Introduction to Introduction to Design of Genomic Design of Genomic

Clinical TrialsClinical TrialsRichard Simon, D.Sc.Richard Simon, D.Sc.

Chief, Biometric Research BranchChief, Biometric Research BranchNational Cancer InstituteNational Cancer Institutehttp://brb.nci.nih.govhttp://brb.nci.nih.gov

Biometric Research Branch Biometric Research Branch WebsiteWebsite

brb.nci.nih.govbrb.nci.nih.gov

Powerpoint presentationsPowerpoint presentations Reprints & Technical ReportsReprints & Technical Reports BRB-ArrayTools softwareBRB-ArrayTools software Web based Sample Size Planning Web based Sample Size Planning

OutlineOutline IntroductionIntroduction

BiomarkersBiomarkers ValidationValidation

Targeted enrichment designTargeted enrichment design Stratification designsStratification designs Prospective-Retrospective DesignsProspective-Retrospective Designs Prognostic biomarkersPrognostic biomarkers Clinical Trial Designs with adaptive Clinical Trial Designs with adaptive

identification of indication for treatmentidentification of indication for treatment Development and Validation of Classifiers Development and Validation of Classifiers

with High Dimensional Datawith High Dimensional Data

Different Kinds of Different Kinds of BiomarkersBiomarkers

Endpoint biomarkerEndpoint biomarker A measurement made on a patient before, during and after A measurement made on a patient before, during and after

treatment to determine whether the treatment is workingtreatment to determine whether the treatment is working Surrogate endpointSurrogate endpoint PharmacodynamicPharmacodynamic Intermediate endpointIntermediate endpoint

Prognostic biomarkersPrognostic biomarkers Measured before treatment to indicate long-term outcome for Measured before treatment to indicate long-term outcome for

patients untreated or receiving standard treatmentpatients untreated or receiving standard treatment Single arm study of patients receiving a particular rx can identify Single arm study of patients receiving a particular rx can identify

patients with good prognosis on that rxpatients with good prognosis on that rx Those patients may not benefit from that rx but they don’t need additional rxThose patients may not benefit from that rx but they don’t need additional rx

Predictive biomarkersPredictive biomarkers Measured before treatment to identify who will benefit from a Measured before treatment to identify who will benefit from a

particular treatmentparticular treatment Single arm study with response endpointSingle arm study with response endpoint RCT with survival or dfs endpointRCT with survival or dfs endpoint

Cardiac Arrhythmia Cardiac Arrhythmia Supression TrialSupression Trial

Ventricular premature beats was Ventricular premature beats was proposed as a surrogate for survivalproposed as a surrogate for survival

Antiarrythmic drugs supressed Antiarrythmic drugs supressed ventricular premature beats but ventricular premature beats but killed patients at approximately 2.5 killed patients at approximately 2.5 times that of placebotimes that of placebo

Surrogate EndpointsSurrogate Endpoints

It is extremely difficult to properly validate a It is extremely difficult to properly validate a biomarker as a surrogate for clinical outcome.biomarker as a surrogate for clinical outcome.

It is not sufficient to demonstrate that the surrogate It is not sufficient to demonstrate that the surrogate is correlated with clinical outcomeis correlated with clinical outcome That responders live longer than non-responders does not That responders live longer than non-responders does not

establish response as a valid surrogate endpoint establish response as a valid surrogate endpoint Proper validation requires a series of randomized Proper validation requires a series of randomized

trials with both the candidate biomarker and trials with both the candidate biomarker and clinical outcome measuredclinical outcome measured Demonstrate that differences between randomized Demonstrate that differences between randomized

treatment arm with regard to the candidate surrogate are treatment arm with regard to the candidate surrogate are consistent with differences with regard to clinical outcomeconsistent with differences with regard to clinical outcome

It is often more difficult and time It is often more difficult and time consuming to properly “validate” an consuming to properly “validate” an endpoint as a surrogate than to use the endpoint as a surrogate than to use the clinical endpoint in phase III trialsclinical endpoint in phase III trials

Using Intermediate Endpoints Not Using Intermediate Endpoints Not Established as Surrogates of Established as Surrogates of

Clinical BenefitClinical Benefit Biomarkers can be useful in phase I/II studies as Biomarkers can be useful in phase I/II studies as

measures of treatment effectmeasures of treatment effect they need not be validated as surrogates for clinical they need not be validated as surrogates for clinical

benefitbenefit Unvalidated surrogates can also be used for Unvalidated surrogates can also be used for

interim “futility analyses” of phase III trials (e.g. interim “futility analyses” of phase III trials (e.g. seamless phase II/III). The trial should continue seamless phase II/III). The trial should continue accrual and follow-up to evaluate true endpoint if accrual and follow-up to evaluate true endpoint if treatment effect on biomarker is sufficienttreatment effect on biomarker is sufficient Conditional surrogate endpointsConditional surrogate endpoints

Can be used for developing predictive biomarkers Can be used for developing predictive biomarkers in phase II studies or in adaptive signature in phase II studies or in adaptive signature designsdesigns

