Workshop PAEDIATRIC INVESTIGATION PLAN - …

1 Birka LehmannAGAHW orkshopPAEDIATRIC INVESTIGATION PLANHow to Adapt Clinical Development to the Particularities of Paediatrics?13. -14. 01. 2009 BonnMedicinal ProductsNew requirements for marketing authorisation & Information and TransparencyRegulation (EC) No 1901/2006 Regulation 1901/2006 Regulation726/2004 Directive2001/83 SmPC& PLClinical trials in minor&databasePublic databaseMA requirements&InformationGuideline: EthicalConsiderationSmPC GuidelineGuidance:Public informationDirective2001/20 Commission Regulation (EC) No 2049/2005*Scientific Advice(SAWP)Scientific Advice = free off chargeSmall & Medidium SizedEnterprisesCommunication from theCommission The PAEDIATRIC INVESTIGATION plan (PIP)Notice to Applicants EMEA s/PDCO s expectations and experiences with submitted PIPs, Regulatory requirements for PIPs with new drugs, marketed and out-of-patent drugs New PAEDIATRIC formulationsPIP and Consequences Clinical trials appliction.

2 Ethics Committees & national competent authority Validation of MA application COMPLIANCE CHECK MA with SmPC & PLMA & Summary of Product Characteristics & Package leafletMarketing authorisation (MA) application/Validation/compliance checkEMEA/NCA*Ethics Committee & **national competent authorityEvaluation of MA**-Dossier(210days)CHMP/NCA Clinical Trials ApplicationPDCO/PIP(60/120 days)Opinion of PDCO on PIPEMEAD ecision to applicantEU-Commission oderNCAD ecision on MAEC* & NCA** Selected age group(s) ..should cover all subsets of the PAEDIATRIC population, including neonates,which are notcovered by a.

3 Strategy in relation to clinical aspects(PIP indications and age subsets)EfficacySafetyDose/dosage Age appropriate formulationPre-term InfantTerm NewbornInfant/ToddlerChildAdolescent< 36 weeks0-27 days28 days2 1112 end of17 gestation-23 monthsyearsyearsSurvivalAdaptation Growth Training MaturationThe PAEDIATRIC INVESTIGATION plan (PIP) EMEA s/PDCO s expectations and experiences with submitted PIPs, Regulatory requirements for PIPs with new drugs, marketed and out-of-patent drugs New PAEDIATRIC formulationsNew:CommCommPIP 24 September 2008 Condition PAEDIATRIC INVESTIGATION plan indication proposed therapeutic indication Reg.

4 1901/200612 December 2006 Art 2(2) PAEDIATRIC INVESTIGATION plan indication - condition Condition vs - definition of waiver requestThe specific medicinal product or class of medicinal products is likely to beineffective or unsafe in part or all of the PAEDIATRIC populationThe disease or condition for which the specific medicinal product or class isintended occurs only in adult populationsThe specific medicinal product does not represent a significant therapeuticbenefit over existing treatments for PAEDIATRIC patientsBased on the provisions set out in Article 11-13 of the PAEDIATRIC Regulation.

5 The PDCO proposes to grant a class waiver for the following indications (condition)publication 21 April 2008 New:CommCommPIP 24 September 2008 Condition PAEDIATRIC INVESTIGATION plan indication proposed therapeutic indication Reg. 1901/200612 December 2006 Art 2(2) PAEDIATRIC INVESTIGATION plan indication - condition Condition vs - definition of waiver requestContent of PDCO opinion/EMEA decisionInformation in cover letter EMEA s/PDCO s expectations and experiences with submitted PIPs, Regulatory requirements for PIPs with new drugs, marketed and out-of-patent drugs New PAEDIATRIC formulationsRegulation (EEC) No 1901/2006 CORE.

6 PAEDIATRIC INVESTIGATION plan (PIP)Application for marketing authorisation for medicinalproducts Article = application of new medicinal productswith PIP and results of studies according to PIP Article = Line-Extensions (with SupplementaryProtection Certificate/Patent) Article 30 PAEDIATRIC Use Marketing Authorisation (PUMA) - off patent medicinal productsNew:Communication from the CommissionThe PAEDIATRIC INVESTIGATION plan (PIP)24 September 2008 SECTION 1 FORMAT AND CONTENT OF APPLICATIONSFOR AGREEMENTOR MODIFICATION OF A PAEDIATRIC INVESTIGATION plan ANDREQUESTS FOR WAIVERS OR - GENERAL PRINCIPLES AND FORMATT hesame application form(see the Annex to this guideline) should beused whether requesting agreement to a PAEDIATRIC INVESTIGATION plan , a waiver, a deferral or a combination thereof.

7 Different parts (Part A to Part F)of the application are provided to fulfil the different types of C: Application for productspecific waiversPart E: Application : Synopsis/outline of protocol of each of the planned and/orongoing clinical studies or trials type of study, study design, type of control (placebo or active control with dose to be used) and justification, location (regions), test(s) products; dosage regimen; route of administration, objective(s) of the study, number of subjects (M/F), ages, number per ICH age groups or other relevant age group, duration of treatment including the duration of post-treatment observation, main inclusion/exclusion criteria, parameters or endpoints (primary, secondary), sample size (more or less detailed as appropriate), power calculation.

8 Describe effect size expected, options in case of recruitment issues, interim analyses and stopping rules, statistical methods (Statistical methods used to compare groups for primaryoutcome, and for additional analyses if relevant).New:The PAEDIATRIC INVESTIGATION plan (PIP)Design of clinical trialsFeasibility of the trial to be performedSize of trialEthnic groups (genetic characteristics)Blinded/un-blindedUse of placebo (not withholding effective treatment) Comparator (unlicensed??)Pain, distress and fear minimisationRisk assessment and monitoringBenefit and measures of benefitPaediatric INVESTIGATION plan (PIP)AdolescentChildInfant/ToddlerTerm NewbornPre-term InfantThe PAEDIATRIC INVESTIGATION plan (PIP)AdultExtrapolation: ?

9 Efficacy Safety?Guidelines on indication/conditionsAddendum (Annex) for PAEDIATRIC populationWhy? Diagnostic Endpoints measurement/monitoring MonitoringAddendum for PAEDIATRIC populationWhy? EndpointsThe suitability of 6-Minutes Walk Testas a primary endpoint should bediscussed considering it is influenced byage, .. and degree of motivation Other endpoints could include functional tests( cardiopulmonary exercise testing, shuttle walk test), biomarkers, or thedevelopment of a PAH-specific quality of life questionnaire.(Possible) Recommendation Endpoints? Pulmonary vascular resistanceInvasive (right cardiac catheterization) / non-invasiv(echocadiography/Doppler) for children under (6?)

10 Years of age correlationclinical scoreDevelopment of a CHMP Guidelineon the Clinical Investigations of Medicinal Productsfor the treatment of Pulmonary HypertensionUp-date of guidelinesEXAMPLEPart E: ApplicationsdeferralsPursuant to Article 20(1) of the PAEDIATRIC regulation, a request may be made for deferral of the initiation or completion of some or all of themeasures .With reference to the timelines stated in Section , and to which-indication, -route of administration-pharmaceutical form. -The application should specify the age group to which it applies. For timelines, specific months and years should be given also in relation to thedevelopment in for deferrals should be justified on scientific and technical grounds or on grounds related to public health and the PAEDIATRIC regulation requires that a deferral be granted when.