No Heading
Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24–25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- AAPS:
-
American Association of Pharmaceutical Sciences
- BQL:
-
below quantifiable limit
- CDER:
-
Center for Drug Evaluation and Research
- CMS:
-
Centers for Medicare & Medicaid Services
- CLAS:
-
Clinical Ligand Assay Society
- CLIA:
-
Clinical Lab Improvement Amendments
- GLP:
-
good laboratory practices
- LBABFG:
-
Ligand Binding Assay Bioanalytical Focus Group
- LOD:
-
lower limit of detection
- LLOQ:
-
lower limit of quantification
- NCCLS:
-
National Committee for Clinical Laboratory Standards
- PD:
-
pharmacodynamic
- PK:
-
pharmacokinetic
- OIVD:
-
Office of in Vitro Diagnostics Device Evaluation and Safety
- QCs:
-
quality controls
- ULOQ:
-
upper limit of quantification
References
1. J. A. DiMasi, R. W. Hansen, and H. G. Grabowski. The price of innovation: new estimates of drug development costs. J. Health Econ. 22:151–185 (2003).
2. G. Levy. Mechanism-based pharmacodynamics modeling. Clin. Pharmacol. Ther. 56:356–358 (1994).
3. C. C. Peck, W. H. Barr, L. Z. Benet, J. Collino, R. E. Desjardins, D. E. Furst, J. G. Harter, G. Levy, T. Ludden, and J. H. Rodman. Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. Pharm. Sci. 81:600–610 (1992).
4. W. A. Colburn. Selecting and validating biologic markers for drug development. J. Clin. Pharmacol. 37:355–362 (1997).
5. P. R. Jadhav, M. U. Mehta, and J. V. S. Gobburu. How biomarkers can improve clinical drug development. Am. Pharm. Rev. 7:62–64 (2004).
6. E. Zerhouni. Medicine. The NIH Roadmap. Science 302:63–72 (2003). Available at http://nihroadmap.nih.gov.
7. F. D. A. March 2004 report. Innovation or stagnation: challenge and opportunity on the critical path. Available at http://www.fda.gov/oc/initiatives/criticalpath/.
8. G. J. Downing. Biomarkers and Surrogate Endpoints: Clinical Research and Applications. Proceedings of the NIH-FDA Conference held on 15–16 April 1999. Elsevier, New York, 2000.
9. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69:89–95 (2001).
10. R. R. Bowsher. Analytical validation of assays for novel biomarkers. Presentation at AAPS Workshop, Method Validation and Measurement of Biomarkers in Nonclinical and Clinical Samples in Drug Development, Salt Lake City, Utah, 2003.
11. J. A. Wagner. Early clinical development of pharmaceuticals for type 2 diabetes mellitus: from pre-clinical models to human investigation. J. Clin. Endocrinol. Metab. 87:5362–5366 (2002).
12. J. A. Wagner. Overview of biomarkers and surrogate endpoints in drug development. Dis. Markers 18:41–46 (2002).
13. J. Berger and J. A. Wagner. Physiological and therapeutic roles of peroxisome proliferator-activated receptors. Diabetes Technol. Ther. 4:163–174 (2002).
14. U. Krishnamurti and M. W. Steffes. Glycohemoglobin: a primary predictor of the development or reversal of complications of diabetes mellitus. Clin. Chem. 47:1157–1165 (2001).
15. D. A. Dillon. Molecular markers in the diagnosis and staging of breast cancer. Semin. Radiat. Oncol. 12:305–318 (2002).
16. R. Dates, M. Schmitt, and N. Harbeck. Advanced statistical methods for the definition of new staging models. Recent Results Cancer Res. 162:101–113 (2003).
17. B. N. Swanson. Delivery of high-quality biomarker assays. Dis. Markers 18:47–56 (2002).
18. I. C. H. Guidelines. Text on validation of analytical procedures, Q2A. International Conference on Harmonization, Geneva, Switzerland, 1994.
19. V. P. Shah, K. K. Midha, S. Dighe, I. J. McGilveray, J. P. Skelly, A. Yacobi, T. Layloff, C. T. Viswanathan, C. E. Cook, R. D. McDowall, K. A. Pittman, and S. Spector. Analytical methods validation: bioavailability, bioequivalence, and pharmacokinetic studies. Pharm. Res. 9:588–592 (1992).
20. V. P. Shah, K. K. Midha, J. W. A. Findlay, H. M. Hill, J. D. Hulse, I. J. McGilvary, G. McKay, K. J. Miller, R. N. Patnaik, M. L. Powell, A. Tonnelli, C. T. Viswanathan, and A. Yacobi. Bioanalytical method validation. A revisit with a decade of progress. Pharm. Res. 17:1551–1557 (2000).
