onsensus Framework for Assay Validation for …...Consensus Framework for Assay Validation for Biomarker Qualification November 22, 2018 Steven P Piccoli PhD Head, Clinical Biomarkers,

Consensus Framework for Assay Validation for Biomarker QualificationNovember 22, 2018

Steven P Piccoli PhDHead, Clinical Biomarkers, OncologyGlaxoSmithKline

11th EBF Open Forum

Introduction to Biomarker Qualification

– Confusion reigns!

– What does the word “qualification” mean in Biomarker Qualification?

– It is not qualification of an assay but qualification of the biomarker itself

– Biomarker “qualification” does not include clinical utility but does include clinical validation!

November 22, 201811th EBF Open Forum 2

Introduction to Biomarker Qualification

– When does one need qualified biomarkers?

– In drug development, biomarkers have different uses:– Exploratory (Internal) vs. Decisional (Regulatory Oversight)

– Why qualify? – Need for decisional biomarkers that can be used across multiple drug development programs

– Qualified biomarkers are quite rare!


Biomarker Qualification Definition

– Qualification is a formal regulatory review and endorsement/acceptance process of biomarkers for their use as Drug Development Tools (DDT) by US FDA, EMA, and PMDA.

– “Qualification is a conclusion that within the stated context of use, the biomarker can be relied upon to have a specific interpretation and application in drug development and regulatory review.”


Biomarker Qualification

– Qualification results in scientific acceptance and regulatory certainty of the biomarker

– Once qualified, acceptable use information will be publicly available

– BQ is the formal acceptance of the biomarker by FDA for use in drug development

– BQ does not designate that a biomarker is acceptable for clinical practice or as an IVD

Biomarker qualification

Biomarker validation (analytical, clinical)

Biomarker testing

Biomarker discovery


Foundation for Qualification of Drug Development Tools

6

Total Kidney

Volume in ADPKD

PhRMA-FDA Workshop

Brookings

Meeting

BMQ

Guidances and MAPPs

FDA-EMA collaboration

CPIM

Meeting/workshop

LOS

LOS

(7)

Survey Plasma fibrinogen in

COPD

2008 2009 2010 2011 2013 2014 2015

CPIM introduced

IOM meeting

2nd nephrotox

BMs

Cardiac toxicity BMs

Guidance DDT Qualification (final)

Invasive Aspergillosis BM

CDER DDT Qualificatio

n MAPP

HHMI Level of Evidence Meeting

LOS (1)

Brookings Meeting

LOI Harmonization

FR notice - BQ survey

OND survey

1st nephrotox BMsGuidance DDT Qualification (draft)

CPIM Guidance

and MAPP

Histopath Guidance (draft)

Quarterly EMA-FDA teleconferences

2007 2012 2016

M-CERSI Meeting

FDA-FNIH Workshop

2006 2017

White Paper

CP Opportunities List LO

S (5)

LOS (1)

AAPS Crystal City V on Draft BMV

AAPS Crystal City VI – BMV Biomarkers

10th

WRIB

11th

WRIB

Non-FDA Meeting/workshop

After S Buckman-Garner, FDA 2017 PSTC / FDA Scientific WorkshopNovember 22, 201811th EBF Open Forum 6

Biomarker Qualification Framework



BEST Biomarker Categories and DDT Uses



Over the last several years, FDA as well as others in the scientific community have co-sponsored several workshops aimed at advancing the discussion around biomarker qualification. Of particular importance are the analytical factors that must be considered when assessing the robustness and reliability of a biomarker assay used to qualify a biomarker. Under the leadership of the Critical Path Institute (C-Path), the Biomarker Assay Collaborative Evidentiary Considerations Writing Group has developed a draft framework outlining key criteria and best practices for biomarker assay performance expectations and validation. On June 14-15, 2017, The Duke-Margolis Center for Health Policy (Washington, DC) convened a two-day public workshop that served as a forum for broader input and feedback on this framework, with the goal of creating alignment on the evidentiary considerations for the analytical validation of biomarker assay.

