The ICH E5 Guidance:The ICH E5 Guidance:A Regulatory Perspective A Regulatory Perspective

on its on its Evolution and Evolution and

ImplementationImplementation

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

Director, Office of BiostatisticsDirector, Office of Biostatistics

CDER, FDACDER, FDA

For presentation at the

2nd Kitasato -Harvard Symposium, October 22-23, 2001

Outline of talkOutline of talk The evolution of the E5 Guidance from the The evolution of the E5 Guidance from the

perspective of a working group memberperspective of a working group member

Key aspects of the final E5 GuidanceKey aspects of the final E5 Guidance

The intent of bridging studies and gaining The intent of bridging studies and gaining experience with foreign clinical trials done in experience with foreign clinical trials done in compliance with ICH Guidances compliance with ICH Guidances

Some specific issues of study design and study Some specific issues of study design and study objectives for bridgingobjectives for bridging

Concluding remarks with regard to Concluding remarks with regard to implementation of E5 and experienceimplementation of E5 and experience

The evolution of the E5 The evolution of the E5 Guidance from the Guidance from the

perspective of a working perspective of a working group membergroup member

Topic proposed to the ICH Steering Topic proposed to the ICH Steering Committee in 1992 by Japan Committee in 1992 by Japan

Signed off in February, 1998 after many Signed off in February, 1998 after many years of effort regarding what should be years of effort regarding what should be its purpose, focus, content, and guidanceits purpose, focus, content, and guidance

I was one of two FDA expert working I was one of two FDA expert working group members in the six party working group members in the six party working group (regulator and industry reps from group (regulator and industry reps from the US, Europe, Japan)the US, Europe, Japan)

Evolution of ConceptsEvolution of Concepts

Objectives: What is the guideline about ?Objectives: What is the guideline about ?

Amount of detail and flexibility in advice (decision Amount of detail and flexibility in advice (decision trees, early emphasis was on Phase 1) trees, early emphasis was on Phase 1)

Operational definition of ethnicity ( term region used Operational definition of ethnicity ( term region used in general sense)in general sense)

Later emphasis placed on ‘evidence’ needed in each Later emphasis placed on ‘evidence’ needed in each region to conclude efficacy and safetyregion to conclude efficacy and safety

Two situations : Retrospective - what other data, Two situations : Retrospective - what other data, given a completed application; Prospective - Planning given a completed application; Prospective - Planning multi-regional drug development strategies multi-regional drug development strategies

Evolution of concepts (cont.)Evolution of concepts (cont.)

Similarity of issues to E4 (dose-response) and to E7 (special Similarity of issues to E4 (dose-response) and to E7 (special populations, Geriatrics)populations, Geriatrics)

Acceptance of data - Generalizability /extrapolation of phase 3 Acceptance of data - Generalizability /extrapolation of phase 3 efficacy/safety resultsefficacy/safety results

Algorithms to clearly show paths to follow for acceptance of Algorithms to clearly show paths to follow for acceptance of foreign dataforeign data

Triage the amount of information needed according toTriage the amount of information needed according to

profile of the drug, the intended population, clinical profile of the drug, the intended population, clinical experiences with drug (why E5 is not too prescriptive)experiences with drug (why E5 is not too prescriptive)

When is additional information needed: Bridging dataWhen is additional information needed: Bridging data

Key Features of E5Key Features of E5

Operational definition of ethnic factorsOperational definition of ethnic factors

Clinical Data Package Fulfilling Clinical Data Package Fulfilling Regulatory Requirements in New Regulatory Requirements in New RegionRegion

Extrapolation of Foreign Clinical Data Extrapolation of Foreign Clinical Data to New Region (role of ethnic factors)to New Region (role of ethnic factors)

