Central to success? Reliable data in trials6 July 2015
Since the 1990s, many sponsor companies have chosen to outsource their sample testing to central laboratories. Capable of handling logistics as well as data management, these labs often function as a one-stop shop for a wide range of essential requirements. But how does this framework compare with specialised local laboratories? Clinical Trials Insight explores the pros and cons of each with business management expert Robert Hoek, global outsourcing manager for Roche.
Data collection lies at the heart of any clinical trial. If you're hoping to develop a new drug, your success or failure is likely to be determined by the results of laboratory testing. It is therefore crucial that all the data you record is clear, unbiased and accurate.
While this sounds simple enough in principle, it can be somewhat harder in practice, at least when you're dealing with multicentre trials. In these cases a quandary arises: how can multiple local labs ensure that their results are meaningfully collated and compared? When investigator sites are based all across the world, it can be extremely difficult to guarantee consistency from one lab to the next.
This has historically caused some problems. One famous example was the University Group Diabetes Programme (UGDP) study of 1970, in which patient eligibility for the study was determined in various local labs. Their admission, or otherwise, was based partially upon the results of a glucose tolerance test.
While most of the clinics assessed patients' level of whole blood glucose, four of the clinics looked at serum glucose levels, which has a higher cut-off point for defining diabetes.
This means that certain centres enrolled fewer people with mild diabetes, introducing an element of bias. It was just one of the study's numerous - and now notorious - methodological flaws.
The standardised model
For many trial designers, the solution is a central laboratory, which eliminates the risk of inconsistency. Rather than analysing test results across local labs and then consolidating results, the biosamples are sent to one single test facility. Because the same analytic method platform is used each time, you are left with easily combinable data.
In the last few decades we have seen a real shift toward this form of trial design. Beginning in the US in the 1990s, and eventually expanding to cover global trials, the central laboratory is becoming ever more prevalent. This trend has been expedited as regulations become more harmonised across the globe and logistics providers develop their offerings.
Robert Hoek, a business manager responsible for outsourcing biomarker services for early phase clinical trials, believes there are multiple reasons that pharmaceutical companies might have a preference for a central laboratory.
"The reasons why central labs were introduced in the 1990s are still valid today," says Robert Hoek, an independent outsourcing specialist, who is currently at Roche. "Standardised methods, standardised data and one electronic data transfer are obviously attractive features."
As well as securing the quality of lab data, central labs afford other possibilities. Certain local labs may lack all the facilities they need, particularly in under-resourced regions, whereas a well-chosen central lab is more likely to offer the right equipment.
The lab can also function as a kind of one-stop shop, responsible not just for lab tests and reports, but also for coordinating deliveries with courier services. Typically, it will offer a standardised specimen kit tailored towards each trial and will train its staff in efficient specimen handling.
Through outsourcing this part of the process to a central laboratory service provider, the sponsor company stands to free up time to focus on their core competencies. Most likely, the trial will be able to get underway without delay and meet all budget milestones.
"Nowadays the contracting process has become more complex as well, due to legal matters, so having one contract instead of many is also an advantage," says Hoek.
It's also probable that the results derived from a central lab will be easier to defend to regulatory authorities. After all, less variation in central lab results makes it easier for trial sponsors to assemble meaningful statistics.
And, in recent years, analysis of biomarkers - potentially an integral part of the decision-making process for therapeutic and regulatory decision-making - has become a key trend. In some cases, regulatory agencies may well require supporting biomarker (and corresponding assay) data for drug submission. Consequently, selecting an assay might require more vigorous validation than sponsors, most often concerned with routine safety tests, are used to. This could well impact contract research organisation (CRO) selection.
"Although a central laboratory still performs the routine safety testing, these days more and more of its services relate to biomarker testing," Hoek points out. "In these cases a central laboratory that is also able to perform the biomarker analysis brings advantages to Pharma, as the logistics will be far easier."
He also reveals that when it comes to biomarkers, it can be challenging to find CROs that are interested in supporting early phase trials where the volume is still low.
"The cost for method development and validation is significant, while the revenue from the analytical testing is still low," he opines. "So a pharmaceutical company often ends up working with niche providers in phase I and II, and then transfers the methods to larger CROs moving towards phase III."
Cost and sample integrity
He also cautions that central laboratories aren't always the most appropriate choice for sponsors' outsourcing needs, particularly in the field of oncology, where prompt safety test results are needed.
"Generally sites prefer to work with their local laboratory," he says. "The local processes are tailored and the nurses know exactly how things work. Results are available sooner. And, if things aren't clear, direct communication channels already exist for quick resolution. A smooth process at the sites increases compliance."
