The Sildenafil Controversy

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1 The Sildenafil Controversy Chronology European Development Revatio (Sildenafil) Orphan Drug designation: & Paediatric Investigation Plan: Marketing Authorisation in EU: PAH Adults EMA pos opinion: PAH p aed pop 1 17 years European Commission MA: PAH 1 17 years European Medicines Agency/Paediatric Committee Paediatric Investigation Plan: EMEA PIP01-08 medicinal product = sildenafil Main issues for the medicinal product Medical need Relevant age groups 0/(1) 17 years Studies: PAH: Study A & Extension Study A PPNH: Study A (deferred) 1

2 European Medicines Agency (EMA) Committee for Human Medicinal Products (CHMP) positive opinion Paediatric population Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart Disease. = recommendation to European Commission for EU MA EMA /Summary of Product Characteristics Spring Indication Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see section 5.1) 4.2 Posology Paediatric Population The safety and efficacy of Revatio in children below 1 year of age has not been established. No data are available. There is a limited experience in patients below 7 years of age (see section 5.1). For paediatric patients aged 1 year to 17 years old, the recommended dose 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 1 tablet) three times a day. Higher doses are not recommended in paediatric patients (see section 5.1). Dosing Treatment of paediatric patients aged 1-17 with pulmonary arterial hypertension. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. The proposed doses are 10 mg TID for low weight patients (<20 kg) and 20 mg TID in patients whose weight is 20 kg. Randomised, double-blind, multi-center, placebo controlled parallel group, dose ranging. Patients: 1-17 years, with Primary PAH or PAH secondary to congenital heart disease or collagen vascular disease. Drug administered: low, medium, high sildenafil dose, administered according to body weight or placebo. Subjects were stratified according to weight and developmental ability to perform the CPX test. Endpoints: Primary: Cardiopulmonary exercise testing at week 16 (for developmentally able). Secondary: Haemodynamic assessments, WHO, QoL, TTCW (tertiary). Allocation to Treatment Groups by Weight 8 2

3 Primary Endpoint: Exercise testing Peak VO2 normalized to body weight assessed by the CPX test (cycle ergometry), evaluated at week 16 in those subjects who were developmentally able to perform the CPX test. Borderline statistical significance Main Secondary Endpoints: 1. Haemodynamic assessment Significant changes in PRVI and CI; in line with changes seen in the adult study. PVRI Wood units*m2, Cardiac Index mpulmonary Artery pressure 9 10 Safety Short term safety (double-blind data) in line with adult data (headache and GIT). TTCW not conclusive due to short study duration (16 w). Deaths are assessed as not treatment related. Associated with functional class III or IV at baseline No biologically plausible explanation for the observed imbalance of deaths. 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). Selection of Patients: Age, WHO functional class, Aetiology Age: Less haemodynamic efficacy in younger patients, probably due to better haemodynamic baseline in younger patients. Differences in efficacy per age is not expected. A step-wise approach is preferable (older investigated first). Limited database should be mentioned in SmPC. WHO functional class: Around 30% in FC WHO I 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 *Highest hazard ratio 11 Aetiology: Difficult to classify younger patients into FC based on physical activity = no specific statement in SmPC 12 3

