Validating Bioanalytical Methods for Biomarker Quantitation: A Regulatory Document Review

INTRODUCTION. Biomarkers are used to assess normal physiological processes in the body; to diagnose and select therapy for various diseases; and to develop new drugs. The increasing use of biomarkers as drug development tools necessitates improvements in analytical quantification methods.

AIM. This study aimed to review and summarise data on validation of bioanalytical methods for biomarker quantification.

DISCUSSION. The analysed regulatory documents were issued by International Council for Harmonisation (ICH), as well as Food and Drug Administration (FDA), including the Biomarker Assay Collaborative Evidential Considerations Writing Group and Critical Path Institute (C-Path); European Medical Agency (EMA); Eurasian Economic Commission (EEC); and other publicly available research platforms (including PubMed, Web of Science, RSCI (eLIBRARY.RU), and Google Scholar online databases) primarily published in 2014–2024. Analytical and clinical biomarker validation was examined, alongside with analytical validation stages and key validation parameters of the bioanalytical method depending on the objective (analysis for pharmacokinetics, bioequivalence, and toxicokinetics studies; biomarker analysis in drug development and for diagnosis in preclinical and clinical studies). Proposed is an algorithm for choosing biomarker analytical validation level depending on the method (chromatography, ligand-binding methods using reagent kits for various purposes) and the issues to be addressed.

CONCLUSIONS. Confirming biomarker method suitability as per the objectives is similar to a common validation procedure of bioanalytical methods. A broad and detailed scientific discussion of biomarker analysis validation is needed, since a comprehensive scheme developed for this complex procedure will contribute to more reliable use of biomarkers, improved quality of studies within this process, and resulting safe and effective new medicinal products.

1. Miroshnichenko II, Ptitsyna SN. Biomarkers in the modern medical and biologic practice. Biomedical Chemistry. 2009;55(4):425–40 (In Russ.). EDN: KWROID

2. Kochetov AG, Lyang OV, Zhirova IA, Ivoilov OO. Laboratory diagnostics in medicine. Therapeutic Archive. 2020;92(4):4–8 (In Russ.). https://doi.org/10.26442/00403660.2020.04.000501

3. Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. https://doi.org/10.1067/mcp.2001.113989

4. Osipova TV, Bukhman VM. Biomarkers of translational medicine. Rus J Biotherapy. 2018;17(1):6–13 (In Russ.). https://doi.org/10.17650/1726-9784-2018-17-1-6-13

5. Ansari D, Aronsson L, Sasor A, et al. The role of quantitative mass-spectrometry in the discovery of pancreatic cancer biomarkers for translational science. J Transl Med. 2014;12:87. https://doi.org/10.1186/1479-5876-12-87

6. Nasyrova RF, Sivakova NA, Lipatova LV, et al. Biological markers of the antiepileptic drugs efficacy and safety: Pharmacogenetics and pharmacokinetics. Siberian Medical Review. 2017;(1):17–25 (In Russ.). https://doi.org/10.20333/2500136-2017-1-17-25

7. Don ES, Tarasov AV, Epshtein OI, Tarasov SA. The biomarkers in medicine: search, choice, study and validation. Russian Clinical Laboratory Diagnostics. 2017;62(1):52–9 (In Russ.). EDN: YHEYHX

8. Bakker E, Hendrikse NM, Ehmann F, et al. Biomarker qualification at the European Medicines Agency: a review of biomarker qualification procedures from 2008 to 2020. Clin Pharmacol Ther. 2022;112(1):69–80. https://doi.org/10.1002/cpt.2554

9. Metelskaya VA, Zhatkina MV, Gavrilova NE, et al. Validation of combined markers of the presence and severity of coronary atherosclerosis. Russian Journal of Preventive Medicine. 2020;23(6–2):65–71 (In Russ.). https://doi.org/10.17116/profmed20202306265

10. Metelskaya VA, Gavrilova NE, Zhatkina MV, et al. A novel integrated biomarker for evaluation of risk and severity of coronary atherosclerosis, and its validation. J Pers Med. 2022;12(2):206. https://doi.org/10.3390/jpm12020206

