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The Central Issue

Microbiological testing is very important in all clinical trials – it is the organisational structure of the laboratory stage in any trial for a new medicinal product, and can involve the following:
  • Tests which require quick medical decisions or routine analyses – usually performed in a local lab that is a structural or affiliated subdivision of a clinical centre (study site)
  • Tests with a high level of result unification – for example, assessment of drug safety panel, lab diagnostics, or simple pharmacodynamic studies – or, in cases where the required tests cannot be performed in local labs, specialised central labs are used
  • Tests which are not routinely performed, but are required by the study protocol – for example, pharmacokinetic studies, brand new methods of molecular diagnostics or complex pharmacodynamic studies – and use special labs

Basic principles and criteria for selecting central labs are applicable to the majority of studies where a wide variety of pathologies are involved (1). However, a certain exception concerns the area of antimicrobial agents’ development, in particular the part that requires cultivation and identification of microorganisms.

In such cases, the use of only central labs faces some systematic problems. First, it is important to understand that microbiology studies are regulated by national standards, especially in terms of antibiotics susceptibility tests, culture media for microorganism growth, the method for identification, and quantitative assessment, all of which vary for each particular country (2). The second crucial aspect concerns the wider logistical requirements – in other words, the timelines and conditions of biosample delivery. This is because the reporting of results is very important for microbiology studies, as the loss or damage of certain samples during transportation may be irrevocable.

Central versus Local

The essential requirement of microbiological studies is the collaboration between two qualified labs – central and local/regional. This is considered to be the main requirement and standard for conducting microbiological research. The idea can be exemplified by several trials of similar design carried out by our company, where results revealed a discrepancy in pathogens identification in a regional lab and re-identification performed in a central lab. The analysis of about 100 cases of discrepancies in pathogens identification (approximately 3% of total amount of purified pathogens) proved that the results of repeated re-identification confirmed the correctness of the regional or local labs’ conclusions in 40% of cases. Thus, the collaboration of central and local/ regional labs as consecutive, double quality controls of microbiological results is an appropriate way to conduct the lab portion within clinical trials.

However, while the use of central labs is unquestionable, the principle of selecting local labs and commercial, regional labs is uncertain for the majority of sponsors (3).

In our research, we drew on the data of 30 clinical trials conducted in Central and Eastern European countries. The trials included more than 300 clinical sites with approximately 10,000 patients. The main indications were non-complicated urinary tract infection, intra-abdominal infection, and hospital-acquired and community-acquired pneumonias. This article depicts the problems of local labs in Central and Eastern European countries (3), since regional laboratories are to meet the same requirements as the central ones, which must conform to national regulatory standards (1).

Quality Control

Microbiological testing in the framework of clinical trials requires highly qualified lab staff and a wellorganised work process. During the majority of haematological and biochemical tests, automated and programmable complexes are used and included in the basic system of quality control. Detailed manuals and clear instructions, as well as standard sources of reagents, simplifies the qualification of the staff to just pressing buttons in a certain order. As a result, the control and audit of such labs is made more comprehensive.

As for a microbiological lab, everything is much more complicated. During each stage of the research – from obtaining biological material to the determination of the microorganisms’ identification and their antibiotic sensitivity panel – lab personnel should follow instructions and standard procedures, as well as understand the essence and meaning of the operations. Moreover, Good Clinical Laboratory Practice (GCLP) compliance is crucial to determine the appropriate microorganisms and to generate adequate recommendations for the treatment of patients. However, the licensing and national certification of labs in Eastern Europe does not imply control of lab functioning. The technical suitability of the premises, fire safety and general sanitary standards, for example, are left to evaluation. Local labs do not possess the independent certification of the International Organization for Standardization, and do not even try to obtain it.

When organising microbiological studies – according to the basic GCLP requirements, as well as project-specific features – it is unfortunately the case that microbiological tests, as part of clinical trials conducted by local microbiological labs in Central and Eastern Europe and Russia, will usually face a number of challenges.

These can be divided into two main groups: basic difficulties related to the routine functioning of the local microbiology labs, and project-specific difficulties reflecting the unique characteristics of a certain protocol.

