Emerging Trends in Emerging Trends in Regulatory Biostatistics -Regulatory Biostatistics -

What might be their impact ? What might be their impact ?

Robert T. O’Neill Ph.D.Robert T. O’Neill Ph.D.

Director, Office of BiostatisticsDirector, Office of Biostatistics

Office of Translational Sciences, CDEROffice of Translational Sciences, CDER

Presented at the VII Graybill Conference on "Biopharmaceutical Statistics" June 12-13, 2008 ; Colorado State UniversityHilton Fort Collins , Fort Collins, Colorado

Outline Outline

The current environment - trendsThe current environment - trends

Global drug development Global drug development

Guidance development - consensus Guidance development - consensus buildingbuilding

Quantitative safety assessmentQuantitative safety assessment

Personalized medicine - benefit / riskPersonalized medicine - benefit / risk

Future needsFuture needs

The current The current environmentenvironment

Public expectations for drug regulation Public expectations for drug regulation and monitoringand monitoring

Track record for product development Track record for product development successsuccess

Increasing amounts of data - does it pay Increasing amounts of data - does it pay off and inform - is it being used off and inform - is it being used

Emerging science - is statistics involved ?Emerging science - is statistics involved ?

Increased resources - FDA is hiring but Increased resources - FDA is hiring but Europe is notEurope is not

The EnvironmentThe Environment

FDAAA and its implicationsFDAAA and its implications

Staffing recruitmentStaffing recruitment

Fellowships - Reagan Udall FoundationFellowships - Reagan Udall Foundation

New ResponsibilitiesNew Responsibilities

Guidance development - whyGuidance development - why

Non Inferiority designsNon Inferiority designs

Adaptive designsAdaptive designs

Future - multiple endpoints, missing dataFuture - multiple endpoints, missing data

Emerging science -dealing with itEmerging science -dealing with it

Modeling and simulation - disease modification claimsModeling and simulation - disease modification claims

Genomics and personalized medicineGenomics and personalized medicine

Quality by design - auditing and inspection strategiesQuality by design - auditing and inspection strategies

The science of safety/risk assessment - benefit / risk - life cycle The science of safety/risk assessment - benefit / risk - life cycle evaluationevaluation

http://www.fda.gov/oc/initiatives/criticalpath/

http://www.fda.gov/oc/initiatives/advance/reports/report0508.html.

The Emerging Science of SafetyThe Emerging Science of Safety

The medical literature and editors recognize a need to improve the reporting of safety outcomes

Safety First/Safe UseSafety First/Safe Use

Overview of a New Overview of a New CDER InitiativeCDER Initiative

Rationale: Rationale: New Realities in the 21New Realities in the 21stst Century Century

Two decades ago Two decades ago patients and clinicians lacked patients and clinicians lacked effective treatments for most major life-threatening effective treatments for most major life-threatening illnessesillnesses

Congress and the President gave FDA increased resources Congress and the President gave FDA increased resources and mandates to expedite development and patient access to and mandates to expedite development and patient access to new drugs [e.g., PDUFA 1992, FDAMA 1997]new drugs [e.g., PDUFA 1992, FDAMA 1997]

TodayToday many more treatments are available, but many more treatments are available, but patterns of drug use and guiding information have patterns of drug use and guiding information have shifted dramatically. Patients and clinicians need more shifted dramatically. Patients and clinicians need more accurate, up-to-date and understandable information accurate, up-to-date and understandable information to ensure safe useto ensure safe use

Congress and the President has given FDA increased Congress and the President has given FDA increased authority, resources and responsibility to oversee post-authority, resources and responsibility to oversee post-market safety and better inform patients and clinicians to market safety and better inform patients and clinicians to enable safe use [FDAAA 2007]enable safe use [FDAAA 2007]

PurposePurpose

To ensure drug safety throughout To ensure drug safety throughout the drug lifecycle by giving pre-the drug lifecycle by giving pre-marketing drug review and post-marketing drug review and post-marketing safety an equal focus marketing safety an equal focus

To develop multiple strategies to To develop multiple strategies to influence the safe and appropriate influence the safe and appropriate use of drugsuse of drugs

The Multi-Regional Multi-The Multi-Regional Multi-center Studycenter Study

Increasingly used in drug Increasingly used in drug product developmentproduct development

Some Experience withSome Experience with statistical reviews of NDA’s statistical reviews of NDA’s

and Clinical Studiesand Clinical Studies

Summary of review of 7 years of Summary of review of 7 years of clinical studies involving foreign clinical studies involving foreign clinical data in NDA’sclinical data in NDA’s

21 NDA submissions whose decisions 21 NDA submissions whose decisions depended upon analysis and depended upon analysis and interpretation of treatment effects in interpretation of treatment effects in multi-regional trialsmulti-regional trials

John Lawrence evaluation of large John Lawrence evaluation of large cardiovascular outcome studiescardiovascular outcome studies

Of 1,926 clinical trials analyzed by OB during FY01-Of 1,926 clinical trials analyzed by OB during FY01-FY07:FY07:

41% were domestic; 50% foreign-domestic; and 9% 41% were domestic; 50% foreign-domestic; and 9% foreign.foreign.

Of all subjects enrolled in these trials:Of all subjects enrolled in these trials:30% were U.S.; 63% domestic-foreign; and 7% 30% were U.S.; 63% domestic-foreign; and 7%

foreign.foreign.

