diseños adaptativos y otros diseños innovadores. el punto de vista de los reguladores

Diseños adaptativos y Diseños adaptativos y otros diseños otros diseños innovadores.innovadores.

El punto de vista de los El punto de vista de los reguladoresreguladores..

Ferran TorresFerran TorresHospital Clínic Barcelona / Universitat Autònoma Barcelona. Hospital Clínic Barcelona / Universitat Autònoma Barcelona.

EMA:EMA:

Scientific Advice Working Party (SAWP)Scientific Advice Working Party (SAWP)

Biostatistics Working Party (BSWP). Biostatistics Working Party (BSWP). [email protected]@uab.es 11

http://http://ferran.torres.name/docencia/amifeferran.torres.name/docencia/amife

Documentation

[email protected]@uab.es 22

DisclaimerDisclaimer

The views expressed are those of the speaker The views expressed are those of the speaker and not necessarily those of the AEMPS or EMEAand not necessarily those of the AEMPS or EMEA


Hoy nos Hoy nos hablará un hablará un reguladorregulador

The idea of The idea of adaptive designadaptive design Allow for Allow for mid-trial design modifications mid-trial design modifications based on based on

information from in- and outside the trial without information from in- and outside the trial without compromising on the false positive error rate.compromising on the false positive error rate.

The option to modify the design of an ongoing The option to modify the design of an ongoing clinical trial is clinical trial is intuitively appealingintuitively appealing– to to improve the performance improve the performance of the running trialof the running trial– to to correct misjudgments correct misjudgments in assumptionsin assumptions

Only adaptive designs (if carefully planned and Only adaptive designs (if carefully planned and conducted) conducted) guarantee a strict type I error control guarantee a strict type I error control in in case of design modifications in on-going clinical case of design modifications in on-going clinical trials trials

[email protected]@uab.es

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Issues of flexibility

Early stopping (futility, early rejection)Early stopping (futility, early rejection)

Selection of treatmentsSelection of treatments

Modification of the total sample sizeModification of the total sample size

Treatment allocation ratiosTreatment allocation ratios Modification of statistical analysis (Modification of statistical analysis (Choosing “optimal” scores …)Choosing “optimal” scores …)

Insertion or skipping of interim analysesInsertion or skipping of interim analyses

Population (change of inclusion/exclusion criteria, subgroups)Population (change of inclusion/exclusion criteria, subgroups)

Changing goals (non-inferiority Changing goals (non-inferiority →superiority)→superiority)

Modification of endpointsModification of endpoints

Adaptive dose-findingAdaptive dose-finding . . .. . .

Writing amendments for “online” design modifications will not be Writing amendments for “online” design modifications will not be solution in general! An amendment will not ensure that the type I solution in general! An amendment will not ensure that the type I error is controlled! error is controlled!


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Common issues in regulatory Common issues in regulatory discussions on adaptive designsdiscussions on adaptive designs

Dose

Independent replication

Exploratory studiesTotality of evidence for

regulatory decision making:

comprehensive planning,

compare strategies

Multiple adaptations

Type I error control

White space or thinking time?


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EMEA Reflection PaperEMEA Reflection Paper

Key principlesKey principles

A minimal prerequisite is the control of the A minimal prerequisite is the control of the pre-specified pre-specified type I errortype I error

Post hocPost hoc changes to the design of an already changes to the design of an already ongoing phase III trial are not recommendedongoing phase III trial are not recommended

If design changes are anticipated If design changes are anticipated the number the number of design modifications should be limitedof design modifications should be limited


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ChallengesChallenges JustificationJustification Pre-specificationPre-specification Bias, integrity of the trialBias, integrity of the trial HeterogeneityHeterogeneity Confidentiality/firewallsConfidentiality/firewalls Operational flexibility, substantial amendmentsOperational flexibility, substantial amendments Procedures for monitoring, decision-makingProcedures for monitoring, decision-making Impact on conduct and regulatory acceptanceImpact on conduct and regulatory acceptance

Early phases of drug development Early phases of drug development v.v. phase III phase III


SAWP & BSWPSAWP & BSWP SAWP:SAWP:

– Multidisciplinary group of 28 experts (complementary Multidisciplinary group of 28 experts (complementary scientific competences)scientific competences)

