mhra powerpoint template - european commission · k prasad/mhra 5/20/2011 7 ppv and npv are...

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5/20/2011K Prasad/MHRA 1

Biomarkersemerging role, limitations and

requirements (regulatory view point)

K Prasad

MHRA, UK / PGxWP

Cardiologist (GSTT)

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Aspects to discussTypes of BM Predictive vs Prognostic

PK vs PD

Safety vs Efficacy

Single vs Multiple

Data Prospective vs Retrospective

RCT vs others

Characteristics Sensitive vs specific

High and low cut offs

Requirements Validation vs Qualification

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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

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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?!

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Decision rules ( cut off points);

difficult?!!!

ALT or ALT +Bili for liver injury

www.fda.gov/ohrms/dockets/ac/04/briefing/

DRB1*07 and DQA1*02.

For BMs that quantify physiological states or therapeutic resp, cut

off points crucial; higher the better, lower values useful

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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) ”.

http://www.ema.europa.eu/pdfs/human/ich/38063609endraft.pdf

Definitions

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, 2007

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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

Predictive Vs Prognostic

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

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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)

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From Association a Predictive marker

Assumption: Genotyping is 100% accurate for UGT1A1*28 allele (& thus

neutropenia)

Clinical Sensitivity Clinical Specificity PPV* NPV*

Innocenti 0.5 0.94 0.5 0.94

Rouits 0.29 0.95 0.57 0.85

Marcuello 0.18 0.92 0.4 0.79

Ando 0.15 0.97 0.57 0.8

Overall 0.22 0.95 0.5 0.83

* PPV, positive predictive value; NPV, negative predictive value.

Balance neutropenia and efficacy in 7/7 positive patients:

Dose reduction may be unnecessary for 50%, with unknown consequences

Slide from

FDA Website

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Retrospective data

Consider if,

• retrospective analysis of prospectively defined relationship (exploratory).

• Retrospective analysis of retrospectively

identified relationship

Or if

• Marker of safety

• Marker of efficacy

Could be similar to Blind man’s buff (or bluff)

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Abacavir Carbemazepine Warfarin

Marker HLA-B*5701 HLA B* 1502 CYP 450 SNPs+ VKORC1

Discovery Retrospective Retrospective retrospective

Confirmatory

evidence

Prospective study Retrospective

Prospective study not

feasible

Variable level

Replication Yes Yes ongoing

Validity Clear evidence Clear evidence of harm Evidence of association

Dosing alteration??

Utility Clear Clear Contradictory

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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…

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KRAS storyoWild 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, 2010

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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..

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Regulatory initiatives development of BMs/ PGx / Strat Med?

Established BM qualification procedure;

Development of regulatory guidance

Reflection paper on Co development of

diagnostics and drugs;

EMA/CHMP/641298/2008

(released- 2 Q of 2010)- for review.

Guideline on Evaluation of PGx in context

of PK studies; EMA/CHMP/37646/2009

Reflection paper on methodological issues

associated with PG BM & Patient

selection (Due for release soon)

Guideline- EMA/.CHMP/72894/2009

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