6/22/2013 Chronology European Development Revatio (Sildenafil) The Sildenafil Orphan Drug designation : 03.12.2003 & 27.02.2007 Controversy Paediatric Investigation Plan: 17.03.2010 Marketing Authorisation in EU : PAH Adults 28.10.2005 EMA pos opinion: PAH p aed pop 1 – 17 years 17.03.2011 European Commission MA: PAH 1 – 17 years 04.05.2011 European Medicines Agency/Paediatric Committee Paediatric Investigation Plan: EMEA-000671-PIP01-08 medicinal product = sildenafil Main issues for the medicinal product • Medical need √ • Relevant age groups 0/(1) – 17 years • Studies: PAH: Study A1481131 & Extension Study A1481156 PPNH: Study A1481276 (deferred) 1
6/22/2013 EMA European Medicines Agency (EMA) Assessment Report/Summary of Product Characteristics Committee for Human Medicinal Products (CHMP) Spring 2011 4.1 Indication positive opinion Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity Paediatric population or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart Treatment of paediatric patients aged 1 year to 17 years old with disease (see section 5.1) pulmonary arterial hypertension. 4.2 Posology Efficacy in terms of improvement of exercise capacity or pulmonary Paediatric Population haemodynamics has been shown in primary pulmonary hypertension The safety and efficacy of Revatio in children below 1 year of age has not and pulmonary hypertension associated with congenital heart been established. No data are available. There is a limited experience in patients below 7 years of age (see section 5.1). Disease. For paediatric patients aged 1 year to 17 years old, the recommended dose = recommendation to in patients ≤ 20 kg is 10 mg (1 ml of compounded suspension) three times a day and for patients > 20 kg is 20 mg (2 ml of compounded suspension or European Commission for EU MA 1 tablet) three times a day. Higher doses are not recommended in paediatric patients (see section 5.1). Assessment Report Assessment Report Dosing Randomised, double-blind, multi-center, placebo controlled parallel group, dose ranging. Patients : 1-17 years, with Primary PAH or PAH secondary to congenital heart • “Treatment of paediatric patients aged 1-17 with disease or collagen vascular disease. Drug administered : low, medium, high sildenafil dose, administered according pulmonary arterial hypertension. Efficacy has to body weight or placebo. Subjects were stratified according to weight and been shown in primary pulmonary hypertension developmental ability to perform the CPX test. Endpoints : Primary : Cardiopulmonary exercise testing at week 16 (for and pulmonary hypertension associated with developmentally able). Secondary : Haemodynamic assessments, WHO, QoL, TTCW (tertiary). congenital heart disease.” Allocation to Treatment Groups by Weight • The proposed doses are 10 mg TID for low weight patients (<20 kg) and 20 mg TID in patients whose weight is ≥ 20 kg. 8 2
6/22/2013 Assessment Report Assessment Report Main Secondary Endpoints: 1. Haemodynamic assessment Primary Endpoint: Exercise testing Significant changes in PRVI and CI; in line with changes seen in the adult study. Peak VO2 normalized to body weight assessed by the CPX test (cycle ergometry), evaluated at week 16 in those subjects who were developmentally PVRI Wood units*m2, able to perform the CPX test. Borderline statistical significance Cardiac Index mPulmonary Artery pressure 9 10 Assessment Report Assessment Report Safety Selection of Patients: Age, WHO functional class, Aetiology Short term safety (double-blind data) in line with adult data (headache and GIT). Age: Less haemodynamic efficacy in younger patients, probably due to better TTCW not conclusive due to short study duration (16 w). haemodynamic baseline in younger patients. Differences in efficacy per age is not expected. Deaths are assessed as not treatment related. A step-wise approach is preferable (older investigated first). Limited database Associated with functional class III or IV at baseline should be mentioned in SmPC. No biologically plausible explanation for the observed imbalance of deaths. WHO functional class: Around 30% in FC WHO I TTCW (post hoc) HR* of high and low dose groups: 1.59, (95%CI: 0.70 to 3.63) HR* high- and medium-dose groups: 1.28 (95%CI: 0.64 to 2.58). Higher sildenafil doses are not recommended in paediatrics with PAH. Longer term safety data need to be followed-up in addition to extrapolation from adult indication * H ighest hazard ratio Aetiology: Difficult to classify younger patients into FC based on physical activity = no specific statement in SmPC 11 12 3
