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
CLASS
VIGOR
Rotavirus
SMART
N
N
N
N
N
=
=
=
=
=
84,192
8059
8076
68,038
26,355
(1995)
(2000)
(2000)
(2006)
(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
Basic
Research
Prototype
Design or
Discovery
Preclinical
Development
Clinical Development
Market
Application
Critical Path
FDA
Filing/Approval
& Launch
Preparation
Approval
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
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
1900
1950
2000
Year of Statistical Contributions
2010
Pace of Statistical Contributions
The Sky is
the Limit
1900
1950
2000
Year of Statistical Contributions
2010