– 11 annual meetings11 annual meetings– Advice to sponsors on all aspects of drug Advice to sponsors on all aspects of drug

development: development: quality, non clinical, clinical quality, non clinical, clinical non-product related issues (e.g. on non-product related issues (e.g. on new statistical approachnew statistical approach or or

validation of a scale)validation of a scale) qualification of biomarkersqualification of biomarkers

Biostatistics Working Party:Biostatistics Working Party:– 10 10 members (plus observers)members (plus observers)– 3 F2F annual meetings + 10 TC3 F2F annual meetings + 10 TC


European Regulatory ActivitiesEuropean Regulatory Activities Internal discussions and external Internal discussions and external

networkingnetworking

Reflection paper published Oct 2007Reflection paper published Oct 2007 Consultation period March – Sept 2006Consultation period March – Sept 2006

http://www.emea.europa.eu/pdfs/human/http://www.emea.europa.eu/pdfs/human/ewp/245902enadopted.pdfewp/245902enadopted.pdf

EMEA / EFPIA workshops on adaptive EMEA / EFPIA workshops on adaptive designsdesigns– 14th Dec 200714th Dec 2007

http://www.emea.europa.eu/pdfs/http://www.emea.europa.eu/pdfs/conferenceflyers/conferenceflyers/report_adaptivedesigns.pdfreport_adaptivedesigns.pdf

– 2nd April 20092nd April 2009

0

10

20

30

40

50

60

2005 2006 2007 2008

Year

Nr o

f SA

or P

A let

ters

???

“adaptive” and/or “flexible” in SA letters

Which came first the chicken or the egg? [email protected]@uab.es 1212

Survey of SAWP proceduresSurvey of SAWP procedures

Broad range of therapeutic indications Broad range of therapeutic indications – including anti-– including anti-fungal, HIV, uveitis, anti-biotic, Type II diabetes, colorectal fungal, HIV, uveitis, anti-biotic, Type II diabetes, colorectal cancer, glioblastoma, multiple sclerosis, NSCLC … cancer, glioblastoma, multiple sclerosis, NSCLC …

About About one-third one-third are are orphan drugsorphan drugs..

Vast majority were as confirmatory studies Vast majority were as confirmatory studies (not surprising as (not surprising as this is the most common topic for SAWP advice) including this is the most common topic for SAWP advice) including numerous requests for adaptive designs as single pivotal numerous requests for adaptive designs as single pivotal trialstrials

Adaptive designs in pure Adaptive designs in pure phase II trials, phase II/III, phase IIIphase II trials, phase II/III, phase III

Most common proposals are Most common proposals are sample size re-estimationsample size re-estimation, , seamless phase II/III designs seamless phase II/III designs with treatment (dose) selection with treatment (dose) selection or both togetheror both together


Survey of SAWP proceduresSurvey of SAWP proceduresSummary findingsSummary findings

Tendency to keep the number of Tendency to keep the number of interim analysis as interim analysis as small as possiblesmall as possible

1 interim analysis: ~65% , 2 interim analysis ~29%1 interim analysis: ~65% , 2 interim analysis ~29% Adaptations should be limited to one interim analysisAdaptations should be limited to one interim analysis

TimingTiming of interim results of interim results Adaptations should be based on a reasonable amount of data. Adaptations should be based on a reasonable amount of data.

Too early interim analysis are discouragedToo early interim analysis are discouraged (e.g., survival data (e.g., survival data might be too pre-mature)might be too pre-mature)

n=2 proposals of adaptive designs with the option to n=2 proposals of adaptive designs with the option to change the statistical analysis methodology at interimchange the statistical analysis methodology at interim (e.g., switch from Cox proportional hazards model to parametric Weibull (e.g., switch from Cox proportional hazards model to parametric Weibull model)model)

There is a wide range on There is a wide range on other questions other questions concerning concerning adaptive designsadaptive designs


Survey of SAWP procedures Survey of SAWP procedures

Key findingsKey findings

In In ~20-25% ~20-25% there were concerns regarding there were concerns regarding type I error controltype I error control..• treatment selection (!!!)treatment selection (!!!)• sample size reassessmentsample size reassessment• no adjustment at allno adjustment at all• type I error only simulated although methods with strict type I error type I error only simulated although methods with strict type I error

would be availablewould be available

Not endorsing adaptive design without strict type I error Not endorsing adaptive design without strict type I error control is control is

• not due to a not due to a negative positionnegative position towards adaptive designs towards adaptive designs per seper se• but due to a but due to a positive positionpositive position towards the importance of type I error towards the importance of type I error

control in clinical trials.control in clinical trials.