Regulatory Regulatory consequencesconsequences

Non approvalsNon approvals

4 of 22 not approved because of 4 of 22 not approved because of regional heterogeneityregional heterogeneity

9 of 22 approvable but more 9 of 22 approvable but more information needed - regional information needed - regional heterogeneityheterogeneity

Need another studyNeed another study

Labeling limitations or information - MeritLabeling limitations or information - Merit

Study Undertaken by FDA Study Undertaken by FDA statisticians to evaluate statisticians to evaluate possibility of systematic possibility of systematic

regional differencesregional differences

Major cardiovascular outcome studies Major cardiovascular outcome studies evaluated over the last 10 yearsevaluated over the last 10 years

Overall study result statistically Overall study result statistically positive, ie. demonstrated overall positive, ie. demonstrated overall effecteffect

Region never pre-specified as a factor Region never pre-specified as a factor to be evaluated statisticallyto be evaluated statistically

16 independent studies16 independent studies

difference of log-hazard ratios

Study % US

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5

311

452

273

94

45

196

437

388

49

7410

7411

912

313

2914

1715

9016

Estimates and confidence intervals for difference between US and Non-US treatment effects for each study

J. Lawrence

In 13 of 16 , US log hazard above 0

A figure

From the label

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.

FDA Amendments Act of 2007FDA Amendments Act of 2007FDAAAFDAAA

Guidance DevelopmentGuidance DevelopmentFDA actively leading FDA actively leading

consensus and direction on consensus and direction on critical topicscritical topics

Adaptive clinical study designsAdaptive clinical study designs

Exploratory and confirmatoryExploratory and confirmatory

Non-Inferiority study designsNon-Inferiority study designs

Current literature is inadequateCurrent literature is inadequate

Missing data in clinical trialsMissing data in clinical trials

Statistics alone cannot address itStatistics alone cannot address it

Statistics has not added much - yetStatistics has not added much - yet

MultiplicityMultiplicity

Enrichment designs, biomarkers, personalized Enrichment designs, biomarkers, personalized medicine medicine

Advancing Innovative Trial Advancing Innovative Trial DesignDesign

Why the need for a Guidance Why the need for a Guidance on Non-Inferiority Studies ?on Non-Inferiority Studies ?

Guidance in available documents is Guidance in available documents is not sufficientnot sufficient

Confusion in current usageConfusion in current usage

Naïve usageNaïve usage

Need for direction on approachesNeed for direction on approaches

Clarity on when the design is Clarity on when the design is appropriateappropriate

Statistics in MedicineStatistics in Medicine

Special Issue: Special Issue:Non-Inferiority Trials: Non-Inferiority Trials: Advances in Concepts Advances in Concepts

and Methodology and Methodology

Volume 22, Issue 2, 2003Volume 22, Issue 2, 2003

Quantitative Safety Quantitative Safety AssessmentAssessment

What do we mean ?What do we mean ?

Emerging Science of Emerging Science of Quantitative Safety Quantitative Safety

AssessmentAssessment

Causal analysisCausal analysis

Propensity score matchingPropensity score matching

Cumulative meta-analysisCumulative meta-analysis

Rare eventsRare events

Prediction, prognostic, positive Prediction, prognostic, positive predictive valuepredictive value

Multiple recurrent event methodsMultiple recurrent event methods

Time to event analysis for risk exposureTime to event analysis for risk exposure

Visual graphics to aid interpretation Visual graphics to aid interpretation of multivariate, multiple event data of multivariate, multiple event data (safety and efficacy), and motivate (safety and efficacy), and motivate model formulation for later analysis model formulation for later analysis or summary presentations or summary presentations

Begin with the electronic Begin with the electronic chronological patient record to aid chronological patient record to aid patient level interpretation (patient patient level interpretation (patient profile viewer)profile viewer) Build on this for population (group) Build on this for population (group) estimates and comparisonsestimates and comparisons

Exposure history of test treatment - time course

Time of occurrence and duration of ADE’s

Exposure history of concomitant medications -time course

Lab data

Primaryoutcome

Patient time line graph for clinical trial data, AE’s, med. exposures, labs, outcomes

Seriousevent

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 MedicinePersonalized MedicineWhat does that mean ?What does that mean ?

Where are we going - the Where are we going - the futurefuture

Resources - very promising for Resources - very promising for FDAFDA

Outside of the US FDA, the picture Outside of the US FDA, the picture is not as rosy - can modern is not as rosy - can modern product development flourish product development flourish without statistical resourceswithout statistical resources

Reagan-Udall Foundation for the Reagan-Udall Foundation for the Food and Drug AdministrationFood and Drug Administration

Summary of Key ProvisionsSummary of Key Provisions

““The purpose of the foundation is to advance the The purpose of the foundation is to advance the mission of the Food and Drug Administration to mission of the Food and Drug Administration to

modernize medical, veterinary, food, food modernize medical, veterinary, food, food ingredient, and cosmetic product development, ingredient, and cosmetic product development,

accelerate innovation, and enhance product safety.”accelerate innovation, and enhance product safety.”

Fellowships and applied projects useful to the Fellowships and applied projects useful to the academic communityacademic community

BioinformaticsBioinformaticsAccess to data, RCT and Access to data, RCT and

manufacturing quality assurancemanufacturing quality assurance

Standards for clinical trial data- Standards for clinical trial data- CDISCCDISC

Access to all clinical trials at the Access to all clinical trials at the patient level data - not summary patient level data - not summary data in articles or websitesdata in articles or websites

The quality by design concept for The quality by design concept for modern RCT’s - FDA’s mandate to modern RCT’s - FDA’s mandate to monitor and inspectmonitor and inspect

We are looking for a

few good statisticians