roche molecular medicine laboratories biomarkers in personalized health care: opportunities,...

Roche Molecular Medicine Laboratories

Biomarkers in Personalized Health Care: Opportunities, Challenges, ApproachesKlaus Lindpaintner

Roche Molecular Medicine Laboratories

Case Report 1: Ms. Silvia R., 28

• Started on imipramine 25 mg tid

• No improvement 3 weeks later

• Dose increased to 50 mg tid

• No improvement 3 weeks later

• Switched to paroxetine 20 mg qd

• No improvement 3 weeks later

• One week later admitted to hospital in critical condition after attempted suicide

Depression

• Patient w/ pneumonia treated w/ antibiotics and w/ codeine for cough

• On treatment day 4 patient was found unresponsive

• Transfer into ICU, life support: intubation, respirator

• Supportive care was successful – patient recovered fully

Case report 2: Joon C., MD, 34Pneumonia

1997 Diagnosis: breast cancer Prognosis: 3 years to live

On her 55. birthday…

On January 12, 2006

Case Report 3: Ms. Regula SBreast Cancer

Case Report 4: Patient #45

Day 15Baseline

Metastatic malignant melanoma

Proper treatments – improper dose

• Gene test for CYP450-2D6, indicates ultra-rapid variant in both patients

• Resulting in

• Ineffective dose in case 1

• Effective overdose in case 2

Drug metabolism Inherited differences affect drug effects

Pro-drug activation Same principle – turned on its head

Ineffective

Adverse events

nl HER2

HER2

Personalized Approach to the patientExample: breast cancer, Herceptin®

Breast cancer facts: 700,000 new cases in Europe and the US -- 200,000 deaths One in 10 women will contract breast cancer in her life-time

Breast cancer facts, updated: 2/3 of all patients: 7 years survival 1/3 of all patients: 3 years survival

growth factor Her2 - growth factor Her2 +

Diagnosis for Ms Regula S.:

(1) Biopsy: + (2) HerCep-Test: + Herceptin® therapy initiated

BRAF KinaseAn Important Mediator of Cellular Proliferation

MembraneRTK

Y-PY-P Ras GTP

Other Effectors

Growth Factors

RAF

MEK

ERK

P

P

Nuclear TranslocationGene Expression

BRAFV600E

MEK

ERK

P

P

Abnormal CellularProliferation

Normal signaling

Oncogenic signaling

Arrested

Personalized health careTwo fundamentally different concepts, one consequence• Genetic Concept – Archibald Garrod, (sulphonal-induced

porphyria)– Molecular variant is immaterial to disease– Inherited susceptibilities to xenobiotics (drugs, nutrients)– Generally affects pharmacokinetics– Static– Example; CyP450, UGT

• Molecular Concept – Disease Cause-Effect Targeting– Molecular variant fundamentally important to disease pathology– “rewriting the textbook of medicine” based on molecular

understanding– Generally affects pharmacodynamics, causation-driven treatments– Dynamic– Example: Her2, BRAF

Case Report 5: State of the PharmacopoeiaA call for more effective and safer drugs

1 Spears et al., Trends Mol Med, 2001; 2 Lazarou et al., JAMA, 1998

Drug Response Rate, %

An

alg

esic

s

0

20

40

60

80

Can

cer

Efficacy Safety

Case Report 6: NME track recordStep-change needed in pharmaceuticals development

Sources: FDA/CDER Data, PhRMA data, Price Waterhouse Coopers analysis, Pharma 2020

R&D spend

New Molecular Entities (NME)$ 47 bn

$ 17 bn 17

53

1996 2007

Case report 7: New technologiesExpanding our understanding of diseases

IHC/ISH

BenchmarkMicroarrayanalysis

AmpliChip Sequencing

Real-time PCR

TaqMan

Multiplexproteins

Impact

Elecsys

ELISA

Healthcare Pressures:

Benefit-Risk Ratio

Economic Pressures:

Benefit-Cost Ratio

New Technologies:

Expanded Capabilities

Need for highly differentiated medicinesthat have a clear impact on individual and public health

Only truly innovative medicines will find acceptance

Innovative ~ Personalized

PHC as Key Driver of Change Key to enabling highly differentiated medicines

Messages: Personalized Healthcare

• Essential to progress in individual patient care

• Conceptually nothing new

• Requires thoughtful, differentiated consideration:Context and Information Content

Personalized Healthcare

•General considerations

•Qualification and Utility of Biomarkers

•Study Design Considerations

•Economical and Ethical Considerations

Opportunities & Challenges

Personalized Healthcare

•General considerations

•Qualification and Utility of Biomarkers

•Study Design Considerations

•Economical and Ethical Considerations

Opportunities & Challenges

Personalized Health CareA definition

Discovery and development of pharmaceuticals and diagnostics that better account for human variation and for the diverse molecular basis of disease.

