Revised Points to Consider for Biomarker-Based Drug Approvals from Investigator-Initiated Trials in Rare Cancer Patients in Japan

1. Publication Details

Issued March 19, 2024 (provisional translation as of March 2025). Joint notification from Director of Pharmaceutical Evaluation Division and Director of Medical Device Evaluation Division, Pharmaceutical Safety Bureau, Ministry of Health, Labour and Welfare. https://www.pmda.go.jp/files/000274874.pdf

2. Background

This revision addresses policy on approval applications for drugs developed by investigator-initiated clinical trials in patients with rare cancer, where approval for corresponding companion diagnostics (CDx) cannot be submitted simultaneously. It incorporates handling for cases where in vitro diagnostics or medical devices approved for other indications are used as clinical trial assays. References previous notifications: “Notification on Approval Application of In Vitro Companion Diagnostics and Corresponding Therapeutic Products” (PFSB/ELD Notification No. 0701-10, dated July 1, 2013); “Points to consider for application for approval of drugs to be administered based on specific biomarkers that were developed by investigator-initiated clinical trials in patients with rare cancer” (PSEHB/PED Notification No. 0224-5 and PSEHB/MDED Notification No. 0224-1, dated February 24, 2023). https://www.pmda.go.jp/files/000274874.pdf

3. Policy Intent

To revise the previous joint notification by organizing policy on approval applications when in vitro diagnostics approved for other indications are used as clinical trial assays to identify subjects in investigator-initiated clinical trials for rare cancer drugs, allowing partial change approval prior to CDx approval under specific conditions. https://www.pmda.go.jp/files/000274874.pdf

4. Target Products

Drugs for which a partial change approval application is planned based on results from investigator-initiated clinical trials in patients with rare cancer, and where the marketing authorization holder of in vitro diagnostics cannot submit the approval application for the corresponding CDx at the same time. https://www.pmda.go.jp/files/000274874.pdf

5. Eligibility Criteria

A drug must meet all of the following:

1. The marketing authorization holder plans to make a partial change approval application based on the results obtained by an investigator-initiated clinical trial in patients with rare cancer.
2. The marketing authorization holder of in vitro diagnostics cannot submit the approval application for the corresponding CDx at the same time.
3. The applicant can explain that the efficacy and safety of the drug is expected to be equivalent to those in the subjects of the clinical studies when the relevant drug is used based on the results of cancer genome profiling test using a gene mutation analysis program, etc., that obtained a regulatory approval.
4. In vitro diagnostics approved for other indications are used as a clinical trial assay to identify subjects in the investigator-initiated clinical trial, and it can be explained that the efficacy and safety equivalent to those in subjects of the clinical studies will be expected when the relevant drug is used based on the results obtained from the relevant in vitro diagnostics or other alternative in vitro diagnostics. https://www.pmda.go.jp/files/000274874.pdf

6. Consultation Procedures

Request consultation in advance with Pharmaceutical Evaluation Division by submitting the attached “Application for consultation on drugs developed by an investigator-initiated clinical trial for rare cancer for which approval application for CDx cannot be made at the same time as the approval application for the relevant drug.” The form includes company name, requester details, contact information, preferred consultation dates, target drug and proposed indications, brand name and approval number of gene panel test or in vitro diagnostics used at enrollment (or alternative), rationale for equivalence of performance to clinical trial assay, and status of consultation with PMDA’s Office of New Drug regarding CDx development policy. https://www.pmda.go.jp/files/000274874.pdf

7. Approval Application and Review Expectations

For eligible drugs, a partial change approval application of the drug may be made prior to CDx approval application. Whether the in vitro diagnostics not approved as corresponding CDx can be used for identifying eligible patients will be determined in the drug review and described in the review report. https://www.pmda.go.jp/files/000274874.pdf

8. Procedure After Approval (Post-marketing Obligations)

Even after drug launch, discussions with marketing authorization holders of in vitro diagnostics should be continued for CDx development. https://www.pmda.go.jp/files/000274874.pdf

9. Practical Considerations

The notification applies to drugs falling under both (1) and (2) and either (3) or (4) in eligibility. Use of non-CDx in vitro diagnostics for patient identification is subject to final review determination. This revision builds on the 2013 notification on companion diagnostics and therapeutic products. Inform medical institutions and authorization holders; provide instructions. The Japanese original prevails in case of inconsistency. https://www.pmda.go.jp/files/000274874.pdf

10. Effective Date

Effective from March 19, 2024. https://www.pmda.go.jp/files/000274874.pdf