EBF Position on Biomarker Assay validation

Transcription

1 EBF Position on Biomarker Assay validation Presenters: Philip Timmerman/Marianne Scheel Fjording on behalf of the EBF 7 th JBF Meeting March 2016 Tokyo, Japan

2 Outline 1. Biomarkers and EBF 2012 (Philip) The EBF Recommendation 2. Biomarkers and EBF 2015 (Marianne) Preparing for CC-VI Connecting EBF and CC-VI 3. Biomarkers and Scientific Validation (Philip) How does SV fit in BM validation a draft discussion htt-sp:// 2

3 Outline 1. Biomarkers and EBF 2012 (Philip) The EBF Recommendation 2. Biomarkers and EBF 2015 (Marianne) Preparing for CC-VI Connecting EBF and CC-VI 3. Biomarkers and Scientific Validation (Philip) How does SV fit in BM validation a draft discussion htt-sp:// 3

4 EBF Recommendation

5 EBF Recommendation on method establishment and bioanalysis of Biomarkers in support of drug development. Philip Timmerman 1*, Christian Herling 2, Daniela Stoellner 3, Birgit Jaitner 3, Susanne Pihl 4, Karen Elsby 5, Neil Henderson 5, Begona Barroso 6, Stephanie Fischmann 7, Arjen Companjen 8, Amanda Versteilen 8, Stewart Bates 9, Clare Kingsley 10, Ulrich Kunz 11 1 Janssen R & D, 2 NovoNordisk, 3 Novartis, 4 Lundbeck, 5 AstraZeneca, 6 Astellas, 7 Abbott, 8 Crucell, 9 GlaxoSmithKline, 10 Quotient Bioresearch, 11 Boehringer-Ingelheim, Bioanalysis 4(15), August 2012) + Pointer in Biomarkers in Medicine August 2012, Vol. 6, No. 4, Pages Mar

6 2 examples Or All measured with PK assay A&P But in both cases inappropriate 28-Mar

7 EBF recommendation 4 pillars 28-Mar

8 1 4 pillars Drivers for BM assay validation 1. Observed or anticipated biomarker level changes 28-Mar

9 4 pillars Drivers for BM assay validation Observed or anticipated biomarker level changes 2. Development Phase in which a biomarker is measured 28-Mar

10 4 pillars Drivers for BM assay validation Observed or anticipated biomarker level changes 2. Development Phase in which a biomarker is measured 3. Decisions taken from the biomarker data efficacy decisions safety decisions 28-Mar

11 4 pillars Drivers for BM assay validation Observed or anticipated biomarker level changes 2. Development Phase in which a biomarker is measured 3. Decisions taken from the biomarker data efficacy decisions safety decisions 4. Fit of assay with Regulated Bioanalysis Guidelines 28-Mar

12 4 pillars Drivers for BM assay validation Observed or anticipated biomarker level changes 2. Development Phase in which a biomarker is measured 3. Decisions taken from the biomarker data efficacy decisions safety decisions 4. Fit of assay with Regulated Bioanalysis Guidelines Above classification are superimposable - should be applied in concert to tailor an BA strategy in support of a Biomarker 28-Mar

13 1 2 Decision Tree Mar

14 2012: EBF recommendation Analysis of BM using a novel assay. Analysis of BM using an existing assay. htt-sp:// 14

15 Analysis of biomarkers using a novel assay. Fail? Understand biology of BM Translate BM biology and science into Bioanalysis Qualify assumptions Success Agree on final assay requirements Analysis of BM using a novel assay. Set up the assay Analyze samples 15

16 Analysis of biomarkers using an existing assay.? Existing BM platform Flowchart: New Biomarker Analysis of BM using an existing assay. Overlay BM assay performance on BM request No BM assay performance and BM request fits Close fit Agree on final assay requirements Set up assay and analyze samples Yes Analyze samples htt-sp:// 16

