A History of Stats at the FDA

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					A History of Stats at
      the FDA


            Mary A. Foulkes, Ph.D.
       U.S. Food And Drug Administration
    Office of Biostatistics and Epidemiology
  Center for Biologics Evaluation and Research




   2006 FDA/Industry Statistics Workshop
The views presented are my own and do
 not represent the official view of the
   U.S. Food and Drug Administration
             FDA Centers
• Center for Biological Evaluation and Research
  (CBER)
• Center for Drug Evaluation and Research
  (CDER)
• Center for Device and Radiological Health
  (CDRH)
• Center for Food Safety and Applied Nutrition
  (CFSAN)
• Center for Veterinary Medicine (CVM)
• National Center for Toxicological Research
  (NCTR)
       OUTLINE
•   Early years
•   Kefauver-Harris Amendments
•   Grandfather
•   Women, Kids and Animals
•   Globalization
•   Critical Path and Beyond
A Public Outcry for a New Law
• Upton Sinclair’s book, The
  Jungle, drew attention to
  adulterated meat
• Meat sales dropped by 1/3
• Roosevelt was persuaded to
  sign Pure Food and Drugs
  Act on June 30, 1906
  along with the Meat
  Inspection Act
• 1906 Act transformed a
  scientific bureau into a
  regulatory agency that
  would become FDA
     Pre-1962
• Safety
• Advertising
An original 1-gallon bottle of Elixir Sulfanilamide




        Wax, P. M. Ann Intern Med 1995;122:456-461
Public Health Reports, January/February 2000, Volume 115
       Pre-1962
•   Safety
•   Advertising
•   Elixir Sulfanilamide
•   LD 50
•   Bioassay
    Kefauver-Harris Amendments
Evidence consisting of adequate and well-controlled
investigations, including clinical investigations, by experts
qualified by scientific training and experience to evaluate
the effectiveness of the drug involved, on the basis of
which it could fairly and responsibly be concluded by such
experts that the drug will have the effect it purports or
is represented to have under the conditions of use
prescribed, recommended, or suggested in the labeling or
proposed labeling thereof.


                                      FD & C Act Section 505(d)
    Kefauver-Harris Amendments
Evidence consisting of adequate and well-controlled
investigations, including clinical investigations, by experts
qualified by scientific training and experience to evaluate
the effectiveness of the drug involved, on the basis of
which it could fairly and responsibly be concluded by such
experts that the drug will have the effect it purports or
is represented to have under the conditions of use
prescribed, recommended, or suggested in the labeling or
proposed labeling thereof.


                                      FD & C Act Section 505(d)
       1962 and Beyond
• DESI (1938 – 1962) drugs –
  Grandfathered
• Fed Reg 1970 – “appropriate
  statistical methods”
• Orphan Drug Act 1983
• 1990’s – Expanding demographics
  (Age, Gender)
• FDAMA 1997
FDA Biometry and Epidemiology Methodology Advisory Committee
The American Statistician, 1968
                             JASA, 1999

• Treatment of insomnia - triazolam
• Re-analysis of 25 plcbo-contr trials
• Mixed-effects regression models –
  using all available data
• Diff btw trials and spontaneous
  reports – Recommend: longer term,
  high dose studies
    A priori Analysis Plan
“Still, it is an error to argue in front
    of your data. You find yourself
  insensibly twisting them around to
              fit your theory.”

            Sherlock Holmes in
      The Adventure of Wisteria Lodge
Control of Type I error
•   Primary and secondary outcomes
•   Composite endpoints
•   Power
•   Essential Multiplicity
•   Implications for design
              Subgroups
•   Age enrollment to match indication
•   Gender
•   Demographics
•   Pediatric Rule
           Other Issues
•   Active/placebo/historical controls
•   Adaptive trials
•   Combination products
•   Adverse Events/MedDRA/Data Mining
•   Multiplicity
•   Endpoints
•   QA/QC
Group Sequential Boundaries
Interim Monitoring
•   Outcome trials
•   Serious morbidity/mortality
•   Minimize risks
•   Futility
•   Regulatory implications
     Large Safety Studies
•   Ibuprofen   N   =   84,192   (1995)
•   CLASS       N   =   8059     (2000)
•   VIGOR       N   =   8076     (2000)
•   Rotavirus   N   =   68,038   (2006)
•   SMART       N   =   26,355   (2006)
           Counterterrorism
                   “Animal Rule”

“Evidence
  Needed to
  Demonstrate
  Effectiveness
  of New Drugs
  When Human
  Efficacy
  Studies are
  not Ethical or
  Feasible”
             Counterterrorism
Under Animal Rule,
use data from two
species to predict
human responses:
•   Anthrax
•   Botulism
•   Plague
•   Smallpox
•   Tularemia
•   Viral hemorrhagic
     fevers
                  ICH
• International Conference on
  Harmonisation of Technical Requirements
  for Registration of Pharmaceuticals for
  Human Use
• Regions: EU, Japan, US
• Observers: WHO, others
• Co-sponsors: EC, UFPIA, MHW, JPMA,
  FDA, PhRMA
Int’l Conf on Harmonisation
•   E-3 Clinical Study Reports
•   E-5 Acceptance of foreign data
•   E-6 Good Clinical Practice
•   E-8 Gen’l Consid’s for Clinical Trials
•   E-9 Statistical Principles
•   E-10 Choice of control groups
Critical Path and Beyond
   •   Design efficiency
   •   Conduct efficiency
   •   Targetted therapies
   •   Imputation
   •   Simulation
   •   Extrapolation
  Critical Path and Beyond
                                                                        FDA
 Basic     Prototype    Preclinical                              Filing/Approval
Research   Design or   Development        Clinical Development       & Launch
           Discovery                                               Preparation




                                                    Market         Approval
                                                  Application




                                      Critical Path
Critical Path and Beyond
 •   Improved trial efficiency
 •   Better prospective planning
 •   Use of prior information
 •   Handling of missing data
 •   Analysis of multiple endpoints
 •   Addressing non-inferiority
“Random Sample” of recent FDA Statisticians
Celebrating 100 Years of Public Service
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions




 1900           1950                2000    2010

        Year of Statistical Contributions
Pace of Statistical Contributions
                                   The Sky is
                                   the Limit




 1900           1950                2000    2010

        Year of Statistical Contributions

				
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posted:10/30/2008
language:English
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