Venous blood collection systems using evacuated tubes: a systematic review focusing on safety, efficacy and economic implications of integrated vs. combined systems

Introduction

In modern medicine, over 70 % of clinical diagnoses are based on laboratory test results [1, 2]. Therefore, providing the clinical laboratory with biological samples that fully represent the patient’s status is mandatory. Literature indicates that there is still the need to improve diagnostic quality [3, 4]. Improving laboratory data largely depends on reducing errors in the pre-analytical phase [4], [5], [6]. Approximately 60–70 % of the laboratory error is generated from the diagnostic test order to sample analysis [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Insufficient pre-analytical sample quality could invalidate the entire diagnostic-therapeutic process, both in terms of patient outcomes and healthcare-associated costs [6]. Sample quality is strictly related to the collection procedure, devices, materials, and additives used, the pre-analytical sample treatment, and the transport and storage conditions [6, 17].

Among biological specimens, venous blood has a high diagnostic value, and venous blood collection systems (VBCS) play a key role in the pre-analytical phase [18]. Several studies have reported that the majority of non-compliances occur during venous blood sample collection, resulting in hemolysed samples, insufficient volume, unsuitable sample quality, clotted samples, or other problems compromising the analysis [19, 20].

VBCSs using evacuated tubes typically consist of a blood collection needle or a winged set with or without an integrated safety system, a tube holder and one or more evacuated blood collection tubes with a pierceable stopper [8]. These well-defined combinations of medical devices and in vitro diagnostic devices are generally brought to market by manufacturers as a complete set [21], but the possibility of purchasing different devices separately and using a combination of devices from other sets, even with the same intended use, are considered by clinical laboratories as possible options to achieve specific sampling tasks or to reduce costs [8].

The assessment and procurement of VBCSs is often an underestimated problem, although the importance of the preanalytical phase for the safety and quality of the entire diagnostic process is known in practice and clearly reported in the literature [21]. The complexity of evaluating the range of VBCSs available on the market is further complicated by the possibility that tender-based procurement processes end up with the acquisition of components made by different manufacturers, whose mutual compatibility may not have been verified in terms of both safety and performance of the entire blood collection system [22].

European Regulation on Medical Devices 2017/745 (MDR) defines a system as “a combination of products, either packaged together or not, which are intended to be interconnected or combined to achieve a specific medical purpose” [23]. EU Regulation on in Vitro Diagnostic Medical Devices 2017/746 (IVDR) specifies the requirements to claim the compatibility of a device when used together with one or more other devices in accordance with its intended purpose, as the ability to: “(a) perform without losing or compromising the ability to perform as intended, and/or (b) integrate and/or operate without the need for modification or adaption of any part of the combined devices, and/or (c) be used together without conflict/interference or adverse reaction” [24]. The Working Group for Preanalytical Phase (WG-PRE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) indicates that the manufacturer can claim a system composed of multiple CE-marked devices or products as integrated when the combination of the different parts is proved safe and does not compromise the performance of the individual components, as soon as the system as a whole is used in accordance with the intended purpose [25]. When these conditions are met, the system can be considered an integrated system. Taking into account the definition of compatibility given in the EU IVDR [24] and the concept of integration indicated by the EFLM WG-PRE [25], the following definitions were formulated and adopted in this study:

1. Integrated VBCS: venous blood collection system made up of components (blood collection needle/set, tube holder and evacuated blood collection tube) from a single manufacturer or from different manufacturers who declare the mutual compatibility of components within the indications for use of the system and of the individual components;

2. Combined VBCS: venous blood collection system made up of components (blood collection needle/set, tube holder and evacuated blood collection tube) for which there is no mutual compatibility statement issued by the manufacturer of each component or by the natural or legal person responsible for assembling the system from devices already on the market.

This study aimed to retrieve and analyse available evidence on the safety, efficacy, and economic implications of using VBCSs, focusing on differences between integrated and combined systems. The findings are discussed considering the current European regulatory framework.

Materials and methods

A systematic review was implemented to identify documents reporting on differences in safety, effectiveness, performance, and costs between integrated and combined VBCSs. The protocol, developed by the authors, was not registered before the study’s publication because of confidentiality clauses in the contracted research activity.

Results

The literature search and document screening process is summarized in Figure 1, showing the retrieved documents and the reasons for exclusion according to the flow chart for systematic reviews of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) model [27].

Figure 1:

Flowchart of the systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA 2020) model [27].

PubMed search identified 308 documents (306 unduplicated). A total of 54 documents were read in full. The analysis of the 54 documents and related bibliographic references and the scanning of online resources made available by scientific and standardisation organisations led to the identification of 24 documents. Overall, 20 documents published between 2010 and 2021 were included in this review; 11 of them were identified via database search and nine via other methods. The document’s characteristics are summarised in Table 2. The level of evidence of the included studies according to SORT quality definitions for diagnostic study [26], was level 2 and 3 for four and 16 documents, respectively. Nineteen documents provided evidence on quality/efficacy/performance, seven dealt with safety aspects and seven with cost/procurement. Two documents covered all three domains of interest.

