Biomarkers emerging role, limitations and requirements (regulatory view point) K Prasad MHRA, UK / PGxWP Cardiologist (GSTT)

Transcription

1 Biomarkers emerging role, limitations and requirements (regulatory view point) K Prasad MHRA, UK / PGxWP Cardiologist (GSTT) 1

2 Aspects to discuss Types of BM Predictive vs Prognostic PK vs PD Safety vs Efficacy Single vs Multiple Data Characteristics Requirements Prospective vs Retrospective RCT vs others Sensitive vs specific High and low cut offs Validation vs Qualification 2

3 Commonly asked Questions Level of evidence required for a BM in regulatory terms? Are RCT s mandatory for BM?? (& diagnostic) When will retrospective data be acceptable? BMs as Surrogate end points diagnostic tests and their development 3

4 Limitations/ uncertainties for BMs; Represent an additional burden Need to establish the BM context. (Why, When and How should new replace old?) Define Sensitivity and Specificity Establish reliability and discriminatory ability Cut off points?! 4

5 Decision rules ( cut off points); difficult?!!! ALT or ALT +Bili for liver injury DRB1*07 and DQA1*02. For BMs that quantify physiological states or therapeutic resp, cut off points crucial; higher the better, lower values useful 5

6 Definitions Qualification. is a conclusion that the biomarker data submitted support use of the BM in drug discovery, drug development or post approval studies and where appropriate, in regulatory decision making ( ICH E-16). Validation;..establishing documented evidence that a process or system, when operated within established parameters, can perform effectively and reproducibly to produce a biomarker ( ± medicinal product), that meets its pre-determined specifications and quality attributes...validity. traditionally settled by debate, consensus and the passage of time ;..AAPS Journal,

7 Predictive Vs Prognostic PPV and NPV are influenced by prevalence of the marker rates in the population Enriched design study does not validate the marker or define its utility ( BM/Dis + vs BM/Dis- subjects ). E..g, Her-2 and trastuzumab and EGFR antibodies For Predictive markers regulatory oversight is crucial. Predictive values need to be generated in populations that reflect anticipated clinical use. May need complex trial designs 7

8 Retrospective data Often based on associations.. Inability to replicate the results Winner s Curse (first result is usually best) often -overestimation of Effect size underpowered FU studies (sample sizes) Phenotype heterogeneity.. Bias (various) 8

9 From Association a Predictive marker Assumption: neutropenia) Genotyping is 100% accurate for UGT1A1*28 allele (& thus Clinical Sensitivity Clinical Specificity P P V* N P V* I nnocenti Rouits Marcuello Ando Ov erall * P PV, positive predictive value; NPV, negative predictive value. Slide from FDA Website Balance neutropenia and efficacy in 7/7 positive patients: Dose reduction may be unnecessary for 50%, with unknown consequences 9

10 Retrospective data Could be similar to Blind man s buff (or bluff) Consider if, Or if retrospective analysis of prospectively defined relationship (exploratory). Retrospective analysis of retrospectively identified relationship Marker of safety Marker of efficacy 10

11 Abacavir Carbemazepine Warfarin Marker HLA-B*5701 HLA B* 1502 CYP 450 SNPs+ VKORC1 Discovery Retrospective Retrospective retrospective Confirmatory evidence Prospective study Retrospective Variable level Prospective study not feasible Replication Yes Yes ongoing Validity Clear evidence Clear evidence of harm Evidence of association Dosing alteration?? Utility Clear Clear Contradictory 11

12 Caveats for Retrospective data sets Data from Well conducted RCT Biological sample availability from all subjects or majority of the subjects ( from RCT) Prospectively stated hypothesis appropriate analysis plan Adequately powered study.. Replication 12

13 KRAS story owild type vs mutant KRAS, Impact on PFS; o Retrospective analysis; (prosp defined) Several Interesting issues; Prognostic or Predictive 2nd Renewal- suggested that use of Vectibix in mutated KRAS may be detrimental a Safety BM. Relationship with B RAS, NRAS, etc.. (??) De Rook W et al; Lancet oncol, 11:753-62,

14 Tests/ Companion diagnostics [in EU] Drug device or Drug test Not part of Pharmaceutical legislation Outside of remit of EMA/ many national agencies Medical Devices Directives / In Vitro Diagnostics (98/79/EC) Limited guidance from EMA possible Guidance on co development Guidance on methodological issues /clinical trial methods (Genomic markers) Cost/ HTA impact etc.. 14

15 Regulatory initiatives development of BMs/ PGx / Strat Med? Established BM qualification procedure; Guideline- EMA/.CHMP/72894/2009 Guideline on Evaluation of PGx in context of PK studies; EMA/CHMP/37646/2009 Development of regulatory guidance Reflection paper on Co development of diagnostics and drugs; EMA/CHMP/641298/2008 (released- 2 Q of 2010)- for review. Reflection paper on methodological issues associated with PG BM & Patient selection (Due for release soon) 15

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