Integrating Biospecimen Collection into Clinical Research

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1 Integrating Biospecimen Collection into Clinical Research Janet E Dancey, MD, FRCPC Ontario Institute for Cancer Research Program for High Impact Clinical Trials National Cancer Institute of Canada Clinical Trials Group

2 My Biases and Beliefs The integration of biospecimens with reliable clinical data is critical to advance molecular findings from the laboratory to the clinic. Highest quality biospecimens are collected on standardized protocols for prespecified purpose(s) and maintained in central facilities with appropriate quality control/quality assurance. Highest quality clinical data are collected in randomized controlled clinical trials. The highest quality studies performed on biospecimens are those conducted based on a well supported hypothesis, with well evaluated assays performed on appropriate biospecimens with results correlated to clinical outcomes with statistical design that provides certainty in the results. The specific resources to conduct high quality biospecimen research must be available.

3 My Biases and Beliefs Clinical research (and life) is a series of compromises some of which are worth making and some of which are not.

4 My Biases and Beliefs Clinical research (and life) is a series of compromises some of which are worth making and some of which are not. Science Feasibility Impact?

5 Biospecimen Collection for Biomarker Development: Challenges Potential biomarker discovery outpaces validation studies. BUT (have) rarely led to clinical use. WHY? validating cancer biomarkers can be hard. Multidisciplinary collaboration between clinicians, laboratory scientists, pathologists, imagers, and statisticians and industry over a period of years. Different cultures/goals/priorities. Buy-in from collaborators is essential.

6 Reasons for Lack of Useful Biomarker Results Insufficient numbers of samples Trial stopped early Therapy ineffective Poor accrual Specimens not collected, lost, spoiled Results not interpretable/convincing Specimens issues Assay issues Lack of effect/correlation Drug inactive Marker lacks prognostic/predictive correlation Statistical Issues Results delayed Slow accrual and/or delayed analysis of correlatives Standards change

7 Integrating Biospecimen Collection into Clinical Research Determining value-added What is the question/purpose? (Is there one?) ( Is it an important one?) Are the proposed specimens optimal/adequate to address the question/purpose? Can the proposed specimens be collected, handled, stored to address the question? Are the proposed numbers of specimens likely to be analyzed adequate to address the question? Is the proposed assay method optimal/adequate? Is the proposed clinical trial and statistical analysis optimal/adequate? What is the likely impact of the result?

8 Biospecimen Research Questions Diagnostic Early detection (screening), enabling intervention at an earlier and potentially more curable stage than under usual clinical diagnostic conditions Monitoring of disease response during therapy, with potential for adjusting level of intervention (e.g. dose) on a dynamic and personal basis Risk assessment leading to preventive interventions for those at sufficient risk Prognosis, allowing for more aggressive therapy for patients with poorer prognosis Prediction of safety or efficacy of a therapy, thereby providing guidance in choice of therapy

9 Types of Biomarkers Diagnostic Early Detection (screening) Monitoring Risk Assessment Prognostic Predictive of Safety or Efficacy The first three the focus is on identifying the disease (present/absent).

10 Types of Biomarkers Diagnostic Early Detection (screening) Monitoring Risk Assessment Prognostic Predictive of Safety or Efficacy The last three are attempting to predict the future. (more or less likely to have event)

11 Will the Specimens be Adequate? Challenges in Acquiring Specimens Difficulties obtaining tissue Patient consent (advanced/recurrent disease) Biopsy precedes study & unavailable Relevance of original diagnostic specimen (if 2 nd line) or primary tumour (if metastatic) Risks of additional biopsy procedure Collection & preservation

12 Will the Specimens Be Adequate? Consider: Type, Number, Timing, handling, shipping, storage Demands on patients/clinic/laboratory staff Technical requirements of the proposed analysis Likely impact/plan for handling missing/inadequate specimens Can the question still be answered?

