Preparing for a career Preparing for a career in regulatory biostatistics -in regulatory biostatistics -

What does it take ? What does it take ?Robert T. O’Neill Ph.D.Robert T. O’Neill Ph.D.

Director, Office of BiostatisticsDirector, Office of BiostatisticsOffice of Translational Sciences, CDEROffice of Translational Sciences, CDER

For presentation at the 17th annual International Chinese Statistical Association Applied Statistics Symposium ; June 4-7th, 2008

Outline of IssuesOutline of Issues

What is regulatory statisticsWhat is regulatory statistics Where do you learn Where do you learn OpportunitiesOpportunities Training the next generationTraining the next generation

The science of regulatory The science of regulatory statisticsstatistics

The field of regulatory statistics evolved from the The field of regulatory statistics evolved from the need to apply statistical principles and practices to need to apply statistical principles and practices to implement regulations developed to promote and implement regulations developed to promote and protect the public health by facilitating the protect the public health by facilitating the development of effective and safe medical products. development of effective and safe medical products. The modern era began about 1970The modern era began about 1970

Many statisticians have begun careers in FDA and Many statisticians have begun careers in FDA and moved to industry or academic positions where they moved to industry or academic positions where they built upon their regulatory statistics backgroundbuilt upon their regulatory statistics background

There are about 105 biostatisticians in CDER, and There are about 105 biostatisticians in CDER, and about that many more in all of FDA, established about that many more in all of FDA, established programs in CBER, CDRH, CFSAN and CVM and NCTRprograms in CBER, CDRH, CFSAN and CVM and NCTR

http://www.fda.gov/cder/Offices/Biostatistics/

What is the role of What is the role of biostatistician in a biostatistician in a

regulatory agency and regulatory agency and how did it evolvehow did it evolve

The need for biostatisticians was created The need for biostatisticians was created by the regulations and standards for by the regulations and standards for efficacy and safetyefficacy and safety

What shaped this roleWhat shaped this role Culmination of accumulating experienceCulmination of accumulating experience The development and evolution of the The development and evolution of the

discipline of regulatory statisticsdiscipline of regulatory statistics International roles, influences and eventsInternational roles, influences and events

Major Events Impacting Major Events Impacting Determination of Determination of

EvidenceEvidence The 1962 Kefauver-Harris Amendments: the The 1962 Kefauver-Harris Amendments: the

foundation for experimental evidence as the foundation for experimental evidence as the basis for drug approvalsbasis for drug approvals

The 1970 definition of ‘Adequate and well The 1970 definition of ‘Adequate and well controlled investigations’: the foundation for controlled investigations’: the foundation for statistical principles: the concept of hypothesis statistical principles: the concept of hypothesis testing and estimation, randomization, blindingtesting and estimation, randomization, blinding

The 1986 NDA Rewrite: the foundation for The 1986 NDA Rewrite: the foundation for documentation of evidence, including statistical documentation of evidence, including statistical evidence and introduction of the integrated evidence and introduction of the integrated efficacy and safety section -efficacy and safety section -

Major Events Impacting Major Events Impacting Determination of Evidence Determination of Evidence

(cont.) (cont.) The The 19881988 Guideline for the Format and Content Guideline for the Format and Content

of the Clinical and Statistical Sections of an of the Clinical and Statistical Sections of an applicationapplication

1992; Subpart H - Accelerated Approval of New Drugs for Serious or Life-threatening Illnesses - surrogate endpoints (AIDS crisis)

The 1997 1997 Food and Drug Modernization Act Food and Drug Modernization Act (FDAMA); a modification of the substantial (FDAMA); a modification of the substantial evidence criteriaevidence criteria

The The 1998 1998 ICH Statistical Principles for Clinical ICH Statistical Principles for Clinical Trials: the foundation for global understanding , Trials: the foundation for global understanding , harmonization and implementation of statistical harmonization and implementation of statistical principlesprinciples

Roles in the career of a Roles in the career of a regulatory biostatisticianregulatory biostatistician

Statistical review team memberStatistical review team member Entry level and senior reviewerEntry level and senior reviewer Expert statisticianExpert statistician Applied researcherApplied researcher

Leadership, manager , policy developmentLeadership, manager , policy development Office Director, DeputyOffice Director, Deputy Division Director, DeputyDivision Director, Deputy Associate DirectorAssociate Director

Other organizational rolesOther organizational roles Bioinformatics, training, compliance, epidemiologyBioinformatics, training, compliance, epidemiology

What does a regulatory What does a regulatory statistician do ?statistician do ?

Evaluate , critique large numbers of clinical studies, with Evaluate , critique large numbers of clinical studies, with access to patient level data - data base management skillsaccess to patient level data - data base management skills Make recommendations inference and evidenceMake recommendations inference and evidence

Prepare and deliver public advisory committee Prepare and deliver public advisory committee presentations that are video taped, webcastpresentations that are video taped, webcast

Write reports that may be available publically through FOI Write reports that may be available publically through FOI Develop and Negotiate statistical and clinical guidancesDevelop and Negotiate statistical and clinical guidances

Domestic and international (ICH)Domestic and international (ICH) Dispute resolutionsDispute resolutions Administrative hearings (rarely)Administrative hearings (rarely)

Influence, educate colleaguesInfluence, educate colleagues Interactions with multiples audiences, including industry Interactions with multiples audiences, including industry

statisticians, consultants, and academicsstatisticians, consultants, and academics

An advisory committee An advisory committee biostatistician - a special biostatistician - a special

government employee government employee (SGE)(SGE)

Usually an academic with minimum Usually an academic with minimum conflicts of interestconflicts of interest