4 Dosing Dose Based on PVRI (study A mpap plus cardiac extension Peak A ): VO 2 Peak VO2 pulmonary mean Excercice index 1 year vascular pulmonary testing resistance index arterial pressure Week 16 TTCW Time to clinical worsiening Low dose (+) (+) + (+) % Death (1 year) Funct. Class III/IV Mid dose + (+) (+) (+) % High dose + (+) + (+) + (+) 17% Combined + (+) Upon CHMP request, additional data provided in the group of children who could exercise showed modest correlations between PVRI/CI/FC/physician global assessment and VO2. However the results are in line with the adult pivotal study which is reassuring regarding clinical relevance of the results. Analysis shows equivalent exercise response in adults six minutes walk test (6MWT) and paediatrics Cardiopulmonary Exercise Testing (CPET) in non-invasive simultaneous measurement of the cardiovascular and respiratory system during exercise to assess a patient s exercise capacity (CPET) compared to placebo Relevant endpoints - Exercise capacity. This can be used as a primary endpoint in developmentally able children. Due to the extensive 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 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. - 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 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 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. The effect on health-related quality of life (HRQL) could be measured as a secondary endpoint acknowledging that indirect assessment by involving the child s parents/carers is inevitable for the younger patient groups. Weight and 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 particular serum markers (BNP, cytokines), Doppler echocardiography (as adjunctive tool to cardiac catheterisation) MRI imaging and accelerometry. Treatment duration Clinical safety specifications Exposure data for the trials performed in paediatric patients (<17 years) has been added to the RMP. The post-marketing exposure in patients between 0 and 18 years old is patient-years. A literature review for sildenafil citrate in PAH identified 23 paediatric controlled trials, case series and case reports dating from 1999 to Paediatric patients aged from 26 weeks old (gestational age) to 18 years are recorded as receiving sildenafil. The dose of sildenafil ranged from 0.25 mg/kg to 2 mg/kg 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 issues for paediatric patients. Two paediatric studies i.e. study A and its long-term extension study A , constitute the clinical support to the submission for the use of Revatio in paediatric PAH. Treatment duration An updated Risk Management Plan (RMP Version 5.0) is included in the dossier where the paediatric updates have been made to the current EMA approved version (Version 4.3). In parallel to this variation, application the Applicant is also updating RMP Version 4.3 with further details of the pharmacovigilance plan for Revatio solution for injection. The Applicant proposes that once details of the pharmacovigilance plan have been agreed with CHMP, that the paediatric version (Version 5.0) is updated with this information prior to approval. 4

5 Conclusions The Revatio Paediatric study is the largest conducted paediatric study (around 220 patients). Established efficacy of vasodilators in adult PAH supports a pragmatic approach in assessment of these drugs in paediatrics. Invasive haemodynamic data are feasible for all age groups. No single parameter could be advocated; PVRI and CI appear most important. Correlation of results of different parameters together and with adult data helps in interpretation of results and to support the CHMP indication. The presenting aetiology and Functional Class may be different in paediatrics compared to adults with implications for the indication as been taken into account by the CHMP decision. There is an unmet medical need. 17 Decision EMEA/H/C/638/II/28: to include a paediatric indication in the Revatio Summary of Product Characteristics was submitted to the CHMP on 12 February 2010 and approved on 2 May EMEA/H/C/638/II/041: to include the safety information from the Data Management Committee assessment of the long term study A (A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil in the Treatment of Subjects Who Have Completed Study A ), submitted to the CHMP in September This variation updated the Revatio SmPC to include information on the increase in mortality seen in the paediatric study A with increased dose, and a warning that higher than recommended doses should not be used in paediatric patients with PAH. A Direct Healthcare Professional Communications (DHPCs) was sent. EMA: Pharmacovigilance Risk Assessment Committee (PRAC) Pharmacovigilance /PSUR update January 2013 Sildenafil REVATIO (CAP) Evaluation of a PSUR procedure Background Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cgmp) specific phosphodiesterase type 5 (PDE5). Revatio, a centrally authorised medicine containing sildenafil, is used in the treatment of patients with pulmonary arterial hypertension (PAH). Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of Revatio, and issued a recommendation on its marketing authorisation. Summary of recommendation(s) and conclusion Based on the review of the data on safety and efficacy, the risk-benefit balance of Revatio (sildenafil) in the approved indication(s) remains favourable. The PRAC recommended the maintenance of the current terms of the marketing authorisation The MAH should closely monitor cases of non-arteritic anterior ischemic optic neuropathy (NAION), hearing loss, aneurysms, artery dissections and vaso-occlusive crisis in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease. The frequency of submission of PSURs should remain once yearly and the next PSUR should be submitted to the EMA within 70 days of the next data lock point. Other Medicinal Products for PAH (non authorised for paediatrics) Prostacyclin analogues Epoprostenol, Iloprost, Treprostinil (2017/2025) Endothelin receptor antagonists Ambrisentan, Bosentan (approved paediatric formulation), (withdrawn: Sitaxentan), Macitentan (ongoing) PDE5 inhibitors Others Tadalafil (2020) Riociguat (sgc stimulator), Imatinib mesilate (protein-tyrosine kinase inhibitor) AeG1 5

6 Slide 20 AeG1 please delete imatinib, as it was withdrawn from EMA/FDA and Japan. Please mark riocgiuat as "ongoing assessment" El Gazayerly, mw. dr. A.N., 6/7/2013

7 ?The Sildenafil Controversy? 6