Test evaluation: major challengesahead – Opportunities abound

The world of laboratory medicine is in a state of flux. The publication of the NHS Long Term Plan, ¹ for example, promulgates that by 2021, newly formed ‘Pathology Networks’ across England will enable improved test turnaround times, increased access to more complex tests and better career opportunities for healthcare scientists at less overall cost. Appropriately, in 2018, seven Genomic Laboratory Hubs were established with mobilization towards consolidated provision. Such ambitions will undoubtedly necessitate significant transformation in the future provision of pathology services. This, in hand with the promise of the 100,000 Genomes Project, and cautious optimism regards the burgeoning field of precision medicine, ² may herald a paradigm shift in laboratory diagnostics.

At the EU level, May 2017 witnessed publication of the In Vitro Diagnostic Medical Device Regulation (IVDR) 2017/746. ³ The IVDR replaces the incumbent In Vitro Diagnostic Medical Device Directive 98/79/EC and will become fully applicable in 2022, allowing a five-year transition period to the new Regulations for EU Member States. Notably, the IVDR has expanded the clinical evidence requirements for new In Vitro Diagnostic (IVD) to include evidence of scientific validity (the association of an analyte with a clinical condition or a physiological state), analytical performance (the ability of a device to correctly detect or measure a particular analyte) and clinical performance (the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state in accordance with the target population and intended user). These should support the intended use of the IVD product, for assessment of expected clinical benefits and potential harm.

The World Health Organization (WHO) recently published the Model List of Essential In Vitro Diagnostics (EDL) in recognition that IVDs are an essential component to advance universal health coverage, address health emergencies and promote healthier populations. The EDL is also intended to complement the WHO Model List of Essential Medicines and enhance their rational and safe use. ⁴ The EDL will be reviewed annually through a WHO call for applications to add IVD tests, with applicants required to provide information on clinical accuracy or impact of the proposed IVD.

One would foresee that these organizational and regulatory developments may have significant ramifications for laboratory medicine, not least in terms of biomarker evaluation, translation and adoption of medical tests for clinical practice. This happens on the backdrop of an apparent translational inertia within the biomarker development pipeline, where few molecular or ‘omics’-based tests have evidenced progress towards clinical application, despite significant research investment. ⁵

The problems concerning study design and reporting within the biomarker research pipeline are numerous and well documented,^6,7 and concerns highlighting questionable analytical performance of commercial immunoassays for candidate biomarker validation studies must not be underestimated. ⁸ Recommendations have been proposed to address these current challenges facing biomarker discovery and qualification,^7,9 along with dynamic frameworks for test evaluation to guide performance criteria,^7,10 supplemented by guidance for the selection and implementation of IVD tests. ¹¹

Common to this plethora of sign-posting along the biomarker journey is recognition that a clearly defined clinical question at the outset of biomarker development and test evaluation is an absolute prerequisite, based on the ‘intended use’ of the test. In other words, what is the ‘unmet clinical need’ for the new test? ¹² In appreciating the purpose and role of the test, the (indirect) link between the testing, test results and patient outcomes can be drawn by defining the downstream clinical management decisions that the test informs. Hence, it is logical to commence biomarker development and test evaluation by first analysing the current clinical care pathway, utilizing an outcome-focussed approach, to define and validate the unmet clinical need for, and intended use of the new test, to influence clinical practice and patient outcomes. ¹³

In this volume of the Annals of Clinical Biochemistry, Lord et al. (including the present authors) present a five-step approach to set clinical performance specifications for a new biomarker. The ambition of this article is to aid researchers in biomarker discovery during collaborations with clinical groups, helping them to assess the potential intended use of new biomarkers as medical tests, by considering the proposed clinical benefits to the patient. In providing practical guidance to improve the design and interpretation of clinical performance studies, the hope is to mitigate research waste, by assessing whether early biomarker performance justifies further downstream evaluation.

Studies on clinical effectiveness can help refine analytical and clinical performance specifications, following an iterative and dynamic test evaluation approach. ¹⁰ Yet, the paucity of evidence for new lab tests is testament to the complexity of IVD test evaluation. Indeed, a systematic overview of diagnostic Horizon scan reports for point-of-care testing, mapping the various aspects of test evaluation evidence against a published framework, found the median time to complete a test evaluation cycle was nine years. ¹⁴

Notwithstanding the challenges outlined, laboratory professionals have the opportunity to play a vital role in the future development and evaluation of IVD medical tests, helping to identify gaps in clinical pathways where novel biomarker-based tests have the potential to improve patient outcomes. This is a fundamental aspect of the evolving role of the laboratory medicine professional, driven by innovative diagnostics and delivery of laboratory services more focussed on the value of laboratory information, including diagnostic stewardship and consultation on laboratory test selection and interpretation in the context of patient clinical status. ¹⁵

Equipped with practical guidance to define benefits and harms of testing to set appropriate clinical performance specifications, the profession can increase the efficiency of laboratory diagnostics, aligning analytical and clinical performance to clinical effectiveness, enabling improved interpretation of test results of specific purpose within the clinical pathway, guiding positive intervention, towards better patient care.