An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles

Abstract

Objective: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers.

Design: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles.

Results: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence.

Conclusion: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Keywords: colorectal adenomas; colorectal cancer; colorectal cancer screening.

Figure 1

The multistep screening pathway characteristic of organised screening programmes and demonstrating the one-step and two-step strategies as discussed in principle 2. How the principles relate to steps and outcomes are identified by the numbers in parentheses. Colours identify important outcomes relevant to detection.

Figure 2

Diagrammatic outline of a trial design appropriate for comparing non-invasive tests in the initial phases of test evaluation. Paired testing is conducted in a single cohort where an individual does both the new and the comparator test, whereas parallel testing is where study participants are randomised to one or the other test. Neg, negative result; Pos, positive result.

Figure 3

Goals, context and approach for each phase of evaluation, together with the hurdle identifying justification to advance to the next phase. Note that clinical status must be ascertained by colonoscopy. CRC, colorectal cancer; ROC, receiver operating characteristic.

Figure 4

Study design frameworks applicable to phase III studies. (A) Design appropriate to determine test accuracy where all cases undergo colonoscopy, but intention-to-screen outcomes cannot be ascertained (comparison of a comparator with the new test can be paired in a single cohort or parallel in separate cohorts). (B) Design appropriate for estimating intention-to-screen outcomes and where the accuracy of the new test can be compared with that of a non-invasive comparator either when colonoscoping only test-positive individuals (compare true-positive and false-positive fractions) or all participants (sensitivity and specificity). Neg, negative result; Pos, positive result.