An overview of the draft concept paper on “quantitative measurements of endogenous biomarkers for drug developments”; regulatory importance and future directions 「医薬品開発においてヒト内因性物質をバイオマーカーとして利用する際の定量分析法に関する留意点」 Takayoshi Suzuki, JBF Biomarker TF A process lead to the concept paper • Focused on the quantitative measurements of endogenous substances because of time limitation • A need for a guidance to measure endogenous substances as biomarkers. • Preceding LC-MS and LBA guidelines • Endogenous substances including biomarkers are out of scope in these guidelines. • Difficult points for a measurements of endogenous substances to follow the LC and LBA guidelines were discussed. • Considerations for those points were summarized. Considerations for “quantitative measurements of endogenous biomarkers for drug developments” (Draft paper by the JBF TF) 1. Introduction 2. Application 3. Matrix 4. Standards 5. Specificity 6. Calibration curve 7. Detection Limit 8. Accuracy & Precision 9. Robustness 10. Kit s はじめに適用マトリックス標準物質（標準品）選択性検量線定量下限真度・精度安定性キット Please refer to the poster presentation for detail 2．Applications（適用） • 開発後期の臨床試験 Later-stage clinical studies • 安全性評価に用いるバイオマーカーについては開発初期から適応するのが望ましい場合もある。Applicable for safety biomarkers from initial stage if they are important • 患者の層別化を目的としたバイオマーカーは対象外 Biomarkers for patient selection (CDx) are excluded • 対象となる分析法はLC,GC-(MS)とLBA LC, GC (-MS) and LBA as methodology • 分析対象物質は定量分析可能な内因性物質とし、臨床検査項目等のバリデーション済みの内因性物質は除く Targets are quantitatively measurable endogenous substances, excluding already validated clinical laboratory tests Reviewing the draft concept paper • There are some difficulties to reach the consensus on the draft paper with PMDA • Mainly because of the usage of the term “biomarker” in the introduction part. • More discussion will be necessary. But I have learned some discrepancy between regulators and developers Needs for a guidance • Guideline or guidance can sometimes promote a development. • Guideline or guidance can reduce the unnecessary data for submission. • Guideline or guidance can promote agreement between regulators and developers Ultimate purpose of building guideline is to facilitate approval process in drug application Trends in Japanese Regulator • Comfortable without a guideline – Feel no needs for guidelines for items that never became a problem Trends in Japanese Developer • Uncomfortable without a guideline – Try to follow available similar guidelines “Self-discipline” 自己規制 Guideline is not a “law” • No need to follow the guideline when there are enough scientific reasons to ignore it. • There are always exceptions that do not necessary follow the guideline. • It is important to think about the scientific justification rather than just follow the guideline. • In such sense, it is better to have no guideline to promote the innovative development Biomarkers vs Endogenous substances Biomarkers Endogenous substances Target for the concept paper Biomarkers vs Companion Diagnostics Biomarkers Companion Dx Classification of biomarkers • Substances – Protein/Peptide, DNA, RNA, miRNA, Cell • Methods for detection – LBA, LC-MS, RT-PCR, NGS, microarray, FCM • Quantitative or Qualitative • Purpose – Companion Dx, efficacy, toxicity, ADME • Timing to be used – Early development, preclinical/clinical phase, Later stage for application data Fit for the “Purpose” • What is the purpose for measuring biomarkers? • Different level of requirements should be set depending on the purpose. • Companion Dx has highest level of requirements for biomarker • Validation of the biomarker for the purpose is important before measuring it. Importance of the Companion Dx • Necessary for the development of new drugs with a selection of proper patients • Co-development of new drugs and the companion Dx is required • New paradigm for drug development is required? Who plays an important role for the developments of the companion Dx • Traditionally diagnostic company is responsible • Needs collaboration with the diagnostic company • Who covers the risk for the failure of drug development • Establishments of new biomarkers and tests for their measurements are very significant at the initial stage of development. Pharmaceutical companies should play an important role for companion diagnostics ! Towards an establishment of a guidance for biomarker measurements in drug developments • General considerations for biomarkers • Promote a usage of biomarkers for drug developments • What is agreeable or useful guidance for regulators and developers? • Considerations for the companion Dx “Japanese regulators should have strong visions and policies on regulation to promote medical innovations." Chia-Feng Lu, Lawyer at Baker & McKenzie Acknowledgement • JBF Biomarker Taskforce members • 西川班バイオアナリシス分科会バイオマーカーワーキンググループ