Use of biomarkers expected to be critical to facilitate this differentiation.

Personalized Medicine, Biomarkers Pharmacogenetics:An altogether new concept??

• Finding the optimal treatment for every patient is as old as medicine: differential diagnosis

• 530 BC: Pythagoras observes that some peopletolerate the ingestion of fava-beans, others not

1960 AD: glucose-6-phosphate-dehydrogenase deficiency recognized as the cause

1990 AD: SNPs in the G6PD gene characterized

• Tailoring treatments to drug-specific test results is nothing new. Example: antibiotics

– Gram-positive bacteria: e.g. penicillin derivatives– Gram-negative bacteria: e.g. aminoglycosides– M. tuberculosis: isoniazid/rifampin/pyrazinamide

Biomarkers and Personalized Health CareWhat is new – and why now?

• Since~1980: Availability of powerful, highly parallel new screening methods (omics) makes hypothesis-free search for new biomarkers and for new treatment approaches a reasonable proposition.

• Since ~2000: Paradigm shift(?): maturation of these basic cell and molecular biology tools makes them newly applicable to later-stage R&D and clinical practice as robust, reliable diagnostics

Translation of extant, older as well as newly emerging knowledge into clinical practice

Complexity of ScienceA biomarker might be more difficult to find than a drug

Biomarker = Any biological parameter used as indicator of disease process or drug response

Potentially valuable

Early stage assessment

1

10’s

100’s

1000’s biomarkers

Clinical use

Exploratory

Biomarker Development – RequirementsSignificant hurdles

Generation of a biomarker hypothesis

Develop prototype assay

Identification of candidate markers

Discovery Clinical validation of candidate markers using assay

Assay refinement & development IVD test

Regulatory test approval

Validation Distribution to laboratories

Auditing for result consistency

CommercialisationClinician/Lab education

Confirmatory Phase

Dx launch/ Post-launch assessment

Biomarker development

Making PHC happenA complex undertaking

Target Selectio

n

Exploratory PhaseDiscove

ryPhase

Research

Companion diagnosticfeasibility & attractiveness

Tailored prescribing & monitoring

Target identification

Patient selection

Research assay Technically validated assayClinically validated IVD assay

Develop CommercialiseLead

Generation/

Optimisation

Phase 0 Phase I Phase II Phase III FilingMarket

Phase IV

PoC

Personalized Healthcare

•General considerations

•Qualification and Utility of Biomarkers

•Study Design Considerations

•Economical and Ethical Considerations

Opportunities & Challenges

“Responders”, “Non-Responders” Reality Check

0

10

20

30

40

50

60

70

80

resp

on

se (

%)

individual patients

31%

0

10

20

30

40

50

60

70

80

resp

on

se (

%)

individual patients

43%

22%

Regulatory agency benchmark: 35% improvement/response (hypothetical)

AN

Biomarker test performance, qualificationDiverse considerations

• Analytical performance: QC and accreditation of labs

• Clinical validity: retrospective/observation studies

• Clinical utility: prospective intervention trials

• Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

Biomarker test performance, qualificationDiverse considerations

• Analytical performance: QC and accreditation of labs

• Clinical validity: retrospective/observation studies

• Clinical utility: prospective intervention trials

• Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

Analytical performance… not a foregone conclusion

Biomarker test performance, qualificationDiverse considerations

• Analytical performance: QC and accreditation of labs

• Clinical validity: retrospective/observation studies

• Clinical utility: prospective intervention trials

• Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

Study DesignJustifying the (implicit) conclusions?

Patients and MethodsChemotherapy-naive patients with advanced NSCLC with 1 clinical characteristic associatedwith EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate.ConclusionsFirst-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

Biomarker test performance, qualificationDiverse considerations

• Analytical performance: QC and accreditation of labs

• Clinical validity: Proper study design essential retrospective/observation studies

• Clinical utility: prospective intervention trials

• Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

labeled DNA target

Oligonucleotide probe

** **

*

The Roche CYP450 AmplichipPioneering technology and the challenge of clinical utility• Broad allelic coverage of known

variants, for many ethnic groups(CYP2D6 and CYP2C19)

• Introduced micro-array technology to diagnostics

• CE, FDA Certified – first-in-class device

• Analytical Performance (new gold standard) Clinical Validity Clinical Utility (psychiatry, CVD): t. b. d.

Ultimately: need to demonstrate incremental cost-effectiveness ratio acceptable to payers a new era of “ph III studies” in Dx

Context: Tamoxifen and CYP450 2D6Testing prior to treatment?