Summary of design featuresSummary of design features

For DiscussionFor Discussion

No ‘white space’ / No ‘white space’ / thinking timethinking time– Sponsor riskSponsor risk

Maintenance of homogenous trial / Assessment of heterogeneity

UncontroversialUncontroversial

Dose selection Dose selection frameworkframework

Phase II data already Phase II data already availableavailable

Unequivocal Type I error Unequivocal Type I error controlcontrol

No sponsor involvement No sponsor involvement (though senior personnel (though senior personnel informed)informed)

Non-adaptive pivotal Non-adaptive pivotal study also availablestudy also available


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Areas still controversialAreas still controversial Adaptive designs as single pivotal study

Population (inclusion / exclusion criteria)

Change to primary endpoint based on internal information discouraged

Sponsor involvement –Strictly limited involvement has been cautiously accepted, in particular if not single pivotal study–“sponsor involvement discouraged” remains current standard

Informative adaptations in open-label trials

Design adaptations with limited or no experienceDesign adaptations with limited or no experience


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Conclusions Conclusions (1/2)(1/2) Flexible designs are an excellent tool to deal with

unexpected findings

But…

Design modifications should be justified and pre-specified

Address control of the type I error, estimates for the treatment effect

In late phase trials flexibility should be used care- and thoughtfully to maintain integrity and persuasiveness of the results

Too early looks may be strongly misleading


Conclusions Conclusions (2/2)(2/2)

Homogeneity of different stages (e.g., treatment effect Homogeneity of different stages (e.g., treatment effect before and after adaptive interim analysis)before and after adaptive interim analysis)

Integrity and interpretation must be preservedIntegrity and interpretation must be preserved

Need for operational flexibility / rigorous procedures, Need for operational flexibility / rigorous procedures, firewallsfirewalls

Promote use of adaptive designs where appropriate: Promote use of adaptive designs where appropriate: Exploratory studiesExploratory studies Difficult experimental situationsDifficult experimental situations Confirmatory studies where efficiency gains do not compromise Confirmatory studies where efficiency gains do not compromise

basis for regulatory decision or present unacceptable ‘risk’ to basis for regulatory decision or present unacceptable ‘risk’ to trial / trial programme.trial / trial programme.

Further consideration to be given to unresolved issuesFurther consideration to be given to unresolved issues


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References Reflection Paper on Methodological Issues in Confirmatory Clinical Reflection Paper on Methodological Issues in Confirmatory Clinical

Trials planned with an Trials planned with an adaptive designadaptive design ((CHMP/EWP/2459/02CHMP/EWP/2459/02))

Points to Consider on Points to Consider on MultiplicityMultiplicity issues in Clinical Trials issues in Clinical Trials (CPMP/EWP/908/99)(CPMP/EWP/908/99)

Points to Consider on Application with 1.) Meta-analyses and 2.) Points to Consider on Application with 1.) Meta-analyses and 2.) One One Pivotal studyPivotal study (CPMP/2330/99) (CPMP/2330/99)

Points to Consider on Points to Consider on SwitchingSwitching between Superiority and Non- between Superiority and Non-inferiority (CPMP/EWP/482/99)inferiority (CPMP/EWP/482/99)

Points to Consider on Choice of the Points to Consider on Choice of the Non-Inferiority Margin Non-Inferiority Margin (CPMP/EWP/2158/99)(CPMP/EWP/2158/99)

Guideline on Guideline on Data Monitoring Committees Data Monitoring Committees (CHMP/EWP/5872/03)(CHMP/EWP/5872/03)

Statistical Principles for Clinical Trials. Statistical Principles for Clinical Trials. ICHE9ICHE9. (. (CPMP/ICH/363/96)CPMP/ICH/363/96)

FDAFDA: Adaptive Design Clinical Trials for Drugs and Biologics: Adaptive Design Clinical Trials for Drugs and Biologics (Draft feb-(Draft feb-2010)2010)


[email protected]@uab.es [email protected]@uab.es 2121

http://ferran.torres.name/docencia/amife

Gracias por su atención!!Gracias por su atención!!

diseños adaptativos y otros diseños innovadores. el punto de vista de los reguladores

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trial design modifications

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number of design modifications

online design modifications

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