Integrating an exploratory BM in an early clinical stage in Pharma R&D
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1 Integrating an exploratory BM in an early clinical stage in Pharma R&D Ulrich Kunz, Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
2 Content of Workshop 1. Introduction 2. Getting information about BM1: Assay request process (Biology of the BM and intended use) 3. Translation into a bioanalytical strategy: Choice of an analytical method for BM1 4. Validation of the BM assay for the first phase I study 5. Sample measurement: results and data evaluation 6. Outcome and consequences on the further development U. Kunz, June
3 Overview of the (ideal) Process of identifying BM for early clinical studies at BI Lead Optimization Literature Research Teams Clinical development Plan Disease Indication Teams Biomarker Medical Subteam (responsible for BM strategy, Pk, Pharmacometrics, Statistics, Clinical, Preclinical, Research, lead: TMCP) TMCP-Plan Project strategy early clinical development Outlook on late stage clinical development (planned studies, population, which BM and why) Contacts to external researchers Translatorical Studies Bioanalytical support (assay feasibility, search for methods, reagents, assay development, validation, measurement of samples transfer to other sites) Start of clinical development U. Kunz, June
4 Flow for biomarker method establishment BM Medical Subteam, Translational Medicine and BM expert: BM strategy Assay request process Understanding biology and intended use of BM TM & CP plan CTP (Expl. BM) + Analyt. Workplan Analyze samples 1. phase I study Fail Bioanalyst + Sponsor: Qualify BM assumptions + evaluate assay performance Validation plan Success Bioanalyst + Sponsor (TMBE): Translation into a Bioanalytical strategy and assay design Feasibility study/ method set up and validation Level 3/Screening assay Bioanalyst + Sponsor: Agree on future intended use of BM and assay requirements Continuing clinical and analytical interpretation of data from further studies (monitoring of assay performance) CTP (Expl. BM) + Analyt. Workplan Analyze samples Phase II study (Re-) Validation plan + Validation Report Set up/modify and validate the level 2/qualified assay U. Kunz, June
5 Assay request process Sponsor (Translational Medicine and Biomarker Experts) has to provide sufficient information prior to start of any lab activities Comprehensive questionaire to fill out: General status of method, BM and scope of analytical activities Structure and Biology of BM Intended use of BM results Prerequisites for the analytical method Planned clinical studies Thereafter, joint discussion between sponsor and bioanalyst: Practical aspects of requested lab support U. Kunz, June
6 BI tiered method validation approach for BM assays Tiered approach: Validation level may change dependent on: intended use of data, clinical qualification status of BM and knowledge about BM-assay and BM Level 3 (Screening assay) Level 2 (Qualified assay) Explorative biomarker To gain experience with the biomarker and the biomarker assay Comparability within a single study (narrow time window) Explorative and probable valid biomarker Comparability within a central lab over several studies (e.g. whole development) Level 1 (Cross) validated assay) Confirmatory biomarker (probable valid, valid) Comparability between labs External by diagnostic companies or CRO labs with extensive cross validation, Global reference system established and proven metrological traceability Advantages: Fast, flexible and cost effective (avoid frontloading of work) U. Kunz, June
7 How BM1 was nominated as explorative BM for phase I clinical study - very late, phase I clinical trail has already started - BI Research Teams Start of phase I clinical trial Literature BM1 Disease Indication Teams Biomarker Medical Subteam (responsible for BM strategy, lead: TMCP) Contacts to external researchers Translatorical Studies Interim analysis planned Clinical development Plan Amendment to Clinical Trial Protocol 1. Phase 1 study TMCP-Plan Version 2 Bioanalytical support (search for methods, validation, measurement of samples) U. Kunz, June