Prognostic & Predictive Prognostic & Predictive BiomarkersBiomarkers

Many cancer treatments benefit only a minority Many cancer treatments benefit only a minority of patients to whom they are administeredof patients to whom they are administered Particularly true for molecularly targeted drugsParticularly true for molecularly targeted drugs

Being able to predict which patients are likely to Being able to predict which patients are likely to benefit would benefit would save patients from unnecessary toxicity, and enhance save patients from unnecessary toxicity, and enhance

their chance of receiving a drug that helps themtheir chance of receiving a drug that helps them Help control medical costs Help control medical costs Improve the success rate of clinical drug developmentImprove the success rate of clinical drug development

Prognostic and Predictive Prognostic and Predictive Biomarkers in OncologyBiomarkers in Oncology

Single gene or protein measurementSingle gene or protein measurement e.g. HER2 protein staining 2+ or 3+e.g. HER2 protein staining 2+ or 3+ HER2 amplificationHER2 amplification KRAS mutationKRAS mutation

Scalar index or classifier that Scalar index or classifier that summarizes contributions of multiple summarizes contributions of multiple genes/proteinsgenes/proteins Empirically determined based on genome-Empirically determined based on genome-

wide correlating gene expression to wide correlating gene expression to patient outcome after treatmentpatient outcome after treatment

Prognostic Factors in OncologyPrognostic Factors in Oncology

Most prognostic factors are not used Most prognostic factors are not used because they are not therapeutically because they are not therapeutically relevantrelevant

Most prognostic factor studies do Most prognostic factor studies do not have a clear medical objectivenot have a clear medical objective They use a convenience sample of They use a convenience sample of

patients for whom tissue is available. patients for whom tissue is available. Generally the patients are too Generally the patients are too

heterogeneous to support heterogeneous to support therapeutically relevant conclusionstherapeutically relevant conclusions

Pusztai et al. The Oncologist 8:252-8, Pusztai et al. The Oncologist 8:252-8, 20032003

939 articles on “prognostic markers” or 939 articles on “prognostic markers” or “prognostic factors” in breast cancer in “prognostic factors” in breast cancer in past 20 yearspast 20 years

ASCO guidelines only recommend routine ASCO guidelines only recommend routine testing for ER, PR and HER-2 in breast testing for ER, PR and HER-2 in breast cancercancer

““With the exception of ER or progesterone With the exception of ER or progesterone receptor expression and HER-2 gene receptor expression and HER-2 gene amplification, there are no clinically amplification, there are no clinically useful molecular predictors of response to useful molecular predictors of response to any form of anticancer therapy.”any form of anticancer therapy.”

Prognostic Biomarkers Can Prognostic Biomarkers Can be Therapeutically Relevantbe Therapeutically Relevant

<10% of node negative ER+ breast <10% of node negative ER+ breast cancer patients require or benefit cancer patients require or benefit from the cytotoxic chemotherapy from the cytotoxic chemotherapy that they receivethat they receive

OncotypeDxOncotypeDx 21 gene RTPCR assay for FFPE tissue21 gene RTPCR assay for FFPE tissue

Key Features of OncotypeDx Key Features of OncotypeDx DevelopmentDevelopment

Identification of important therapeutic decision Identification of important therapeutic decision contextcontext

Prognostic marker development was based on Prognostic marker development was based on patients with node negative ER positive breast cancer patients with node negative ER positive breast cancer receiving tamoxifen as only systemic treatmentreceiving tamoxifen as only systemic treatment Use of patients in NSABP clinical trialsUse of patients in NSABP clinical trials

Staged development and validationStaged development and validation Separation of data used for test development from data used Separation of data used for test development from data used

for test validationfor test validation Development of robust assay with rigorous analytical Development of robust assay with rigorous analytical

validationvalidation 21 gene RTPCR assay for FFPE tissue21 gene RTPCR assay for FFPE tissue Quality assurance by single reference laboratory operationQuality assurance by single reference laboratory operation

B-14 Results—Relapse-Free B-14 Results—Relapse-Free SurvivalSurvival

338 pts

149 pts

181 pts

0 2 4 6 8 10 12 14 16Time (yrs)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Relapse-Free Survival

Low R isk (RS < 18) In termediate R isk (R S 18 - 30) H igh R isk (RS 31)

p<0.0001

Paik et al, SABCS 2003

Predictive BiomarkersPredictive Biomarkers In the past often studied as un-In the past often studied as un-

focused post-hoc subset analyses of focused post-hoc subset analyses of RCTs.RCTs. Numerous subsets examinedNumerous subsets examined Same data used to define subsets for Same data used to define subsets for

analysis and for comparing treatments analysis and for comparing treatments within subsetswithin subsets

No control of type I errorNo control of type I error

Statisticians have taught physicians Statisticians have taught physicians not to trust subset analysis unless the not to trust subset analysis unless the overall treatment effect is significantoverall treatment effect is significant This was good advice for post-hoc data This was good advice for post-hoc data

dredging subset analysisdredging subset analysis For many molecularly targeted cancer For many molecularly targeted cancer

being developed, the subset analysis will being developed, the subset analysis will be an essential component of the primary be an essential component of the primary analysis and analysis of the subsets will analysis and analysis of the subsets will not be contingent on demonstrating that not be contingent on demonstrating that the overall effect is significantthe overall effect is significant

