Transcript ONEILL-Graybill talk -2008final

Emerging Trends in Regulatory
Biostatistics What might be their impact ?
Robert T. O’Neill Ph.D.
Director, Office of Biostatistics
Office of Translational Sciences, CDER
Presented at the VII Graybill Conference on "Biopharmaceutical Statistics"
June 12-13, 2008 ; Colorado State University
Hilton Fort Collins , Fort Collins, Colorado
Outline
 The current environment - trends
 Global drug development
 Guidance development - consensus building
 Quantitative safety assessment
 Personalized medicine - benefit / risk
 Future needs
The current environment
 Public expectations for drug regulation and
monitoring
 Track record for product development success
 Increasing amounts of data - does it pay off and
inform - is it being used
 Emerging science - is statistics involved ?
 Increased resources - FDA is hiring but Europe is
not
The Environment

FDAAA and its implications

Staffing recruitment





Fellowships - Reagan Udall Foundation
New Responsibilities
Guidance development - why

Non Inferiority designs

Adaptive designs

Future - multiple endpoints, missing data
Emerging science -dealing with it

Modeling and simulation - disease modification claims

Genomics and personalized medicine

Quality by design - auditing and inspection strategies
The science of safety/risk assessment - benefit / risk - life cycle evaluation
http://www.fda.gov/oc/initiatives/criticalpath/
http://www.fda.gov/oc/initiatives/advance/reports/report0508.html.
The Emerging Science of Safety
The medical literature and editors recognize a need to
improve the reporting of safety outcomes
Safety First/Safe Use
Overview of a New CDER
Initiative
Rationale:
New Realities in the 21st Century
 Two decades ago patients and clinicians lacked effective
treatments for most major life-threatening illnesses

Congress and the President gave FDA increased resources and
mandates to expedite development and patient access to new drugs
[e.g., PDUFA 1992, FDAMA 1997]
 Today many more treatments are available, but patterns of drug
use and guiding information have shifted dramatically.
Patients and clinicians need more accurate, up-to-date and
understandable information to ensure safe use

Congress and the President has given FDA increased authority,
resources and responsibility to oversee post-market safety and better
inform patients and clinicians to enable safe use [FDAAA 2007]
Purpose
 To ensure drug safety throughout the drug
lifecycle by giving pre-marketing drug
review and post-marketing safety an equal
focus
 To develop multiple strategies to influence
the safe and appropriate use of drugs
The Multi-Regional Multi-center
Study
Increasingly used in drug product
development
Some Experience with
statistical reviews of NDA’s and
Clinical Studies
 Summary of review of 7 years of clinical
studies involving foreign clinical data in
NDA’s
 21 NDA submissions whose decisions
depended upon analysis and interpretation
of treatment effects in multi-regional trials
 John Lawrence evaluation of large
cardiovascular outcome studies
Of 1,926 clinical trials analyzed by OB during FY01-FY07:
41% were domestic; 50% foreign-domestic; and 9% foreign.
Of all subjects enrolled in these trials:
30% were U.S.; 63% domestic-foreign; and 7% foreign.
Regulatory consequences
 Non approvals
 4 of 22 not approved because of regional
heterogeneity
 9 of 22 approvable but more information
needed - regional heterogeneity
 Need another study
 Labeling limitations or information - Merit
Study Undertaken by FDA
statisticians to evaluate possibility
of systematic regional differences
 Major cardiovascular outcome studies
evaluated over the last 10 years
 Overall study result statistically positive,
ie. demonstrated overall effect
 Region never pre-specified as a factor to be
evaluated statistically
 16 independent studies
Estimates and confidence intervals for difference
between US and Non-US treatment effects for each study
In 13 of 16 , US log hazard above 0
Study
% US
1
31
2
45
3
27
4
5
9
4
6
19
7
43
8
38
9
10
4
74
11
74
12
9
13
3
14
15
29
17
16
90
-1.5
-1.0
-0.5
0.0
0.5
difference of log-hazard ratios
J. Lawrence
1.0
1.5
A figure
From the label
FDA Amendments Act of 2007
FDAAA
Among the provisions of the law, FDAAA
reauthorizes user fees [PDUFA IV] and increases
the resources that CDER will have available for
ensuring product safety in the new drug review
process, monitoring drug safety after product
marketing, and reviewing consumer television
ads that are voluntarily submitted to FDA.
FDAAA also reauthorizes key programs for
ensuring safe use of drug products in children by
encouraging more research into developing
treatments for children.
Guidance Development
FDA actively leading consensus and
direction on critical topics

Adaptive clinical study designs

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Non-Inferiority study designs

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Exploratory and confirmatory
Current literature is inadequate
Missing data in clinical trials

Statistics alone cannot address it

Statistics has not added much - yet

Multiplicity

Enrichment designs, biomarkers, personalized medicine
Advancing Innovative Trial Design
Why the need for a Guidance on
Non-Inferiority Studies ?
 Guidance in available documents is not
sufficient
 Confusion in current usage
 Naïve usage
 Need for direction on approaches
 Clarity on when the design is appropriate
Statistics in Medicine
Special Issue:
Non-Inferiority Trials:
Advances in Concepts and
Methodology
Volume 22, Issue 2, 2003
Quantitative Safety Assessment
What do we mean ?
Emerging Science of
Quantitative Safety Assessment
 Causal analysis
 Propensity score matching
 Cumulative meta-analysis
 Rare events
 Prediction, prognostic, positive predictive value
 Multiple recurrent event methods
 Time to event analysis for risk exposure
Visual graphics to aid interpretation of
multivariate, multiple event data (safety and
efficacy), and motivate model formulation
for later analysis or summary presentations
Begin with the electronic chronological
patient record to aid patient level
interpretation (patient profile viewer)
Build on this for population (group)
estimates and comparisons
Patient time line graph for clinical trial data, AE’s, med. exposures, labs, outcomes
Exposure history of test
treatment - time course
Time of occurrence and
duration of ADE’s
Exposure history of
concomitant medications time course
Primary
outcome
Serious
event
Lab data
Display of the duration of treatment and follow up and the timing of
increases in ALT for the 500 patients in a study receiving a "low" and
a "high" dose treatment
Personalized Medicine
What does that mean ?
Where are we going - the future
 Resources - very promising for FDA
 Outside of the US FDA, the picture is not
as rosy - can modern product development
flourish without statistical resources
Reagan-Udall Foundation for the
Food and Drug Administration
Summary of Key Provisions
“The purpose of the foundation is to advance the mission of the
Food and Drug Administration to modernize medical, veterinary,
food, food ingredient, and cosmetic product development,
accelerate innovation, and enhance product safety.”
Fellowships and applied projects useful to the academic
community
Bioinformatics
Access to data, RCT and manufacturing
quality assurance
 Standards for clinical trial data- CDISC
 Access to all clinical trials at the patient
level data - not summary data in articles or
websites
 The quality by design concept for modern
RCT’s - FDA’s mandate to monitor and
inspect
We are looking
for a few good
statisticians