8 TMCP Plan The Translational and Biomarker strategy for this program has two main objectives: 1. Identify disease specific markers that change early after treatment with drug and correlate with clinical endpoints. 2. Identify mechanistic or disease specific markers that can predict clinical response to treatment with drug Efficacy Markers in the target tissue:... Disease Markers in Peripheral Blood : BM1 is a marker shown to be highly expressed in both the target tissue and serum of patients and higher levels correlated with higher clinical symptoms. Changes in serum levels of BM1 will also be assessed for PK/PD correlations. BIOMARKER ANALYSIS STRATEGY In collaboration with TransMed Experts and biomarker groups model-based analysis of efficacy or safety biomarker data may be conducted. The impact of serum levels of BM1 protein concentrations on the longitudinal, population model-based analysis of clinical outcomes is planned as an exploratory analysis using study data. U. Kunz, June
9 Assay request: Biology of BM1 Structure of BM (link to proteome database) relevant literature Biological Variability within and between populations (e.g. Differences Healthy Volunteers Patients) Presence in biological context, e.g. monomer, multimer (mono-, hetero-), splice variants, homologies, chemical isomers Interaction with other matrix compounds (binding proteins, receptor, drug...) Circadian rhythm known? Influence of extrinsic factors (e.g. fasted non-fasted, coagulation...)? Stability of BM (any hints for instability?) Preferred matrix Protein MW: 6 kda, cationic, cystein rich Some available about use of BM1 as biomarker in clinical studies Lit: Patient level > healthy volunteers (< 1ng/mL) Variability between patients high, correlation with disease status Several similar proteins present in blood, no info about multimers, commercial available anti-bm1 antibodies and kits states selectivity regarding BM1 Unknown, interaction with anionic peptides possible Lit: no evidence observed in healthy serum BM1 levels Lit: no large differences found in serum samples taken from the same individuum after a two year interval!! Serum and plasma (depending on what aliquots are remaining for BM1) U. Kunz, June
10 Assay request: Intended use of BM1 Biomarker category Known: Physiological Response Pd-Biomarker Option: Outcome Related Pd-Biomarker? Planned evaluation of results (for details please see: Trial Statistical Analysis Plan) Intended purpose What is the expected effect during treatment? not known about 50% 1-50% % % >1000% Which Lower Limit Of Quantification of the assay is needed? 1. Relative change from baseline levels during treatment 2. Correlation of baseline levels and clinical symptoms Outcome related BM: 1. How much reduction of peripheral levels of BM1 at week X do we need to achieve a 80% reduction in clinical symptoms at week 12? 2. Are baseline levels of BM1 predictive of clinical response? 3. Is BM1 a surrogate marker for clinical symptoms, independent of mechanism specific intervention? PK/PD with BM1 data. Reduction > 50% = 1-50% of baseline Healthy volunteer levels (Lit: about 1ng/mL) Information about existing analytical methods and current experience Lit about use of commercial kits and own ELISAs Kits from multiple vendors available U. Kunz, June
11 Assay request: Intended use of BM1 1. Expected number of samples in first studies? 2. Timelines of first studies 3. Interim analysis necessary? Use in further studies? Useful in other indications/projects? 1. About 300 in phase I, about 1000 in phase II (per indication) 2. Already running, about 3 month from now on (for interim)!!!!! 3. Yes after third dose cohort Yes, most likely phase II, support PK/PD modelling through expansion of kinetic data (together with mrna expression) Yes, data might support the transition into alternative indication/diseases U. Kunz, June
12 Question 1 1. Was the available information about BM1 and its intended use sufficient? What was missing? What assay format would you choose? U. Kunz, June
