Biomarkers and Surrogate Biomarkers and Surrogate

Endpoints in Drug DevelopmentEndpoints in Drug Development Technical and Regulatory ConsiderationsTechnical and Regulatory Considerations

  

Gracie Lieberman,Gracie Lieberman,GenentechGenentech2006 FDA/Industry Workshop

ContentContentChanging landscapeChanging landscapeEfficacy surrogate endpoints used for Efficacy surrogate endpoints used for approval – case studiesapproval – case studies– HerceptinHerceptin– IressaIressa

Surrogate endpoints in proof of concept Surrogate endpoints in proof of concept trials trials – Selecting sub-populationSelecting sub-population– Selecting doseSelecting dose

Role of mechanism-based biomarkers Role of mechanism-based biomarkers – PET studies in cancerPET studies in cancer

Changing landscapeChanging landscapeIn the past 15-20 years:In the past 15-20 years:– Better molecular understanding of diseasesBetter molecular understanding of diseases– Earlier, more precise diagnosisEarlier, more precise diagnosis– New targeted, improved therapiesNew targeted, improved therapies

Impact on clinical trialsImpact on clinical trials– Assessment of improvements in clinically meaningful endpoints Assessment of improvements in clinically meaningful endpoints

require enrolling many patients and then following them for a require enrolling many patients and then following them for a long time.  long time. 

Emerging needEmerging need– Develop strategies for reducing the time and cost of drug Develop strategies for reducing the time and cost of drug

development.  development.  – Use of surrogate endpoints either in proof-of-concept or label-Use of surrogate endpoints either in proof-of-concept or label-

enabling trials. enabling trials. Defined in clinical practice and used by clinicians to monitor and Defined in clinical practice and used by clinicians to monitor and treat patientstreat patientsNew mechanism-driven biomarkers New mechanism-driven biomarkers

Endpoint considerationsEndpoint considerations

Study defined endpoints supporting product Study defined endpoints supporting product labelinglabeling– Demonstrate clinically meaningful benefitDemonstrate clinically meaningful benefit– Relevant to a specific indication and study populationRelevant to a specific indication and study population– Reliable and reproducibleReliable and reproducible

Study defined endpoints supporting early Study defined endpoints supporting early decisionsdecisions– Correlated with clinically meaningful outcomesCorrelated with clinically meaningful outcomes– Relevant to a specific indication and study populationRelevant to a specific indication and study population– Sensitive to small sample sizesSensitive to small sample sizes

Pharmacodynamic markersPharmacodynamic markersSurrogate endpointsSurrogate endpoints

Case StudiesCase Studies

Herceptin – PFS as an endpointHerceptin – PFS as an endpoint

Iressa – Risks of accelerated approvalIressa – Risks of accelerated approval

Herceptin in MBCHerceptin in MBC

Herceptin a is recombinant DNA-derived Herceptin a is recombinant DNA-derived humanized monoclonal antibody that humanized monoclonal antibody that targets HER2, the protein product of c-targets HER2, the protein product of c-erbB-2.erbB-2.In September 1998 Herceptin was approved In September 1998 Herceptin was approved for:for:– First line treatment in combination with paclitaxel First line treatment in combination with paclitaxel

in MBC patients whose tumors overexpress HER2.in MBC patients whose tumors overexpress HER2.

The primary endpoint used was not overall The primary endpoint used was not overall survival (OS) but progression free survival survival (OS) but progression free survival (PFS).(PFS).

PFS as a primary endpointPFS as a primary endpoint

How to assure objectivity and minimize biasHow to assure objectivity and minimize bias– Randomized, placebo control studyRandomized, placebo control study

Weekly placebo infusions for monthsWeekly placebo infusions for months

Impact on enrollmentImpact on enrollment

– Strict schedule of efficacy assessmentStrict schedule of efficacy assessment– Independent review of radiographic imagesIndependent review of radiographic images

Process for collecting imagesProcess for collecting images

Assessment of skin lesions required distribution of Assessment of skin lesions required distribution of cameras to sitescameras to sites

– Strictly define rules for missing dataStrictly define rules for missing dataIndependent review of images not availableIndependent review of images not available

PFS as a primary endpointPFS as a primary endpoint

The challenge continuesThe challenge continues– 21% enrolled in the first year21% enrolled in the first year– Protocol amendment to remove placeboProtocol amendment to remove placebo

Impact on primary endpoint (PFS)Impact on primary endpoint (PFS)

– Invoke real time independent review of Invoke real time independent review of radiographic imagesradiographic images

Primary endpoint had to be confirmed by the review Primary endpoint had to be confirmed by the review committeecommittee

