the approval application. If the waiver strategy is selected, the appropriateness of the WoE evaluation should be discussed with PMDA.

Why It Matters

Carcinogenicity studies have usually been conducted in two species, rat and mouse. The ICH S1B (R1) guideline introduces a WoE concept for evaluating carcinogenicity and deciding whether a two-year rat study would add value to assessment of human risk. The document connects this approach with the 3Rs: using alternative methods, reducing the number of animals used, and reducing animal pain. Its rationale is that studies with low value for human safety may be avoided when the evidence supports that conclusion, while the overall risk assessment remains comprehensive.

The document also recognizes that applying the WoE approach requires a discussion of the evidence and its interpretation. A consultation made before key information is available may not support that discussion: PMDA places particular emphasis on histopathological examination results from the final report of the 26-week rat repeated-dose toxicity study. The questions and answers therefore clarify when to seek consultation, what information to include, and what to do if the evidence changes.

Key Recommendations

1. Plan for the required pre-consultation meeting. A pre-consultation meeting is required before an S1B (R1) consultation. An application for the consultation can be made only if, based on the materials submitted and the issues outlined at that meeting, it is determined that an S1B (R1) consultation is possible. Consultation materials must be submitted approximately 13 weeks before the consultation.
2. Prepare a substantive draft for the pre-consultation where possible. PMDA recommends submitting the draft consultation materials whenever possible, so it can comment on aspects that are insufficiently explained. If a draft cannot be submitted, an outline of the materials, with supplementary explanations, may be submitted. If many issues remain to be arranged at the pre-consultation, PMDA may ask the developer to prepare material to resolve them and request another pre-consultation meeting.
3. Explain the evidence and the developer’s reasoning. Consultation materials should describe whether the drug target is novel, the rationale for the highest dose in the 26-week rat repeated-dose toxicity study, relevant histopathological findings (including changes judged to have no toxicological significance), and the developer’s discussion of each WoE element. When literature is used, provide an outline of it and explain the considerations drawn from it. For literature on carcinogenic modification related to the target’s biological properties and primary pharmacological action, research information about both promotion and inhibition of carcinogenic potential and include the findings. If the developer wishes to dismiss a finding of concern, the document says a detailed explanation is required.
4. Wait for the final 26-week rat study report before seeking an exemption consultation. The document says it is difficult to apply for an S1B (R1) consultation before the final report of the 26-week rat repeated-dose toxicity study is available. It advises requesting the required pre-consultation after obtaining that report, because the guideline gives special emphasis to the study’s results and histopathological considerations.
5. Evaluate WoE even when a two-year rat study is planned. The document says the ICH S1B (R1) guideline recommends WoE evaluation for all developed products requiring carcinogenicity studies under the ICH S1A guideline, to determine whether a two-year rat study should be conducted. Conducting that study without adequate WoE assessment is not recommended from the perspective of the 3Rs. If the WoE evaluation supports conducting the study, retain the rationale and describe the background in CTD section 2.6.6 and/or the two-year rat carcinogenicity study report. PMDA agreement on the appropriateness of the plan does not need to be obtained before starting the study.
6. Discuss the assessment separately with each authority for which an application is planned. In global development, an exemption consultation based on the WoE assessment should be discussed with each regulatory authority to which a marketing application will be submitted. The document notes that authorities may differ in their conclusions.
7. Revisit the assessment if relevant new evidence appears. If new results or information arise after a consultation concludes that the two-year rat study is unnecessary, evaluate their effect on the WoE assessment and review whether the study is needed. Examples include a positive mouse carcinogenicity study result, new information about the drug target’s biological properties or pharmacological mechanism (including carcinogenicity information about other drugs with the same mechanism), and tumorigenesis information from clinical studies. Discussion of the reevaluation with PMDA is also recommended, as appropriate, to reduce the chance that differences in views affect the development schedule or approval application.
8. Place the assessment in the application materials. If the two-year rat study is exempted under ICH S1B (R1), prepare a carcinogenicity assessment report describing the background and reasons for the decision. Store it in “Module 4.2.3.4, Rodent Carcinogenicity,” and provide the WoE assessment results in CTD section 2.6.6. If new results or information arise after the consultation, update the report.

