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In 2019, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Preanalytical Phase Working Group (WG-PRE) developed a specific checklist - called PREDICT - to avoid preanalytical diagnostic errors in clinical trials.
This checklist focuses in particular on the most important pre-analytical aspects of blood sample management in clinical trials:
- Test selection
- Patient preparation
- Sample collection
- Management and storage
- Sample transportation
- Pre-test sample collection
Laboratory errors
Errors happen, even in laboratory diagnostics. Although many efforts have been made to improve standardization and harmonization of various activities throughout the testing process, in vitro diagnostics is a relatively safe environment compared to other diagnostic disciplines. Most of these errors (approximately 60-70%) are due to manual activities in the pre-analytical phase, followed by post-analytical errors (approximately 20-30%) and analytical errors. The various consequences of these potential errors include increased patient risk and waste of economic resources as well as organizational problems inside and outside the laboratory. Pre-analytical quality is an essential requirement of clinical trials because there is a tangible risk that some clinical trials will not deliver the actual results due to a variety of laboratory errors, including those that occur in the pre-analytical phase.
Laboratory tests in clinical trials
Laboratory diagnostics play an essential role in clinical trials, as many diagnostic tests are used to determine whether or not a trial participant meets the eligibility criteria; they are also used to assess baseline values of many parameters, which may then be modified by the clinical intervention, as well as to demonstrate the efficacy of investigational products and to monitor the safety of trial participants throughout the clinical trial.
The adoption of stringent pre-analytical requirements is as mandatory for clinical diagnostic tests as it is for clinical trials, as the risk of errors in the latter scenario can result in several unfavorable consequences (e.g. rejection of samples due to non-compliance in the pre-analytical phase could subsequently lead to the exclusion of not only the specific samples, but also the entire data of the person concerned).
Failures in clinical trials
There is consolidated evidence that the risk of a misleading clinical trial result (i.e. a positive or negative result) is higher than the risk of a false positive result. i.e. a positive or negative result) is particularly high - i.e. an event that falls under the traditional concept of "lost in translation from the bench to the bedside", which encompasses the failure to translate basic research findings into effective clinical interventions.
There are many factors that lead to the failure of a clinical trial (apart from lack of efficacy or safety concerns about the intervention), including:
- Different human response to the interventions compared to that observed in preclinical models
- Lack of human and/or economic resources
- Poor study design
- Inaccurate site selection
- Poor recruitment numbers or a high number of dropouts
- Problems with patient safety
- Poor study conduct or inadequate (statistical) analysis of data
Among these various factors, diagnostic errors (including pre-analytical errors) are usually overlooked as a potential cause of clinical trial failure, although there is growing evidence to suggest the opposite.
A recent report published by Schultze and Irizarry identified the main sources of uncertainty in laboratory data obtained during safety assessment studies:
- Unfamiliarity with standard operating procedures (SOPs)
- Misidentification of samples
- Equipment malfunction
- Failure of quality control
- Test failures
It is worth noting, that the risk of clinical trial failure due to delayed processing of blood samples for glucose testing has also been highlighted. Indeed, blood tubes that cannot be centrifuged for up to 24 hours after vein collection will experience a gradual (false) drop in glucose concentration, which may ultimately affect the interpretation of data used to assess the health status of potential study participants. In multi-center studies, the use of different types of blood collection tubes or additives can be a source of divergent results, which greatly affects statistical interpretation.
In addition, the use of inappropriate pre-analytical procedures or failure to follow standard operating procedures for the collection, processing and storage of biospecimens has been shown to introduce a negative bias in trial results and can also affect the reproducibility of scientific data.
It is critical to have a standardized recording and documentation system for all pre-analytical conditions during the process of patient preparation, biospecimen collection and storage to rule out pre-analytical bias in future studies. In particular, the cumulative risk of preanalytical bias gradually increases with the complexity of the study, being lower for single-centre studies, intermediate for multicentre studies characterized by multiple peripheral sampling sites and local testing, and predictably highest for multicentre studies involving many peripheral sampling sites and a single reference laboratory (i.e. centralized testing). In the latter case, not only do local procedures for blood sample collection and handling need to be standardized, but strict harmonization of local administration and sample transport to reference laboratories is also required.