Routine Malfunctioning

The main reason for the routine malfunctioning of microbiological labs is a human factor. Unlike the heads of haematological or biochemical labs, who act as managers or supervisors, microbiologists believe that their research is creative and scientific, and the head of a microbiology lab is both the leading expert and scientist. This means that internal rules are set according to individual qualification levels and ways of process maintenance. Accordingly, some elements of functioning have no formal procedures; the standard form of registering results is rarely used. Lab registers are often filled in illegibly, with the primary results frequently recorded on slips of paper, which can lead to deviations in equipment control and service, for example.

It is also impossible to guarantee that the reagents and materials used by the local lab during the whole trial period are supplied by the same manufacturer, which may impact the accuracy of the results. Another reason for the ineffective lab process may be the insufficient level of personnel qualification, which results from specificity work in a microbiological lab. For instance, the use of a biochemical analyser or haemocytometer is strictly regulated, and training templates are usually attached to the user manual. However, microbiological trials are characterised by a large number of procedures, for which there is no training or documentation. Training is usually conducted via a ‘follow my example’ approach.

Local microbiological labs are not provided with information systems, reflecting the existing difficulties in regulating procedures. This drawback is not crucial because the number of patients is relatively small – but it does hamper the proper level of quality checking. However, such irresponsible maintenance of documentation does result in the reluctance of the local labs to supply verified data. This is because it is easier and cheaper for them to do a new test than to confirm data accuracy.

Furthermore, local microbiological labs suffer from problems concerning the quality control of investigation organisations. One of the reasons for this is financial difficulties and the other, surprisingly, is under-qualified staff. The control of culture media, the presence and use of appropriate control strains, the monitoring of sterility and potential contamination, as well as the current conditions of allocated pathogens storage, are all performed in unsuitable ways. As a result, site monitors or auditors without a special lab qualification cannot determine the number of, or reasons for, deviations that lead to the production of unreliable and/ or invalid data. To avoid the collection of wrong data, a visit with a qualified lab expert is therefore required. However, if a lab expert finds a huge number of deviations, there is a risk of data disqualification for a particular clinical centre or for the whole study.

Case Study

In one example, sponsors wanted to use the ‘local labs-central lab’ scheme for two clinical trials: pneumonia and complicated urinary tract infection, which involved trials in 200 sites across 40 countries. The specialists from pre-qualification local labs found that more than 70% of the local labs selected for the trials (including the US and Western European countries) faced difficulties with implementing microbiological tests in accordance with protocol requirements. These problems were consistent across all study stages; for example, the lab staff obtained saliva, instead of the required phlegm, during selection of biological material.

More regular problems were also a concern, such as the quality and staining of Gram smears of individual culture media, especially since it was manufactured directly in the lab. Furthermore, the identification and storage of purified pathogens was characterised by deviations. It was also difficult to form correct panels of antibiotics for susceptibility tests, and the use of non-standard protocol led to an inadequate assessment of quantitative microbiological parameters.

In both trials, companies and sponsors had to turn down the use of local labs and launch a ‘clinical centres-regional labs-central lab’ scheme. Needless to say, in the pneumonia study, even the US site had to change its scheme.

Set Standards

Another project focused on the quantitative analysis of pathogens in urine, in the case of urological infections. The FDA gives clear instructions about the procedure of determining drug efficacy according to the quantitative culture of urine. However, Western European and Latin American countries use procedures that cannot estimate the required degree of microorganism eradication. In general, a semi-quantitative procedure is used and validation is optional, although, according to the American Society of Microbiology, the McFarland standards are preferred.

The preparation of every local lab for the required method needs additional supplies, training and validation. In most cases, it is impossible to fully implement because labs tend to have a lack of financial interest. Ideally, however, all regional labs should use only validated procedures required by the FDA; the project price may be higher, but valid data is guaranteed.

Problem Labs

It must be emphasised that regional labs are not the solution to all problems. Overall, only 30% of inspected local labs meet the goals and objectives of the clinical trials carried out. Furthermore, in our evaluations of local labs located in various regions of the world (Western Europe, ex-Socialist countries and South America), we have determined the following problem areas:

  • 45% of labs had no usage of or reference to internationally accepted microbiology guidelines
  • Not all types of tests were available in all labs – for example, in more than 50% of assessed local labs in Russia, Romania and Argentina there was no anaerobic culture, and there was no local lab in Moldova which performed this test
  • More than 50% of local labs did not double-check data entry
  • Over 50% of labs had a lack of ATCC strains with traceable origin
  • Almost all labs had gaps in data documentation and archiving
However, the majority of labs did express a desire to take part in a clinical trial with the motivation of improving the quality of lab work, through consultations with sponsor and contract research organisation (CRO) specialists. About half of the problematic local labs can reach the acceptable quality level through cooperation with a CRO. This means that two-thirds of local labs can be included in clinical trials.

