Preparing for a career in regulatory biostatistics - What does it take ?

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Preparing for a career in regulatory
biostatistics - What does it take ?

• Robert T. ONeill Ph.D.
• Director, Office of Biostatistics
• Office of Translational Sciences, CDER

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

• What is regulatory statistics
• Where do you learn
• Opportunities
• Training the next generation

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The science of regulatory statistics

• The field of regulatory statistics evolved from
  the need to apply statistical principles and
  practices to implement regulations developed to
  promote and protect the public health by
  facilitating the development of effective and
  safe medical products. The modern era began about
  1970
• Many statisticians have begun careers in FDA and
  moved to industry or academic positions where
  they built upon their regulatory statistics
  background
• There are about 105 biostatisticians in CDER, and
  about that many more in all of FDA, established
  programs in CBER, CDRH, CFSAN and CVM and NCTR

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http//www.fda.gov/cder/Offices/Biostatistics/
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What is the role of biostatistician in a
regulatory agency and how did it evolve

• The need for biostatisticians was created by the
  regulations and standards for efficacy and safety
• What shaped this role
• Culmination of accumulating experience
• The development and evolution of the discipline
  of regulatory statistics
• International roles, influences and events

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Major Events Impacting Determination of Evidence

• The 1962 Kefauver-Harris Amendments the
  foundation for experimental evidence as the
  basis for drug approvals
• The 1970 definition of Adequate and well
  controlled investigations the foundation for
  statistical principles the concept of hypothesis
  testing and estimation, randomization, blinding
• The 1986 NDA Rewrite the foundation for
  documentation of evidence, including statistical
  evidence and introduction of the integrated
  efficacy and safety section -

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Major Events Impacting Determination of Evidence
(cont.)

• The 1988 Guideline for the Format and Content of
  the Clinical and Statistical Sections of an
  application
• 1992 Subpart H - Accelerated Approval of New
  Drugs for Serious or Life-threatening Illnesses -
  surrogate endpoints (AIDS crisis)
• The 1997 Food and Drug Modernization Act
  (FDAMA) a modification of the substantial
  evidence criteria
• The 1998 ICH Statistical Principles for Clinical
  Trials the foundation for global understanding ,
  harmonization and implementation of statistical
  principles

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Roles in the career of a regulatory
biostatistician

• Statistical review team member
• Entry level and senior reviewer
• Expert statistician
• Applied researcher
• Leadership, manager , policy development
• Office Director, Deputy
• Division Director, Deputy
• Associate Director
• Other organizational roles
• Bioinformatics, training, compliance, epidemiology

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What does a regulatory statistician do ?

• Evaluate , critique large numbers of clinical
  studies, with access to patient level data - data
  base management skills
• Make recommendations inference and evidence
• Prepare and deliver public advisory committee
  presentations that are video taped, webcast
• Write reports that may be available publically
  through FOI
• Develop and Negotiate statistical and clinical
  guidances
• Domestic and international (ICH)
• Dispute resolutions
• Administrative hearings (rarely)
• Influence, educate colleagues
• Interactions with multiples audiences, including
  industry statisticians, consultants, and academics

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An advisory committee biostatistician - a special
government employee (SGE)

• Usually an academic with minimum conflicts of
  interest
• Difficult job
• Requires unique skill mix
• Goes beyond understanding the science and the
  statistics
• Multi-disciplinary committee
• Voting is often the decision making choice

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Training and Experience as a critical part of the
career path in regulatory biostatistics

• A reviewer of clinical and pre-clinical data
  within the context of scientific and regulatory
  standards of evidence
• A policy maker
• A decision maker
• A negotiator
• An educator
• A speaker
• A writer

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Subject matter expertise

• Impact of regulations and health care on mission
  of FDA
• Drug development
• Pre-Clinical and clinical study design and
  analysis methodology
• Exploration / Confirmation
• New proposals adaptive, enrichment
• Surveillance and life cycle risk assessment
• Epidemiology, observational study methods, causal
  inference, propensity score methods, multiple
  events
• Data mining strategies
• Meta-analytic methods - individual and study
  level covariates - not traditional literature
  based meta-analysis
• Data base management, programming, scientific
  computation
• Modern process control and quality by design
  methods for manufacturing- non invasive testing,
  development of standards and setting
  specifications (wastage and safety)

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Statistical areas

• Clinical trials all aspects (read ICH E9)
• Experimental designs for clinical trials
• Repeated measures,Time to event, K period
  designs, Adaptive methods
• Methods development, application
• All areas dealing with FDA guidances
• Pre-clinical animal study designs
• Chemistry , manufacturing, contols, specification
  setting and monitoring
• Simulation practices - modern protocol planning
  and scenario planning - not of a just a single
  study but a series of studies or a development
  program

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Statistical areas

• Epidemiology
• Observational data methods Cohort and case
  control studies
• Large data base and outcomes based study methods
• Meta-analytic methods or combining
• Multiplicity - outcomes, subgroups - very
  important for inferential claims
• Prediction, prognosis, differential benefit and
  harm - important for understanding the difference
  between individual and group prediction and
  personalized medicine
• Sampling, surveys
• Exploratory bayesian , frequentist and
  likelihood strategies

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Some Training that FDA provides to our staff

• Statistical courses/ seminars/ workshop
• Subject matter courses/ seminars/
• Genomics, nanotechnology, drug safety evaluation,
  
• Speaking, enunciation, toastmasters, negotiating

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Designing Quality into Clinical Trials
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Biostatistics and StatisticsBroadening the field
of application

• Quality by design - modern quality control - in
  process control and specification setting and
  monitoring - designing quality into the design
  space
• The manufacturing process - heparin
• The clinical trial
• Sampling - clinical trial auditing and
  inspections - consumer surveys and OTC label
  comprehension studies
• Micro-array , SNP, genomics marker identification
  and validation studies
• Study design and analysis to support choice of
  and validation of patient reported outcomes in
  clinical trials
• Scientific computing, large scale data base
  analysis and data mining, record linkage studies,
  health records analysis

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FDA Statisticians Collaborate with and are
professionally involved in external activities

• Professional society involvement
• Organizing meetings externally - with Phrma, ASA,
  DIA, SCT, ISCA, IBS

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Training the next generationEducation and
training vs experience in the career path

• Experience , case studies, breadth of involvement
• Interest in continual learning vs. comfort zone
• Academic contributions need to be aligned with
  needs of society and reality of modern health
  care
• FDA providing case study material to the academic
  sector
• Fellowships

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We are looking for a few good statisticians