THE SHIFT TO A CENTRALIZED LABORATORY APPROACH IN CLINICAL RESEARCH

By: Yan Mardian

Clinical research is a vital aspect of the healthcare industry that aims to improve patient outcomes and advance medical knowledge. One of the critical components of successful clinical research is accurate and reliable laboratory testing. However, laboratory testing can be challenging to standardize, and results can vary significantly depending on the testing facility, personnel, equipment, and even factors like local temperature and humidity. A central laboratory provides standardized testing services that ensure consistency and reliability across different sites in multi-site studies. Therefore, there is a growing need for incorporating centralized reference laboratories in clinical research.

What is the difference between a local lab and a central lab?

As its name suggests, a central laboratory is an advanced laboratory where all the samples obtained from a trial’s investigator sites are centrally processed and tested using standardized procedures and equipment. By contrast, a local laboratory is any laboratory that may perform limited testing for one or a few study sites as part of a multi-site study. While local labs may have advantages when it comes to processing times, they typically do not offer the deep range of specialty testing services (e.g., flow cytometry, genomics, etc.) and high-quality combinable data that a central lab can provide.

Commonly, centralized reference laboratories provide specialized laboratory testing services to multiple research sites. These facilities have state-of-the-art technologies, experimental assays, and experienced staff who can perform various tests. The central laboratory concept was first implemented in the mid-1980s in the United States, driven by the need for a more rigorous way to collect, combine, and report trial data from different clinical sites. In the mid-1990s, the creation of a European Union simplified cross-border transportation in Western Europe and triggered the setup of central laboratories in Europe. The main goal among central labs was a consolidation of the test results and data originating from different clinical sites.

Combining for consistency

In multi-center trials, clinical laboratory testing can generally be performed in the local laboratory of each participating site or in a central laboratory. Routine tests such as complete blood cell counts, general chemistries, and urinalysis are usually performed at the respective local laboratory of each participating site since specimens must be analyzed immediately for accurate results. Special tests such as drug concentration, antibody titres, genetic testing, and culture-based assays are best performed in a central laboratory. Though researchers may assume that various methods for measuring or evaluating an analyte produce the same results, they may not be aware of the variability in results between methods or environments. As all laboratories do not use the same analytic methods, measurement principles, calibrators, and reagents, the study test results may vary based on the laboratory, making comparing results from different laboratories difficult. Fundamentally, having multiple local labs perform separate testing and then combining the results into a single database can introduce an element of variation in the data that can not be separated out or easily understood.

The central lab core value is consistency. A centralized reference laboratory can help reduce the risk of errors and natural variation in laboratory testing. When different laboratories use different testing methods, equipment, personnel, environments, etc., comparing results and identifying potential errors or explaining variation can be challenging. Centralized reference laboratories are essential for maintaining the quality and accuracy of laboratory testing. They have strict quality control measures to minimize errors and ensure consistent results across different studies and locations. By using a centralized reference laboratory, specimens from all sites are processed using the same testing methods and equipment, making it easier to identify potential errors and ensure that results are accurate, reliable, and inherently less variable. This ensures that all samples are tested the same way, reducing variability and improving the consistency of results. Using a centralized reference laboratory gives researchers confidence in their results, which is essential for accurate diagnoses and effective treatments. Standardization is crucial for clinical research, enabling researchers to compare results across different studies and locations.

When local laboratories perform testing, their results will be inherently different, not due to a lack of skill or capability, but due to natural variation arising from factors that simply cannot be controlled. Central laboratory testing, on the other hand, offers “combinable data” generated from the same analytic method platform to correlate and standardize results. The end product is that a result from a central laboratory is similar regardless of the site the specimen came from. In contrast, local laboratories use many different analytic methods, often breaking down into “low, medium, and high” between local labs. Less variation in central lab results also makes it easier for trial sponsors to assemble meaningful statistics. Ultimately, results from the central laboratory are easier to defend to regulatory agencies, and in some cases, centralized testing is required by those agencies. Central labs promote scientifically objective results through independence of action on a contractual basis with the sponsor, transparency via a durable audit trail, and are responsible to governmental regulatory bodies through licensing and certification. These conditions work to remove bias due to local pres-sure, whether cultural, economic, medical, political, or scientific. Thus, scientific objectivity in clinical trial results carries its value through active work to avoid the accusation of and exposure to improper influence.

