Technical Guidance on Development of In Vitro Companion Diagnostics and Corresponding Therapeutic Products in Japan

1. Background

With advancements in human genome and proteome analysis, biological molecules involved in diseases (such as malignant tumors) have been identified. This has enabled personalized medicine, including therapeutic products based on molecule expression or mutations and patient selection using biomarkers. The Japanese government supports this through the “Strategic Market Creation Plan” under the “Japan Revitalization Strategy” (Cabinet approval on June 14, 2013), aiming to extend healthy life expectancy. In vitro diagnostics (IVDs) used for selecting therapeutic products are called “in vitro companion diagnostics.” Their performance directly affects therapeutic product efficacy and safety. Cooperation between developers is essential for simultaneous availability. Basic concepts are outlined in the “Notification on Approval Application for In Vitro Companion Diagnostics and Corresponding Therapeutic Products” (PFSB/ELD Notification No. 0701-10, dated July 1, 2013). https://www.pmda.go.jp/files/000153149.pdf

2. Purpose

This guidance organizes technical information for developers of therapeutic products and in vitro companion diagnostics to facilitate development and approval reviews. It covers clinical trials for therapeutic products related to in vitro companion diagnostics, timing of diagnostic validation, clinical significance, concordance studies, and more. Strict compliance is not required; consultations with PMDA on a case-by-case basis are recommended. https://www.pmda.go.jp/files/000153149.pdf

3. Scope

Applies to in vitro companion diagnostics and corresponding therapeutic products as defined in the Director Notification. Section 2.1 assumes patient identification mainly using diagnostics based on existing knowledge, with subsections 2.1.1 and 2.1.3 focused on molecular targeted drugs but applicable to others, such as optimizing dosage or discontinuation decisions. https://www.pmda.go.jp/files/000153149.pdf

4. Basic Principle

For in vitro companion diagnostic applications, data supporting performance are required. For therapeutic products, data must show clinical utility of the validated diagnostic in identifying treatable patients. https://www.pmda.go.jp/files/000153149.pdf

5. Clinical Trials for Therapeutic Products Related to In Vitro Companion Diagnostics

5.1 Handling of Biomarker-Negative Patients in Early Development Phase of Molecular Targeted Drugs, etc.

In molecular targeted drug development, patients may be limited to biomarker-positive cases. However, excluding negative patients hinders risk-benefit comparisons and clinical cut-off validation. Include both in early phases (e.g., exploratory studies) unless unlikely to show efficacy (from non-clinical/clinical data) or high toxicity risks unreasonable exposure. Base on pre-trial information; consult PMDA on design. https://www.pmda.go.jp/files/000153149.pdf

5.2 Necessity to Conduct Prospective Confirmatory Clinical Trials

Principle: Prospective randomized controlled trials for efficacy/safety verification. Retrospective analyses using stored samples are exploratory; if suggesting utility in positive patients, conduct separate prospective trials. Elaborate designs to evaluate biomarker qualification. Exceptions (consult PMDA): ethical difficulties, inappropriateness, or acceptable retrospective evaluation if meeting specific conditions (well-planned RCTs, validated methods, predefined hypothesis, multiplicity adjustment, consistent results from ≥2 trials). https://www.pmda.go.jp/files/000153149.pdf

5.3 Points to Consider in Conducting Prospective Confirmatory Clinical Trials

Plan assuming prior biomarker-negative inclusion/analysis. Select design based on data; may include both positive/negative if exploratory data suggests utility in negatives. Specify protocol details: randomization, blinding, hypothesis, sample size, multiplicity. https://www.pmda.go.jp/files/000153149.pdf

6. Development of Therapeutic Products and Timing of Validation of In Vitro Companion Diagnostics

Use fully validated diagnostics in confirmatory studies for proper patient identification. Validation includes analytical and clinical (cut-off) aspects. Consult PMDA if cut-off unclear due to small samples. Clinical validation evaluated in therapeutic product review; analytical in diagnostic review. Justify cut-off in applications; collaborate on filings. https://www.pmda.go.jp/files/000153149.pdf

7. Evaluation of In Vitro Companion Diagnostics

7.1 Clinical Significance of In Vitro Companion Diagnostics

Evaluated via therapeutic product clinical trials using the diagnostic. Developers must cooperate, sharing trial info (e.g., product names, methods, results summaries) for approval explanations. https://www.pmda.go.jp/files/000153149.pdf

7.2 Concordance Studies of In Vitro Companion Diagnostics

Basic view: If diagnostic not used in confirmatory trials, evaluate concordance with clinical trial methods or standards (e.g., WHO, JCTLM, CLSI, JCCLS). Select justifiable controls based on standards. Considerations: Use samples from therapeutic trials; if not, use equivalent criteria with proper management. Assess detection range, measurable range, predictive values around cut-off, and concordance. Ensure good positive/negative predictive values; discuss discrepancies. https://www.pmda.go.jp/files/000153149.pdf

7.3 Analytical Test Validation of In Vitro Companion Diagnostics

Clarify for reliability: accuracy, precision (repeatability, intermediate precision, reproducibility), reaction specificity factors, measurement range, analytical cut-off, reference standards, sample collection/processing/storage, assay conditions, non-specific reactions, false results prevention. Explain changes' concordance via validation results. https://www.pmda.go.jp/files/000153149.pdf

8. Explanation of Terms

• Biomarker: Measurable characteristic indicating biological processes, pathogenesis, or pharmacological responses.
• Clinical Utility: Improvement in therapeutic product efficacy/safety via biomarker measurement; enhances benefit-risk balance.
• Biomarker Qualification: Biomarker's reliability in reflecting response and supporting dosing (per ICH E16).
• Analytical Test Validation: Proves test reliability via managed precision, accurate measurement, reproducible results.
• Clinical Test Validation: Proves test's ability to predict disease/phenotype via sensitivity/specificity.
• Clinical Cut-Off: Value dividing biomarker-positive/negative based on risk-benefit; guides treatment.
• Concordance Study: Evaluates IVD concordance with controls for precision. https://www.pmda.go.jp/files/000153149.pdf

9. Practical Considerations

Developers of therapeutic products and in vitro companion diagnostics should cooperate closely. Consult PMDA on a case-by-case basis for specific designs and validation approaches. This guidance positions companion diagnostics development within personalized medicine frameworks. https://www.pmda.go.jp/files/000153149.pdf

10. Effective Date

The guidance was issued on December 24, 2013 (PMDA Notification No. 1224029), with an administrative notice dated December 26, 2013. https://www.pmda.go.jp/files/000153149.pdf