Qualified managerial work with 30-50 local labs in the frame for just one clinical trial is rather difficult for sponsors or CROs to manage. Experience shows that clinical research associates can neither adequately pinpoint lab problems, nor predict them. In such cases, it is much easier and cheaper to work with a dozen regional labs, which are known to stick to standard procedures and quality control.

Financial Interests


Another challenge to the conduct of the microbiological aspect of a clinical trial is the ambiguous legal status of a local lab, and the ensuing financial and administrative contradictions. For example, for lab studies, the routine security panel number of analyses is predefined by protocol and depends on the amount of patients included in the study, which is reflected in the calculation of the research grant. On the other hand, for microbiological tests, it is impossible to know in advance the number of isolated pathogens; percentage of negative cultures; duration of treatment followed by a selection of biological samples; ratio of aerobic and anaerobic bacteria; and required amount of microbiological blood analyses. Therefore, the financial interests, as well as financial guarantees for quality control, are minimal for local microbiological labs. However, in the case of regional labs, payment is done according to an agreed price list, as an integral part of the study contract, in strict accordance with the amount of work which is carried out. As a result, for a small trial with a limited number of sites (8-12) the use of local microbiological labs (within the 30% of the labs mentioned above) is possible. Nevertheless, it should be taken into account that during the selection of these sites, the assessment of the suitability and qualification is of great importance.

Conclusion


For larger projects – the majority of Phase 2 and 3 microbiological studies – it is better to use regional labs (2). At face value, this choice is more expensive because of the cost of delivery of biological samples to the testing site (from the clinical centre to a regional lab). However, on the plus side, the quality of work will be much higher. Furthermore, the cost of postal delivery can be optimised due to the quantity and location of the relevant labs – for example, Russia may have more than one lab, whereas the Baltic States, on the contrary, may use one for several countries.

Theoretically, a third option for organising such projects is possible: an ongoing monitoring and management of local labs by qualified CRO specialists. With this approach, as practice shows, the cost of this part of the project could be less than the postage for shipping samples.

References


1. Karelin A, Belotserkovsky M, Khokhlova V and Kumar A, Balance of evidence, International Clinical Trials, pp62-64, May 2013
2. Khokhlova V, Stetsiouk O, Karelin A and Belotserkovsky M, Central and Eastern Europe – The right region for antibacterial drug development, with Romania as the place of choice, Journal for Clinical Trials 4(2): pp52-60, 2011
3. Karelin AA and Belotserkovsky MV, Regional laboratories: Where and what for? Journal of Antimicrobials, Photon 128: pp218-220, 2013


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About the Authors

Andrey Karelin, PhD, DrSci, is Director Laboratory Support Services at PSI CRO, and graduated in Biology from Moscow State University. Before joining PSI in 2001, he worked at the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry as the Head of Laboratory. Andrey is the author or co-author of more than 100 publications in scientific journals and collections.

Maxim Belotserkovsky, MD, PhD, MBA, is Head of Medical Affairs at PSI CRO. He is a board-certified physician in internal medicine, rheumatology, anesthesiology, intensive care and haemodialysis, as well as a certified Associate Professor of Pathological Physiology. Maxim has more than 20 years’ experience in clinical research as an investigator and clinical research professional. He is also the author or co-author of more than 130 publications.

Veronika Khokhlova, PhD, is a Senior Laboratory Specialist at PSI CRO. Before joining PSI in 2005, she worked for more than 15 years for the Russian Academy of Science as a Senior Research Associate.

Olga Sazonova, PhD, is a Senior Laboratory Specialist at PSI CRO. Before joining PSI in 2008, she worked for five years for the Russian Academy of Sciences as a contracted and staff researcher.
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Andrey Karelin
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Maxim Belotserkovsky
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Veronika Khokhlova
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Olga Sazonova
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