Data Management and Integrity

Laboratory data collection and management in clinical trials are becoming increasingly complex, especially in multi-center or biomarker-guided trials. Working with multiple laboratories, whether regional, reference, or analytical/esoteric, amplifies the risks associated if poor data management processes exist. In addition, numerous contracts, data agreements, timelines, and procedures can increase the workload for clinical trial management staff. Utilizing a consolidated data management platform allows the integration of complex, high-volume information collected from multiple laboratories, ensuring the delivery of clean, merged data according to exact user specifications. This function is particularly pertinent as today’s trials produce large quantities of data from geographically disparate sources that may be using a variety of platforms. A single, coordinating laboratory data management team operating under a single data transfer agreement can coordinate the programming, coding, cleaning, and conditioning of data from disparate sources. Potential benefits are consistency, fast query resolution, and identification of integrity issues. In the case of local labs, the Clinical Research Coordinator (CRC) has to share the reference range manuals with the Clinical Research Associate (CRA), and the CRA enters the reference ranges in the clinical database (eDC). In the case of the central lab, manual data entries of reference ranges are not needed. In local lab settings, harmonization may become a prerequisite, especially in multi-center trials. The compatibility of data generated by multiple laboratories is not guaranteed due to different methods, reagents, calibrators, etc., used, and management of data from multiple sites is difficult and requires more effort for statistical analysis than what is needed.

In addition, centralized reference laboratories provide a secure and reliable location for the storage of samples. Samples are stored in a controlled environment under consistent conditions, which helps to ensure their quality and integrity. This is particularly important for long-term studies, enabling researchers to access samples for future testing and analysis. As trial sponsors, whether academic institutions, companies, or contract research organizations, continue to preserve more biological specimens for future research efforts, tracking and managing patient samples requires considerable work and coordination. The centralized digital storage of sample information improves productivity, efficiency, compliance, and data integrity.

Cost-benefit analysis

Cost savings is a significant consideration as well. One of the critical benefits of a centralized reference laboratory is that it saves time and money for researchers. Consolidation enables a laboratory to standardize pre-analytic, analytic, and post-analytic practices in microbiology and offers cost savings on instruments, reagents, and personnel. Researchers can send their samples to a single laboratory, which reduces costs and saves time. A number of authors have recently estimated the expenditure in clinical trials for laboratory services to be above $1 billion (€750 million). Such laboratory services include preclinical and clinical lab testing. It is envisioned that the proportion of this analytical budget spent at central laboratories in contrast to local laboratories will continue growing.

Investigators (and sponsors) expect lab results to be reported immediately after the central lab receives the samples. Result reporting within 12 to 24 hours may be easy to achieve for routine testing methods. Interestingly, for more complex and specialized methods, the frequency of running a specific assay in the laboratory directly depends on the number of samples received. The high cost of instrumentation (up to $250,000) and reagents ($1000 for a kit to test approximately 40 samples), in addition to the need for qualified technicians, explains why laboratories need a minimum batch size to offer competitive lab fees to sponsors. A small laboratory processing 50 or 100 samples a day may only receive five to 10 samples for a specific immunology method. This imaginary laboratory would only be able to run the immunology as say two to three times a month at a rather high cost per unit. The chances are very high that small laboratories refer their samples to larger laboratories (often hospital-based laboratories with poor quality standards and missing cross-validation data). A central laboratory with the capability to process 5000 or more samples per day may have the advantage of both offering competitive prices and reporting lab results with the shortest delays.

However, logistical issues can also be cost-problematic in a central lab setting, especially when transporting specimens to a centralized location. The geographic location of the study site is also an important factor in the selection process when looking for a central laboratory. From a logistical point of view, selecting a central European lab for a U.S.-only study would not be a good idea since it would require shipping all samples over the Atlan-tic. In general, courier costs, schedules, and routes are of critical importance. For instance, timely inoculation of specimens into microbiology culture media provides the best opportunity to recover infectious disease pathogens. Likewise, delays in transport and extreme environmental conditions can lead to false-negative culture results. Transporting specimens also raises the risk of getting lost en route to the central laboratory. Excellent communication between laboratories and couriers, remote and central hospitals, and ordering clinicians is essential to successfully managing these issues, especially if problems arise.

In summary, a high-quality centralized reference laboratory is a critical component of clinical research that enables researchers to conduct accurate and reliable laboratory testing. It provides a centralized location for specialized and standardized laboratory testing services, access to specialized testing and expertise, saves time and money, reduces the risk of errors and biases, enables the evaluation of new diagnostic technologies, and provides a secure and reliable location for the storage of samples. Ultimately, results from the central laboratory are ideal for achieving meaningful analysis and reporting to regulatory agencies. The laboratory plays a significant role in ensuring better patient outcomes by improving the quality and accuracy of laboratory testing.

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