Table 6.
Evidence levels as defined by different sources
| Evidence level | CIViC | [7] | Evidence level 2 | Oncokb.org | Pct.mdanderson.org (PMID: 25863335) | Andre et. al. (PMID: 25344359) | Proposed |
|---|---|---|---|---|---|---|---|
| A / Tier 1 | Validated association - proven/consensus association in human medicine | Alteration has matching FDA approved or NCCN recommended therapy | 1A | FDA-approved biomarker and drug in this indication | Drug is FDA-approved for the same tumor type harboring a specific biomarker | Molecular alteration validated in several robust early phase trials or at least one phase III randomized trials. Alteration validated in the disease under consideration, targeted therapies have shown to be uneffective in patients who are lacking the genomic alteration | Drug is FDA-approved for the same tumor type harboring a specific biomarker |
| 1B | An adequately-powered, prospective study with biomarker selection/stratification, or a meta-analysus/overview demonstrates a biomarker predicts tumor response to a drug or that the drug is clinically effective in a biomarker-selected cohort in the same tumor type. | Molecular alteration validated in several robust early phase trials or at least one phase III randomized trials. No evidence that the therapy does not work in the absence of the molecular alteration | An adequately-powered, prospective study with biomarker selection/stratification, or a meta-analysus/overview demonstrates a biomarker predicts tumor response to a drug or that the drug is clinically effective in a biomarker-selected cohort in the same tumor type. | ||||
| 1C | Molecular alteration validated in several robust early phase trials or at least one phase III randomized trials. Level I molecular alteration, but not in the disease under consideration | ||||||
| B | Clinical evidence - clinical trial or other primary patient data supports association | 2A | Standard-of-care biomarker and drug in this indication but not FDA-approved | Large-scale retrospective study demonstrates a biomarker is associated with tumor response to the drug in the same tumor type. This could be a prospective trial where biomarker study is the secondary objective, or an adequately powered retrospective cohort study or a case-control study | Efficacy of targeting molecular alteration suggested in single and underpowered phase I/II trials. Alteration validated in the disease under consideration, targeted therapies have shown to be ineffective in patients who are lacking the genomic alteration | Large-scale retrospective study demonstrates a biomarker is associated with tumor response to the drug in the same tumor type. This could be a prospective trial where biomarker study is the secondary objective, or an adequately powered retrospective cohort study or a case-control study | |
| 2B | FDA-approved biomarker and drug in another indication, but not FDA or NCCN compendium-listed for this indication | Clinical data that the biomarker predicts tumor response to drug in a different tumor type | Efficacy of targeting molecular alteration suggested in single and underpowered phase I/II trials. No evidence that the therapy does not work in the absence of the molecular alteration | Clinical data (analogue 1A-2A) that the biomarker predicts tumor response to drug in a different tumor type | |||
| 2C | Efficacy of targeting molecular alteration suggested in single and underpowered phase I/II trials. Level I molecular alteration, but not in the disease under consideration or anecdotal evidence of response to targeting molecular alteration in single patient case reports | Single unusual responder (or case study) show a biomarker is associated with response to drug, supported by scientific rationales | |||||
| C / Tier 2 | Case study - individual case reports from clinical journals | Alteration has matching therapy based on evidence from clinical trials, case reports, or exceptional responders | 3A | Clinical evidence links biomarker to drug response in this indication but neither biomarker or drug are FDA-approved or NCCN compendium-listed | Single unusual responder (or case studies) show a biomarker is associated with response to drug, supported by scientific rationales | Target suggested by preclinical studies. Preclinical studies include human samples, cell lines and animal models | Preclinical data (in vitro or in vivo models and functional genomics) demonstrates that a biomarker predicts response of cells to drug treatment in the same tumor type |
| D / Tier 3 | Preclinical evidence - in vivo or in vitro models support association | Alteration predicts for response or resistance to therapy based on evidence from pre-clinical data (in vitro or in vivo models) | 3B | Clinical evidence links biomarker to drug response in another indication but neither biomarker or drug are FDA-approved or NCCN compendium-listed | Preclinical data (in vitro or in vivo models and functional genomics) demonstrates that a biomarker predicts response of cells to drug treatment | Target suggested by preclinical studies. Preclinical studies that lack either cell lines or animal models | Preclinical data (in vitro or in vivo models and functional genomics) demonstrates that a biomarker predicts response of cells to drug treatment in a different tumor type |
| E / Tier 4 | Inferential association - indirect evidence | Alteration is a putative oncogenic driver based on functional activation of a pathway | 4A | Preclinical evidence associates this biomarker to drug response, where the biomarker and drug are NOT FDA-approved or NCCN compendium-listed | Target predicted but lack of clinical or preclinical data. Genomic alteration is a known cancer-related gene | Inferential association between biomarker and treatment response. | |
| 4B | Target predicted but lack of clinical or preclinical data. Genomic alteration is not known as cancer-related gene |