Table 1.

Sources of clinical utility evidence for decision-making in the nine case studies.

Marker	Main Study Design	Study size (patient numbers)	Sponsor	Decision-making Impact
Breast cancer recurrence (a) Oncotype DX® and (b) MammaPrint® (Prognostic/predictive in BrCa)	Retrospective RCT cohorts RCTs	(a)688 [4] +651 [5] +895 [6] (b)Prognostic: 117 [9] +295 [10] +307 [11] +123 [12], Predictive: 241 [13] (a)11248 [7] (b)6600 [14]	Diagnostic manufacturer Public research body Public research bodies	Generating clinical utility can yield inclusion in clinical guidelines and positive reimbursement decisions at a favourable price for test developers.
HER2 (Trastuzumab in metastatic and early stage BrCa)	RCTs	469 [16] 3676 [19]	Drug developer Drug developer	Positive reimbursement decision for drug-diagnostic in a specific subpopulation based on health gains and cost-effectiveness.
EGFR mutations (1st line TKI treatment in NSCLC)	RCTs RCTs	1217 [25] 165 [26] 173 [27]	Drug developer Drug developer	Drug rescued because of a predictive, ex post companion diagnostic. Obtained first line indication
KRAS mutations (Anti-EGFR monoclonal antibodies in CRC)	Retrospective cohort analysis of an RCT	1198 [39]	Drug developer and Public research body	Decision-makers are willing to consider evidence generated ex post as sufficient to change recommended treatment protocols.
BCR-ABL transcript (TKI treatment in CML)	RCT	1106 [42]	Drug developer	Actionable, clinical information allowed for full incorporation into clinical guidelines; however, issues with inter- and intra-laboratory variability may impact patient management thus health outcomes.
CYP2C19 (Clopidogrel in ACS)	Retrospective RCT cohort+Healthy volunteers Prospective cohort study Proof-of concept RCT	1477+162 [52] 4471 [57] (Terminated early)187 [58]	Public research body Payer Diagnostic manufacturer	The clinically significant and validated predictive effect would allow for health care efficiencies in the treatment of ACS. New POC test could improve implementation in clinical practice.
HLA-B*5701 (ABC in HIV)	Retrospective case control RCT	408 [59] 1956 [59]	Drug developer Drug developer	Prospective screening for first-line treatment is cost-effective in specific sub-populations. Treatment guidelines recommend abacavir only if patients have tested negative for HLA-B*5701.
Viral load (Pegylated interferon and ribavirin in hepatitis C)	Retrospective analyses of RCT data	1016 [61] 260 [62]	Drug developer Public research body	Testing becomes fundamental for predicting treatment outcome, reducing treatment side-effects and avoiding futile treatment and subsequent costs in non-responding patients.
PreDx® DRS (Risk in Type 2 diabetes)	Retrospective analysis of a sub-cohort of a lifestyle interventional trial	6784 [67,68]	Assay developer (trial funded by a public research body)	Although the score has been proven significantly better than other available methods and similar to the gold standard, uptake has been very limited. Data may not be generalisable to the whole population, and payers may not want to cover the test in addition to fasting glucose testing.