11

Europe & USA:Europe & USA:Interactions on Pediatric Clinical Interactions on Pediatric Clinical

TrialsTrialsDr. Dianne MurphyDr. Dianne Murphy

Director, Office of Pediatric TherapeuticsDirector, Office of Pediatric TherapeuticsOffice of the Commissioner,Office of the Commissioner,

Food and Drugs AdministrationFood and Drugs Administration

April, 2008April, 2008

22

OverviewOverview

Differences: US legislation and EU lawDifferences: US legislation and EU law

Principles of Interactions between FDA Principles of Interactions between FDA and EMEAand EMEA

Process and Scope of Work to DateProcess and Scope of Work to Date

Scientific information exchanged and Scientific information exchanged and types of issues discussedtypes of issues discussed

SummarySummary

33

EMEAEMEAEuropean European

CommissionCommission

• 27 Member States:27 Member States: (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxemburg, The Netherlands, Portugal, Spain, Sweden, United Kingdom, Estonia, Latvia, Lithuania, Czech Republic, Slovak Republic, Poland, Hungary, Slovenia, Malta, Cyprus, Bulgaria & Romania)

• EEA countries:EEA countries: Norway, Iceland, Liechtenstein

• Observers:Observers: Croatia, Turkey, Macedonia

• EFTA Switzerland excludedEFTA Switzerland excluded

23 languages!23 languages!

The European context: The European context: regulatory frameworkregulatory framework

44

55

The European context: The European context: regulatory frameworkregulatory framework

EMEA is not an FDA for Europe!EMEA is not an FDA for Europe!Member States have pooled their Member States have pooled their sovereignty for authorisation of sovereignty for authorisation of medicinesmedicinesEMEA coordinates the existing EMEA coordinates the existing scientific resources of Member Statesscientific resources of Member StatesAn interface with all partnersAn interface with all partnersAll parties linked by an IT network All parties linked by an IT network (EudraNet)(EudraNet)

66

The European Regulatory The European Regulatory FrameworkFramework

EMEA’s centralized process coordinates the EMEA’s centralized process coordinates the assessmentassessment by representatives from the by representatives from the member statesmember statesApproval Approval recommendationrecommendation is from an EMEA is from an EMEA committee (CHMP) comprised of member committee (CHMP) comprised of member states. (Pediatric Committee has members from states. (Pediatric Committee has members from the CHMP)the CHMP)Approval Approval authorizationauthorization is from European is from European CommissionCommissionCompany can opt for individual country Company can opt for individual country assessment & approval in certain casesassessment & approval in certain cases

77

Differences between Europe and Differences between Europe and USA USA PediatricPediatric Processes Processes

US: Can ask for US: Can ask for indicationindication that does not that does not exist in adults or not approved for exist in adults or not approved for marketing in adultsmarketing in adults

EU: Significant Therapeutic Benefit or EU: Significant Therapeutic Benefit or Fulfilled Therapeutic need Fulfilled Therapeutic need vsvs US US Meaningful Therapeutic Benefit or Meaningful Therapeutic Benefit or Substantial number of pediatric patients.Substantial number of pediatric patients.

88

Differences between Europe and Differences between Europe and USA Pediatric Processes (cont’d)USA Pediatric Processes (cont’d)US has 2 separate triggering processes US has 2 separate triggering processes (incentive and requirement) that are only (incentive and requirement) that are only partially coordinated by a pediatric committee partially coordinated by a pediatric committee while Europe has 1 pediatric law. while Europe has 1 pediatric law. Europe has a “centralized” procedure.Europe has a “centralized” procedure.All appropriate applications are submitted for All appropriate applications are submitted for review by a Pediatric Committee which review by a Pediatric Committee which addresses the studies needed for the Pediatric addresses the studies needed for the Pediatric Investigational Plan (PIP), waivers and deferrals. Investigational Plan (PIP), waivers and deferrals. The incentive is also linked to the PIP.The incentive is also linked to the PIP.In the US only those studies in response to a In the US only those studies in response to a Written Request are eligible for the incentiveWritten Request are eligible for the incentive

99

Differences between Europe and Differences between Europe and USA Pediatric ProcessesUSA Pediatric Processes

European filing of a product for an adult European filing of a product for an adult indication can be denied if it does not have indication can be denied if it does not have the required pediatric plan, waiver or the required pediatric plan, waiver or deferral; not possible in USdeferral; not possible in US

European process is asking for more European process is asking for more definitive information definitive information earlyearly in in development processdevelopment process

US: Has required pediatric focused PM US: Has required pediatric focused PM safety reviews with public presentation.safety reviews with public presentation.

