Methodological issues ( som e) relating to patient selection- CHMP - - PowerPoint PPT Presentation

Sc Scienc ience to Clinic workshop; Oc e to Clinic workshop; Oct 2012 t 2012

Methodological issues ( som e) relating to patient selection-

CHMP Reflection paper

K Prasad, MD, FRCP MHRA

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012

Overview

• Background
• Personalised medicine and Regulation
• Why do we need a Guidance /RP?
• So what does the paper say?
• What next?

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012

Biomarkers, patients and Regulation

BMs

• repres

represent an additional test burden nt an additional test burden

• Need qualificatio

Need qualification and validatio n and validation

• Need context of the

Need context of the BM. BM.

(Why, When and How to replace ‘old’ Why, When and How to replace ‘old’ with ) ith ) “new” “new” ? ?

• Need ‘reliability’

Need ‘reliability’ and nd ‘discriminatory ability’ ‘discriminatory ability’

• Need cut off points?!

Need cut off points?!

Com m only asked Questions

• How do we qualify/ validate the

How do we qualify/ validate the marker marker

• Level of evidence required for a

Level of evidence required for a BM/PGBM in regul BM/PGBM in regulatory te tory terms? rms?

• Are RCT’s

Are RCT’s mandatory andatory for BM ?? for BM ??

• When will retrospective data be

When will retrospective data be acceptable? acceptable?

• BMs as Surrogate end points

BMs as Surrogate end points

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Regulatory Objective! Regulatory Objective!

…. ….to enable Safe Safe and Effective Effective use of the medicinal product i.e., i.e., influence clinical practice

influence clinical practice

Evaluation & recommendations need to be Evaluation & recommendations need to be Evaluation & recommendations need to be Evaluation & recommendations need to be

• Scientifically robust
• Clinically relevant
• Practical to implement

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Predictive biomarker T

C

Predic tive effect

T C

Survival probability

Survival time

Blue Line --Marker (–) Blue Line --Marker (–) Red Red Line --Marker (+) Line --Marker (+)

C C TT Survival probability Survival time

No biomarker effect

W hat are w e need w ith BMs

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Genomic BMs, scope of inclusion in labelling.

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Reflection Paper

Aims;

• to identify products where genomic biomarkers influenced the development
• r raised questions
• to identify and streamline regulatory expectations
• to discuss the CHMP experience and concerns

Scope; Restricted mainly to centralised MAAs and other major safety issues discussed at CHMP relating to genomic biomarkers So; It is not a detailed review It is not a detailed review of literature on method

• f literature on methodologies of genomi
• logies of genomic m

c marker arker application application

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012

Clinical Trial Designs ( 1 ) Clinical Trial Designs ( 1 )

Such a design may be Such a design may be adopted if the results of the adopted if the results of the testing will not be readily testing will not be readily available at the clinical sites available at the clinical sites for informing randomisation for informing randomisation

Placebo Drug

May test all or some ALL subjects Interac Interaction n analysis between analysis between treatment and test treatment and test

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Importance of samples/ BM data from Importance of samples/ BM data from majority of subjects in a CT majority of subjects in a CT

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KRAS story

• Wild type v

Wild type vs mutant KRAS tant KRAS, I , Impa pact on ct on PFS; PFS;

• Retrospective analysis; (prosp

Retrospective analysis; (prosp defined) defined)

Several Interesting issues; Several Interesting issues;

• Prognostic or Predictive

Prognostic or Predictive

• 2nd Renewal-

2nd Renewal- suggested that

suggested that use use

• f
• f Vectibix in mutated KRAS may be

Vectibix in mutated KRAS may be detrimental detrimental –a marker of safety.

a marker of safety.

• Relationship with B RAF,

Relationship with B RAF, NRAS, NRAS, Not defined Not defined De Rook W et al; De Rook W et al; Lancet oncol, 11:753-62, 2010 Lancet oncol, 11:753-62, 2010

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012

Test + Test -

ALL tested ALL tested ALL subjects ALL subjects

Drug Placebo

Drugs would be integrally Drugs would be integrally linked with availability and linked with availability and use of the biomarker test at use of the biomarker test at the time of approval. the time of approval. No information on No information on efficacy or safety efficacy or safety

Clinical Trial Designs ( 2 ) Clinical Trial Designs ( 2 )

Enriched or targeted design Enriched or targeted design Enriched or targeted design Enriched or targeted design

12

Do we need marker –ve subjects??

Breast cancer and Herceptin

• ~ 30% of all Br Ca are Her-2 (+)
• IHC staining 1+ to 3 + is not infallible
• (~20% discordance between CTA & test)
• Reports of response in Her (-) ve

subjects?

Vem urafenib in m elanom a BM+ or negative BM+ or negative freq frequency is not ency is not such an issue such an issue

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Marker by RX- I nteraction Design

MARVEL Trial-- erlotinib

Answ ers lim itations of unselected or enriched designs; but impacts sample size and expense..

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Observations on Trial designs

 Predictive values need to be generated in

populations that reflect anticipated clinical use.

 Enriched design often does not validate the

marker (!) or define its utility in the broad population.

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Abacavir Abacavir Carbemazepine Carbemazepine Warfarin Warfarin

Marker Marker HLA-B*5701 HLA B* 1502 CYP 450 SNPs+ VKORC1 Discove Discovery Retrospective Retrospective Retrospective Confirmatory Confirmatory evidence evidence Prospective Prospective study study Retrospective Retrospective Prospective study Prospective study not feasible not feasible Variable Variable Replication Replication Yes Yes

• ngoing

Validity Validity Clear evidence Clear evidence of harm Evidence of association Dosing alteration?? Utility Utility Clear Clear Clear Clear Contradictory Contradictory

Safety m arkers and clinical trials

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Population and predictive ability;

recent exam ple

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Population and predictive ability;

‘Old’ exam ple

Predictive ability in a particular population will be event/ incidence dependent. Rarer the event, more difficult to establish evidence.

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Retrospective data/ analyses

 Often based on associations.. Inability to replicate the results

• Winner’s Curse

Winner’s Curse (first result is usually best)

• often -overestimation of Effect size
• underpowered FU studies (sample sizes)
• Phenotype heterogeneity..

 Bias (various)

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Caveats for Retrospective data analysis

• Ideally, data from well conducted RCT
• Biological sample or BM status availability from

all or majority of the subjects (from RCT)

• Prospectively stated hypothesis & appropriate

analysis plan

• Replication
• Biological plausibility &
• difference between BM+ vs BM- is clear

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012

Experience at CHMP:

A Number of open questions

• When is a RCT mandatory?
• Is retrospective identification

and validation BM acceptable?

• Are BM (-) patients be required

in trials ?

• Can we use Adaptive designs??

Can we use Adaptive designs?? Answers (May be !?)

• Most of the time (

Most of the time ( alm

almost st everyt everytim ime)

• Yes –depends on the

Yes –depends on the circumstances circumstances.

• Clearly situation dependent

Clearly situation dependent ‘A lot of post-hoc analyses’ and

“Pharm acoepi-PGx” experience is lim ited

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012

Adaptive designs

Sc Scienc ience to Clinic workshop; London Oc e to Clinic workshop; London Oct 2012 t 2012