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Level of Evidence

Discovery and method of verification of biomarker that can be utilized in clinical sites

There is a trend of increase in the importance of biomarker and algorithm that can be clinically utilized in Precision Medicine and Personalized Medicine. Although the most ideal methodology for the development of biomarker and algorithm that can direct the prognosis and appropriateness of anti-cancer agent (prediction) after the surgery is randomized prospective clinical test, it displays the characteristics of inefficiency from the perspectives of cost and time consumed.

Biomarker-based prospective clinical test, given its characteristics, takes approximately 10 years and costs that exceed several hundred million won. Accordingly, the methodology of using the Archived Sample was developed for the purpose of discovery and verification of efficient biomarker. Moreover, the method of distinction that presents the medical usefulness of the biomarker discovered and verified has been development.

Level of Evidence Type of study
Ia Systematic reviews of randomized controlled trials (RCTs)
Ib Individual RCTs with narrow confidence internal
IIa Systematic reviews of cohort studies
IIb Individual cohort studies and low-quality RCTs
IIIa Systematic reviews of case-control studies
IIIb Case-control studies
IV Case series and poor quality cohort and case-control studies
V Expert opinion

Biomarker and algorithm for the purpose of determination of the prediction of prognosis or appropriateness of anti-cancer agent can be acknowledged universally from the perspective of the clinical usefulness if LOE is equipped with the conditions of the stage I. In particular, for the development of biomarker and algorithm related to the appropriateness of anti-cancer agent, biomarker and algorithm verified in the prospective clinical test or verified with the clinical test samples collected in the randomized prospective clinical test for the usefulness of the past drugs are essential.

    Requisites for the verification of biomarker and algorithm by using the randomized prospective clinical test sample are as follows:
  1. 1) Number of the samples with statistical power (randomized selection is essential for the appropriateness of the anti-cancer agent)
  2. 2) Verification of the analytical performance must be carried out in advance prior to verification
  3. 3) Methodology for evaluation of biomarker and algorithm needs to be established and documented prior to the biomarker verification test
  4. 4) Separate verification works needs to be executed by using samples collected from similar clinical test

Elements of tumor marker studies that constitute Levels of Evidence determination

category A
Prospective
B
Prospective using archived sample
C
Prospective / observational
D
Retrospective / Observational
Clinical Trial PCT designed to address tumor marker Prospective trial not designed to address tumor marker, but design accommodates tumor marker utility
Accommodation of predictive marker requires PRCT
Prospective observational registry, treatment and follow-up not dictated No prospective aspect to study
Specimen Specimens collected, processed, and assayed for specific marker in real time Specimens collected, processed, and archived prospectively using generic SOPs. Assayed after trial completion Specimens collected, processed, and archived prospectively using generic SOPs. Assayed after trial completion. Specimens collected, processed and archived with no prospective SOPs
Statistical Design Study powered to address tumor marker question Study powered to address therapeutic question and underpowered to address tumor marker question Study not prospectively powered at all.
Retrospective study design confounded by selection of specimens for study
Study not prospectively powered at all.
Retrospective study design confounded by selection of specimens for study
Validation Although preferred, validation not required Requires one or more validation studies Requires subsequent validation. Result very likely to be play of chance Requires subsequent validation.

* PCT : prospective controlled trial, PRCT : prospective randomized controlled trial

Revised determination of Levels of Evidence using elements of tumor marker studies

Level of Evidence Category Validation studies available
I A None required
I B One or more with consistent results
II B None or inconsistent results
II C 2 or more with consistent results
III C None or 1 with consistent results or inconsistent results
IV-V D NA

* Use of Archived Specimens in Evaluation of Prognostic and Predictive Biomarkers.
J Natl Cancer Inst 2009;101:1446 -1452, Nov 4, Paik et al.

Oncotype Dx Breast Cancer of Genomic Health, which is a product for which the prognosis and appropriateness of anti-cancer agent on breast cancer have been verified in the USA, is also a product developed and verified in the clinical test samples for which drug efficacy was verified.


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