Medical need Relevant age groups 0/(1) 17 years Studies: PAH: - - PowerPoint PPT Presentation

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The Sildenafil Controversy

Chronology European Development

Revatio (Sildenafil)

Orphan Drug designation: 03.12.2003 & 27.02.2007

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

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)

European Medicines Agency/Paediatric Committee

Paediatric Investigation Plan: EMEA-000671-PIP01-08 medicinal product = sildenafil

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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

Assessment Report/Summary of Product Characteristics

Spring 2011

4.1 Indication Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity

• r 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).

Assessment Report 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.

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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

Assessment Report

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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

Assessment Report

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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

Assessment Report

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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).

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

Safety

Assessment Report

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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: Aetiology: Difficult to classify younger patients into FC based on physical activity = no specific statement in SmPC Assessment Report

Around 30% in FC WHO I

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Assessment Report Dosing

Based on (study A1481156 plus extension A1481131): Dose PVRI

pulmonary vascular resistance index

mPAP

mean pulmonary arterial pressure

cardiac index

Peak VO 2 Excercice testing Week 16 Peak VO2

1 year

TTCW

Time to clinical worsiening

Death (1 year)

Funct. Class III/IV

Low dose (+) (+) + (+) ++ + 9% Mid dose + (+) (+) (+) + + 12% 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.

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 14429 patient-years. A literature review for sildenafil citrate in PAH identified 23 paediatric controlled trials, case series and case reports dating from 1999 to 2009. 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 A1481131 and its long-term extension study A1481156, constitute the clinical support to the submission for the use of Revatio in paediatric PAH.

Assessment Report 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.

Assessment Report Treatment duration

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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. Assessment Report

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 2011.

• EMEA/H/C/638/II/041: to include the safety information from the Data

Management Committee assessment of the long term study A1481156 (A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil in the Treatment of Subjects Who Have Completed Study A1481131), submitted to the CHMP in September 2011. This variation updated the Revatio SmPC to include information on the increase in mortality seen in the paediatric study A1481156 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
• Tadalafil (2020)
• Others
• Riociguat (sGC stimulator), Imatinib mesilate (protein-tyrosine

kinase inhibitor)

AeG1

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

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?The Sildenafil Controversy?