Discussion

According to Plebani et al. [8], assumptions leading healthcare facilities to opt for purchasing combined VBCSs include the following: (i) dividing the VBCS into separate parts allows a larger number of manufacturers (e.g., needle-only or tubes-only manufacturers) to bid for the benefit of increased competition and availability; (ii) the collection and processing of blood samples are “essential” activities for which it is sufficient to use devices that comply with the requirements imposed by the CE marking; iii) a single-side manufacturers’ declaration of compatibility of their devices with any other device available on the market guarantees mutual compatibility and integrability of different components. More generally, there is a lack of awareness of the possible risks associated with the use of combined systems, basing the choice of the device mainly on the indication of use [40], neglecting the aspects of mutual compatibility and integrability of the components. When purchasing procedures are centralised, the possibility of intervention by the clinical laboratory in the tender process is also limited, with scarce or null interaction between those who set tender requirements for VBCSs acquisition and those who use the VBCSs in the clinical practice. Overall, there is still a general underestimation of the importance of phlebotomist practices and of blood sample quality for the entire diagnostic and therapeutic process [6] and of the added value of laboratory diagnostics [45].

According to current MDR and IVDR EU regulations, manufacturers of integrated systems should guarantee full compatibility between each component in terms of both safety and efficacy [23, 24]. Moreover, EU Directive 2010/32, implementing the Framework Agreement on prevention from sharp injuries in the hospital and healthcare sector, underlines the importance of providing medical devices incorporating safety-engineered protection mechanisms [46]. Often, the functionality of the protection mechanisms relies on full component compatibility.

Annex I of the EU IVDR concerning the “General safety and performance requirements”, Chapter II, regarding the requirements of performance, design and manufacture, specifies, in point 13.1, that “If the device is intended for use in combination with other devices or equipment, the whole combination, including the connection system, shall be safe and shall not impair the specified performances of the devices. Any restrictions on use applying to such combinations shall be indicated on the label and/or in the instructions for use” [24]. Annex I, Chapter II, point 13.5 (and similarly Annex I, Chapter II, point 14.5 of MDR) specifies that “devices that are intended to be operated together with other devices or products shall be designed and manufactured in such a way that the interoperability and compatibility are reliable and safe” [23, 24].

Typically, manufacturers of integrated VBCSs provide disclaimers advising that whenever changing any manufacturer’s collection tube type, size, handling, processing or storage condition for a particular laboratory assay, the laboratory personnel should review the tube manufacturer’s data and their data to verify the reference range for a specific instrument/reagent system. Based on such information, the laboratory can decide if a change is appropriate. In this context, the attribution of responsibility for the safety and effectiveness of the VBCS is well-defined, and the roles and responsibilities between device manufacturers and users are sufficiently differentiated.

Otherwise, when similar devices replace one or more components of a VBCS, but for which there is no evidence of maintaining safety and performance when used in this combination, a combined but not integrated system, or more simply a combined system, is considered. In most cases, these combined systems are not validated for clinical use [25], and there is no documented evidence that the combined system is safe and effective. Indications for use of the individual components typically refer to different integrated VBCSs and may not be superimposable. In this scenario, compatibility between the components is not guaranteed.

Article 22 of EU Regulation 2017/745 identifies specific responsibilities and obligations for the natural or legal persons who place a combination of medical devices on the market as a “system” [23]. Indeed paragraph 1 states that “Natural or legal persons shall draw up a statement if they combine devices bearing a CE marking with the following other devices or products, in a manner that is compatible with the intended purpose of the devices or other products and within the limits of use specified by their manufacturers in order to place them on the market as a system: (a) other devices bearing the CE marking; (b) in vitro diagnostic medical devices bearing the CE marking in conformity with Regulation (EU) 2017/746”. Paragraph 2 of the same article states that, “in the statement made pursuant to paragraph 1, the natural or legal person shall declare that: (a) they verified the mutual compatibility of the devices and, if applicable other products, in accordance with the manufacturers’ instructions and have carried out their activities in accordance with those instructions; (b) [omissis]; (c) the activity of combining devices and, if applicable, other products as a system or procedure pack was subject to appropriate methods of internal monitoring, verification and validation” [23].

