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Level of
Evidence

Comprehensive Biomarker Discovery and Validation for Clinical Practice

As the trend toward precision or personalized medicine continues, a biomarker and algorithm which can be implemented in clinical use have become more important than ever. Scientifically, a prospective randomized clinical trial remains the best method for screening and developing biomarkers and algorithms for prognostics (ie, predictive of prognosis) and prediction (ie, in terms of response to chemotherapy), but this method has been found to be inefficient in time and cost.

Biomarker-based clinical trials take about 10 years and are quite expensive. A suggestion for more effective clinical trials is using archived sample from high-quality datasets, as a result, a new clinical trial approach, prospectively designed retrospective validation trial, was established to provide reliable evaluations of the clinical validity or medical utility of prognostic and predictive biomarkers.
The prognosis and predictive biomarkers and algorithms with evidence at the highest level of evidence (LOE) I (Level 1) can be credited to support the clinical utility. The clinical efficacy of biomarkers and algorithms should be validated using archived samples from a prospective randomized clinical trial of existing drug or a prospective clinical trial.

To evaluate the clinical utility of prospectively designed retrospective clinical trials using archived samples, several conditions must be satisfied:
1) Archived samples must be available on a sufficiently large number of patients to permit appropriately powered analyses and to ensure that the patients included in the biomarker evaluation are clearly representative of the patients.
2) Substantial data on analytical validity of the test must exist.
3) The analysis plan for the biomarker study and the design of the trial(s) whose samples were selected for analysis should be appropriate for the evaluation of a companion diagnostic.
4) For multigene classifiers, the mathematical form of combining the individual components weights, and cut points should be specified beforehand.
5) The results must be validated in at least one or more similarly designed studies using the same assay techniques.

Elements of Tumor Marker Studies that constitute Levels of Evidence Determination

Cate
gory
A
Pro
spective
B
Pro
spective
using archived
sample
C
Pro
spective /
Obser
vational
D
Retro
spective /
Obser
vational
Clinical
Trial
PCT* designed to address tumor marker Pro
spective trial not designed to address tumor marker, but design accom
modates tumor marker utility

Accom
modation of predictive
marker requires PRCT**
Pro
spective obser
vational registry, treatment and follow-up not dictated
No pro
spective aspect to study
Patients and patient data Pro
spectively enrolled, treated, and followed in PCT
Pro
spectively enrolled, treated, and followed in clinical trial and, especially if a predictive utility is considered, a PRCT addressing the treatment of interest
Pro
spectively enrolled in registry, but treatment and follow-up standard of care
No pro
spective stipulation of treatment or follow-up; patient data collected by retro
spective chart review
Speci
men
collec
tion,
proce
ssing,
and
archival
Specimens collected, processed, and assayed for specific marker in real time Specimens collected, processed, and archived pro
spectively using generic SOPs.

Assayed after trial com
pletion
Specimens collected, processed, and archived pro
spectively using generic SOPs.

Assayed after trial com
pletion
Specimens collected, processed and archived with no pro
spective SOPs
Statis
tical
Design
Study powered to address tumor marker question Study powered to address thera
peutic question and under
powered to address tumor marker question
Study not pro
spectively powered at all.

Retro
spective study design con
founded by selection of specimens for study
Study not pro
spectively powered at all.

Retros
pective study design con
founded by selection of specimens for study
Vali
dation
Result unlikely to be play of chance

Although preferred, validation not required
Result more likely to be play of chance that A but less likely than C

Requires one or more validation studies
Result very likely to be play of chance

Requires sub
sequent validation studies
Result very likely to be play of chance

Requires sub
sequent validation

*PCT : Prospective Controlled Trial, **PRCT : Prospective Randomized Controlled Trial
***SOPs : Standard Operation Practices

Level 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

Category A: Prospective Clinical Trial
Category B: Prospective Clinical Trial using Archived Sample
Category C: Prospective Clinical Trial (Observational)
Category D: Retrospective Clinical Trial (Observational)

Use of Archived Specimens in Evaluation of Prognostic and Predictive Biomarkers. J Natl Cancer Inst 2009;101:1446-1452, Nov4, paik et al.