13 Is the Proposed Assay(s) Adequate/Optimal? Analytical/Laboratory Validation (Laboratory performance) How well are you measuring the measurand? Precision / Reproducibility Method Comparison LoB, LoD, LoQ Linearity Stability Clinical Laboratory Standards Institute (CLSI) Is it fit for proposed purpose i.e. on the proposed biospecimens? Clinical Validation ( Qualification ) Does the test have clinical utility? Does it have added value over standard tests? FDA guidance : Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests issued in final form in March, 2007,

14 Is the proposed clinical trial and statistical analysis optimal/adequate? Phase 1 Determine dose/schedule for further testing Few patients Heterogenous Pharmacodynamic markers to support dose selection Phase 2 Screen for antitumour activity Relatively few patients for subset analysis May not have a control arm (cannot distinguish prognostic vs predictive) Drug may not be active Predictive markers present at baseline Pharmacodynamic markers that are surrogates for clinically measured anti-tumour effects Phase 3 biomarkers related to clinical benefit Relatively few patients for subset analysis Specimen collection may be suboptimal Drug may be inactive Predictive markers; prognostic markers Surrogate markers for clinical benefit

15 Biospecimens for Biomarkers in Proof of mechanism Phase 1 Trials: Utility When toxicity may be insufficient to determine active dose/schedule Unlikely to occur at dose/exposure that affects the target Due to off target effects and effects on target are uncertain To target a specific degree of target inhibition to avoid significant toxicity When pharmacokinetics may be insufficient to determine active dose/schedule Assay lacking Pharmacokinetics in plasma does not match effect in tissues

16 Phase 1 Trial Assessment of Target Effects - Requirements Agent with acceptable preclinical activity, toxicology, pharmacology Known association of target effect and tumour activity Well-characterized assay % change in target or target level associated with efficacy Concentration/exposure required for target effect Time course for effect on target, duration, recovery Threshold of detection and CV of target measurements Target effect on tumour vs other tissues (eg PBMC, Skin, Buccal) Collection, processing, shipping, storage effects known/optimized Usual target values and variability in human tissue known Patients tumours have relevant target Commitment from investigators/patients mandatory requirement (just like PK)

17 Biospecimen/Biomarkers for Phase 2/3: Predictive markers The Goal: Selection/Indentification of patients likely to benefit (or elimination of those least likely to benefit) Considerations: Drug activity Treatment effect across patient subsets. Prevalence of the subset(s) of patients with sensitive disease or at risk for toxicity. Assay performance i.e sensitivity/specificity/predictive value. Specimens requirement Trial design to distinguish treatment and prognostic effects

18 Caveats for Assessing Treatment Effects in Biomarker Defined Groups Biomarker defines a subgroup with a different prognosis from historical outcome data from trials done in an unselected group E.g. ER+ is both prognostic and predictive If the outcome with standard treatment is not well defined and/or the outcome of interest is PFS/OS consider a randomized controlled phase 2 design If a trial is designed to assess treatment effects in Marker+ and/or Marker- groups False positives will dilute effect in marker+ group False negatives will dilute the apparent differences in treatment effect between marker defined groups. Specimen loss or assay failure will increase the sample size Trial may be 2-4x size of a conventional study

19 Biomarker Identification: Improving the numbers (and the odds of success) Multi-Stage-Phase 2 Trials Stage 1 Stage 2 Stage 3 Signal of activity Close if minimal level of activity not met Identify promising level of activity worth further evaluation Expand accrual of patients with samples to assess predictive biomarker(s) Evaluation Across Phase 2/3 Trials Trial 1 Trial 2 Combined analysis Trial 3

20 Challenges in Data Analysis & Interpretation Samples sizes (with available specimens) in single study generally too small for definitive marker analyses Many endpoints, markers, and subgroups might be examined Combining over different studies difficult Different patient populations Different assay methods Different sample collection/storage methods Identify relevant studies? Publication bias Description limited REMARK reporting guidelines (McShane et al, 2005: JNCI, NCPO) might help facilitate pooled analyses Some large prospective marker trials will be needed MINDACT Study TAILORx Study N0723 MARVEL Study Assay improvements to reduce noise in marker measurements

