Elsevier

Clinica Chimica Acta

Volume 427, 1 January 2014, Pages 49-57
Clinica Chimica Acta

Special report
From biomarkers to medical tests: The changing landscape of test evaluation

https://doi.org/10.1016/j.cca.2013.09.018Get rights and content

Highlights

  • Financial and regulatory pressures change the landscape of biomarker evaluation.

  • It is unclear what evidence is sufficient for proving that testing improves outcomes.

  • We describe the pathway of a biomarker to becoming a medically useful test.

  • We present a cyclical test evaluation framework and define its key components.

  • The framework aims to support the understanding of key stakeholders.

Abstract

Regulators and healthcare payers are increasingly demanding evidence that biomarkers deliver patient benefits to justify their use in clinical practice. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and decisions about their appropriate use.

This paper by a multidisciplinary group of the European Federation of Clinical Chemistry and Laboratory Medicine describes the pathway of a laboratory assay measuring a biomarker to becoming a medically useful test. We define the key terms, principles and components of the test evaluation process. Unlike previously described linearly staged models, we illustrate how the essential components of analytical and clinical performances, clinical and cost-effectiveness and the broader impact of testing assemble in a dynamic cycle. We highlight the importance of defining clinical goals and how the intended application of the biomarker in the clinical pathway should drive each component of test evaluation. This approach emphasizes the interaction of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performances to achieve improved outcomes.

The framework aims to support the understanding of key stakeholders. The laboratory profession needs to strengthen collaboration with industry and experts in evidence-based medicine, regulatory bodies and policy makers for better decisions about the use of new and existing medical tests.

Introduction

There is an increasing awareness that the introduction of costly new medical interventions, including medical tests, can only be justified if they deliver proportionate benefits to patients. Increased public, media and political awareness of the harms from medical tests has come from debates about the potential for over-diagnosis in asymptomatic patients [1] and concerns about the harms of direct-to-consumer testing [2]. Weaknesses of the current systems to assure the quality and clinical utility of in vitro medical devices (IVDs) have been pointed out [3]. Amidst all this, the regulatory environment for therapeutic and diagnostic technologies is changing rapidly. Revisions of the European directives on medical [4] and in vitro diagnostic devices [5] are being prepared in parallel. The ability of novel medical tests to improve health outcomes is also becoming more central in discussions about their market entry and reimbursement. The increasing requirements for clinical benefits and patient safety mirror public and political pressures for more transparency. These processes are affecting the way novel medical tests and biomarkers are being developed, and are likely to reshape the landscape of medical test evaluation. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and in clinical and policy decisions about the appropriate use of laboratory tests.

Over the past decade landmark advances have been made to define the types of evidence required to evaluate medical tests and distinguish between the different phases of test evaluation from discovery to assessment of cost-effectiveness [6], [7], [8], [9], [10]. There is less guidance, however, about the most efficient approaches to produce this evidence and judging whether it is adequate for proving the clinical effectiveness of biomarkers.

The evaluation of medical tests differs from comparable processes for therapeutic interventions. One of the most important differences is that medical testing rarely improves health outcomes directly. Testing is usually part of a more complex clinical pathway where test results guide treatment decisions, which include a variety of medical actions and processes. All of these shape the final health outcomes for the patients tested. Test evaluation therefore requires the consideration of all the consequences of clinical management decisions that are guided by the test results. An understanding of these more complex concepts for test evaluation is becoming essential for informed decision making by all potential stakeholders.

To help address these issues, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has formed a Working Group on Test Evaluation which consists of laboratory professionals, clinical epidemiologists, health technology assessment experts and representatives of the in vitro diagnostics industry. The primary purpose of this working group is to provide key stakeholders, i.e. laboratory professionals, clinicians, researchers, manufacturers, policy makers and purchasers, with guidance and practical tools for assessing the clinical benefits of in vitro medical tests. In this introductory paper, the working group outlines the key principles and defines some of the key components of contemporary approaches to test evaluation, such as analytical performance, clinical performance, clinical effectiveness, cost-effectiveness, and the broader impact of testing on social, psychological, legal, ethical, societal, organizational and other consequences. We additionally present a framework for the evaluation of medical tests that integrates these components into a dynamic process. We illustrate the key principles and components with examples from the literature on Hemoglobin A1c (HbA1c) and cardiac markers, including cardiac Troponins (cTn) and B-type natriuretic peptides (BNP).

Section snippets

Key definitions and principles

There is no international consensus on the terminology related to test evaluation and numerous definitions exist in the literature. Table 1 lists a number of alternative terms and illustrates the proposed definitions with examples.

Under the general umbrella term of medical tests, which encompasses tests from all clinical disciplines, specialties, or types (laboratory, histopathology, imaging, and others), we define and focus this paper on in vitro medical tests only; yet the key messages

Key components of test evaluation

Within the evaluation process of medical tests, we can distinguish between five essential components. Laboratory professionals are familiar with the assessment of analytical performance (Table 1). This refers to the ability of a laboratory assay to conform to predefined technical specifications [7], [20]. Specific elements of analytical performance include analytical sensitivity and specificity, limit of detection and quantitation, measurement range, linearity, metrological traceability,

The test evaluation framework

The sequence of activities that describe the pathway of newly discovered biomarkers from the “bench to the bedside” has been described in the literature [8], [9], [10], [21], [24]. A systematic review identified at least 19 different test evaluation frameworks [10]. The evaluation process for medical tests has been described in these frameworks in a linear fashion, similarly to the staged evaluation of drugs.

Only certain elements of test evaluation are addressed before in vitro medical tests

Conclusions

There is an increasing awareness that the introduction of new technology can lead to increased costs which are often not in direct proportion to the benefits for patients. This is particularly the case where new technologies offer only marginally better alternatives to existing processes. Healthcare funders and regulators are indicating that such marginal improvements are less likely to be funded or reimbursed in the future. Professional, public and government organizations have criticized the

Acknowledgments

The Working Group wishes to thank the European Federation of Clinical Chemistry and Laboratory Medicine for supporting its work. Roche Diagnostics is thanked for supporting the Working Group with an independent educational grant to EFLM.

Role of sponsor

Neither the funding organization (EFLM) nor the independent educational support by Roche Diagnostics influenced the content of this paper. This publication reflects the collective view of the working group. The authors include representatives from

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