Palivizumab for immunoprophylaxis of respiratory syncitial virus bronchiolitis in high risk infants

Transcription

1 NCCHTA 09 July 2008

2 HTA 06/29 1 Title of the project: Palivizumab for immunoprophylaxis of respiratory syncitial virus bronchiolitis in high risk infants 2 Name of TAR team and project lead TAR team: Project lead: Post held: Official address: West Midlands Health Technology Assessment Collaboration (WMHTAC), University of Birmingham Amanda Burls Director of WMHTAC Department of Public Health & Epidemiology, University of Birmingham, Edgbaston, Birmingham B15 2TT Telephone number: Fax number: address: a.j.burls@bham.ac.uk 3 Plain English Summary Respiratory syncytial virus (RSV) is a very common infection in young children, with up to half of all infants becoming infected by the age of one. A proportion of children with RSV are seriously affected by the virus and may need to be hospitalised due to life-threatening complications such as bronchiolitis (inflammation of the smaller airways of the lung) and pneumonia. Children who are at high risk of hospitalisation for these reasons include premature babies, children with chronic lung disease due to abnormal development of the lungs or cystic fibrosis, children who were born with certain types of heart problems and children who have limited resistance to disease due to a weakened immune system. As many as one in five of these high risk infants may need to be hospitalised and some may require admission to an intensive care unit. RSV is a seasonal disease, with epidemics occurring annually from October to March in the UK. Beyond supportive care (such as mechanical assistance with breathing, intravenous fluids and oxygen) the only treatment available for RSV infection is Protocol 09/07/2008 1

3 ribavirin. Ribavarin may be of some benefit after infection but its use requires hospitalisation which increases the risk of spreading the infection, it is costly and has a number of unwanted side effects. Strategies to prevent infection are therefore of considerable interest. Attempts to develop a vaccine to prevent RSV infection have so far been unsuccessful but another type of product, palivizumab (sold under the brand name of Synagis) which may be useful in preventing or reducing the severity of RSV infection is available for use in the UK. Common side effects of palivizumab include a reaction at the site of the injection and fever. Rare side effects, occurring in less than one in a hundred children, include infections, blood disorders, respiratory problems, rash, diarrhoea and vomiting. Our report aims to address the best way for the health service to use palivizumab in children at high risk of developing serious complications following RSV infection. If clinical trials show that it is successful in reducing serious consequences of RSV in these children, the health service needs to know if these benefits are worthwhile given the cost of treating all such children before they become infected and the unpleasant consequences for the child, including the need for multiple injections and the side effects of the treatment. 4 Decision problem 4.1 Purpose of the report To estimate the cost-effectiveness of immunoprophylaxisof RSV using palivizumab (a monoclonal antibody) in different subgroups of children at high risk of serious morbidity from RSV infection. 4.2 Intervention Synagis is indicated for the prevention of serious lower respiratory tract disease requiring hospitalisation caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease. The licence specifies the following high risk groups: Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the RSV season Children less than 2 years of age and requiring treatment for bronchopulmonary dysplasia within the last 6 months. Children less than 2 years of age and with haemodynamically significant congenital heart disease. The recommended dose of palivizumab is 15 mg/kg of body weight, injected intramuscularly, given once a month during anticipated periods of RSV risk in the Protocol 09/07/2008 2

