Laboratory scientists continue to strive toward achieving inter laboratory harmonization as elegantly examined by Drs. Miller and Myers in a recent NACB Blog.1 While the terminology of achieving equivalency may differ (e.g., combinability, comparability, normalization, harmonization), the concepts are similar—to unify test results among laboratories. We are familiar with strategies used to accomplish these tasks. Regulatory agencies that govern CAP/CLIA accredited laboratories mandate that we participate in external proficiency testing (e.g. CAP); alternative test material, including:
• NIST (National Institutes of Standards and Technology,
• EQAS (Evaluation Quality Assurance System) ,
• HOST (Hormone Standardization Program) ,
• NGSP (National Glycohemoglobin Standardization Program),
• LSP (Lipid Standardization Program), and
the calibrator hierarchy for In Vitro Diagnostic (IVD) testing as described in ISO 17511 are among those in use.
In large multicenter clinical trials, there is a need to examine changes within and across subjects to determine safety and efficacy during long term clinical studies. Testing can be extensive and analyte panels are closely examined for minute changes that may indicate drug response. Middle and late stage trials, as one would expect, are quite large and often involve data generated in laboratories located worldwide. Strategies for specimen testing and data management are quite complex. Building upon the aforementioned standardization systems we currently employ, how do we achieve data combinability in clinical trials within the environment of different analytical and data management approaches, as compared to “local clinical laboratories”?
Local laboratories, as the name implies, are local to investigator sites. These institutions are advantageous when safety analyses (testing that may immediately impact patient care) and quick turn-around-time (TAT) are required. They are convenient for ambulatory patients. Testing is done on site and therefore costs are kept to a minimum. This approach, however, may include constraints in the areas of collection, management and logistics. As opposed to local laboratories, clinical trial optimization often involves utilization of Clinical Research Organizations (CRO). These entities are numerous and diverse (as a quick Google search would indicate) and capitalize on managing all aspects of clinical trials from study set-up and logistics to final data transmission. Paramount to these organizations are Central Laboratory Services (CLS) that encompass processes from shipping of specialized patient kits to kit receipt, testing and resulting of laboratory data.
The power behind the ability to establish the claim of combinability has certain underlying global themes; one of the most important is analytical testing. Their use of identical platforms for specimen testing worldwide (e.g., same software versions, reagents, SOPs, and QC lots, ranges, and rules) assures clients that results will be consistent among sites. Additional similarities within CROs include:
1) Tight monitoring of QA/QC within and between sites;
2) Regulatory processes that are routinely practiced and continual inspection readiness, including regulatory agencies and individual sponsors;
3) Rigorous method validations and SOPs that are instituted globally;
4) Continuity in data collection, processing, reporting procedures, and logistics;
5) Global reference ranges where possible or appropriate.
While these aspects only represent a snapshot of the expectations of CLS, the underlying premise of laboratory testing, whether locally or globally, is the assurance of data combinability.
Certainly there are challenges that are encountered while establishing these high standards. Importing and exporting specimens, reagents and other necessary materials to complete testing can be demanding. Manufacturer’s kits can be altered, suspended or re-configured, triggering method comparison studies at the very least and impacting global operations. However, building upon best practices and having solid strategies to achieve combinability demonstrate the success of the laboratories in this specialization of the clinical testing industry.
How does your laboratory assure combinability between regional/satellite centers?