Patients and investigators compliancePatients and investigators compliance– Turn-around review time was criticalTurn-around review time was critical– Offer cross-over to control patientsOffer cross-over to control patients

PFS as a primary endpointPFS as a primary endpoint

ConclusionsConclusions– In September 1998 Herceptin was approved In September 1998 Herceptin was approved

based PFSbased PFS

– Survival as a secondary endpoint was Survival as a secondary endpoint was statistically significantstatistically significant

– 65% of control patients crosses-over to 65% of control patients crosses-over to receive Herceptinreceive Herceptin

– Two years later the survival benefit Two years later the survival benefit continued to be presentcontinued to be present

Sub-group analysis impacted by crossoverSub-group analysis impacted by crossover

Case StudiesCase Studies

Herceptin – PFS as an endpointHerceptin – PFS as an endpoint

Iressa – Risks of accelerated approvalIressa – Risks of accelerated approval

Iressa in NSCLCIressa in NSCLC

Iressa a quinazoline-based small molecule, Iressa a quinazoline-based small molecule, an EGFR TK inhibitoran EGFR TK inhibitor

In phase I objective responses observed in In phase I objective responses observed in NSCLCNSCLC

Two phase II monotherapy trialsTwo phase II monotherapy trials– Response rate (RR) as primary endpointResponse rate (RR) as primary endpoint– Two dose groupsTwo dose groups

May 2003 - Accelerate approval for 3May 2003 - Accelerate approval for 3rdrd line line monotherapy use based on RRmonotherapy use based on RR

Accelerated approval - risksAccelerated approval - risksNeed to conduct large, confirmatory trialsNeed to conduct large, confirmatory trials– What if negative?What if negative?

Despite meaningful responses in recurrent Despite meaningful responses in recurrent NSCLC patients, Phase III trials failed to show NSCLC patients, Phase III trials failed to show any significant clinical benefitany significant clinical benefitApproval was revoked in June 2005Approval was revoked in June 2005– The medicine should be used only in cancer patients who have The medicine should be used only in cancer patients who have

already taken the medicine and whose doctor believes it is helping already taken the medicine and whose doctor believes it is helping them. New patients should not be given Iressa because in a large them. New patients should not be given Iressa because in a large study Iressa did not make people live longer.study Iressa did not make people live longer.

What went wrong?What went wrong?– Patient selection ?Patient selection ?– Dose/schedule ?Dose/schedule ?

Can this be avoided?Can this be avoided?

Demonstrating clinical benefit with molecular-Demonstrating clinical benefit with molecular-targeted agents is more complex than with targeted agents is more complex than with conventional cytotoxic agentsconventional cytotoxic agents– Selection of sub-population: who is most likely to Selection of sub-population: who is most likely to

benefitbenefit– Identification of optimal biological doseIdentification of optimal biological dose

Answers before phase III – is this achievable Answers before phase III – is this achievable

Proof-of-concept trialsProof-of-concept trials– Is PFS a sufficient endpointIs PFS a sufficient endpoint

Sub-population selectionSub-population selection

Complex processComplex process

Tissue samples requiredTissue samples required– Blood/serum feasibleBlood/serum feasible– Tumor samples are challengingTumor samples are challenging

Missing dataMissing data

Archival samples not always relevantArchival samples not always relevant

Randomized, controlled studies requiredRandomized, controlled studies required– Stratification by biomarker for sub-population selectionStratification by biomarker for sub-population selection

At randomization or during analysisAt randomization or during analysis

– Not possible to distinguish between a prognostic and Not possible to distinguish between a prognostic and predictive biomarker without a proper controlpredictive biomarker without a proper control

Biomarker based population selectionBiomarker based population selectionPFS with no control armPFS with no control arm

Gordon et al. J Clin Oncol. 2005;23:16S (abstract 5051).Gordon et al. J Clin Oncol. In press.

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0 100 200 300 400

pHER2+ tumors trend toward longer PFS Treatment effect or natural course of disease?