11. Konradi AO. Biomarkers, types and role in personalized medicine. Russian Journal for Personalized Medicine. 2022;2(3):6–16 (In Russ.). https://doi.org/10.18705/2782-3806-2022-2-3-6-16

12. Tikhonova GA, Kotov OV, Markin AA. Biomarkers in the practice of biology and medicine (Literature review. Part 1). Technologies of Living Systems. 2023;20(2):18–26 (In Russ.). https://doi.org/10.18127/j20700997-202302-02

13. Tikhonova GA, Kotov OV, Markin AA. Biomarkers in the practice of biology and medicine (Literature review. Part 2). Technologies of Living Systems. 2023;20(4):5–18 (In Russ.). EDN: WTPEOX

14. Kalishyan MS. Biological markers in modern veterinary practice. Russian Journal of Veterinary Pathology. 2022;(4):40–8 (In Russ.). https://doi.org/10.23947/1682-5616-2022-4-40-48

15. Vavilova VA, Faustova NM, Peleshok AA, et al. S100b protein as a biological marker of nerve tissue damage in laboratory animals in preclinical studies. Translational Medicine. 2024;11(4):342–50 (In Russ.). https://doi.org/10.18705/2311-4495-2024-11-4-342-350

16. Miroshnikov MV, Sultanova KT, Makarova MN, et al. Complex assessment of the functional state of the urinary system in preclinical studies. Part 2. Markers of nephrotoxicity (Review). Regulatory Research and Medicine Evaluation. 2024;14(4):448–62 (In Russ.) https://doi.org/10.30895/1991-2919-2024-631

17. Lee JW, Devanarayan V, Barrett YC, et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res. 2006;23(2):312–28. https://doi.org/10.1007/s11095-005-9045-3

18. Chau CH, Rixe O, McLeod H, Figg WD. Validation of analytic methods for biomarkers used in drug development. Clin Cancer Res. 2008;14(19):5967–76. https://doi.org/10.1158/1078-0432.CCR-07-4535

19. Hunter DJ, Losina E, Guermazi A, et al. A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. Curr Drug Targets. 2010;11(5):536–45. https://doi.org/10.2174/138945010791011947

20. Lowes S, Ackermann BL. AAPS and US FDA Crystal City VI workshop on bioanalytical method validation for biomarkers. Bioanalysis. 2016;8(3):163–7. https://doi.org/10.4155/bio.15.251

21. Selby PJ, Banks RE, Gregory W, et al. Methods for the evaluation of biomarkers in patients with kidney and liver diseases: Multicentre research programme including ELUCIDATE RCT. Southampton (UK): NIHR Journals Library; 2018. https://doi.org/10.3310/pgfar06030

22. Ohtsu Y, Tanaka S, Igarashi H, et al. Analytical method validation for biomarkers as a drug development tool: points to consider. Bioanalysis. 2021;13(18):1379–89. https://doi.org/10.4155/bio-2021-0173

23. Ohtsu Y, Matsumaru T, Katashima M, et al. Biomarker assay validation for clinical trials: a questionnaire survey to pharmaceutical companies in Japan. Bioanalysis. 2019;11(2):55–60. https://doi.org/10.4155/bio-2018-0257

24. Mathews J, Amaravadi L, Eck S, et al. Best practices for the development and fit-for-purpose validation of biomarker methods: a conference report. AAPS Open. 2022;8:2. https://doi.org/10.1186/s41120-021-00050-1

25. Khan MU, Bowsher RR, Cameron M, et al. Recommendations for adaptation and validation of commercial kits for biomarker quantification in drug development. Bioanalysis. 2015;7(2):229–42. https://doi.org/10.4155/bio.14.274

26. Procenko VN, Ivkov AG. Validation and verification of quantitative methods of clinical laboratory studies. Laboratory Diagnostics. Eastern Europe. 2019;8(2):171–9 (In Russ.). EDN: AIPHJT