1. Establish methods for specimen collection and processing and appropriate storage conditions to ensure the suitability of specimens for use with the omics test.
2. Establish criteria for screening out inadequate or poor-quality specimens or analytes isolated from those specimens before performing assays.
3. Specify the minimum amount of specimen required.
4. Determine the feasibility of obtaining specimens that will yield the quantity and quality of isolated cells or analytes needed for successful assay performance in clinical settings.
5. Review all available information about the standard operating procedures (SOPs) used by the laboratories that performed the omics assays in the developmental studies, including information on technical protocol, reagents, analytical platform, assay scoring, and reporting method, to evaluate the comparability of the current assay to earlier versions and to establish the point at which all aspects of the omics test were definitively locked down for final validation.
6. Establish a detailed SOP to conduct the assay, including technical protocol, instrumentation, reagents, scoring and reporting methods, calibrators and analytical standards, and controls.
7. Establish acceptability criteria for the quality of assay batches and for results from individual specimens.
8. Validate assay performance by using established analytical metrics such as accuracy, precision, coefficient of variation, sensitivity, specificity, linear range, limit of detection, and limit of quantification, as applicable.
9. Establish acceptable reproducibility among technicians and participating laboratories and develop a quality assurance plan to ensure adherence to a detailed SOP and maintain reproducibility of test results during the clinical trial.
10. Establish a turnaround time for test results that is within acceptable limits for use in real-time clinical settings.
Model development, specification, and preliminary performance evaluation
11. Evaluate data used in developing and validating the predictor model to check for accuracy, completeness, and outliers. Perform retrospective verification of the data quality if necessary.
12. Assess the developmental data sets for technical artifacts (for example, effects of assay batch, specimen handling, assay instrument or platform, reagent, or operator), focusing particular attention on whether any artifacts could potentially influence the observed association between the omics profiles and clinical outcomes.
13. Evaluate the appropriateness of the statistical methods used to build the predictor model and to assess its performance.
14. Establish that the predictor algorithm, including all data pre-processing steps, cutpoints applied to continuous variables (if any), and methods for assigning confidence measures for predictions, are completely locked down (that is, fully specified) and identical to prior versions for which performance claims were made.
15. Document sources of variation that affect the reproducibility of the final predictions, and provide an estimate of the overall variability along with verification that the prediction algorithm can be applied to one case at a time.
16. Summarize the expected distribution of predictions in the patient population to which the predictor will be applied, including the distribution of any confidence metrics associated with the predictions.
17. Review any studies reporting evaluations of the predictor’s performance to determine their relevance for the setting in which the predictor is being proposed for clinical use.
18. Evaluate whether clinical validations of the predictor were analytically and statistically rigorous and unequivocally blinded.
19. Search public sources, including literature and citation databases, journal correspondence, and retraction notices, to determine whether any questions have been raised about the data or methods used to develop the predictor or assess its performance, and ensure that all questions have been adequately addressed.
Clinical trial design
20. Provide a clear statement of the target patient population and intended clinical use of the predictor and ensure that the expected clinical benefit is sufficiently large to support its clinical utility.
21. Determine whether the clinical utility of the omics test can be evaluated by using stored specimens from a completed clinical trial (that is, a prospective–retrospective study).
22. If a new prospective clinical trial will be required, evaluate which aspects of the proposed predictor have undergone sufficiently rigorous validation to allow treatment decisions to be influenced by predictor results; where treatment assignments are randomized, provide justification for equipoise.
23. Develop a clinical trial protocol that contains clearly stated objectives and methods and an analysis plan that includes justification of sample size; lock down and fully document all aspects of the omics test and establish analytical validation of the predictor.
24. Establish a secure clinical database so that links among clinical data, omics data, and predictor results remain appropriately blinded, under the control of the study statistician.
25. Include in the protocol the names of the primary individuals who are responsible for each aspect of the study.
Ethical, legal, and regulatory issues
26. Establish communication with the individuals, offices, and agencies that will oversee the ethical, legal, and regulatory issues that are relevant to the conduct of the trial.
27. Ensure that the informed consent documents to be signed by study participants accurately describe the risks and potential benefits associated with use of the omics test and include provisions for banking of specimens, particularly to allow for ‘bridging studies’ to validate new or improved assays.
28. Address any intellectual property issues regarding the use of the specimens, biomarkers, assays, and computer software used for calculation of the predictor.
29. Ensure that the omics test is performed in a Clinical Laboratory Improvement Amendments-certified laboratory if the results will be used to determine treatment or will be reported to the patient or the patient’s physician at any time, even after the trial has ended or the patient is no longer participating in the study.
30. Ensure that appropriate regulatory approvals have been obtained for investigational use of the omics test. If a prospective trial is planned in which the test will guide treatment, consider a pre-submission consultation with the US Food and Drug Administration.