a history of stats at the fda mary a. foulkes, ph.d. u.s. food and drug administration office of...
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A History of Stats A History of Stats at the FDAat the FDA
Mary A. Foulkes, Ph.D.U.S. Food And Drug Administration
Office of Biostatistics and EpidemiologyCenter 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 CentersFDA Centers• Center for Biological Evaluation and Center for Biological Evaluation and
Research (CBER)Research (CBER)
• Center for Drug Evaluation and Research Center for Drug Evaluation and Research (CDER)(CDER)
• Center for Device and Radiological enter for Device and Radiological Health (CDRH)Health (CDRH)
• Center for Food Safety and Applied Center for Food Safety and Applied Nutrition (CFSAN) Nutrition (CFSAN)
• Center for Veterinary Medicine (CVM)Center for Veterinary Medicine (CVM)• National Center for Toxicological National Center for Toxicological
Research (NCTR)Research (NCTR)
OUTLINEOUTLINE
• Early years• Kefauver-Harris
Amendments• Grandfather• Women, Kids and Animals• Globalization• Critical Path and Beyond
A Public Outcry for a New A Public Outcry for a New LawLaw
• 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-1962Pre-1962
• Safety• Advertising
Wax, P. M. Ann Intern Med 1995;122:456-461
An original 1-gallon bottle of Elixir Sulfanilamide
Public Health Reports, January/February 2000, Volume 115
Pre-1962Pre-1962
• Safety• Advertising• Elixir
Sulfanilamide• LD 50 • Bioassay
Kefauver-Harris Kefauver-Harris AmendmentsAmendments
Evidence consisting of Evidence consisting of adequate and well-adequate and well-
controlledcontrolled investigations, including clinical investigations, including clinical
investigations, by experts qualified by scientific investigations, by experts qualified by scientific
training and experience to evaluate the training and experience to evaluate the
effectiveness of the drug involved, on the basis of effectiveness of the drug involved, on the basis of
which it could fairly and responsibly be concluded which it could fairly and responsibly be concluded
by such experts that the drug will have the effect by such experts that the drug will have the effect
it purports or is represented to have under the it purports or is represented to have under the
conditions of use prescribed, recommended, or conditions of use prescribed, recommended, or
suggested in the labeling or proposed labeling suggested in the labeling or proposed labeling
thereof.thereof.FD & C Act Section 505(d)FD & C Act Section 505(d)
Kefauver-Harris Kefauver-Harris AmendmentsAmendments
Evidence consisting of Evidence consisting of andand investigations, including clinical investigations, investigations, including clinical investigations,
by experts qualified by scientific training and by experts qualified by scientific training and
experience to evaluate the experience to evaluate the effectivenesseffectiveness of the of the
drug involved, on the basis of which it could fairly drug involved, on the basis of which it could fairly
and responsibly be concluded by such experts and responsibly be concluded by such experts
that the drug will have the effect it purports or is that the drug will have the effect it purports or is
represented to have under the conditions of use represented to have under the conditions of use
prescribed, recommended, or suggested in the prescribed, recommended, or suggested in the
labeling or proposed labeling thereof.labeling or proposed labeling thereof.
FD & C Act Section 505(d)FD & C Act Section 505(d)
adequaadequatete
well-controlledwell-controlled
1962 and Beyond1962 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
• 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
JASA, 1999
A prioriA priori Analysis Plan 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 errorControl of Type I error
• Primary and secondary outcomes
• Composite endpoints• Power• Essential Multiplicity• Implications for design
• Age enrollment to match indication
• Gender• Demographics• Pediatric Rule
SubgroupsSubgroups
Other IssuesOther Issues
• Active/placebo/historical controls• Adaptive trials• Combination products• Adverse Events/MedDRA/Data
Mining• Multiplicity• Endpoints• QA/QC
Group Sequential Group Sequential BoundariesBoundaries
Interim MonitoringInterim Monitoring• Outcome trials• Serious morbidity/mortality• Minimize risks• Futility• Regulatory implications
Large Safety StudiesLarge 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)
CounterterrorismCounterterrorism
“Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies are not Ethical or Feasible”
“Animal Rule”
CounterterrorismCounterterrorism
• Anthrax• Botulism• Plague• Smallpox• Tularemia• Viral hemorrhagic
fevers
Under Animal Rule, use data from two species to predict human responses:
ICHICH
• 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 Int’l Conf on HarmonisationHarmonisation
• 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
Basic Research
Prototype Design or Discovery
Preclinical Development Clinical Development
FDA Filing/Approval
& Launch Preparation
Market Application
Approval
Critical Path
Critical Path and Beyond
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 Random Sample” of recent FDA
StatisticiansStatisticians
Celebrating 100 Years of Public Celebrating 100 Years of Public ServiceService
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
1900
1938 1950
1962 19
80 2000 2010
Pace of Statistical ContributionsPace of Statistical Contributions
Year of Statistical Year of Statistical ContributionsContributions
The Sky The Sky is the is the LimitLimit