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1. Use of nDx 1 Software is only available to partners who are registered separately in Novomics.

2. You must pass the certification procedure on the next screen before you can use the software.

3. Click the "Certification" button to install it automatically on your connection PC.

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* Contact us : +82-2-2068-3700

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.