An overview of the draft concept paper on “quantitative measurements of endogenous

biomarkers for drug developments”; regulatory importance and future directions

Takayoshi Suzuki, JBF Biomarker TF

「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」

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”

1. Introduction はじめに

2. Application 適用

3. Matrix マトリックス

4. Standards 標準物質（標準品）

5. Specificity 選択性

6. Calibration curve 検量線 7. Detection Limit 定量下限

8. Accuracy & Precision 真度・精度

9. Robustness 安定性

10. Kit s キット

(Draft paper by the JBF TF)

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 un-necessary 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

Endogenous substances

Biomarkers

Target for the concept paper

Biomarkers vs Companion Diagnostics

Companion Dx

Biomarkers

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

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