MutationsCopy number changes

TranslocationsExpression profile

Treatment

Types of Validation for Types of Validation for Prognostic and Predictive Prognostic and Predictive

BiomarkersBiomarkers Analytical validationAnalytical validation

Pre-analytical and post-analytical Pre-analytical and post-analytical robustnessrobustness

Clinical validationClinical validation Does the biomarker predict what it’s Does the biomarker predict what it’s

supposed to predict for independent datasupposed to predict for independent data Clinical utilityClinical utility

Does use of the biomarker result in Does use of the biomarker result in patient benefitpatient benefit

Clinical UtilityClinical Utility Benefits patient by improving Benefits patient by improving

treatment decisionstreatment decisions Depends on context of use of the Depends on context of use of the

biomarkerbiomarker Treatment options and practice Treatment options and practice

guidelinesguidelines Other prognostic factorsOther prognostic factors

Clinical Utility of Clinical Utility of Prognostic BiomarkerPrognostic Biomarker

Prognostic biomarker for identifying patientsPrognostic biomarker for identifying patients for whom practice standards imply cytotoxic for whom practice standards imply cytotoxic

chemotherapychemotherapy who have good prognosis without chemotherapywho have good prognosis without chemotherapy

Prospective trial to identify such patients Prospective trial to identify such patients and withhold chemotherapyand withhold chemotherapy

TAILORxTAILORx ““Prospective plan” for analysis of archived Prospective plan” for analysis of archived

specimens from previous clinical trial in specimens from previous clinical trial in which patients did not receive chemotherapywhich patients did not receive chemotherapy OncotypeDx OncotypeDx

Marker Strategy DesignMarker Strategy Design

MINDACT DesignMINDACT Design

Clinical Utility of Predictive Clinical Utility of Predictive BiomarkerBiomarker

Predictive biomarker for identifying the Predictive biomarker for identifying the patients who benefit from a specific patients who benefit from a specific regimen and/or the patients who do notregimen and/or the patients who do not

Prospective RCT of new regimen versus Prospective RCT of new regimen versus control with tissue prospectively collected control with tissue prospectively collected and assayed and patients classified as test and assayed and patients classified as test + or test – + or test – Sample size established to have enough test + Sample size established to have enough test +

patients for separate analysis of new regimen patients for separate analysis of new regimen versus control and enough test – patients for versus control and enough test – patients for separate analysis of new regimen versus controlseparate analysis of new regimen versus control

Focused analysis on a single completely Focused analysis on a single completely prospectively defined biomarker classifierprospectively defined biomarker classifier

Prospective Co-Prospective Co-Development of Drugs and Development of Drugs and

Companion DiagnosticsCompanion Diagnostics1.1. Develop a completely specified genomic Develop a completely specified genomic

classifier of the patients likely to benefit from classifier of the patients likely to benefit from a new druga new drug

• Single gene/proteinSingle gene/protein• Gene expression signatureGene expression signature

• Screen genes using microarraysScreen genes using microarrays• Develop classifier for RT-PCR platformDevelop classifier for RT-PCR platform

• Pre-clinical, phase II data, archived specimens from Pre-clinical, phase II data, archived specimens from previous phase III studiesprevious phase III studies

2.2. Establish analytical validity of the classifierEstablish analytical validity of the classifier3.3. Use the completely specified classifier to Use the completely specified classifier to

design and analyze a new clinical trial to design and analyze a new clinical trial to evaluate effectiveness of the new treatment evaluate effectiveness of the new treatment with a pre-defined analysis plan that preserves with a pre-defined analysis plan that preserves the overall type-I error of the study.the overall type-I error of the study.

Guiding PrincipleGuiding Principle The data used to develop the classifier The data used to develop the classifier

should be distinct from the data used to should be distinct from the data used to test hypotheses about treatment effect test hypotheses about treatment effect in subsets determined by the classifierin subsets determined by the classifier Developmental studies can be exploratoryDevelopmental studies can be exploratory Studies on which treatment effectiveness Studies on which treatment effectiveness

claims are to be based should be definitive claims are to be based should be definitive studies that test a treatment hypothesis in studies that test a treatment hypothesis in a patient population completely pre-a patient population completely pre-specified by the classifierspecified by the classifier

New Drug Developmental New Drug Developmental Strategy I Strategy I

Restrict entry to the phase III trial based Restrict entry to the phase III trial based on the binary predictive classifier, i.e. on the binary predictive classifier, i.e. targeted designtargeted design

Using phase II data, develop predictor of response to new drugDevelop Predictor of Response to New Drug

Patient Predicted Responsive

New Drug Control

Patient Predicted Non-Responsive

Off Study

Developmental Strategy (II)Developmental Strategy (II)

Develop Predictor of Response to New Rx

Predicted Non-responsive to New Rx

Predicted ResponsiveTo New Rx

ControlNew RX Control

New RX