Soluble biomarkers development in osteoarthritis: from discovery to personalized medicine

Figures & data

Figure 1. Overview of the path from biomarker discovery to clinical qualification.

Table 1. Intended use of biomarkers in clinical trial.

Intended use	Clinical endpoint	Clinical benefit
Diagnosis	Threshold values related to OA phase (early/late)Burden of disease	Stratification of patients with phase-characterized OA
Prognosis	Intra-subject variation related to OA risk factor	Stratification of patients based on risk of progression
Clinical surrogacy: Response to treatment	Intra-subject variation related to DMOAD treatment	Drug efficacy and compliance, companion
Clinical surrogacy: Safety	Intra-subject variation related to (serious) adverse events	Early signs of toxicity during treatment and drug safetyNote: This step requires agreement with regulatory authorities as an FDA registerable endpoint.

Table 2. Five phases of drug development.

Stage of drug development	Purpose
Preclinical	Assess drug safetyAssist with selection of animal models and lead compoundsAssess drug mechanism of action
Phase I trial	Assessing mode of actionAssist with dose finding and selectionAssess safety via surveillance of effects on joint metabolism
Phase II trials	Potentially early objective indicator of drug effectAssist in identifying the minimal effective dose and dose response profileMultiple Comparison Procedure Modeling (MCP-Mod) – how modeling and simulation during Phase II can aid dose selection for Phase III clinical trials in OA
Phase III trials	Increase study power through enrichment of an appropriate target populationShorten duration of trialClinical trial simulations based on biomarkers to gain approval for different dose range not in original trialEnrichment for progressors to reduce trial sample size and increase power
Phase IV	Cost-effective surveillance of safety post-marketing of drugLikely mandated if conditional approval is granted on the basis of a surrogateIdentification of subgroup of patients which are responders or non-respondersMonitoring of drug effectiveness and safety in real life condition

Table 3. FDA classification for medical device.

	Control level	Related Codes of Federal Regulation (CFR)
Class I low to moderate risk	general controls	21 CFR 860 section 501, 502, 510, 516, 518, 519 and 520
Class II moderate to high risk	general controls and special controls	As mentioned above+ device specific controls
Class III high risk	As mentioned above + premarket approval (PMA)	As mentioned above+ premarket approval (21 CFR 814, 21 CFR 860 section 513, 515)

Table 4. List (non-exhaustive) of changes in the EC guidance.

Classification	As device class increases from A to D the regulatory controls also increase. In class D evaluation is made by Medical Device Coordination Group. Companion kits are automatically classified in C.
Economical operators	From manufacturers to distributors, they all have legal responsibility in case of non-conformities.
Batch release	A Qualified Person (QP) has to be designated in order to validate the release of a new product lot.
Traceability	Unique Device Identifier (also called UDI code) on each product component.
Post Marketing Surveillance (PMS)  and vigilance	Inspired by ISO13485. All severe incidents have to be communicated into a European Portal on the web offering an easy access to everybody.
Notified bodies	Extension of competencies. Unexpected audit frequency depending on product classification.
Clinical evidence	Correlation between test results and patient health modifications is mandatory.

Table 5. Summary of the current guidance on analytical validation processes specific to biomarkers.

Performance	Description
Selectivity/specificity	Is the study of interferences from substances physico-chemically similar to the analyte (cross-reactivity) and the study of matrix effects which should be evaluated by parallelism between diluted samples and diluted standards, which is also called dilution linearity.
Accuracy	Expresses the closeness of agreement between the value that is accepted either as the conventional true value or an accepted reference value and the value found (Kraus et al., 2011). It is also called trueness.
Precision	Expresses the closeness of agreement between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions (Kraus et al., 2011). Precision may be considered at three levels defined here below (repeatability, intermediate precision and reproducibility).
Repeatability	Expresses the precision under the same operating conditions over a short interval of time and is also termed intra-assay precision or within-run precision.
Intermediate precision	Expresses within-laboratories variations: different days, different operators, different equipment, different lots of reagents, etc. It is also called between-run precision or inter-assay precision.
Reproducibility	Expresses the precision between laboratories and is also called beta-test.
Recovery	Is the extraction efficiency of an analytical process, reported as a percentage of the known amount of an analyte carried through the sample extraction and processing steps of the method (FDA et al., 2013).
Sensitivity	Is defined as the lowest analyte concentration that can be measured specifically by an analytical procedure. This definition also includes Limit Of Quantitation (LOQ), Limit Of Detection (LOD) and Limit Of Blank (LOB).
Limit of Quantitation (LOQ)	Is the lowest amount of an analyte in a sample that can be quantitatively determined with acceptable precision and accuracy (FDA et al., 2013). It is also called Lower Limit Of Quantitation (LLOQ).
Limit of detection (LOD)	Is the lowest amount of analyte in a sample that can be detected and reliably distinguished from the LOB.
Limit Of Blank (LOB)	Is the highest apparent analyte concentration expected to be found when replicates of a sample containing no analyte are tested (Armbruster & Pry, 2008).
Robustness	Measures the capacity of a bioanalytical method to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage (Kraus et al., 2011).
Stability	The chemical stability of an analyte in a given matrix under specific conditions for given time intervals (FDA et al., 2013). It is assessed in several days. Stability evaluations should cover the expected sample handling and storage conditions, including conditions at the clinical site, during shipment, and all other secondary sites.

Kraus VB, Burnett B, Coindreau J, et al. (2011). Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage 19:515–42

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FDA, USDOHAHS, CDER, CVM. (2013). Guidance for industry: bioanalytical method validation. Revision 1 ed. Silver Spring (MD): Food and Drug Administration

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Armbruster DA, Pry T. (2008). Limit of blank, limit of detection and limit of quantitation. Clin Biochem Rev 29:S49–52

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