Bridging StudiesBridging Studies

Global Development StrategiesGlobal Development Strategies

Ethnic Factor DefinitionEthnic Factor Definition

intrinsic factors: characteristics associated intrinsic factors: characteristics associated with the drug recipient (ADME studies)with the drug recipient (ADME studies)

race, age, gender, organ dysfunction, race, age, gender, organ dysfunction, genetic polymorphismgenetic polymorphism

extrinsic factors: characteristics associated extrinsic factors: characteristics associated with the environment and culture in which with the environment and culture in which one lives (clinical outcomes)one lives (clinical outcomes)

clinical trial conduct, diet, tobacco and clinical trial conduct, diet, tobacco and alcohol use, compliance with prescribed alcohol use, compliance with prescribed medicationsmedications

Assessing a medicine’s Assessing a medicine’s sensitivity to ethnic sensitivity to ethnic

factorsfactors(part of the screening (part of the screening

process)process)

Properties of a compound making Properties of a compound making it more likely to be sensitive:it more likely to be sensitive:

Metabolism by enzymes known Metabolism by enzymes known to show genetic polymorphismto show genetic polymorphism

High likelihood of use in a High likelihood of use in a setting of multiple co-setting of multiple co-medicationsmedications

Assessment of the Clinical Assessment of the Clinical Data Package (CDP) for Data Package (CDP) for

acceptabilityacceptability

Question 1: Meets regulatory Question 1: Meets regulatory requirements - yes/norequirements - yes/no

Question 2: Extrapolation of foreign data Question 2: Extrapolation of foreign data appropriate - yes/noappropriate - yes/no

Question 3: Further clinical study (ies) Question 3: Further clinical study (ies) needed for acceptability by the new needed for acceptability by the new region - yes/noregion - yes/no

Question 4: Acceptability in the new Question 4: Acceptability in the new region - yes/noregion - yes/no

Meets regulatory Meets regulatory requirementsrequirements

Issues of evidenceIssues of evidence

Confirmatory evidence; two or more studies Confirmatory evidence; two or more studies showing treatment effectsshowing treatment effects

Interpreting results of foreign clinical trials which Interpreting results of foreign clinical trials which provide that evidence (may be one study, or all provide that evidence (may be one study, or all studies, or part of a study)studies, or part of a study)

Which study designs provide evidenceWhich study designs provide evidence

Active control / non-inferiority designsActive control / non-inferiority designs

Placebo or active control / show a difference Placebo or active control / show a difference designsdesigns

The sources of data for an The sources of data for an application application

(implementation)(implementation)

All clinical studies for efficacy All clinical studies for efficacy performed in foreign regionperformed in foreign region

One study in the United States, One study in the United States, one or more foreign clinical one or more foreign clinical studiesstudies

Multi-center/ multi-region clinical Multi-center/ multi-region clinical trials form the basis for efficacytrials form the basis for efficacy

Considerations for Considerations for evaluating clinical evaluating clinical

efficacy between regionsefficacy between regions Study design differences Study design differences

Magnitude of treatment effect sizesMagnitude of treatment effect sizes

Effect size variability; subgroup differencesEffect size variability; subgroup differences

Impact of intrinsic factors - determined when ?Impact of intrinsic factors - determined when ?

Impact of Extrinsic factorsImpact of Extrinsic factors

trial conduct and monitoringtrial conduct and monitoring

usage of concomitant medicationsusage of concomitant medications

protocol adherenceprotocol adherence

Bridging StudiesBridging Studies

WhenWhen

WhyWhy

What typeWhat type

E5 is purposely vague on how to do this or what their design should be

Study design and study Study design and study objectivesobjectives

(need examples and (need examples and experience)experience)

What type of bridging study would be helpful for What type of bridging study would be helpful for extrapolation -extrapolation -

PK/PDPK/PD

Another clinical trial of the primary clinical Another clinical trial of the primary clinical endpointendpoint

equivalence/non-inferiority: treatment equivalence/non-inferiority: treatment effect acceptably close - margin or deltaeffect acceptably close - margin or delta

dose response study dose response study

superiority design - estimate treatment superiority design - estimate treatment effect size for comparisoneffect size for comparison

Issues of Statistical Issues of Statistical Design and Study Design and Study Analysis/InferenceAnalysis/Inference

E5 did not attempt to deal with E5 did not attempt to deal with statistical design or analysis issues.statistical design or analysis issues.