What is more, not all clinical trials involve biosamples. Certain types of test - CT scans for example - require highly specialised medical equipment, which is typically only available in hospitals. In these instances, investigator sites may work together with their local radiology facility for immediate interpretation of results.
The choice between local and central laboratories often comes down to one primary driver: cost. Central laboratories offer clear economies of scale - they can process high volumes of samples and consolidate results into a single database - but these benefits must be weighed against the far higher cost of logistics.
Today's multicentre trials may take place in more than 20 countries around the world, sometimes in remote locations. The central laboratory service provider will need to transport kits into these regions, and transport samples out of them, all the while paying attention to factors such as regulatory discrepancies and temperature management.
The challenges here can be extreme. Take the Russian embargo on the export of biological samples between May and June 2007. Since samples could not leave the country, central laboratory service providers needed to keep a close eye on Russian law and find a way to reroute their shipments to minimise disruption.
On a more quotidian basis, not all clinical staff are necessarily cut out for logistics management. They may be asked to turn their hand to tasks such as kit and invoice preparation, which may not fall within their area of expertise. In this regard, the 'one-stop shop' model has been known to pose some complications.
There is also the issue of poor sample integrity. The samples run the risk of deterioration during transit, particularly when transported from challenging geographies. A certain number will typically have to be withdrawn or recalled, prompting a cascade of delays and adding costs. According to certain estimates, between 2% and 9% of biosamples collected within central laboratories cannot be processed.
Local laboratories avoid these pitfalls. The samples are unlikely to degrade or to suffer detrimental temperature excursions, and the sometimes prohibitive costs of international transit are eliminated.
Think global, act local
It is clear, then, that central laboratory services as classically defined are not right for every trial. Many of today's providers attempt to combine the best of both models by operating a network of harmonised local laboratories that abide by centralised principles.
For instance, a provider may own a number of decentralised labs within a larger geo-cultural region, which means that specimens simply need to be transported to their nearest facility. Through virtue of their proximity, these facilities can provide local support for investigator sites, as well as a better knowledge of the area's culture, language and regulations. While they are often not truly 'local' (in the sense of being next door to an investigator site) they are not so far removed as to cause a logistical headache.
Meanwhile, the benefits of a central lab remain intact. The provider harmonises its operations across all labs, ensuring analytical rigour and regulatory compliance. Each facility benefits from the same IT systems, reporting platforms and standardised operating processes.
As trials become more global in scope, many central labs are working to expand their reach, therefore attracting clients conducting research outside of 'traditional' clinical trial markets. For instance, ACM Global Central Laboratory opened two new lab facilities last year, in Shanghai and Singapore. These now operate in parallel with locations in the US, the UK and India, and have been billed as providing the same capacities and standards in scientific expertise.
In other instances, the global central lab does not own all the relevant facilities, but works with them sufficiently closely to integrate comparable results. Depending on the level of harmonisation, it may be possible to treat this network like a single entity. For this to work, the central lab will need to compare the equipment, methodology and kits used in each laboratory, and address - or adjust to - any differences. It will also need to look at the IT platforms used, ensuring that all data can be transmitted and stored in a way that is easily consolidated.
Networks of this kind have become more feasible in recent years, as safety and screening tests have improved, and disparate platforms have grown more capable of producing concordant laboratory data.
Whatever approach is chosen, the ultimate aim is the same: to supply the sponsor company with a reliable and accurate database from a single source. If the sponsor company chooses to outsource to a central lab service provider, then this is what they will be expecting irrespective of the underlying business model.
Hoek predicts that in the future of clinical outsourcing, results from laboratories will become more and more poolable, and there will be no need to centralise the analysis of routine safety testing.
"Central labs will continue to thrive when organising collection of samples for biomarker testing," he says. "I also expect central labs will play a role in combining the data from the local laboratories, their own biomarker data and biomarker data from third-party labs."
"But I believe there is no perfect lab for every trial," he stresses. "For studies that have a complex laboratory component, a sponsor should request at least two proposals and carefully discuss these with the contractor. Learn how processes will be set up and how the sample collection kits will be designed. There is much more than the bottom-line price."
One thing is certain - the laboratory service provider concept has never been static. Since the first businesses set up shop, they have always been required to adapt their frameworks in response to new market challenges. As clinical trials become more complex - both from an analytical and geographical standpoint - so too do their outsourcing needs. A contractor will sink or swim based on how well they meet these changing demands.
Robert Hoek is an independent business manager, currently employed as global outsourcing manager for Roche. Prior to this position, he worked for the bioanalytical laboratories of PRA Health Science. From 2000 to 2013, Hoek was part of Eurofins Central Laboratory, which developed from a European Central Lab into a global organisation.