1010

PEDIATRIC DIFFERENCES: PEDIATRIC DIFFERENCES: Post-Marketing SAFETYPost-Marketing SAFETY

USA: Mandated pediatric focused review USA: Mandated pediatric focused review of post marketing adverse events and a of post marketing adverse events and a public review of the data, even if the public review of the data, even if the product does not have a pediatric product does not have a pediatric indication (not approved but labeled)indication (not approved but labeled)

EUROPE: If the product is not marketed EUROPE: If the product is not marketed for pediatrics the safety review is not for pediatrics the safety review is not obligatoryobligatory

1111

Principles of Interactions: Principles of Interactions: EU/EMEA and FDAEU/EMEA and FDA

Based on ICH E-11Based on ICH E-11– Pediatric patients should be given medicines that Pediatric patients should be given medicines that

have been appropriately evaluated for their use in have been appropriately evaluated for their use in those populations.those populations.

– Development of product information in pediatric Development of product information in pediatric patients should be timely.patients should be timely.

– Well-being of pediatric patients participating in clinical Well-being of pediatric patients participating in clinical trials should not be compromised.trials should not be compromised.

– This responsibility is shared among companies, This responsibility is shared among companies, regulatory authorities, health professionals and regulatory authorities, health professionals and society as a whole.society as a whole.

1212

Principles of Interactions:Principles of Interactions:EMEA and FDAEMEA and FDA

ObjectivesObjectivesRegular exchange of scientific and ethical Regular exchange of scientific and ethical

information on pediatric development information on pediatric development programs in Europe and the U.S.programs in Europe and the U.S.

– To avoid exposing children to unnecessary To avoid exposing children to unnecessary trials.trials.

– To optimize global pediatric developmentTo optimize global pediatric development

1313

FDA and EMEA: Process of FDA and EMEA: Process of Information ExchangeInformation Exchange

Monthly t-con to discuss product-specific Monthly t-con to discuss product-specific pediatric development:pediatric development:

Pediatric Investigational Plans (PIPs), Written Pediatric Investigational Plans (PIPs), Written Requests (WRs), waivers and deferrals, other Requests (WRs), waivers and deferrals, other development and safety activities.development and safety activities.

Documents are exchanged through a secure Documents are exchanged through a secure link, Eudralink because the majority of the link, Eudralink because the majority of the information exchanged is confidential.information exchanged is confidential.

1414

FDA and EMEA: Scope of Information FDA and EMEA: Scope of Information ExchangedExchanged

From August ‘07 through February ‘08: From August ‘07 through February ‘08: – 119 PIPs with preliminary information received119 PIPs with preliminary information received

– 112 PIPs for which FDA provided scientific 112 PIPs for which FDA provided scientific informationinformation

– 57 PIPs discussed of which 17 were in-depth 57 PIPs discussed of which 17 were in-depth or expanded scientific discussions. or expanded scientific discussions.

1515

Elements of Standard Information Elements of Standard Information Exchanged: EMEAExchanged: EMEA

Monthly, EMEA sends FDA an excel Monthly, EMEA sends FDA an excel spreadsheet that includes the product spreadsheet that includes the product name, active substance, formulation, name, active substance, formulation, approved conditions, proposed PIP approved conditions, proposed PIP indication or proposal to waive or defer indication or proposal to waive or defer pediatric studies.pediatric studies.Summary Reports are sent for some Summary Reports are sent for some products that require expanded scientific products that require expanded scientific discussion. discussion.

1616

Elements of Standard Information: Elements of Standard Information: USAUSA

Monthly, FDA sends EMEA an excel Monthly, FDA sends EMEA an excel spreadsheet that includes:spreadsheet that includes:– the product name; the product name; – active substance; active substance; – information from the WR and, if applicable, information from the WR and, if applicable,

the PREA application (including indication, the PREA application (including indication, types of studies, age studied, date studies are types of studies, age studied, date studies are due); due);

– approved indications; approved indications;

1717

Elements of Standard Information: Elements of Standard Information: USA (continued)USA (continued)

Excel spreadsheetExcel spreadsheet– regulatory status (e.g. end-of-Phase 2 regulatory status (e.g. end-of-Phase 2

meeting, pre-NDA meeting, pediatric studies meeting, pre-NDA meeting, pediatric studies completed and ongoing, waivers and completed and ongoing, waivers and deferrals);deferrals);

– issues (e.g. clinical hold and other safety issues (e.g. clinical hold and other safety concerns)concerns)

