Biomarker Assay as Clinical Laboratory Test -Comparison with Regulated Bioanalysis-

臨床検査におけるバイオマーカー測定 －規制バイオアナリシスとの比較－

Keiko Nakai LSI Medience Corporation

中井 恵子

株式会社ＬＳＩメディエンス

1 6th JBF Symposium, 25 FEB 2015

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

2

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

3

Introduction The use of biomarker is increasingly important in drug development.

It is widely conducted from the screening period to clinical trial study, and the analyte is a variable such as pharmacodynamic marker, toxicological marker, diagnostic marker, monitoring marker, or safety marker.

There are many approaches; in one example, a new analytical method being developed to find new markers, or cases using clinical test data.

In this presentation, attention is being focused on the clinical laboratory test, introducing criteria for registration and accreditation, as well as validation and quality control in our company.

Additionally, the process in the clinical laboratory test will be compared with that of the regulated analysis.

4

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

5

Registration and Accreditation Registration of a clinical laboratory

（衛生検査所登録） ISO15189 Accreditation CAP (College of American Pathologists) Accreditation ISO/IEC17025 Accreditation Association for Promotion of Health Care Service

（医療関連サービスマーク）

ISO27001 Certification PrivacyMark® Registration

ISO14001 Certification

6

Registration and Accreditation (description 1)

Registration of a clinical laboratory （衛生検査所登録）

Registered clinical laboratory: Facility for clinical laboratory test 衛生検査所：疾病の診断や健康診断のための検体検査を受託する施設

Relevant legal provision: Act on clinical laboratory technicians, etc. 関連法律：臨床検査技師等に関する法律施行規則

Accreditation standard: Organization, management, training, facility, quality control, reporting, 認定基準：組織、管理運営、教育、設備、品質管理、結果報告等

ISO15189 Accreditation Quality management system in clinical laboratories

臨床検査室における国際規格

Stipulation: staff, facility, environment, instrument, reagent, test process, reporting 職員、施設及び環境条件、機材、試薬、検査手順、結果報告等を規定

7

Registration and Accreditation (description 2)

CAP (College of American Pathologists) Accreditation International quality assurance for clinical laboratory test

国際的な臨床検査の品質保証

CAP survey: Comparison test for clinical laboratories

CAPサーベイ：臨床検査室間の比較

ISO/IEC17025 Accreditation General requirements for the competence of testing and calibration

laboratories

国際的な試験所及び校正機関の能力に関する認定規格

Accreditation standard: Organization, management, training, facility, quality control, reporting

認定基準：組織、管理運営、教育、設備、品質管理、結果報告等

8

Registration and Accreditation (description 3) Association for Promotion of Health Care Service

（医療関連サービスマーク） Accreditation organization:

Association for Promotion of Health Care Service (APHCS) 認定機関：一般財団法人医療関連サービス振興会

ISO27001 Certification Information security management system

情報セキリュティマネジメントシステムの国際規格

PrivacyMark® Registration Personal information protection recognition system

個人情報保護に関する事業者認定制度

ISO14001 Certification International environmental management system

国際的な環境マネジメントシステム 9

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

10

Validation Parameters and Criteria (as a guide)

11

Parameter Criteria Comment

Detection limit 2SD or S/N≥2-3 --

Quantification limit Precision profile or S/N≥10 --

Calibration curve Within ±15% (Within ±20% at LLOQ)

--

Within-run reproducibility CV ≤10% (N=20) Autoanalyzer CV≤5%

Between-run reproducibility CV ≤15% (N=10) Autoanalyzer CV≤7.5%

Dilution integrity Within ±15% --

Recovery 70 -120% --

Storage stability Within ±15% (N≥5) --

Freeze and thaw stability Within ±15% (N≥5) --

Correlation Slope 0.9-1.1, r≥0.9, considering y-intercept

Comparison with the existing method (reagent)

Reference value N≥100 Gender difference: N≥100 each

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

12

Quality Control

Daily quality control （日常精度管理） Control data Data histogram Upper and lower limit, re-test Test history

External quality control（外部精度管理）

Participation in internal comparison program 検査室間比較への参加

Domestic and international survey

13

14

Multi-step Quality Assurance System

Assurance Standard Master

Database on Test History

・Performance of analyzer ・Standard curve

・Internal control ・QC chart

・Data histogram

・Upper & Lower limit ・Re-test data

・Test history ・Data balance

LEVEL 0 LEVEL 1 LEVEL 2 LEVEL 3 LEVEL 4

15

External Quality Assurance Domestic survey

Japan Medical Association survey

日本医師会精度管理調査

Japan Registered Clinical Laboratories Association survey 日本衛生検査所協会精度管理調査

Japanese Association of Medical Technologies survey 日本臨床検査技師会精度管理調査

Prefectural control survey 都道府県精度管理調査

International survey CAP survey Cell exchange

16

External Quality Assurance (description)

