Method Validation and Measurement of Biomarkers in Nonclinical and Clinical Samples in Drug Development: A Conference Report

Abstract

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.

A systematic literature review of the human skin microbiome as biomarker for dermatological drug development

“…A biomarker is defined as a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention 1, 2. Clinical biomarkers are thought to reflect disease activity and pathophysiology 3, 4. A useful biomarker in any class has to comply with the following general criteria: (i) there must be a consistent response of the biomarker across studies (preferably from different research groups) and drugs from the same mechanistic class; (ii) the biomarker must respond clearly to therapeutic (not supratherapeutic) doses; (iii) there must be a clear dose‐ or concentration‐response relationship; and (iv) there must a plausible relationship between the biomarker, pharmacology of the drug class and disease pathophysiology 4.…”

Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

“…For within-day, the percentage differences measured (5.0% average for M30 and 4.1% average for M65) were within, or at least close to, the normal levels of variability associated with the methods indicating a comparatively small contribution from the biomarker itself. These data are in contrast to many typical plasma PD assays which are often associated with 30% or greater imprecision (Miller et al, 2001;Lee et al, 2005).…”

“…During that study method validation was conducted in accordance with available internationally recognised bioanalytical guidelines established by the pharmaceutical industry, but primarily utilised in drug and safety monitoring (Shah et al, 2000;Miller et al, 2001). There is a growing acknowledgement that these guidelines are not sufficiently flexible to accommodate the many different categories of PD assays that are employed during anticancer drug development of molecularly targeted agents (Lee et al, 2005). It is now also evident that qualification of a biomarker is a multistage process requiring a concerted team effort often paralleling the drug development cycle (Colburn, 2003;Benowitz, 2004;Ransohoff, 2004;Ludwig and Weinstein, 2005).…”

“…A vital component in PD biomarker validation is the establishment of its pretreatment range and inherent biovariability, in order to assess the likelihood that the technology of choice and trial design have the statistical and technological resolving power to discriminate between normal background biologic variation and a drug-induced effect (Lee et al, 2005). In the present paper, analytical validation of a fourth PD assay, the M65 Elisa (Kramer et al, 2004), is described, along with long term stability studies on the antigens for this assay as well as for M30 Apoptosense Kramer et al, 2004).…”

Saturation monitoring of VX15/2503, a novel semaphorin 4D‐specific antibody, in clinical trials

“…(Fig. 6) The fit‐for‐purpose, iterative approach was applied to the validation strategy in that, as the intended use of the data and the associated regulatory requirements changed, the assay was re‐optimized and re‐validated appropriately 24, 25, 26. The prototype assay was developed during the drug discovery phase and initially used to detect binding of anti‐SEMA4D candidates to cellular SEMA4D.…”