Reflection Paper on Drug-Agnostic Companion Diagnostics in Japan

1. Background and policy intent

Issued based on a report from the Pharmaceuticals and Medical Devices Agency (PMDA) as referenced in an Administrative Notice dated July 4, 2022, from the Ministry of Health, Labour and Welfare. Builds upon the Notification on Handling of In Vitro Diagnostics and Medical Device Products aiming Drug-agnostic Companion Diagnostics (Notification No. 0331-1, dated March 31, 2022). PMDA developed this guidance on evaluation for eligibility of drug-agnostic companion diagnostics (drug-agnostic CDx), points to consider in development of relevant in vitro diagnostics and drugs, and includes Questions and Answers (Q&A) in Attachment 2. Purpose: To facilitate development and review of drug-agnostic CDx and related therapeutic products. Note: Concepts are based on current scientific knowledge and may be reviewed/revised as needed with advances in science, technology, and knowledge accumulation. Source: https://www.pmda.go.jp/files/000248182.pdf

2. Target products and eligibility types

Drug-agnostic CDx: When multiple companion diagnostics (CDx) products are approved for the same intended use (target disease, biomarkers, and specimen type) but for different corresponding therapeutic products, these can be designated as drug-agnostic CDx if it is scientifically reasonable to use the test results of any CDx product interchangeably to aid in identifying eligible patients for treatment with the other relevant therapeutic products. Interchangeable use: Scientifically reasonable range determined on a case-by-case basis, considering biomarker characteristics and assay principles. High percentage of concordance in equivalence studies with predicate CDx as a basis for validity. For CDx detecting multiple variants of a specific gene: Concordance demonstrated in typical patient populations; differences limited to rare variants. For CDx with different assay principles (e.g., immunohistochemical staining, in situ hybridization, genetic testing using next-generation sequencer): Possible if discrepancies are manageable, and physicians with sufficient knowledge can identify eligible patients based on test guidance from academic societies, understanding assay characteristics and limitations. Source: https://www.pmda.go.jp/files/000248182.pdf

3. Consultation pathway before approval

For therapeutic products using drug-agnostic CDx in cases where equivalence study conducted between CTA and approved drug-agnostic CDx, demonstrating analytical equivalence, or no equivalence study but analytical equivalence explained via comparison of CTA validation reports with published information on approved drug-agnostic CDx: Consult PMDA in advance via Office of New Drug and Office of In Vitro Diagnostics and/or Office of Medical Devices I. Use categories like CDx development package consultation or clinical trial necessity consultation as needed, in cooperation with marketing authorization holder of drug-agnostic CDx. Attach consultation minutes to application dossier for new therapeutic product approval. Source: https://www.pmda.go.jp/files/000248182.pdf

4. Approval application and review expectations

Eligibility Evaluation Flow for Drug-agnostic CDx: Evaluated based on (i) percentage of concordance in equivalence studies between approved CDx products, and (ii) percentage of concordance in equivalence studies between approved CDx and laboratory validated tests established as a standard method. Supporting references: Peer-reviewed published papers demonstrating concordance; test guidance from relevant academic societies; opinions from medical experts. For Changing Conventional CDx to Drug-agnostic CDx: Application for partial change to modify intended use (not limited to specific therapeutic product). Additional precaution statements in package inserts and risk management based on eligibility assessment report. Consider changes in product design or revalidation of performance if necessary. For Follow-on Drug-agnostic CDx: Submit results of equivalence study with one approved drug-agnostic CDx as rationale for clinical performance. In principle, select predicate product with the same assay principle. Novel assay principles possible, but acceptance criteria for concordance percentage determined case-by-case and discussed with PMDA in advance. Source: https://www.pmda.go.jp/files/000248182.pdf

5. Procedure after approval (post-marketing obligations)

Precautions in Package Inserts for Changed CDx: Healthcare professionals should follow test guidance issued by relevant academic societies. Caution on considering specific characteristics of diagnostic products when selecting assay method and interpreting results. For in vitro diagnostics: Use to identify eligible patients based on thorough knowledge of clinical/analytical performance in inserts. For medical devices: Use based on thorough knowledge of clinical performance and equivalence study results in inserts. Refer to PMDA website to confirm which drug-agnostic CDx can aid in identifying eligible patients for relevant therapeutic products. Source: https://www.pmda.go.jp/files/000248182.pdf

6. Practical considerations and positioning versus other pathways

Q&A Highlights: Q1: Possible to apply same procedures for partial change if interchangeable use is scientifically reasonable (A1: Yes). Q2: Consultation category for cases in 5(2) and (3): Include in major clinical trial consultation; use specific CDx/development package categories if needed (A2: As described). Source: https://www.pmda.go.jp/files/000248182.pdf

7. Effective date

Provisional translation as of April 2023; original notification dated June 28, 2022. Source: https://www.pmda.go.jp/files/000248182.pdf