These legal obligations apply when a third party sets up a combined system to be placed in the market. No such obligation is explicitly required in case the clinical laboratory assembles a combined system for its internal use. However, the need to verify mutual compatibility between devices of a combined system could be considered part of the validation and verification activities the laboratory should perform on combined systems before clinical use [4, 8]. This task should be part of a laboratory quality system according to ISO 15189:2022 “Medical laboratories – Requirements for quality and competence” [47]. In the case of integrated VBCSs, validation is typically performed by the manufacturer, and the laboratory is in charge of verifying the system in the local setting [8]. Conversely, in the case of combined VBCS, validation activity of the whole combined system is typically unavailable from manufacturers, and laboratories should consider undertaking these tasks under their own responsibility [8]. In this scenario, the assignment of responsibilities for validating the safety and effectiveness of the combined system is less defined. Still, a large part of the responsibility is undoubtedly transferred from the manufacturer to the natural or legal person who validates the combined system. Manufacturers typically include specific indications in product documentation, stating that “the devices (blood collection needles/sets, holders and tubes) are designed to be used as a single system, and the integration of devices other than those indicated by the manufacturer is the sole responsibility of the user” [21]. Therefore, the possibility of using separate parts of the blood collection system obtained or purchased from different manufacturers is strongly discouraged by EFLM WG-PRE unless the integration of the new components has not been previously validated by the manufacturer or by other bodies or institutions that have the adequate knowledge to carry out an exhaustive validation process of the combined system in terms of safety and performance, assuming the responsibilities related to the declaration of mutual compatibility of all the system components [25].

Recently, Vanstapel et al. [48] have proposed that laboratory-developed tests (LDTs) can be used in the clinical setting after adequate verification and validation by the laboratory in accordance with quality standard ISO 15189 [47]. However, this contingency solution cannot be directly extended to combined VBCS as the same authors indicate that LDTs should only be applied without suitable commercial devices, which is not the case for VBCSs.

An additional controversial point about combined systems is the manufacturer’s ability to fully support quality assurance aspects and post-market surveillance actions, e.g. complaints in case a device is used in a combined VBCS. Using a combined system that results in a complaint may make it difficult for a manufacturer to provide complete and effective support, as this may be outside the scope of the intended purpose and considered off-label use.

From an ethical perspective, joint EFLM-COLABIOCLI recommendations for venous blood sampling underlined that it is not justifiable to perform serial venipunctures on the same patient to safeguard single-manufacturer compatibility of blood collection system components when individual components from different manufacturers must be used together [44]. In an era of enormous restrictions on resources in health care, the incentive to save money is a legitimate claim, but economic saving should not be at the expense of patients’ and phlebotomists’ safety [49]. Whenever the safety and efficacy of combined VBCS cannot be guaranteed, a number of other ethical implications may arise, including the need to correctly inform the patient and the operators about the additional risks due to the use of combined VBCSs. Further, the availability of VBCSs with different levels of safety and efficacy is debatable in terms of the patient’s right to equity in medical treatment and also in terms of healthcare worker safety, thus fostering the perception of duplicity in medical care. Healthcare providers should maintain transparency, upholding the patient’s right to equitable medical treatment and trust in the healthcare system.

Conclusions

This systematic review found no evidence that combined VBCSs are equivalent to integrated ones regarding safety and efficacy outcomes due to a lack of comparative quantitative studies specifically addressing these aspects. There is an international consensus among scientific societies and product standards that a combined system can impact the safety of operators and patients. In addition, the analytical performances and overall efficacy of combined VBCSs are not guaranteed without whole-system validation and verification of the single components.

Although the allocation of responsibilities for validation and verification of an integrated VBCS is well defined in the EU regulatory framework, relevant guidelines and quality standards, a less clear situation is present for combined VBCSs, without a definition of who is in charge of performing the system validation, or how complaints or product non-conformities, and in general post-market surveillance, can be efficiently implemented.

The need to validate a combined VBCS demands risk-benefit and cost-benefit analyses by the laboratories, implying a non-negligible organisational and economic burden and a significant investment in knowledge acquisition. Also, implications in terms of responsibility and legal liability of the laboratory should be carefully weighed and be part of a comprehensive assessment of safety, efficacy and cost carried out during device procurement.

This review revealed a lack of quantitative comparative studies calling for future comparative assessments based on users’ real-world data and structured patients’ and professionals’ evaluations, other than comparative quantitative analysis of analytical performance and accuracy of combined VBCSs. Randomised controlled clinical trials should be designed and conducted to compare the safety and clinical performance of combined vs. integrated VBCSs. On the other hand, cost evaluation should not be limited to the price of VBCSs purchase, but should include a comprehensive evaluation of direct and indirect costs for the management of risks related to combined VBCSs use, the economic impact of changes in efficacy and safety for both patients and professionals, the investment in knowledge acquisition for the validation and verification of safety and performance of the combined system, as well as the education and training of the of professional for the use of the combined system. Finally, whenever the equivalence in safety and performance of integrated and combined VBCS cannot be sufficiently ascertained, a cost-benefit evaluation is required.