13 Translation into the bioanalytical strategy for (running) phase I and beyond (sponsor + bioanalyst) Biomarker of interest (incl. details about special isoforms or interesting epitopes or assay conditions) Necessary grade of quantification Total BM1 (no infos about isoforms, special selectivity of assays used in lit.) Relative quantitative (comparison of pre-dose levels necessary) Validation level for first study Level 3 (explorative BM, proof of hypothesis from lit, test of assay suitability, no inhouse experience with assay so far = not used in pre-clinic) Special requirements for assay development or validation, (e.g. sampling)? No (nothing known about needs for special sampling procedures, instabilities) Selected technology First choice: commercial ELISA kit (already available, high sensitivity not necessary) in principle LC-MS might be an option Patient samples available (contact)? Location of sample analysis (internal lab, external CRO) Some banked patient samples available Internal until end of phase I (quick results needed) Request to bioanalytical lab: Feasibility and selection out of various commercial assays Validation (level 3) Measurement of phase I samples (serum and plasma) U. Kunz, June
14 Selection of assay/assay feasibility Various BM 1 ELISA kits from different vendors available Several anti-bm1 antibodies and recombinant BM1 available Feasibility test of 6 different ELISA kits from 6 different vendors Tested parameter: Calibration range, curve fitting, signal to noise ratio lowest C/blank Reactivity of two external calibration standards (rec. Protein, synthetic peptide) Test of three individual sera from healthy volunteers + corresponding EDTA plasma in three dilutions (1:1 1:5) Test of a patient serum with expected high endogenous level in several dilutions U. Kunz, June
15 Selection of ELISA kit - Assay feasibility Calibration range, curve fitting, signal to noise ratio lowest C/blank Reactivity of two separate calibration standards (rec. Protein, synthetic peptide) Test of three individual sera from healthy volunteers + corresponding EDTA plasma in three dilutions (1:1 1:5) Test of a patient serum with expected high endogenous level in several dilutions ok ok ok No curve! ok Only 4 calibrators Parallel curves Non parallel Serum>plas ma Parallel curves Non parallel Serum>plas ma Non parallel Parallel 1:5 1:50 Parallel curves Non parallel Serum>plas ma - Conc. Independent response = blank!? - High signals, cannot be blocked with anti-bm1 antibody Parallel curves Sensitivity not sufficient Non parallel - - Non parallel Within replicate precision worth ok ok - ok ok comment preferred Kit does not work What does this kit measure? U. Kunz, June
16 Question 2 2. Has the intended use of BM1 data been translated adequately into the bioanalytical strategy? (choose of assay, feasibility experiments, plans for future validation and analyzing strategy)? U. Kunz, June
17 Assay validation plan, commercial kit#2, validation level 3 Validation plan experiment Calculation, method acceptance VCs (validation samples) Precision Calibration range, LLOQ, ULOQ Parallelism Baseline range Healthy Volunteers Short term stability endog. Analyte Three individual sera (low, mid, high) and EDTA plasma, aliquoted and stored frozen At least 3 runs at 3 day, VCs in independent duplicates Data from at least 3 runs at 3 days, whole curve + blank 4 individuals serum ( Healthy and patients), 4 individuals plasma Tabulate and calculate overall precision (CV), optimal: <30% CV Tabulated back calculated results of Cs, LLOQ = lowest valid C that can be distinguished from blank, ULOQ = highest valid C * highest valid dilution in parallelism exp. linear regression of log transformed values (0.8 < slope < 1.2, r²>0.98) N=12 serum and EDTA plasma Just report mean, min, max, CV, ratio plasma/serum 24h RT, +1, +3 freeze/thaw cycles (-20 C) Two individual samples (2 serum + 2 plasma) in duplicates (VCs), Expected BM effect >50% decrease Relative deviation stressed aliquots vs. frozen reference < 30% U. Kunz, June
