Balance of Evidence Selecting a central laboratory partner for a clinical trial is too often based on subjective factors. But a more objective, project-specific evaluation will help ensure the most appropriate lab is picked The use of central laboratories (CLs) as an independent participant in clinical trials is a widespread practice, particularly given the requirements of regulatory authorities and study sponsors for high-quality, reliable laboratory data and the difficulties faced by local labs in organising the required tests in the country where the trial is being performed (1,2,3). CLs provide services ranging from conducting laboratory assessments and compiling lab test reports, to contracting courier services for delivering lab kits and biosamples to and from medical institutions where diagnostics and treatment of patients takes place (4).
Subjective Decisions Regardless of the important role of CLs in clinical trials – and the often substantial cost involved – it tends to be subjective, rather than objective, factors that influence the selection of a particular lab partner. In interviews with more than 50 sponsors, four reasons were commonly cited: ●● “A good recommendation from a person we know” ●● “One of our colleagues worked with this laboratory” ●● “We know a good specialist in this laboratory” ●● “We had a positive experience with the laboratory when working on a previous study” Another common approach is a sponsor’s mandatory request to use a specific CL with which it has worked before, in a kind of ‘preferred provider’ concept. The problem with this concept is the absence of guarantees that the chosen CL is the optimal choice for the particular study. Before a study starts, many sponsors perform projectspecific audits of pre-selected CLs. This approach is favourable to the preferred provider route since it provides an opportunity to obtain reliable and up-to-date information about the lab. However, it requires time and additional expense, as well as audits of several labs in order to optimise the selection. In addition, a lab audit performed by auditors who do not possess professional laboratory knowledge will not guarantee the high performance of the lab during the study. Furthermore, some consultants offer services to select CLs for clinical trials, but there is often a lack of appropriate criteria for ensuring objective and competitive selection.
A Karelin, M Belotserkovsky, V Khokhlova and A Kumar at PSI
One way to address these issues and ensure a more objective selection of a CL is to use the algorithm set out in Figure 1 and explained here.
Initial Contact For the initial contact (Stage 1), CLs can be pre-selected using a company’s database, references or even an internet search. It is usually sufficient to contact three to five CLs but, as a general rule, the more complex the tests required, the more labs should be approached. For a preliminary contact, a short request about the available tests (with the indication of the study geomix) and general interest in the study is sufficient. Such interest is generally confirmed very quickly, so it is recommended that nonreplying CLs are not approached a second time as their lack of response tends to imply a lack of interest in the project. It takes no more than a week to gather initial information from all labs.
CL Feedback The second contact (Stage 2) is the most difficult and demanding. A CL’s early readiness to participate in a study may not necessarily prove to be the case further down the line. It is important to obtain the CL’s feedback on, for example, study design and logistics, the laboratory’s quality systems and some study-specific questions. Standard forms will enable all the necessary information to be collected in a single step. One suggestion is to use a project-specific pre-qualification questionnaire and a general lab pre-qualification questionnaire, which together contain about 30 questions covering all aspects. Any laboratory that can act as a CL can provide all the requested information quite quickly, within two to three weeks. Selecting a CL requires a cross-functional effort with independent participation from a project manager, who will oversee and approve the selection, as well as a lab specialist and a quality assurance auditor, to request and assess the information that comes in. It is recommended to appoint a qualified lab specialist to coordinate the process.
Figure 1: Optimisation of central laboratory selection process Stage 1
Initiation of lab selection process (initial contacts)
Initial contact letter
Lab 1 Stage 2
Collection of the data (secondary contacts)
Study outline QA questionnaire Project-specific questionnaire Lab 1
Completed questionnaires and accompanying documents Quotas and proposals
Stage 3 Comparative data analysis
Client Project manager
Reporting of the lab selection results
Lab 1 data collection sheet Lab 2 data collection sheet Lab 3 data collection sheet Lab selection report: Recommended lab Back-up lab
Comparative Analysis When potential vendors send back completed questionnaires, along with the copies of requested documents and budget, the next step is to carry out a comparative analysis of the collected information (Stage 3). This can be done by creating a project-specific lab profile for each CL that has expressed an interest. This form contains the questions posed to the CL, its answers, and the comments of the lab specialist and auditor. The CL’s capabilities can then be assessed using the simple scale for each aspect of evaluation: acceptable (fully meets the study specifications and regulatory requirements, with an adequate financial proposal); partially acceptable (corrective actions can be made during negotiations); or not acceptable. Issues to be considered during the evaluation include: ● Quality systems ● Ability to meet protocol specifications ● Logistics ● Data management and IT services ● Additional services ● Budget and reliability of cost estimates ● Regulatory compliance ● Willingness to cooperate ● Previous experience (if available) ● Additional project-specific aspects
The importance of different aspects of the evaluation may change, depending on the lab assessment programme. For example, if a standard safety panel is envisaged in the clinical trial, the most important aspect is to evaluate quality systems and IT, and the auditor should lead the process. On the other hand, in the case of a complicated pharmacodynamic or pharmacokinetic study, the main aspect is the professional opinion of the lab specialist, especially when assessments are related to validating a method or approach that is new for the CL.
