Placement of Biomarker Analysis in a CLIA or Bioanalytical Laboratory

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1 Placement of Biomarker Analysis in a CLIA or Bioanalytical Laboratory SQA National Meeting 29Mar2017 Carolyn Eberhardt, Principal Consultant, QC2 Mark Stiles, Senior Consultant, QC2

2 Comparison of Quality Systems for Bioanalytical vs. CAP/CLIA Laboratories Method Validation Batch Acceptance Criteria Staff training QA oversight

3 Bioanalytical Method Validation Guidelines FDA Guidance for Industry: Bioanalytical Method Validation (May 2001) EMA Guideline on Bioanalytical Method Validation (Feb 2012)

4 Bioanalytical Validation Assessments Accuracy RE 15% (LC MS/MS) RE 20% (ligand binding or hybrid technologies) Precision CV 15% (LC MS/MS) CV 20% (ligand binding or hybrid technologies)

5 Bioanalytical Validation Assessments (Cont.) Sensitivity LLOQ CV & RE 20% (LC MS/MS) LLOQ CV & RE 25% (ligand binding) Selectivity and Matrix Effects At least 6 lots of matrix Hemolyzed and Hyperlipemic

6 Bioanalytical Validation Assessments (Cont.) Dilution Integrity Solution Stability Stock standard Working standard solutions Matrix Stability Benchtop Freeze Thaw Long term Storage

7 Fit for Purpose Validation Assessments Any of the above! Typically Precision and Accuracy Expanded acceptance criteria.

8 CAP/CLIA Method Validation Assessments For unmodified, FDA cleared or approved tests, CLIA requires the laboratory to verify the manufacturer s performance specifications provided in the package insert before reporting patient test results. This applies when the laboratory replaces an instrument (with the same model or a different model) adds a new test to the instrument, or changes instrument manufacturers

9 CLIA LTD Validation parameters For Laboratory Developed Tests (LTDs), CLIA requires the laboratory to establish performance specifications and to validate method performance for the following method characteristics: accuracy precision (within run, between run, between day) reportable range analytical sensitivity and specificity reference intervals CLIA rules and guidances are silent on minimum requirements for validation protocols; however, validation plans, experiments, results and conclusions are reviewed for scientific merit and integrity.

10 CLIA Validation and stability Validation should cover the complete analytical process preanalytical, analytical, and postanalytical However, often times, CLIA laboratories do not assess stability whole blood, freeze/thaw or BTS or LTS

11 State of New York Clinical Trials and Research Tests Not Approved by the FDA Tests performed on specimens from trial participants for participant management under IRB approved research or clinical trials protocols, where the results are reported and are used for clinical decision making. Examples of testing performed for participant management include those that influence enrollment (exclusion or inclusion), safety, or dosing. If results of the tests are used in participant management as described follow the instructions for either commercially distributed or laboratory developed assays, as appropriate. If the results of the tests are not used in participant management, then permit and assay approval is not required. Examples of tests that do not require review and approval include retrospective biomarkers measurements or assays to measure drug concentrations for pharmacokinetic/pharmacodynamics evaluation, and are used to collect aggregate data on drug or treatment efficacy.

12 NYS Validation Once a NYS Permit is obtained for the testing facility, validation packages for all assays conducted at that facility must be reviewed by CLEP (Clinical Laboratory Evaluation Program) If you are unsure if your biomarker assay falls under this purview, you may for guidance: clepcert@health.ny.gov

13 Bioanalytical Batch Acceptance Criteria The traditional accuracy criteria Chromatography assays 15% for standards and QCs, 20% for LLOQ 75% of standards and 67% of QCs (with at least one of each concentration) must be acceptable Ligand binding assays 20% for standards and QCs, 25% for LLOQ 75% of standards and 67% of QCs (with at least one of each concentration) must be acceptable

14 Bioanalytical Batch Acceptance Criteria (Cont.) Total Error (TE) Summation of accuracy (% Bias) and precision (% CV) Used primarily in ligand binding analysis Example: Total Error 30% Std 1 has a CV% = 12 % and a Bias% = 14%; TE = 26% Std 2 has a CV% = 15% and a Bias% = 16%; TE = 31% Action Std 2 fails TE criteria

15 CAP/CLIA Batch Acceptance Criteria QCs at two levels (sometimes three) are placed on the run, not necessarily at any specified intervals Westgard Rules for QCs Uses multi rule criteria Per James Westgard First, a non technical description. When my daughter Kristin was young and living at home, she liked to party. One day when she told me she was again intending to be out late, I felt the need to exert some parental control over her hours. So I told her that if she was out once after three, twice after two, or four times after one, she was in big trouble. That's multirule control.

16 CAP/CLIA Batch Acceptance Criteria (Cont.) Westgard Rules

17 Bioanalytical Staff Training Safety (Chemical Hygiene and Bloodborne Pathogens) Regulatory (GLP, GCP, ERES) Technical (use of equipment and software) Method Training on various extraction techniques such as L L, PPT, and SPE) Qualification on specific method

18 CAP/CLIA Staff Training Safety (Chemical Hygiene and Bloodborne Pathogens) Technical (use of equipment and software) SOP reading Initial method training, on the job mentorship 6 month competency and annual thereafter per CAP

19 CAP/CLIA Assay Performance CAP has a requirement to assess each assay through a Proficiency Testing (PT) Program or an Alternative Assessment if a PT program is not available This is in addition to QCs run on each batch Testing done in a blinded fashion and compared against other laboratories

20 Bioanalytical QA Facility and Process audit Vendor audits Study based audits Protocols/plans Critical phase In Process Data Report

21 CAP/CLIA QA Biannual inspections by CAP/CLIA Internal assessments on off years CAP checklists Usually do NOT conduct study based audits Facility and Process audit Third party laboratory audits Vendor audits

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