Public Workshop: Scientific and Regulatory Considerations for the Analytical Validation of Assays Used in the Qualification of Biomarkers in Biological Matrices


Analytical Validation Considerations in Biomarker Qualification

The Points to Consider Document:• Provides scientific insight into how to address

common bioanalytical obstacles encountered during the validation of biomarker assays for BQ

• Is designed to cover all biomarker classes from diagnostic biomarkers to surrogate endpoints

• Presents an approach that is customizable based on the biomarker class and drug development application

• BQ example for six novel nephrotox biomarkers

The Points to Consider Document is NOT:• A checklist that can be followed without considering

your biomarker and it’s drug development application


White Paper Comment Submissions

Type Organization Group SubmissionsAcademia [MIA]Consulting BioQualQuan – USCRO BioMarkable – BE (2)

LGC Group – UKPacific Biomarkers – US

Covance - USPharmaCadence – USQ2 Solutions – US

Industry Allergan – USBiogen – USBioMarin – USBMS – USGenentech – USIllumina – USMerck – DEPfizer – USRoche – CHUCB – BE

Angelini – ITBMS – USBoehringer Ingelheim – USGenentech – USGlaxoSmithKline – USLilly – USMerck – USPfizer – USRoche – US

Regulatory FDA – US (4)JRG – JP

Society EBF – EUAAPS – US

CHDI Foundation –US


Evidentiary Considerations for BQ Assays

Assay Design and Technology Selection for BQ Assays–Pre-Analytical Considerations–Analytical Performance Requirements–Assay Performance Key ParametersAssay Validation Acceptance Criteria for BQ Assays–Accuracy (Relative) or Bias–Analytical Measurement Range (AMR)–Parallelism–Reproducibility–Selectivity–Specificity–Stability (Sample)

Assay Performance Requirement → Analytically validated method with an understanding of potential sources of variability in the measurement of the biomarker


Considerations for Context of Use

– Central to biomarker qualification– A complete and precise statement that describes the appropriate use of the

biomarker and how the qualified biomarker is applied in drug development and regulatory review.

– Also describes important criteria regarding the circumstances under which the biomarker is qualified.– Aspect of the biomarker that is measured and the form in which it is used for biological

interpretation– Species and characteristics of the animal or subjects studied– Purpose of use in drug development– Drug development circumstances for applying the biomarker– Interpretation and decision/action based on the biomarker


Oft-Ignored Aspects of COU Validation

– Total Analytical Error– Allowable TAE

– Between individual variance (CVG)– Within individual variance (CVI)

– Relationship of clinical requirements to informing analytical requirements


Objectives

– Define the latest scientific and regulatory considerations for the analytical validation of assays for fluid-based biomarkers (any protein, peptide, nucleic acid, lipid or other chemical entity soluble in plasma, urine, saliva, etc.) used in the qualification of DDTs

– Considerations for assay design and technology selection, optimization of pre-analytical factors, core assay performance expectations, and setting minimally acceptable assay performance criteria

– Technology areas covered include singleplex ligand binding (LBA) and immunometric assays, singleplex and multiplex MS assays, and enzyme-based assays.


Can the Assay Discriminate Changes?

– Fit-for-purpose status of a biomarker method is deemed acceptable if the assay is capable of discriminating changes that are statistically significantly different from the intra- and inter-subject variation associated with the biomarker (Lee et al. (2006))

– Desired measurable change vs. physiological variability


Acceptance Criteria Challenges

– How to determine assay acceptance criteria for biomarker assays?

– Biomarker assays ≠ PK assays!!– A priori acceptance criteria established for small and large molecule PK assays – De novo acceptance criteria for biomarker assays are dependent upon unique

physiological behavior

– What are appropriate validation samples??


When is an Assay Considered Validated?