1818

Scientific Information ExchangedScientific Information Exchanged

Status of ongoing pediatric studies Status of ongoing pediatric studies Results of studies conducted in pediatric Results of studies conducted in pediatric patients, including negative studiespatients, including negative studiesSafety concerns, including clinical holds.Safety concerns, including clinical holds.Plans for long-term safety monitoring.Plans for long-term safety monitoring.Differences in endpointsDifferences in endpointsDifferences in trial design Differences in trial design Differences in dosing regimenDifferences in dosing regimen

1919

Scientific Information ExchangedScientific Information Exchanged

Pending Written RequestsPending Written Requests

Waivers (rationale)Waivers (rationale)

Deferrals (e.g. need for additional safety Deferrals (e.g. need for additional safety data in adults before initiating studies in data in adults before initiating studies in pediatric patients)pediatric patients)

Collaboration on conduct of pediatric Collaboration on conduct of pediatric studies with international sites.studies with international sites.

2020

Expanded Scientific DiscussionsExpanded Scientific Discussions

Type of study (e.g. placebo control vs. Type of study (e.g. placebo control vs. active control for antihypertensive agents active control for antihypertensive agents and for treatment of multiple sclerosis)and for treatment of multiple sclerosis)

Choice of comparator for active-controlled Choice of comparator for active-controlled trials (active control may be standard of trials (active control may be standard of care and that may be different)care and that may be different)

2121

Expanded Scientific DiscussionsExpanded Scientific Discussions

Age group(s) to study (e.g. should neonates be Age group(s) to study (e.g. should neonates be included in the study; lower age limit for included in the study; lower age limit for antihypertensive, cholesterol-lowering trials and antihypertensive, cholesterol-lowering trials and topical anti-viral agents).topical anti-viral agents).

ExampleExample: Anti-convulsant requested studies in : Anti-convulsant requested studies in US down to 1 month of age while EMEA US down to 1 month of age while EMEA proposal includes neonates.proposal includes neonates.

Discussion of accuracy in diagnosis of and Discussion of accuracy in diagnosis of and distinguishing between types of seizures in distinguishing between types of seizures in neonates. neonates.

2222

Expanded Scientific DiscussionsExpanded Scientific Discussions

Indications for studyIndications for study

ExampleExample: Anti-fungal product: Anti-fungal product– Differences in indication being sought by the Differences in indication being sought by the

EMEA and the FDA concerning prophylaxis EMEA and the FDA concerning prophylaxis vs. treatment of fungal infections. FDA had vs. treatment of fungal infections. FDA had data from treatment trial studies.data from treatment trial studies.

– FDA has flexibility in determining indication; it FDA has flexibility in determining indication; it is not limited to indication approved in adultsis not limited to indication approved in adults

2323

Expanded Scientific DiscussionsExpanded Scientific Discussions

Choice of efficacy endpointsChoice of efficacy endpoints Examples:Examples:

-For antihypertensive studies: choice of systolic -For antihypertensive studies: choice of systolic blood pressure (BP), diastolic BP or mean BP as blood pressure (BP), diastolic BP or mean BP as the primary endpoint for antihypertensive the primary endpoint for antihypertensive studies.studies.

-For oncology studies of rare tumors: choice of a -For oncology studies of rare tumors: choice of a single primary endpoint (complete response) or single primary endpoint (complete response) or co-primary endpoints (complete response and co-primary endpoints (complete response and survival)survival)

2424

Expanded Scientific DiscussionExpanded Scientific Discussion

Reasons for “failed” studiesReasons for “failed” studies

ExampleExample: Treatment of migraine in : Treatment of migraine in adolescents- discussion of the timing of adolescents- discussion of the timing of the endpoint assessment and the impact the endpoint assessment and the impact of a high placebo response rate on the of a high placebo response rate on the ability to demonstrate a treatment effect.ability to demonstrate a treatment effect.

2525

SummarySummary

Principles of interactions between FDA and Principles of interactions between FDA and EMEA are those of ICH E-11.EMEA are those of ICH E-11.Interactions between FDA and EMEA occur Interactions between FDA and EMEA occur monthly and the process is evolving.monthly and the process is evolving.The overwhelming majority of the information The overwhelming majority of the information exchanged is confidential with documents exchanged is confidential with documents exchanged through a secure link, Eudralink.exchanged through a secure link, Eudralink.The goal is for global pediatric development to The goal is for global pediatric development to avoid exposing children to unnecessary trials avoid exposing children to unnecessary trials and to benefit from each other’s experience.and to benefit from each other’s experience.

2626

The Future= This Special PopulationThe Future= This Special PopulationStill remains largely unstudied: many of the Still remains largely unstudied: many of the

products go “off-patent” before we are ready to products go “off-patent” before we are ready to study this populationstudy this population

2727

2828