18 Assay validation results Validation plan Precision Calibration range, LLOQ, ULOQ Parallelism Baseline range Healthy Volunteers Short term stability endog. Analyte experiment Calculation, acceptance Results 4 runs at 3 days, VCs in independent duplicates 4 runs at 3 days, whole curve + blank 4 individuals serum and 4 plasma N=12 serum and EDTA plasma 24h RT, +1, +3 freeze/thaw cycles (-20 C) Two individual samples in duplicates (VCs), Tabulate and calculate overall precision (CV), target: <30% CV Tabulated back calculated results of Cs, LLOQ = lowest valid C that can be distinguished from blank, ULOQ = highest valid C * highest valid dilution in parallelism exp. linear regression of log transformed values (0.8 < slope < 1.2, r²>0.98) Just report mean, min, max, CV Relative deviation stressed aliquots vs. frozen one < 30% Serum: 4-11% CV (N=8), Plasma: 5-13%CV (N=8) ng eq/ml ok, CV <4% (N=4), %dev: -3% - +5% LLOQ = 0.31 ng eq/ml (1:10) ULOQ = 750 ng eq/ml (1:500) 2 out of 4 non-parallel serum 3 out of 4 non-parallel plasma Serum: Mean 2.6 ng eq/ml (N=11), Min 0.62, Max 6.1, inter-indiv. CV = 71% Plasma: Mean 2.2 ng eq/ml (N=11), Min 0.63, Max 5.1, inter-indiv. CV = 69% Plasma/Serum = 0.85 Serum: stable 24h RT, +1, +3 freeze/thaw cycles (-20 C) Plasma: stable 24h RT, +1, +3 freeze/thaw cycles (-20 C) U. Kunz, June
19 Validation results - Precision Run Date Kit Lot# Curve Number QC Low (ng eq/ml) QC Mid (ng eq/ml) QC High (ng eq/ml) ratio Low/Mid ratio High/Mid 24-Aug-13 #2 V_ Aug-13 #2 V_ Aug-13 #2 V_ Aug-13 #2 V_ mean sd CV 11.0% 3.8% 8.6% 8.1% 9.1% U. Kunz, June
20 Validation results - Parallelism sample: concentrati [ng eq/ml] dilution 1: #P1 #P2 #P3 #P4 #S1 #S2 #S3 #S CV 10% 15% 7% 19% 16% 13% 13% 20% rel. Range 24% 37% 16% 41% 37% 28% 33% 46% linear regression log (1/dilution) log(conc.) slope r² Acceptance criteria: 0.8 < slope < 1.2 AND r² > 0.98 Parallel? Failed! U. Kunz, June
21 Questions 3 3. Has the assay been sufficiently proven/validated prior to start of sample measurements? What experiments are missing, not adequate? U. Kunz, June
22 Discussion with sponsor 1. Assay feasibility tests went fine (kit lot#1) But validation failed (due to different kit lot #2?) -> Consultation with the kit supplier (old lot #1 no longer available, third lot failed too) 2. Unfortunately, not sufficient time for an alternative assay, clinical study has already started -> Consultation with sponsor (Translational Medicine and Biomarker Expert) 3. Decision to continue with this assay as a quasi-quantitative assay. U. Kunz, June
23 Consequence for bioanalysis Keep the validation as it is Avoid reporting of relative concentration values (misleading) Pre-screening of pre-dose samples in various dilutions, titer determination (LLOQ = cut-off), reporting of titers for pre-dose samples only Selection of optimal individual dilution for each subject (upper range of calibration curve) Measurement of all samples of a subject in the fixed optimal dilution Calculation and reporting of post-/pre-dose ratio for post-dose samples -> Discussed in the validation summary and as part of the Analytical Workplan for BM1 measurement in the first study U. Kunz, June
24 Question 4 4. Assay acceptance after validation. What about the consequences of the failed parallelism experiment? quasi-quantitative evaluation of data ok? U. Kunz, June
25 In-study acceptance criteria (technical) General, all samples Is the CV of the response values of the dependent replicates (one preparation of sample in multiple wells) above 25%? IF yes THEN deactivate the whole sample (automatically done by Watson). Dynamic range = Check of calibration curve Are there calibration standards with a relative deviation from nominal/target of more than 20%? IF yes THEN deactivate the whole standard (all replicates). Recalculation of calibration curve Calibration range is truncated if lowest or highest standard failed. IF more than 25% of all replicates were excluded OR less than 5 valid calibration standards are remaining OR r² < 0.98 THEN the plate/run failed; Reject the run; STOP. ELSE continue No target values for QCs! QC results will be monitored and evaluated retrospectively (concentrations + ratios between QC results within 30% of mean). -> focus on comparability of runs not on relative accuracy U. Kunz, June