– Appropriate assay characterization practices must be applied:– Accuracy (Relative)– Analytical Measurement Range (LOD, LLOQ, ULOQ)

– Parallelism (MRD and Prozone)– Reproducibility (Imprecision)– Selectivity

– Specificity– Stability (sample)

– Additional Analytical Parameters (per COU)– Accuracy/Trueness– Robustness

– Ruggedness


Parallelism

– Parallelism is the extent to which the dose-response curve relationship between the calibrator and an unknown specimen is constant for the examined range of concentrations in physiological matrix, i.e., there is no apparent trend or bias toward increasing or decreasing estimates of analyte concentrations over the range of dilutions when a test sample is serially diluted to produce a set of samples having analyte concentrations that fall within the calibration range of the assay

– Parallelism evaluation is not optional!!


Recommended Approach: Inter-assay Precision Method

– This method uses the analytical performance of the assay to determine which dilution results are within statistically relevant limits.

– Acceptance criteria are set at <3 x inter-assay CV (as calculated from the mean CV of Validation samples)

– Recovery results are determined using the neat result as the true target value of the analyte. The % recovery of each subsequent dilution of the sample is then calculated after adjusting each result for dilution.


Comparison of Regulatory Expectations

Crystal City White Papers CDER CDRH CDRH

Partial Method ValidationBioanalytical Full Method

Validation 510(k) PMA

Exploratory / Feasibility Phase of Testing a

For Use in Biomarker Qualification b, c

For Clinical Use (Class II

Medical Devices)d

For Clinical Use (Class III

Medial Devices) d

LBA LC-MS LBA LC-MS LBA LBA

Controls, analytical (validation QC) 3

6 (Lo, Mid, High in duplicate)

6 (3 levels in duplicate)

20 (LLOQ, Lo, Mid, High in 5

replicates) 2 3Duplicates, analytical

(Std) 2 1 2 1 2 2Replicates, sample (for

precision) 5 Det’d with QC's 5Det’d with

QC's - -Sites 1 1 1 1 2 3Operators 1 e 1 1 e 1 2 3Reagent Lots 1 1 h 1 1 h 2 3Runs 6 3 6 3/6 b,c 2 f 2 f

Days 3 3 3 3 20 20Runs/Day 2 1 2 1 2 2


Parameters

Design– Pre-Analytical Considerations– Analytical Performance Requirements– Assay Performance Key Parameters

Validation Acceptance Criteria– Accuracy (Relative) or Bias– Analytical Measurement Range (AMR)– Parallelism– Reproducibility– Selectivity– Specificity– Stability (Sample)

LBA vs. LC-MS

Design– SAME– SAME– SAME

Validation Acceptance Criteria– SAME– SAME– DIFFERENT! (but similar... )– SAME– SAME– SAME– SAME


Other Points to Consider

4-6-15 ≠ 4-6-20 MS vs LBASinglicate ≠ DuplicateRemember Your Brain!!Thank you Jo Goodman!


Status

– White paper V02 finalized for web publication November 2018 – Availability on C-PATH website soon; published in a peer reviewed journal as soon

as feasible– Progress will be communicated at national meetings (AAPS360 2018, EBF 2018,

WRIB 2019)– PTC WP will be used as foundational scientific consensus for FDA guidances

on biomarker analytical assay validation and safety biomarker qualification– Evidentiary considerations for biomarker qualification are required by the FDA


Impact and Next Steps…

– The Points to Consider Document was envisioned to specifically address the assay validation expectations for fluid-based biomarker qualification as a DDT

– However, the document has become more than its original narrow focus… – It has been referred to as a gold standard for assay validation for biomarkers


(Local) Perspective

Men may be divided into two types: men of words and

men of action. The first speaks; the latter act. I am of

the second group.

Pau Audouard Deglaire - Image source: Gaudi and Barcelona Club. Public domain. Antoni Gaudí i Cornet


https://en.wikipedia.org/wiki/en:Pau_Audouard

http://www.gaudiclub.com/ingles/i_update/mar05.asp

https://commons.wikimedia.org/wiki/Antoni_Gaud%C3%AD_i_Cornet

Thank you!

Questions?


Documents

onsensus Framework for Assay Validation for …...Consensus Framework for Assay Validation for Biomarker Qualification November 22, 2018 Steven P Piccoli PhD Head, Clinical Biomarkers,