Project-Specific Profiles An essential part of the profile involves evaluating the adequacy of the CL’s costs. When comparing the budgets proposed by CLs, it should be taken into account that the main elements of the budget may be compiled and calculated in different ways, so transparency of the calculations is the major requirement. While compiling a profile, the lab specialist may ask additional questions and request clarificiations about the budget and other provided information. Even if a CL completes its questionnaires on time, this subsequent process of communication between the CL representative and the lab specialist will reflect the ability of a potential vendor, if selected, to maintain communication with the sponsor at the later stages of a trial. A lack of communication from a CL at this stage
CL selection – at a glance ● Comparative analysis of several potential vendors’ proposals,
made on a competitive basis ● Impartial assessment through independent expert evaluation
of documents performed by qualified laboratory specialist and auditor ● CL selection, based on the best combination of the following:
– Capability of a CL to comply with the protocol requirements – Availability of a satisfactory quality control system in the laboratory, including a set of regulatory documents (licences, certificates, etc) – Adequacy of the logistic solutions offered by the CL (including terms of transportation of the biosamples and proposed duration of their stability) – Acceptability of the budget – Satisfactory level of laboratory management, also proven by previous cooperation
might bring the need to remove it from the the list of potential vendors, since the inability to obtain answers in a timely manner during a trial almost always has a negative impact on the results. The time of the follow-up communication must take no more than one month, which includes obtaining all clarifications.
Final Choices Based on these project-specific laboratory profiles, a final document can be prepared that contains the comparative evaluation and related scores for each CL’s ability to conduct the trial, enabling the sponsor to choose the most appropriate laboratory. It is also recommended to select a back-up CL in case any unresolvable problems arise during negotiations with the favoured lab. The final choice should be agreed by the dedicated lab specialist and auditor and then approved by the project manager. Most CLs that operate in the clinical research sector provide lab test results of a similar quality. Likewise, their IT systems, regulatory compliance documents and quality systems are in most cases acceptable. However, logistics, budgets and laboratory or project management, especially in terms of communication and collaboration with the sponsor, can vary dramatically. It tends to be these latter factors that have a key role when making the final decision on vendor selection. The ultimate decision should be made based on a balanced assessment of all criteria. It should be noted that financial proposals, while clearly very important, should not be given inflated consideration during the selection process at the expense of other aspects. In many cases, laboratories offering overly favourable financial terms, when selected, present the client with a number of bad surprises during the study.
Moving Forward Using the process recommended here, the entire process of selecting and approving a CL should take between four to six weeks, depending on the planned scope and complexity
of laboratory assessments and the sponsor’s specific requirements, allowing the next step – contract negotiations – to begin. The approach should reduce subjective decision-making, help ensure an appropriate and cost-efficient CL is appointed, and minimise the likelihood of having to undertake the complex, laborious and costly task of replacing an unsuitable lab partner while a trial is in progress. References 1. Clinical laboratory improvement amendment. Visit: www.cms.gov/ regulations-and-guidance/legislation/clia/index.html 2. CLIA-related Federal Register and Code of Federal Regulation announcements. Visit: wwwn.cdc.gov/clia/docs/cms-2226-f.htm 3. ISO 15189: 2007: Medical laboratories – Particular requirements for quality and competence 4. Leão Jr F, The local central lab model: With globalisation of trials comes the difficulties of sample logistics. Enter the central laboratory model, Applied Clinical Trials, April 2008
About the authors Andrey Karelin PhD, DrSci (Biology), is Director, Laboratory Support Services at PSI CRO AG. He is a graduate of the Department of Biology, Moscow State University. Before joining PSI in 2001, he worked as the Head of Laboratory at Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry. Email: Andrey.Karelin@psi-cro.com Maxim Belotserkovsky MD, PhD, MBA, is Head of Medical Affairs at PSI CRO AG. He is a board-certified physician in internal medicine, rheumatology, anesthesiology and intensive care, nephrology and haemodialysis; an Associate Professor of Pathological Physiology; and a corresponding member of the Russian Academy of Natural Science. Email: Maxim.Belotserkovsky@psi-cro.com Veronika Khokhlova PhD is a Senior Laboratory Specialist at PSI CRO AG. Before being recruited by PSI in 2005, she worked for more than 15 years as a Senior Research Associate at the Russian Academy of Science. Email: Veronika.Khokhlova@psi-cro.com Akhil Kumar MD is a Medical Director at PSI CRO AG. Previously, he worked for MGI Pharma, also as a Medical Director, and was an independent consultant. He is board-certified in both medical oncology and haematology in the US and is an Assistant Professor of Medical Oncology. Email: Akhil.Kumar@psi-cro.com