Regulatory considerations on the evaluation of companion diagnostics (CDx) in Japan

IntroductionCDx are getting very important in the drug development. Recent trends in developments and regulations of CDx in Japan will be introduced. A regulatory documents on the CDx has been released by the Ministry of... [ view full abstract ]

Introduction

CDx are getting very important in the drug development. Recent trends in developments and regulations of CDx in Japan will be introduced. A regulatory documents on the CDx has been released by the Ministry of Health Labor and Welfare (MHLW) in 2013, Additionally, two administrative notices, “Technical Guidance on Development of In Vitro Companion Diagnostics and Corresponding Therapeutic Products” and “Questions and answers (Q&A) on CDx and corresponding therapeutic products”, have been released. With these notification and administrative notices, Japanese regulation on CDx basically followed the principal of FDA to require co-approval of CDx with its related drug.

In addition, we introduce our approach to establish the reference cell lines for a validation of DNA sequence analysis for the NGS-based CDx. It is desirable to prepare a panel of cell strains with known mutations and provide a stable supply of standard materials

Methods

(Guidance documents)

A review committee was set up with members consisting of experts from industry, academia and government, together with concerned officers in PMDA, and MHLW. Then we classified the CDx based on their characteristics and extracted essential elements. Based on the discussions at the review committee, we prepared an evaluation criteria focused on the follow-on CDx,  

(Standard materials)

Knock-in mutant cell lines were prepared by the Crisper/Cas9 method in the HEK 293/17T cell lines. Knock-in mutants were isolated by direct sequencing of approximately 150 colonies.

Results and Discussion

We have established two guidance documents as “Considerations on the evaluation criteria for clinical performance of the equivalent CDx against an existing product for 1) sequence determinations, and 2) pathological examinations”. The detail of these guidances will be introduced together with a general concept for bridging CDx from a prototype to a final product in the development process

We created new cell lines artificially introduced known mutations by genome editing techniques against clinically useful cancer-related genes. Finally, we obtained knock-in mutant cell lines for 32 cancer-related genes. These cell lines are available from the JCRB cell bank.