17 Combined flowchart More details in Bu slides copied from 2012 EBF presentation 28-Mar

18 Additional reflections With more BM analysis amenable to LC-MS, industry may say/think we can easily reach (20) quality, stimulating regulated bioanalysis standards for BM analysis, but: A significant number of biomarkers are novel and analysis involves the use of cutting edge or developing science High resolution MS novel hyphenated techniques novel LBA/cell based assay formats assays combining LBA and MS technology, Yes, can do! shouldn t mean Yes, let s do! if there is no scientific driver. Yes, let s do! may increase cost with no added value for the patient. Yes, let s do! may jeopardize science to progress. 18

19 So far for history htt-sp:// 19

20 Outline 1. Biomarkers and EBF 2012 (Philip) The EBF Recommendation 2. Biomarkers and EBF 2015 (Marianne) Preparing for CC-VI Connecting EBF and CC-VI 3. Biomarkers and Scientific Validation (Philip) How does SV fit in BM validation a draft discussion htt-sp:// 20

21 2015 pre CC-VI discussions in EBF Survey of 57 statements Quick yes/no answer More a pole than a real survey. Next slides = I feel that Intended to take the temperature of the EBF community on their feelings on a need for Biomarker BMV 26 responses From these 57 statements we took 5 take-home messages htt-sp:// 21

22 Take home messages 1. Generic criteria are difficult for all BM assay 2. Discussion should include all stakeholders 3. Assay requirement can change 4. Look for global consensus 5. Use principles of scientific validation htt-sp:// 22

23 Or in full text 1. a generic acceptance criteria, standardized validation parameters and bioanalytical QC batch concept cannot be fulfilled for all BM assay 2. the discussion on BMV and analysis should include all relevant stakeholders (at least BA, PK, ClinPharm, Pharmacology) 3. assay validation requirement for a particular BM assay can change depending on the progress of the clinical development or the decisions made 4. agencies should look for global consensus on the need and scope for BM Guidance prior to a regional Guidance 5. the principles of scientific validation can help the bioanalytical discussion for BM htt-sp:// 23

24 For some, there was no consensus it may be too early to bring BM assay validation and analysis into a regulatory bioanalytical guideline people like guidance BA acceptance criteria for BM assay validation & analysis should be included in reg. bioanalysis guidelines (question came 3 times in different shades, 3 times 50/50 split) guidelines should not include strict acceptance criteria but general BM assay validation/qualification strategy but maybe not at the same strict level Acceptance criteria recommendations could be provided, but not exact acceptance criteria clinical analyser methods should adhere to the same validation guidelines as non-standard biomarker assays I feel it must be the other way around. Clinical lab, clinical analyzers, best practices and criteria can be a good foundation for a BM guideline for Pharma industry htt-sp:// 24

25 We were passionate about accuracy.the analytical parameter accuracy is misleading in relative quantitative methods and should not be part of a standard validation package for confirmatory BMs. Yes, you are absolutely right, nevertheless there should be some yardstick to which measurements can be compared. I would prefer precision of responses over accuracy. I feel that it can be part of a validation but the meaning of 'accuracy' needs to be well understood and it should not have strict acceptance criteria Reproducibility is better appreciated than accuracy you only can calculate a relative accuracy as drift from a previously determined target value. Accuracy should be part of the validation package, however, with the known limitations due to the relative quantitative assay type. Etc htt-sp:// 25

26 And than, Crystal City VI arrived? Workshop agenda Keynote presentation Brian Booth Session 1A: Creating a discussion framework Session 1B: Challenges in making LBA and LC/MS biomarker assays meet PK assay criteria Session 2: LC MS approaches (traditional and immunocapture) and assay criteria Session 3: LBA approaches and assay criteria: surrogate matrix/buffer, parallelism and stability Session 4: Perspectives and recommendation for assay criteria BMV = Bioanalytical method validation 26

27 Take home messages from CC-VI PK assay? Biomarker Assays are not PK Assays Nor are they the sons/daughters of PK assays Or their distant cousins Or even same species Biomarker assays are not PK assays, and they don t want to grow up to be PK assays either Used with permission from Lauren Stevenson 27

28 Take home messages from CC-VI Biomarkers & Biology Biomarker data are used to make important decisions in your project Assay must be reliable in order to be confident in these decisions Assay validation plays a pivotal role Do you know what you are measuring? What is the purpose of the assay? Assay design reagents? What are the limitations of the assay? What is the precision of the measurement? How do sample handling conditions affect the measurement? 28