検査場所　

中

央

ラ

ボ

一

般

血

液

学

生

化

学

薬

物

内

分

泌

学

免

疫

血

清

学

腫

瘍

関

連

ウ

イ

ル

ス

学

免

疫

血

液

学

細

胞

性

免

疫

学

微

生

物

学

遺

伝

子

関

連

染

色

体

備考

　サーベイ名称 1 2 3 4 5 6 7 8 9 10 11 12

日本医師会 ○ ● ● ● ● ● ● ● ○

日本臨床検査技師会 ○ ● ● ● ● ● ● ● ○

日本衛生検査所協会 ○ ● ● ● ○

全国労働衛生連合会 ○ ● ● ● ○ 外注受託検査あり

　　　〃　鉛・有機溶剤 ○ ● ○ 特殊分析Gのみ

福島県技師会会津支部 ○ ● ○

東京都衛生局 ○ ● ● ● ● ● ○

東京都臨床検査技師会 ○ ● ● ○

山梨県医師会 ○ ● ● ● ● ● ● ● ○

滋賀県技師会 ○ ● ○

兵庫県健康福祉部 ○ ● ○

日本総合健診学会 ▲ ● ● ● ▲ ▲ ▲ ▲　外注受託検査

Cell Exchange ○ ● ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 細胞性免疫のみ

ＣＡＰ ○ ● ● ● ● ● ● ● ● ● ● ● ● ● ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

2014

実施予定月（H26年）

分離分析Gのみ

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

17

18

Comparison with Regulated Bioanalysis

Quality Management Systems

Quality Manual

ISO 15189 CAP

ISO 17025

Pharmaceutical Affairs Law Act on Clinical Laboratory Technicians, etc.

SOPs

Quality Manual

GLP

GCP

ISO 9001

CAP

SOPs

SOPs

Clinical test in clinical trial study and GLP study

Clinical laboratory test

Comparison with Regulated Bioanalysis

19

Parameter Small Molecule (Japanese guideline)

LBA (Japanese guideline)

Clinical laboratory test (LSIM)

Calibration curve Within ±15% (±20% at LLOQ)

Within ±20% (±25% at LLOQ&ULOQ)

Within ±15% (±20% at LLOQ)

Reproducibility Within ±15%, CV ≤15% (N≥5)

Within ±20%, CV ≤20% (N≥6) (±25% at LLOQ&ULOQ) Total error （CV+|RE|）≤30% （≤40% at LLOQ,ULOQ）

Within-run: CV ≤10% (N=20) Between-run: CV ≤15% (N=10)

Matrix effect CV ≤15% (N≥6) -- --

Carry-over Analyte ≤20%, IS ≤5% -- --

Dilution integrity Within ±15%, CV ≤15% Within ±20% %, CV ≤20% Within ±15%

Stability Within ±15% (N≥3) Within ±20% (N≥3) Within ±15% (N≥5)

Others -- -- Reference value

Validation

Comparison with Regulated Bioanalysis

20

Parameter Small Molecule (Japanese guideline)

LBA (Japanese guideline)

Clinical laboratory test (LSIM)

Calibration curve Within ±15% (±20% at LLOQ)

Within ±20% (±25% at LLOQ&ULOQ)

Within ±15% (±20% at LLOQ)

QC samples 3 concentrations Within ±15%

3 concentrations Within ±20%

3 concentrations Within ±2SD

Incurred samples reanalysis

Within ±20%

Within ±30% --

Carry-over Analyte ≤20%, IS ≤5% -- --

Others -- -- External quality control Reference value Data histogram Test history

Analysis of study samples

Contents

• Introduction • Registration and Accreditation • Validation Parameters and Criteria • Quality Control • Comparison with Regulated Bioanalysis • Conclusion

21

Conclusion

The use of biomarker has become increasingly important in drug development.

The usage of biomarkers has recently been implemented in the screening period up to clinical trials, and there are many approaches, including new analytical methods, or cases using clinical test data.

Here, the clinical laboratory test process in LSIM was compared to that of regulated analysis, and it is apparent that they are both conducted in a similar manner.

In all likelihood, these various biomarker methods will be put into practical use and be made available for use for a multitude of purposes.

In the near future, more guidance and guidelines are necessary to expand the usage of biomarkers in a broader range of applications.

22

Acknowledgement

23

• Japan Bioanalysis Forum • LSI Medience Corporation

24

Thank you for your attention !

ご静聴ありがとうございました！