Practical Implications

Interpretation for development planning: the document makes the 26-week rat study report a key input to a consultation about waiving the two-year study. Teams considering that route should plan the consultation sequence around availability of the final report, rather than assuming that an earlier study or an incomplete report will be enough to support the discussion.

Interpretation for evidence preparation: a WoE presentation is more than a collection of study summaries. The developer is expected to explain how each relevant item contributes to the assessment, describe findings that might appear concerning, and give a detailed rationale when disagreeing with such findings. Scientific, nonclinical and regulatory staff may therefore need to coordinate the interpretation of study data, exposure comparisons, pharmacology and published information.

Interpretation for regulatory and application teams: the document separates the consultation decision from the record required in the application. A decision to conduct the two-year study can be supported by a retained rationale and documentation in the study report and/or CTD section 2.6.6; a decision to exempt the study calls for a dedicated assessment report in Module 4.2.3.4 and WoE results in CTD section 2.6.6.

For a consultation package, the document also points to information on the drug’s background and the history leading to consultation; results and interpretation for each WoE element; comparisons of systemic exposure; supporting reports, literature and other relevant information; the latest investigator’s brochure; and, where applicable, other authorities’ decisions and the data supporting those decisions. The implementation guideline excerpt says Japanese materials should be submitted, with English materials also submitted if possible.

Technical Details

What the exposure comparison means. The implementation-guideline excerpt calls for a list comparing systemic exposure to the active ingredient at the proposed approved dosage and administration with exposure at each dose level in pivotal toxicity studies, including the NOAEL and maximum dose. NOAEL means the no-observed-adverse-effect level. The comparison may use Cmax, AUC, or other relevant measures as indicated in the excerpt. If there is a concern about metabolites, include a corresponding comparison of metabolite exposure; an existing list in the Investigator’s Brochure or similar material may be used instead.

Study selection and dose finding. If results from a 26-week rat study are sufficient to help select doses for a two-year rat carcinogenicity study, the 26-week study can be used as a dose-finding study for that carcinogenicity study. The document does not state that it is always suitable; its condition is that the results obtained are sufficient for dose finding.

Consultation materials in more detail. The excerpt from the implementation guideline identifies several categories: material outlining the consultation history and drug background, WoE results and interpretation; exposure-comparison lists for the active ingredient and, if relevant, metabolites; supporting final reports, literature and information, including knowledge of carcinogenicity study results for drugs with similar mechanisms of action; the latest investigator’s brochure; and decisions by foreign regulatory authorities about exemptions under ICH S1B (R1), together with the data submitted to support those decisions, if applicable. The document adds specific discussion points, including target novelty, the dose rationale for the 26-week rat study, histopathological observations and the developer’s interpretation.

Approval-application locations. For an exemption, the carcinogenicity assessment report belongs in CTD Module 4.2.3.4, “Rodent Carcinogenicity,” while results of the WoE assessment should also be provided in CTD section 2.6.6. These locations serve different parts of the application record: the report explains the background and reasons for the decision, and section 2.6.6 presents the assessment results.

Who Should Read It

This document is relevant to nonclinical safety scientists and toxicologists assessing carcinogenicity; pharmacologists and scientists contributing information about a drug target or mechanism; biostatisticians and data reviewers supporting the interpretation of study findings and exposure comparisons; and regulatory affairs and application teams preparing an S1B (R1) consultation or approval submission. It is also useful to clinical development teams who may need to consider new clinical information, such as tumorigenesis findings, in a reassessment after consultation.

It is particularly pertinent when a development team is considering an exemption from the two-year rat carcinogenicity study, deciding whether to proceed with that study based on a WoE evaluation, preparing consultation materials, or updating the assessment after new evidence becomes available.

Official PMDA Source

• Official title: Points to consider for the discussion with PMDA using the ICH S1B (R1) guideline and in the approval application (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Center for Product Evaluation
• Date on the cover: March 24, 2025
• English version: PMDA PDF (marked “Provisional Translation (as of March 2025)”)
• PMDA Early Consideration list: PMDA list page

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA list page. 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, which may change as scientific knowledge develops.

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