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

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



• 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

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1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

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1900

1938 1950

1962 19

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1938 1950

1962 19

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1900

1938 1950

1962 19

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1900

1938 1950

1962 19

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1938 1950

1962 19

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1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



1900

1938 1950

1962 19

80 2000 2010



The Sky The Sky is the is the LimitLimit

Documents

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