Management of preanalytical variability in clinical trials
There are no guidelines for the management of preanalytical variability in clinical trials, and there is no specific guidance for standardizing or harmonizing the different preanalytical steps within a clinical trial, be it single or multicentre. For all these reasons, the PREDICT checklist was developed.
Choosing the most appropriate laboratory tests
Choosing the most appropriate laboratory tests is as important in routine clinical practice as it is in clinical trials. In the latter, it often happens that study protocols are revised and contain outdated, redundant or even useless tests because old habits persist in the preparation of the protocols - together with insufficient or insufficiently updated knowledge about the importance of the tests. The use of the most appropriate and up-to-date laboratory tests in clinical trials - due to their potential usefulness for determining the eligibility of participants, for detecting adverse events and for defining clinical outcomes - is as mandatory here as in routine clinical practice.
The method of analysis should also be selected according to the objective of the test, i.e. it should be determined in advance whether the test is to be used for screening, diagnosis, prognosis, therapeutic monitoring or follow-up. In this way, the analysis, analytical technique and test concentration limits can be selected according to the diagnostic performance and adapted to the intended use of the study protocol.
Patient preparation
It is important that patient preparation for sample collection is standardized. This includes the exact standardization of blood collection from one patient to another when samples are collected at a single center, but a standardized procedure is also essential when blood is collected at different centers. This requires accurate recording of clinical data, followed by strict standardization of fasting time, collection time, abstinence from cigarette smoking and coffee drinking, and a rest period prior to blood collection; the patient must also be in a standardized position during collection.
Collection and handling of blood samples
The study protocol contains clear information on sample type and volume, sample matrix, blood collection device and blood collection tubes/additives as well as the time of tourniquet application, preferred venipuncture site, order of collection and mixing of samples. The use of identical automated tube labelling devices is a viable option to improve standardization.
Preparation, transport and/or storage of blood samples
The risk of analytical bias is lower with centralized testing, but local analysis would limit the risk of pre-analytical bias due to sample transport. Both solutions are suitable as long as a detailed protocol with precisely standardized analytical or pre-analytical procedures is provided. In clinical trials where samples are shipped from distant collection centers to the reference laboratory, it is essential to centrifuge the samples on site if there is a concrete risk that the stability of the analytes in the serum or plasma is compromised during transport. Regardless of whether centrifugation is performed on-site or in the reference laboratory, centrifugation conditions must be standardized and the serum or plasma must be separated as soon as possible after centrifugation.
Sample transport conditions (i.e. time and temperature) must be accurately standardized, recorded and monitored. For samples that cannot be analyzed immediately, they must be stored at different temperatures and storage times according to the available knowledge about the stability of the analytes. Repeated freezing and thawing cycles should usually be avoided, preferably by aliquoting the samples in volumes corresponding to the analytical need before storage according to the study protocol.
Tools such as the platform developed by Groenlandia Tech guarantee traceability in such logistics processes. A key element of the platform is the Nuuk cool box: a device with a real-time control system that optimizes the logistics process, improves the safety of the contents and reduces laboratory costs.
Nuuk guarantees various aspects, such as real-time control of the internal temperature, an integrated alarm system - which informs of any possible impact or damage in the transport process -, full access control where only the original user and the recipient can access the contents, and a cooling technology that can be adapted to different temperature ranges.
Pre-test sample collection
Finally, in clinical trials where biobanks are used for long-term storage of biological material, pre-test sample collection can be an additional critical point. It is recommended that standard operating procedures be made available to all participating laboratories to standardize the procedures for preparing samples for testing; they should also include procedures for thawing and mixing samples and clear guidance that inappropriate samples should not be analyzed. This is particularly important for hemolyzed samples, which are the number one cause of test suppression in clinical laboratories.
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