N-desmethyl-tamoxifen (NDM)

Tamoxifen

CYP3A4/5

4-hydroxy-N-desmethyl-tamoxifen (endoxifen) CYP2D6

Personalized Healthcare

•General considerations

•Qualification and Utility of Biomarkers

•Study Design Considerations

•Economical and Ethical Considerations

Opportunities & Challenges

Study Design Considerations (1) Context: Nature of illness, aim of marker“Biomarker Target Product Profile: First, do no

harm!”

• Serious (life-threatening) illnessDefault: ”don’t withhold in error”; If in doubt: “treat”

• Less serious illnessDefault: “don’t treat in error”; If in doubt: “don’t treat”

Biomarker Target Product Profile

Efficacy marker: High sensitivity

Safety marker: High specificity

Efficacy marker: High specificity

Safety marker: High sensitivity

Less serious illness: don’t prescribe inappropriately

Serious illness: don’t withhold inappropriately

Determined by Context and Information Content

Study Design Considerations (2)

• 2 fundamentally different Objectives– Advancing fundamental understanding, but clinically not

necessarily actionable “p-value”-driven

– Finding clinically actionable biomarkers: information content in given context! “magnitude-of-effect”-driven; p essential but not sufficient

• Indication• Efficacy vs. Safety• Phase of trial

• Effects on Study Design:– Type of specimens – Number of specimens

Defining the Target Product Profile – Controlling Costs – Debunking Myths

Lost in Translation

OR = 1.5

OR =1.15

OR = 9

sens/spec = 55%

sens/spec = 51%

sens/spec = 75%

Different scientific terminologies in research and clinic

Lost in Translation

Posit: significance 0.05, power 85%

Different scientific terminologies in research and clinic

Lost in Translation

n = 936

n = 7456

n = 42

Different scientific terminologies in research and clinic Consequences:

OR = 1.5

OR =1.15

OR = 9

sens/spec = 55%

sens/spec = 51%

sens/spec = 75%

Personalized Healthcare

•General considerations

•Qualification and Utility of Biomarkers

•Study Design Considerations

•Economical and Ethical Considerations

Opportunities & Challenges

Personalized Medicine – Challenges

• Economic

“Exhaustive pharmacogenetic research efforts have narrowed your niche market down

to Harry Finkelstein of Newburg Heights here.”

Economics of stratification drive PHC Creating patient benefits and commercial incentives

Unstratified Medicine

Stratified Medicine

Reduced

Eligible

Patient

Population

Patient benefit:

• Optimal efficacy

• Avoid unnecessary treatment / side effects

• Decreased uncertainty

•Penetration

•Market share

•Duration of therapy

•Adherence

•Line extensions

Economics of stratification drive PHC Creating patient benefits and commercial incentives

Unstratified Medicine

Stratified Medicine

Reduced

Eligible

Patient

Population

Payer Acceptance

The Tightening Reimbursement ClimateBiomarker strategies may be essential

Strategy Incr. Cost UK £

Incr Cost/QUALY

UK £ No test Chemo-Rx alone

26,919 21,030

Positive HerCep Test Chemo-Rx and Herceptin

33,376 24,541

No test Chemo-Rx and Herceptin

49,211 35,920

Elkin et al; J Clin Oncol 2004; 22:854 ff

($/£ conv. rate 1/1/2003, not PPP-adjusted)

NB: National Institute for Clinical Excellence’s (NICE) threshold for approving reimbursement through NHS believed to be ~UK £ 30,000 per QUALY (quality-adjusted life year)

Biomarker AdoptionEvidence counts

Results: In the base case, genotype-guided dosing resulted in better

outcomes, but at a relatively high cost. Overall, the marginal

cost-effectiveness of testing exceeded $170 000 per QALY…

A friendly nudge…

Ethical, Legal, Societal ConsiderationsDo we need to reinvent the wheel?•Autonomy: privacy and respect

•Confidentiality– Patient protection more important

than data protection – GINA – Information content, not type counts:

counter “genetic exceptionalism”

•Beneficence: do good

•No Maleficence: don’t do harm

Biomarkers - Personalized MedicineSummary

• Conceptually nothing new – nothing to be afraid of!

• Essential to progress in individual patient care– Only more differentiated understanding of patients/disease will allow

progress in health care

• Requires thoughtful, differentiated consideration– Avoid black-and-white thinking:

complex disease pathology is complex – context counts– High demand on information-content of test:

Evidence-based implementation– Essential: create win-win scenarios with payers– Not a panacea: we will not always find a biomarker,

but we must always try.

• Motto: Robust (aggressive?) optimism – paired w/ realism and modesty!

No 1-on-1 custom tailoring, but towards a much better fit …

38 4039 39½ 373/4

Remember: All medical decisions/knowledge are based on group-derived (aggregate) data analysis – “individual”data are anecdotal and cannot be validated.

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