21 Determining Added Value A strong differential effect in marker defined patient groups in a trial DOES NOT equal a clinical useful test for making decisions for individual patients

22 Adding Value to Standard Clinical Predictors 1) Head to Head: Marker superior to clinical predictors at predicting outcome. 2) Incremental Improvement: Combination superior to clinical predictors alone. 3) Marker Predictive within Clinical Strata: e.g., HR(+, ) significant within age, tumour grade, tumour size groups. Slide courtesy of G Pennello, FDA

23 Relative Risk vs. Diagnostic Accuracy Marker Event by Time t E No E Relative Risk 3.0 = (30/60)/(10/60) Se 0.75 (30/40) Sp 0.63 (50/80) PPV 0.50 (30/60) NPV 0.83 (50/60) Relative Risk looks good, but Dx accuracy not great limited clinical utility? Example taken from Emir, Wieand, Su, Cha, Analysis of repeated markers used to predict progression of cancer Statist. Med., 17, , Slide courtesy of G Pennello, FDA

24 Hazard Ratio vs. Diagnostic Accuracy NCCTG Mayo Clinic Study. CA15-3 ratio as diagnostic for progression of breast cancer (as determined by physical exam). Hazard Ratio 2.3 (p = ) Se 0.30 (0.17,0.43) Sp 0.82 (0.74,0.89) PPV 0.27 (0.21,0.33) Example taken from Emir, Wieand, Su, Cha, Analysis of repeated markers used to predict progression of cancer Statist. Med., 17, , Slide courtesy of G Pennello, FDA

25 Diagnostic Performance Sensitivity Specificity (TP rate): (TN rate): FP rate: fraction of fraction of fraction of responders non-responders non-responders who test + who test who test + Test is useful if TP rate > FP rate, i.e., sensitivity + specificity > 1. EX. Useless test: sensitivity 0.80, specificity 0.20 Slide courtesy of G Pennello, FDA

26 Diagnostic Performance Positive Negative predictive predictive value (PPV): value (NPV): 1 NPV: fraction of fraction of fraction of test + s who test s who test s who respond don t respond respond Test is useful if PPV + NPV > 1 EX. Useless test: PPV 0.60, NPV 0.40 Slide courtesy of G Pennello, FDA

27 Biospecimen Collection in Clinical Research: Implications Compelling rationale BUT Increased burden on patients/clinical staff Significant coordination effort required Significant increased cost over traditional treatment trials Numbers of patients may be increased and cost/patient will increase Qualification, standardization and QA takes time, energy and money

28 Balance Biomarkers in Therapeutics Development - Considerations Strength of Hypothesis Availability and suitability of specimens Availability and suitability of the biomarker assay Sensitivity, precision, robustness Correlation to effect of interest Variability/heterogeneity effect Biologic, assay, drug effect, Resources available Patients, institutional, investigator, financial

29 Evolution of Biomarkers During Drug Preclinical evaluation of marker Discovery and Development Theoretical and experimental understanding of the disease pathophysiology and agent MOA Assay on biospecimens that can feasibly be collected in trial Preclinical evaluation of assay Epidemiological evidence Prevalence Prognostic sig. Prior clinical experience With agent class With marker Pre-registration Post-registration Phase 2 Trials Phase 3 Trials Meta-analyses Definitive Trials

30 Challenges/Opportunities Target Target Identification Identification and and Validation in Validation in Human Human Cancers Cancers Targeted Targeted Agent Agent Development Development and and Validation Validation Biomarker Development and Validation Coordination of these processes is critical

31 My Biases and Beliefs Clinical research (and life) is a series of compromises some of which are worth making and some of which are not. Science Feasibility Impact