Nor did it deal with statistical Nor did it deal with statistical formulations of concepts such as formulations of concepts such as similarity, extrapolation, generalizabilitysimilarity, extrapolation, generalizability

The systematic study of associations and The systematic study of associations and responses that may differ according to responses that may differ according to ethnic categorization has many design ethnic categorization has many design and analysis aspects.and analysis aspects.

The Spirit and Intent of E5The Spirit and Intent of E5

Not intended to request bridging studies every Not intended to request bridging studies every timetime

Intended to permit the requesting of one Intended to permit the requesting of one ‘confirmatory’ phase 3 clinical trial (bridge study) ‘confirmatory’ phase 3 clinical trial (bridge study) in the region (not specifically defined, nor meant as in the region (not specifically defined, nor meant as ‘country’) if needed or necessary to extrapolate.‘country’) if needed or necessary to extrapolate.

Recognized that there would be a period of time Recognized that there would be a period of time where experience with foreign clinical studies where experience with foreign clinical studies would be accumulated and evaluated - not to be would be accumulated and evaluated - not to be confused with always asking for a new confirmatory confused with always asking for a new confirmatory trial in local region.trial in local region.

E5 allows for a new study E5 allows for a new study in the new region - why is in the new region - why is

that needed ?that needed ?

When all the clinical data is derived from a When all the clinical data is derived from a foreign region and extrapolation is an foreign region and extrapolation is an issueissue

When the experience with clinical trials in When the experience with clinical trials in that region is minimalthat region is minimal

When there is concern with ability to When there is concern with ability to confirm a finding from a study(ies)confirm a finding from a study(ies)

A confirmatory clinical trial is the bridging A confirmatory clinical trial is the bridging study study

Reasons for concernReasons for concern

We observe regional differences in observed We observe regional differences in observed treatment effects within the same study (not treatment effects within the same study (not always clear what is responsible, chance ?)always clear what is responsible, chance ?)

Differences in results of separate independent Differences in results of separate independent studies , each done in different regionsstudies , each done in different regions

What (bridging data) can explain the differences ?What (bridging data) can explain the differences ?

information gained prior to the studiesinformation gained prior to the studies

information gained after studies completedinformation gained after studies completed

Some FDA experienceSome FDA experience

Some licensure applications have contained clinical Some licensure applications have contained clinical trials that appeared to demonstrate efficacy, where trials that appeared to demonstrate efficacy, where all the trials were performed outside the US, but all the trials were performed outside the US, but where several other clinical trials requested to be where several other clinical trials requested to be done in the US did not confirm a treatment effect - no done in the US did not confirm a treatment effect - no identifiable reason - an issue of ‘evidence’ identifiable reason - an issue of ‘evidence’

Type of study design done in the USType of study design done in the US

show a difference (a treatment effect)show a difference (a treatment effect)

non-inferiority active control (indirect inference non-inferiority active control (indirect inference for efficacy)for efficacy)

Multi-regional multi-center trials Multi-regional multi-center trials

Concluding RemarksConcluding Remarks Most experience with foreign trials from Europe (West & East), Most experience with foreign trials from Europe (West & East),

New Zealand, Canada, Latin America - even here the possible New Zealand, Canada, Latin America - even here the possible heterogeneity of treatment effects is being evaluated (Merit - heterogeneity of treatment effects is being evaluated (Merit - metoprolol in CHF)metoprolol in CHF)

Little experience with Asian trials included as primary evidence in Little experience with Asian trials included as primary evidence in NDA applicationsNDA applications

Quality of the trial and its results are the determining factor, not Quality of the trial and its results are the determining factor, not necessarily where it was conductednecessarily where it was conducted

Bridging concept is used in pediatrics - request phase 3 trials in Bridging concept is used in pediatrics - request phase 3 trials in some casessome cases

Is it time to collect our experience on the types of studies being Is it time to collect our experience on the types of studies being conducted ?conducted ?