21. Guidance for industry on bioanalytical method validation: availability. Federal Register 66:28526–28527 (2001).
22. FDA government document. Code of Federal Regulations. Title 21, Vol. 1. Good Laboratory Practice for Nonclinical Laboratory Studies. Revised April 1, 2001.
23. J. W. A. Findlay, W. C. Smith, J. W. Lee, G. D. Nordblom, I. Das, B. S. DeSilva, M. N. Khan, and R. R. Bowsher. Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective. J. Pharm. Biomed. Anal. 21:1249–1273 (2000).
24. K. J. Miller, R. R. Bowsher, A. Celniker, J. Gibbons, S. Gupta, J. W. Lee, S. J. Swanson, W. C. Smith, and R. S. Weiner. Workshop on Bioanalytical Methods Validation for Macromolecules: summary report. Pharm. Res. 18:1373–1383 (2001).
25. B. DeSilva, W. Smith, R. Weiner, M. Kelley, J. Smolec, B. Lee, M. Khan, D. Tracey, H. Hill, and A. Celniker. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm. Res. 20:1885–1900 (2003).
26. W. C. Smith and G. S. Sittampalam. Conceptual and statistical issues in the validation of analytic dilution assays for pharmaceutical applications. J. Biopharm. Stat. 8:509–532 (1998).
27. J. W. Lee, W. C. Smith, G. D. Nordblom, and R. R. Bowsher. Validation of Assays for the Bioanalysis of Novel Biomarkers. In J. C. Bloom and R.A. Dean (eds.), Biomarkers in Clinical Drug Development. Marcel Dekker, New York, 2003, pp. 119–149.
28. A. R. Mire-Sluis, Y. C. Barrett, V. Devanarayan, E. Koren, H. Liu, M. Maia, T. Parish, G. Scott, G. Shankar, E. Shores, S. J. Swanson, G. Taniguchi, D. Wierda, and L. A. Zuckerman. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J. Immunol. Methods 289:1–16 (2004).
29. National Committee for Clinical Laboratory Standards (NCCLS). Document EP5-A: Evaluation of Precision Performance of Clinical Chemistry Devices: Approved Guideline (1999); Document EP6-P: Evaluation of the Linearity of Quantitative Analytical Method: Proposed Guideline (1986); Document EP7-P: Interference Testing in Clinical Chemistry: Proposed Guideline (1986); Document EP9-A: Method Comparison and Bias Estimation Using Patient Samples: Approved Guideline (1995).
30. FDA government document. Code of Federal Regulations. Title 42, Vol. 3. Clinical Laboratory Improvement Amendment. Revised October 1, 2001.
31. J. O. Westgard, P. L. Barry, M. R. Hunt, and T. Grove. A multi-rule Shewhart chart for quality control in clinical chemistry. Clin. Chem. 27:493–501 (1981).
32. J. O. Westgard and G. G. Klee. Quality management. In C. Burtis (ed.), Fundamentals of Clinical Chemistry, 4th ed. WB Saunders, Philadelphia, 1996, pp. 211–223.
33. P. M. Bossuyt, J. B. Reitsma, D. E. Burns, C. A. Gatsonis, P. P. Glasziou, L. M. Irwig, D. Moher, D. Rennie, H. C. de Vet, and J. G. Lijmer. Standards for Reporting of Diagnostic Accuracy. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin. Chem. 49:7–18 (2003).
34. DAKO HercepTest™ Facts, DAKO, Fort Collins, CO, USA, 2000.
35. B. Schweitzer, S. Roberts, B. Grimwade, W. Shao, M. Wang, Q. Fu, Q. Shu, I. Laroche, Z. Zhou, V. T. Tchernev, J. Christiansen, M. Velleca, and S. F. Kingsmore. Multiplexed protein profiling on microarrays by rolling-circle amplification. Nat. Biotechnol. 20:359–365 (2002).
36. W. Shao, Z. Zhou, I. Laroche, H. Lu, Q. Zong, D. D. Patel, S. Kingsmor, and S. P. Piccoli. Optimization of rolling-circle amplified protein microarrays for multiplexed protein profiling. J. Biomed. Biotechnol. 5:299–307 (2003).
37. S. F. Kingsmore and D. D. Patel. Multiplexed protein profiling on antibody-based microarrays by rolling circle amplification. Curr. Opin. Biotechnol. 14:74–81 (2003).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, J., Weiner, R., Sailstad, J. et al. Method Validation and Measurement of Biomarkers in Nonclinical and Clinical Samples in Drug Development: A Conference Report. Pharm Res 22, 499–511 (2005). https://doi.org/10.1007/s11095-005-2495-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-005-2495-9