Median PFSpHER2 positive n=8 20.9 weekspHER2 negative n=20 5.8 weekspHER2 unknown n=27 9.1 weeksAll subjects n=55 6.6 weeks

All patients treated with pertuzumab

Dose/schedule selectionDose/schedule selection

Complex processComplex process– May be indication specificMay be indication specific– May be regimen specificMay be regimen specific

Typical trialTypical trial– RandomizedRandomized– 3 arms3 arms

Control/lower dose/higher doseControl/lower dose/higher dose30-40 subjects per arm30-40 subjects per arm

– PFS as primary endpointPFS as primary endpoint

How is dose selectedHow is dose selected– Better efficacy compared to control - winnerBetter efficacy compared to control - winner

Time to event endpointsTime to event endpointsOptimal vs. sub-optimal doseOptimal vs. sub-optimal dose

Probability that the observed HR Probability that the observed HR 0.75 0.75

True HRTrue HR Number of eventsNumber of events

4040 6060 8080 100100 200200

0.670.67 0.640.64 0.670.67 0.700.70 0.720.72 0.800.80

0.800.80 0.420.42 0.400.40 0.390.39 0.370.37 0.330.33

0.900.90 0.280.28 0.240.24 0.210.21 0.180.18 0.020.02

We need to do better

Mechanism-based biomarkersMechanism-based biomarkers

Demonstrating clinical benefit with molecular-Demonstrating clinical benefit with molecular-targeted agents is more complex than with targeted agents is more complex than with conventional cytotoxic agentsconventional cytotoxic agents– Escalating clinical trials costs and large numbers of Escalating clinical trials costs and large numbers of

patients required for currently used clinical endpoints patients required for currently used clinical endpoints mandate becoming more efficient in determining how mandate becoming more efficient in determining how well new agents can address unmet medical needs. well new agents can address unmet medical needs.

– That efficiency can be achieved by validating That efficiency can be achieved by validating correlations between specific biological mechanisms correlations between specific biological mechanisms of disease and clinical outcomes. of disease and clinical outcomes.

– Easier said than done!Easier said than done!

Mechanism-based biomarkersMechanism-based biomarkers

Technological advances provide great Technological advances provide great opportunity for the development of biomarkersopportunity for the development of biomarkers– Molecular and cellular techniquesMolecular and cellular techniques

Tissue samplesTissue samples– Tumor/blood/surrogateTumor/blood/surrogate

– Imaging technologiesImaging technologies

Current pre-clinical models still have limit ability Current pre-clinical models still have limit ability to predict clinical effectsto predict clinical effects– Biomarkers need to be co-developed with the novel Biomarkers need to be co-developed with the novel

agentagentIn early phases – no clinical dataIn early phases – no clinical dataThis will benefit second generation of the new agents or new This will benefit second generation of the new agents or new indicationsindications

– Systematic way of analyzing and interpreting dataSystematic way of analyzing and interpreting data

Mechanism-based biomarkersMechanism-based biomarkers

PET imagingPET imaging

Use of surrogate endpoints in cancer Use of surrogate endpoints in cancer preventionprevention

PET studiesPET studies

Speed developmentSpeed developmentProvide information about the activity of Provide information about the activity of molecular pathwaysmolecular pathways

Determine if new agents are hitting the targetDetermine if new agents are hitting the target

Measure treatment effectMeasure treatment effect

Tissue samples are not requiredTissue samples are not required

FDG PET in NSCLCFDG PET in NSCLC

Wolfgang Weber et al. J Clin Oncol. 2003;21:2651

FDG PET in LymphomaFDG PET in Lymphoma

L. Kostakoglu, J Nuc Med 43:1018 2002

ChallengesChallengesHow to define metabolic responseHow to define metabolic response– Change in standard uptake values (SUV) that based Change in standard uptake values (SUV) that based

on re-tests can be reliably detectedon re-tests can be reliably detectedArbitrary cut-offArbitrary cut-off

– Optimized thresholds correlated with outcomesOptimized thresholds correlated with outcomesBased on analysis Based on analysis

– What adjustments made for minimum p-valuesWhat adjustments made for minimum p-values

Not applicable to other treatments or indicationsNot applicable to other treatments or indications

Use of core labs in multi-center trials Use of core labs in multi-center trials Not ready as a surrogate efficacy outcome for Not ready as a surrogate efficacy outcome for combination trials combination trials Not all lesions are PET avidNot all lesions are PET avid

Cancer PreventionCancer PreventionPreventing heart diseasesPreventing heart diseases– Lowering cholesterol / blood pressureLowering cholesterol / blood pressure

Surrogate biomarker endpoints for cancer Surrogate biomarker endpoints for cancer prevention trialsprevention trials– Establishment of long term safety and efficacy Establishment of long term safety and efficacy

for preventive drugs is criticalfor preventive drugs is critical– Process for accelerated approval based on Process for accelerated approval based on

biomarkers will be neededbiomarkers will be neededColorectal adenomasColorectal adenomas

– Current development of Current development of mechanism-drivenmechanism-driven biomarkers is critical for future cancer biomarkers is critical for future cancer prevention trials.prevention trials.

Questions?Questions?

Thank you!Thank you!