26 Measurement of study samples Retrospective QC evaluation and run acceptance Run Date Kit Lot# Curve Number QC Low (ng eq/ml) QC Mid (ng eq/ml) QC High (ng eq/ml) ratio Low/Mid ratio High/Mid 30-Sep-13 #2 S_ Sep-13 #2 S_ Sep-13 #2 S_ Oct-13 #2 S_ Oct-13 #2 S_ Jun-14 #4 S_ Jun-14 #4 S_ mean sd CV 9.4% 8.4% 10.1% 9.2% 7.2% mean -30% mean +30% Red values = outliers > 3 * inter-quartile range 1. Test of normal distribution 2. All batches fulfills +-30% acceptance criterion vs. mean of all study runs. All batches are considered comparable and valid. U. Kunz, June
27 Results, Data Transfer and Reporting 1/ PTNO CPEVENT DILUTION RESULT TITER RESULT RATIO PKQ RUN 209 VISIT P735_ VISIT P735_ VISIT P735_ VISIT NOS P735_ VISIT P735_ VISIT P735_ VISIT P735_ VISIT NOS P735_ VISIT P735_ VISIT P735_ VISIT P735_ VISIT NOS P735_ VISIT P735_ VISIT NOS P735_ VISIT P735_ VISIT P735_ VISIT P735_ VISIT P735_ VISIT P735_ VISIT P735_0006 Visit 2 = pre-dose NOS = no sample U. Kunz, June
28 Questions 5 5. Would you agree with the level3 in-study validation concept in which runs are preliminary accepted based on calibration curve data only and QC results are compared retrospectively to identify outlier runs? U. Kunz, June
29 Evaluation of BM1 results Significant dose dependent effect BM1 correlates with physiological effect Hints for an outcome related biomarker (early prediction of efficacy) U. Kunz, June
30 Planning for phase II BM 1 confirmed as very promising physiological response biomarker and maybe outcome related biomarker Team decision to measure BM1 in all phase II studies also in other indications Consequences for bioanalysis: Phase I approach is too much effort for the expected number of samples (Pre-screening/titer determination of pre-dose samples from each subject in order to define optimal dilution) Decision to invest in a complete new inhouse assay development using commercial antibodies MSD for a broader dynamic range Selection of antibodies and calibration standard to increase parallelism and enable a relative quantitative assay Serum only U. Kunz, June
31 Validation of the new MSD BM1 assay, level 2 Validation plan level 2 VCs (validation samples) Precision Calibration range, LLOQ, ULOQ Parallelism Baseline range Healthy Volunteers Short term stability endog. Analyte Calibration sample stability Stock solution stability, banked calibration standard Long term stability serum Sampling robustness Banking of sample control (monitoring samples) experiment Three individual sera (low, mid, high) aliquoted and stored frozen, additional LLOQ sample = higher diluted serum At least 6 runs at 4 days, VCs in independent triplicates Mean values are target for in-study batch acceptance Tabulation of back-calculated results 6 individuals sera ( Healthy and patients) N=24 sera 24h RT, +1, +3, +5 freeze/thaw cycles (-20 C) Three individual samples in triplicates (VCs) Ready-to-use diluted, 2h RT Thawed aliquot in the refrigerator, long-term monitoring at -70 C and -150 C Isochronic sample sets (stressed vs C), 3 individuals Fresh-blood stability, serum coagulation time, interference of hemolysed blood cells Use for long term trends and lot bridging experiments U. Kunz, June
32 Questions After first data available. Decision to develop a complete new assay: overkill or ok? 7. Has this been a typical case study or something special? U. Kunz, June
33 Questions for discussion 1. Was the available information about BM1 and its intended use sufficient? What was missing? 2. Was the intended use of BM1 data translated adequately into the bioanalytical strategy? (choose of assay, feasibility experiments, plans for future validation and analyzing strategy) 3. Has the assay been sufficiently proven/validated prior to start of sample measurements? What experiments are missing, not adequate. 4. Assay acceptance after validation. What about the consequences of the failed parallelism experiment? quasi-quantitative evaluation of data ok? 5. Would you agree with the level3 in-study validation concept in which runs are preliminary accepted based on calibration curve data only and QC results are compared retrospectively to identify outlier runs? 6. After first data available. Decision to develop a complete new assay: overkill or ok? 7. Has this been a typical case study or something special? U. Kunz, June
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