The Statisticians Role in Pharmaceutical Development

Steps in the processCompound delivered from DiscoveryEarly studies Pre Clinical ClinicalDevelopment for market launchRegulatory Submission ApprovalLife Cycle Management

Discovery StepTargeted developmentClinical unmet medical needSeek series of molecules that hit targetSelect candidates which have desired activityTest molecules to quantify effect on target

Target identificationWhat is needed?What features are desired?What is acceptable in terms of risk?Cross functional team comes up with a Target Product Profile

Statisticians Role (high level, experienced)Provide scientific method thinking into the target evaluation processAssess the ability to Quantify effect on target of interest Does animal model translate into humanHow will effective dose be identifiedProvide critical input into quantification of riskAssist in establishing go/no go decision criteria

ChallengesCross functional team members have different goals and needsStatistician needs to be aware of competing needs of stake holdersClinical elegant science, meeting patient needsCommercial optimum product to sellBusiness speed to marketTranslational science may be in infancy, signal in animal model not validated in human disease

Early Clinical StagePharmacokineticsDose findingSingle ascending doseMultiple ascending doseMetabolism and eliminationDrug interaction studies

Early Clinical StageIs the compound safe enough to dose in an effective rangeWhat are the kinetic propertiesLinear dose responseAccumulation on multiple dosing

Statistical responsibilitiesReview of margins from animal dataAgree criteria for stopping dose escalation Plan for Go/No go decisionEnsure program assesses areas of potential safety risk identified in animal tox studies

ChallengesRelatively small sample sizes in studiesDecisions based more on clinical judgment than statisticsStudy designs critical at this stageNeed to get buy in for decision rules put in place

Development for Market LaunchClinical Development PlanWhat needs to be done to support desired claims in world markets (Regulatory requirements)What trials, which drug interaction studiesWhat are the competitors and their profilesIs there something we can demonstrate value for the patient (efficacy or safety)

Aspects of development for marketProof of conceptDose selectionConfirmatory studies (minimum of 2)Long term safety studiesStudies based on propertied of drugThorough QT study for ECG changesInteraction studies based on concomitant use or metabolic pathway

Statistical responsibilities in development phaseStudy design decisionsSelection of Primary endpoints for studiesRisk assessment need to adjust for multiple comparisons?Interim analysesQuantification of decision criteriaData Monitoring Boards

ChallengesStatistics represented at several levelsEnsuring one voice (consistency)Regulatory guidelines in placeCan change during developmentDiffer across regionsNeed to be aware of the environment High visibility failures due to incorrect assumptions are a problemClinical and Commercial input may differNeed good negotiation skills

Regulatory submission and approvalSynthesize the dataProvide thorough structure descriptionProvide standardized information in agreed formatSupport the packageAgree the label

Statistical ResponsibilityProvide plan to synthesize the data across the programEnsure that the data is clearly reported and statements are supported by appropriate statistical analysisPrepare for questions which may come during reviewPrepare presentation for Advisory panel if neededReview label language and address regulatory issues in label

ChallengesWork as integral part of a larger team need to reach consensus on issuesCommercial and drug safety have more influence in this stage need to be able to clarify the statistical issues for non-statisticiansNeed to be able to provide information in a way that facilitates the benefit/risk assessmentIn labeling negotiations need to be aware of who the target audience for the label is

Life Cycle ManagementProduct is on the marketHow to we maximize its valueBroaden the indications for useIdentify patients currently not treatedLook for ways to demonstrate the strength of the product compared to othersLook for economic or quality of life benefits

Statisticians responsibilitiesReview of Ideas for studies supplied by outside researchersMine registration data to identify scientific questions we have a reasonable chance of addressingAssist in developing plan for new clinical indicationsEvaluate the development risks

Statistical Positions and RolesStatistician usually study statisticianStudy Design Concept Plan to protocol Provides link between objectives and variablesProvides design and sample size justificationContributes the statistical analysisWrites Statistical analysis plan detail document for data handling and analysisPerforms analysis and supports the interpretation of results Contributes to Study report and publications and presentations of the data

Statistical Positions and RolesSenior StatisticianSupports Project (several studies at once)Study statistician responsibilitiesLeads delivery teams project management as well as statistical responsibilitiesCross functional leadership Mentor or coach statistician level

Statistical Positions and RolesPrincipal StatisticianSupports Program (several studies at once)Oversees the work of Study statistician delivering a program of workProvides Analysis Plan for project level as template for individual studiesStarts to work more closely with the Global team on risk assessment and mitigation plansUses experience and statistical knowledge to facilitate quantification of risk

Statistical Positions and RolesStatistician Science DirectorBiostatistics leadership within the companyMay have research or other key initiative activities for the company Project leadership roles Global Product StatisticianTherapeutic area Global Statistician

Statistical Positions and RolesGlobal Product StatisticianInput into the Clinical Development PlanReview responsibilities for all study protocols, statistical analysis plans, and documents sent to regulatory authoritiesRepresent statistics for a product in any regulatory interactionsStrategic review of data as it comes in to identify aspects of the drug (risk or benefits)Support the Commercial function by providing scientific approach and clarity around messages

Statistical Positions and RolesTherapeutic Area Global StatisticianInput into the early stage compoundsKeep abreast of the literature to ensure that advice is appropriateLook at the data in the industry landscape to assess development risks Support the Commercial function by providing scientific approach and clarity around possibilities given current knowledge