1Gracie Lieberman, Genentech 2006 FDA/Industry Workshop Biomarkers and Surrogate Endpoints in Drug Development Technical and Regulatory Considerations Gracie Lieberman,Genentech2006 FDA/Industry Workshop
2Content Changing landscape Efficacy surrogate endpoints used for approval – case studiesHerceptinIressaSurrogate endpoints in proof of concept trialsSelecting sub-populationSelecting doseRole of mechanism-based biomarkersPET studies in cancer
3Changing landscape In the past 15-20 years: Impact on clinical trials Better molecular understanding of diseasesEarlier, more precise diagnosisNew targeted, improved therapiesImpact on clinical trialsAssessment of improvements in clinically meaningful endpoints require enrolling many patients and then following them for a long time. Emerging needDevelop strategies for reducing the time and cost of drug development. Use of surrogate endpoints either in proof-of-concept or label-enabling trials.Defined in clinical practice and used by clinicians to monitor and treat patientsNew mechanism-driven biomarkers
4Endpoint considerations Study defined endpoints supporting product labelingDemonstrate clinically meaningful benefitRelevant to a specific indication and study populationReliable and reproducibleStudy defined endpoints supporting early decisionsCorrelated with clinically meaningful outcomesSensitive to small sample sizesPharmacodynamic markersSurrogate endpoints
5Case Studies Herceptin – PFS as an endpoint Iressa – Risks of accelerated approval
6Herceptin in MBCHerceptin a is recombinant DNA-derived humanized monoclonal antibody that targets HER2, the protein product of c-erbB-2.In September 1998 Herceptin was approved for:First line treatment in combination with paclitaxel in MBC patients whose tumors overexpress HER2.The primary endpoint used was not overall survival (OS) but progression free survival (PFS).
7PFS as a primary endpoint How to assure objectivity and minimize biasRandomized, placebo control studyWeekly placebo infusions for monthsImpact on enrollmentStrict schedule of efficacy assessmentIndependent review of radiographic imagesProcess for collecting imagesAssessment of skin lesions required distribution of cameras to sitesStrictly define rules for missing dataIndependent review of images not available
8PFS as a primary endpoint The challenge continues21% enrolled in the first yearProtocol amendment to remove placeboImpact on primary endpoint (PFS)Invoke real time independent review of radiographic imagesPrimary endpoint had to be confirmed by the review committeePatients and investigators complianceTurn-around review time was criticalOffer cross-over to control patients
9PFS as a primary endpoint ConclusionsIn September 1998 Herceptin was approved based PFSSurvival as a secondary endpoint was statistically significant65% of control patients crosses-over to receive HerceptinTwo years later the survival benefit continued to be presentSub-group analysis impacted by crossover
10Case Studies Herceptin – PFS as an endpoint Iressa – Risks of accelerated approval
11Iressa in NSCLCIressa a quinazoline-based small molecule, an EGFR TK inhibitorIn phase I objective responses observed in NSCLCTwo phase II monotherapy trialsResponse rate (RR) as primary endpointTwo dose groupsMay Accelerate approval for 3rd line monotherapy use based on RR
12Accelerated approval - risks Need to conduct large, confirmatory trialsWhat if negative?Despite meaningful responses in recurrent NSCLC patients, Phase III trials failed to show any significant clinical benefitApproval was revoked in June 2005The medicine should be used only in cancer patients who have already taken the medicine and whose doctor believes it is helping them. New patients should not be given Iressa because in a large study Iressa did not make people live longer.What went wrong?Patient selection ?Dose/schedule ?
13Can this be avoided?Demonstrating clinical benefit with molecular-targeted agents is more complex than with conventional cytotoxic agentsSelection of sub-population: who is most likely to benefitIdentification of optimal biological doseAnswers before phase III – is this achievableProof-of-concept trialsIs PFS a sufficient endpoint
14Sub-population selection Complex processTissue samples requiredBlood/serum feasibleTumor samples are challengingMissing dataArchival samples not always relevantRandomized, controlled studies requiredStratification by biomarker for sub-population selectionAt randomization or during analysisNot possible to distinguish between a prognostic and predictive biomarker without a proper control
15Biomarker based population selection PFS with no control arm Time (days)Proportion progression-free0.20.40.60.81.0100200300400Median PFSpHER2 positive n= weekspHER2 negative n= weekspHER2 unknown n= weeksAll subjects n= weeksAll patients treated with pertuzumabpHER2+ tumors trend toward longer PFS Treatment effect or natural course of disease?Gordon et al. J Clin Oncol. 2005;23:16S (abstract 5051).Gordon et al. J Clin Oncol. In press.
16Dose/schedule selection Complex processMay be indication specificMay be regimen specificTypical trialRandomized3 armsControl/lower dose/higher dose30-40 subjects per armPFS as primary endpointHow is dose selectedBetter efficacy compared to control - winner
17Time to event endpoints Optimal vs. sub-optimal dose Probability that the observed HR 0.75True HRNumber of events4060801002000.670.640.700.720.800.420.400.390.370.330.900.2126.96.36.199.02We need to do better
18Mechanism-based biomarkers Demonstrating clinical benefit with molecular-targeted agents is more complex than with conventional cytotoxic agentsEscalating clinical trials costs and large numbers of patients required for currently used clinical endpoints mandate becoming more efficient in determining how well new agents can address unmet medical needs.That efficiency can be achieved by validating correlations between specific biological mechanisms of disease and clinical outcomes.Easier said than done!
19Mechanism-based biomarkers Technological advances provide great opportunity for the development of biomarkersMolecular and cellular techniquesTissue samplesTumor/blood/surrogateImaging technologiesCurrent pre-clinical models still have limit ability to predict clinical effectsBiomarkers need to be co-developed with the novel agentIn early phases – no clinical dataThis will benefit second generation of the new agents or new indicationsSystematic way of analyzing and interpreting data
20Mechanism-based biomarkers PET imagingUse of surrogate endpoints in cancer prevention
21PET studies Speed development Tissue samples are not required Provide information about the activity of molecular pathwaysDetermine if new agents are hitting the targetMeasure treatment effectTissue samples are not required
22FDG PET in NSCLCWolfgang Weber et al. J Clin Oncol. 2003;21:2651
24Challenges How to define metabolic response Change in standard uptake values (SUV) that based on re-tests can be reliably detectedArbitrary cut-offOptimized thresholds correlated with outcomesBased on analysisWhat adjustments made for minimum p-valuesNot applicable to other treatments or indicationsUse of core labs in multi-center trialsNot ready as a surrogate efficacy outcome for combination trialsNot all lesions are PET avid
25Cancer Prevention Preventing heart diseases Lowering cholesterol / blood pressureSurrogate biomarker endpoints for cancer prevention trialsEstablishment of long term safety and efficacy for preventive drugs is criticalProcess for accelerated approval based on biomarkers will be neededColorectal adenomasCurrent development of mechanism-driven biomarkers is critical for future cancer prevention trials.