Difficult job Difficult job Requires unique skill mixRequires unique skill mix Goes beyond understanding the science Goes beyond understanding the science

and the statisticsand the statistics Multi-disciplinary committeeMulti-disciplinary committee Voting is often the decision making choiceVoting is often the decision making choice

Training and Experience Training and Experience as a critical part of the as a critical part of the

career path in regulatory career path in regulatory biostatistics biostatistics

A reviewer of clinical and pre-clinical data A reviewer of clinical and pre-clinical data within the context of scientific and regulatory within the context of scientific and regulatory standards of evidencestandards of evidence

A policy makerA policy maker A decision makerA decision maker A negotiatorA negotiator An educatorAn educator A speakerA speaker A writerA writer

Subject matter Subject matter expertiseexpertise

Impact of regulations and health care on mission of FDAImpact of regulations and health care on mission of FDA Drug developmentDrug development

Pre-Clinical and clinical study design and analysis Pre-Clinical and clinical study design and analysis methodology methodology

Exploration / ConfirmationExploration / Confirmation New proposals: adaptive, enrichment New proposals: adaptive, enrichment

Surveillance and life cycle risk assessmentSurveillance and life cycle risk assessment Epidemiology, observational study methods, causal Epidemiology, observational study methods, causal

inference, propensity score methods, multiple eventsinference, propensity score methods, multiple events Data mining strategiesData mining strategies Meta-analytic methods - individual and study level Meta-analytic methods - individual and study level

covariates - not traditional literature based meta-analysiscovariates - not traditional literature based meta-analysis Data base management, programming, scientific computation Data base management, programming, scientific computation Modern process control and quality by design methods for Modern process control and quality by design methods for

manufacturing- non invasive testing, development of standards manufacturing- non invasive testing, development of standards and setting specifications (wastage and safety)and setting specifications (wastage and safety)

Statistical areasStatistical areas Clinical trials – all aspects (read ICH E9)Clinical trials – all aspects (read ICH E9)

Experimental designs for clinical trialsExperimental designs for clinical trials Repeated measures,Time to event, K Repeated measures,Time to event, K

period designs, Adaptive methodsperiod designs, Adaptive methods Methods development, applicationMethods development, application All areas dealing with FDA guidancesAll areas dealing with FDA guidances

Pre-clinical animal study designsPre-clinical animal study designs Chemistry , manufacturing, contols, Chemistry , manufacturing, contols,

specification setting and monitoringspecification setting and monitoring Simulation practices - modern protocol Simulation practices - modern protocol

planning and scenario planning - not of a just planning and scenario planning - not of a just a single study but a series of studies or a a single study but a series of studies or a development programdevelopment program

Statistical areas Statistical areas

EpidemiologyEpidemiology

Observational data methods Cohort and case control Observational data methods Cohort and case control studiesstudies

Large data base and outcomes based study methodsLarge data base and outcomes based study methods Meta-analytic methods or combiningMeta-analytic methods or combining Multiplicity - outcomes, subgroups - very important for Multiplicity - outcomes, subgroups - very important for

inferential claimsinferential claims Prediction, prognosis, differential benefit and harm - Prediction, prognosis, differential benefit and harm -

important for understanding the difference between important for understanding the difference between individual and group prediction and ‘personalized medicine’individual and group prediction and ‘personalized medicine’

Sampling, surveysSampling, surveys Exploratory – bayesian , frequentist and likelihood strategiesExploratory – bayesian , frequentist and likelihood strategies

Some Training that FDA Some Training that FDA provides to our staffprovides to our staff

Statistical courses/ seminars/ Statistical courses/ seminars/ workshopworkshop

Subject matter courses/ seminars/Subject matter courses/ seminars/ Genomics, nanotechnology, Genomics, nanotechnology,

drug safety evaluation, drug safety evaluation, Speaking, enunciation, Speaking, enunciation,

toastmasters, negotiatingtoastmasters, negotiating

Designing Quality into Clinical Designing Quality into Clinical TrialsTrials

Biostatistics and Biostatistics and StatisticsStatistics

Broadening the field of Broadening the field of applicationapplication

Quality by design - modern quality control - in process Quality by design - modern quality control - in process control and specification setting and monitoring - designing control and specification setting and monitoring - designing quality into the design space quality into the design space The manufacturing process - heparinThe manufacturing process - heparin The clinical trialThe clinical trial

Sampling - clinical trial auditing and inspections - consumer Sampling - clinical trial auditing and inspections - consumer surveys and OTC label comprehension studiessurveys and OTC label comprehension studies

Micro-array , SNP, genomics marker identification and Micro-array , SNP, genomics marker identification and validation studiesvalidation studies

Study design and analysis to support choice of and Study design and analysis to support choice of and validation of patient reported outcomes in clinical trialsvalidation of patient reported outcomes in clinical trials

Scientific computing, large scale data base analysis and data Scientific computing, large scale data base analysis and data mining, record linkage studies, health records analysismining, record linkage studies, health records analysis

FDA Statisticians FDA Statisticians Collaborate with and are Collaborate with and are professionally involved in professionally involved in

external activitiesexternal activities Professional society involvementProfessional society involvement Organizing meetings externally - Organizing meetings externally -

with Phrma, ASA, DIA, SCT, ISCA, with Phrma, ASA, DIA, SCT, ISCA, IBSIBS

Training the next Training the next generationgeneration

Education and training vs Education and training vs experience in the career experience in the career

pathpath Experience , case studies, breadth of Experience , case studies, breadth of

involvementinvolvement Interest in continual learning vs. comfort zoneInterest in continual learning vs. comfort zone Academic contributions need to be aligned Academic contributions need to be aligned

with needs of society and reality of modern with needs of society and reality of modern health carehealth care

FDA providing case study material to the FDA providing case study material to the academic sectoracademic sector FellowshipsFellowships

We are looking for a

few good statisticians