29 Take home messages from CC-VI Consensus Category 1 = most Biomarkers we analyze today Internal decision making Extent of assay validation is up to you! Category 2 Biomarker to support pivotal decision & label claim Assay validation in scope of FDA 29

30 Take home message CC-VI in summary Biomarker Assays PK assays Category 2 Biomarkers are in scope of FDA review Scientific reflections when setting up assays Rethink accuracy Emphasis on precision Parallelism is the key analytical validation experiment Endogenous analyte to define performance and manage change Establish reference range for assay Understand the biology! 30

31 Connecting EBF 2012 and CC-VI EBF Recommendation (the 4 pillars) aligned well with comments of the 2015 pole 2. EBF community was worried on where CC-VI discussions would lead us 3. EBF representatives took EBF discussion points and worries to Baltimore as contribution to CC-VI We did have some fear CC-VI would take the discussions into a direction where expectations on BM validation would become unrealistic CC-VI/FDA EBF 2012 htt-sp:// 31

32 But. Meeting discussions were closely aligned with 2012 EBF Recommendation & feedback from 2015 pole CC-VI/FDA EBF 2012 And FDA expressed they are in learning mode, and do not expect a Guidance in several years to come htt-sp:// 32

33 Outline 1. Biomarkers and EBF 2012 (Philip) The EBF Recommendation 2. Biomarkers and EBF 2015 (Marianne) Preparing for CC-VI Connecting EBF and CC-VI 3. Biomarkers and Scientific Validation (Philip) How does SV fit in BM validation a draft discussion htt-sp:// 33

34 Understanding the interplay Fit for Purpose Tiered Approach 1. Fit for purpose = Lee et. al., 2006 Target = biomarkers and building on the 2003 Biomarker Workshop, a iterative strategy in 4 tiers Preanalytical Considerations and Method Development in-study validation Exploratory method validation Advanced method validation 2. Tiered approach = Viswanathan et al, 2007 Target = metabolites increasing level of validation as compounds progress through development pipeline. Refined to: A science driven fit-for-purpose strategy to apply a predefined appropriate level of bioanalytical quality in preclinical and clinical studies depending on the type of the study, intended use of the concentration data, and/or considering the stage of development. Each tier describes the experiments to be conducted, acceptance criteria to be met and level of documentation required. (EBF, 2014) htt-sp:// 34

35 Understanding the interplay Tiered Approach Scientific Validation Scientific validation Subset of tiered approach. Defining a practical way forward on how to generate scientifically valid data for area where regulatory standards are not required. Current focus of EBF = areas where industry goes in overdrive on trying to comply with regulatory standards: 1. All Urine analysis 2. All tissue homogenate analysis 3. All pre-mad metabolites analysis (ref to ICH(M3) and EMA-DDI) 4. A selection of non-pivotal ED clinical studies (i.e. phase ), SAD/MAD) 5. Non pivotal) Early GLP studies o principles of scientific validation are compatible with GLP regulations htt-sp:// 35

36 Understanding the interplay BM assay validation Scientific Validation Biomarker assay validation not explicitly defined in EBF Recommendation paper on Scientific Validation Principles could fit philosophy of EBF Recommendation paper on Biomarker Assay Validation Refinement of the 4 th pillars htt-sp:// 36

37 Observed or anticipated biomarker level changes 2. Development Phase in which a biomarker is measured 3. Decisions taken from the biomarker data efficacy decisions safety decisions 4. Fit of assay with Regulated Bioanalysis Guidelines 28-Mar

38 Observed or anticipated biomarker level changes 2. Development Phase in which a biomarker is measured 3. Decisions taken from the biomarker data efficacy decisions safety decisions 4. Fit of assay with Scientific validation standards Only than include need for Regulatory standards, since SV standards will likely fit regulatory requirements in many cases 28-Mar

39 1 2 Decision Tree Mar

40 But these ideas are still very fresh and not discussed in EBF community htt-sp:// 40

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