6/22/2013 Assessment Report Dosing Based on (study A1481156 plus extension A1481131): PVRI mPAP cardiac Peak VO 2 Peak VO2 TTCW Dose Death index pulmonary mean Excercice 1 year (1 year) vascular pulmonary testing Time to Relevant endpoints resistance arterial Funct. Week 16 clinical index pressure - Exercise capacity . This can be used as a primary endpoint in developmentally able children. Due to the extensive Class III/IV worsiening experience with the 6 minute walking test 6MWT, it is the preferred exercise capacity testing. However, applicants are encouraged to develop and validate further exercise tests for paediatric development. - Time to clinical worsening . This is the preferred primary endpoint in a PAH clinical program, as it investigates clinical endpoints. Criteria used to define time to clinical worsening in the adult guideline are generally applicable in paediatric Low dose (+) (+) + (+) ++ + 9% development as well, except for deterioration in exercise capacity, which is not applicable for the developmentally unable children. Any further deviations should be justified in the protocol. Mid dose + (+) (+) (+) + + 12% - Haemodynamic parameters . This is an important endpoint in the paediatric studies. It can be used as the primary endpoint to establish the effective dose in children for those medicinal products already used in adult PAH. It can also High dose + (+) + (+) + (+) 17% be used to extrapolate efficacy from the older to the younger age groups. Invasive measurements are currently the only acceptable haemodynamic endpoints. Care should be taken to ensure standardization as much as possible throughout all trial sites, including the sedation/anaesthesia protocol for cardiac catheterisation. The role of non-invasive Combined + (+) + ++ + techniques such as echocardiography is less clear at present, nevertheless such measurements are encouraged to complement the understanding of the disease course and any treatment activity. Upon CHMP request, additional data provided in the group of children who could exercise showed modest correlations The effect on health-related quality of life (HRQL) could be measured as a secondary endpoint acknowledging that between PVRI/CI/FC/physician global assessment and VO2. However the results are in line with the adult pivotal study which indirect assessment by involving the child’s parents/carers is inevitable for the younger patient groups. Weight and is reassuring regarding clinical relevance of the results. length gain are also considered relevant indicators of development, response and well being. Other outcome measures are also encouraged to contribute to validating new endpoints in paediatric PAH studies, in Analysis shows equivalent exercise response in adults six minutes walk test (6MWT) and paediatrics particular serum markers (BNP, cytokines), Doppler echocardiography (as adjunctive tool to cardiac catheterisation) Cardiopulmonary Exercise Testing (CPET) in non-invasive simultaneous measurement of the cardiovascular MRI imaging and accelerometry. and respiratory system during exercise to assess a patient’s exercise capacity (CPET) compared to placebo Assessment Report Assessment Report Treatment duration Treatment duration • An updated Risk Management Plan (RMP Version 5.0) Clinical safety specifications is included in the dossier where the paediatric updates Exposure data for the trials performed in paediatric patients (<17 years) has have been made to the current EMA approved version been added to the RMP. The post-marketing exposure in patients between 0 (Version 4.3). In parallel to this variation, application and 18 years old is 14429 patient-years. A literature review for sildenafil citrate in PAH identified 23 paediatric controlled the Applicant is also updating RMP Version 4.3 with trials, case series and case reports dating from 1999 to 2009. Paediatric further details of the pharmacovigilance plan for patients aged from 26 weeks old (gestational age) to 18 years are recorded as Revatio solution for injection. receiving sildenafil. The dose of sildenafil ranged from 0.25 mg/kg to 2 mg/kg • The Applicant proposes that once details of the and duration of therapy ranged from a single dose to over 15 months. In conclusion, review of the literature did not reveal specific additional safety pharmacovigilance plan have been agreed with CHMP, issues for paediatric patients. that the paediatric version (Version 5.0) is updated Two paediatric studies i.e. study A1481131 and its long-term extension study A1481156, constitute the clinical support to the submission for the use of with this information prior to approval. Revatio in paediatric PAH. 4
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