4 community. Where possible, the first dose should be administered prior to commencement of the RSV season. Subsequent doses should be administered monthly throughout the RSV season. To reduce risk of rehospitalisation, it is recommended that children receiving palivizumab who are hospitalised with RSV continue to receive monthly doses of palivizumab for the duration of the RSV season. For children undergoing cardiac bypass, it is recommended that a 15 mg/kg injection of palivizumab be administered as soon as stable after surgery to ensure adequate palivizumab serum levels. Subsequent doses should resume monthly through the remainder of the RSV season for children that continue to be at high risk of RSV disease. 4.3 Place of the intervention in the treatment pathway(s) Prevention 4.4 Relevant comparators No prophylactic treatment 4.5 Population and relevant sub-groups Infants at high risk of hospitalisation, morbidity or death due to RSV infection, including: Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the RSV season Children less than 2 years of age and requiring treatment for bronchopulmonary dysplasia (chronic lung disease) within the last 6 months Children less than 2 years of age and with haemodynamically significant congenital heart disease Other high risk groups, for example children with cystic fibrosis or immune deficiency Within these broad subgroups, risk of severe infection may be influenced by factors such as sex, age, prior infection with RSV and severity of the underlying condition. 4.6 Key factors to be addressed Clinical outcomes include rate of hospitalisation, intensive care, mechanical ventilation, morbidity and mortality following RSV infection. Costs include the cost Protocol 09/07/2008 3

5 of prophylaxis with palivizumab including costs of administration, and cost of supportive care following RSV infection. Additional considerations include the need for multiple injections and side effects of treatment, dose and frequency of administration, reduction in risk of morbidity for infants who have previously been infected with RSV and long-term consequences of severe RSV infection such as chronic respiratory abnormalities and increased risk of developing asthma. 5 Report methods for synthesis of evidence of clinical effectiveness A systematic review of the evidence for clinical effectiveness will be undertaken following the general principles recommended in the QUOROM statement Population Children at high risk of serious morbidity, hospitalisation or death due to RSV infection, particularly those groups identified in the licence: Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the RSV season Children less than 2 years of age and requiring treatment for bronchopulmonary dysplasia within the last 6 months. Children less than 2 years of age and with haemodynamically significant congenital heart disease. Evidence will also be sought on other high risk groups not included in the licensed indication, such as children with cystic fibrosis or immune deficiency. 5.2 Interventions Immunoprophylaxis with palivizumab 5.3 Comparators No prophylactic treatment 5.4 Outcomes Rate and duration of hospitalisation, use of supportive care, intensive care and mechanical ventilation, morbidity and mortality, side effects of treatment, cost of administration (including factors associated with cost of administration). 1 Protocol 09/07/2008 4

6 5.5 Search strategy A scoping search has been undertaken to identify systematic reviews and metaanalyses and to estimate the volume and nature of primary studies. For the clinical effectiveness review the following sources will be searched: Bibliographic databases: Cochrane Library (Wiley internet version), MEDLINE(Ovid) and MEDLINE In-Process (Ovid), EMBASE (Ovid) and CINAHL (Ovid), Science Citation Index Research registries of ongoing trials including National Research Register, Current Controlled Trials metaregister and Clinical Trials.gov Bibliographies of retrieved papers Relevant internet sources, including FDA and EMEA websites Industry submissions (if available) Contact with experts in the field No language restrictions will be applied. Details of search strategies may be found in Appendix Inclusion criteria Studies will be included if they meet the following criteria: Randomised controlled trials (RCTs) or systematic reviews of RCTs with: Inclusion of at least some high risk infants Use of palivizumab in a preventive setting with dose and frequency comparable to that described in the licence Prognostic studies of morbidity due to RSV Where a mixed population of high risk and non-high risk infants is reported, data will be extracted for the relevant subgroups where possible. Observational studies may be included for consideration of adverse events and other parameters required for the decision analytic model where these are not obtainable from RCTs. Titles and abstracts will be examined for inclusion by two reviewers independently. Disagreement will be resolved by consensus. Protocol 09/07/2008 5

7 5.5.2 Exclusion criteria Non-randomised studies (except for adverse events) Trials conducted exclusively in non-high risk children Trials using a single dose of palivizumab or a dose which is not comparable to that currently used in clinical practice Animal models Preclinical and biological studies Narrative reviews, editorials, opinions Reports published as meeting abstracts only may be excluded where insufficient methodological details are reported to allow critical appraisal of study quality Non-English language papers will not be excluded, but full translations may not be obtainable within the resources available. Where abstracts are provided in English, these papers will be treated as described above. 5.6 Data extraction strategy Data will be extracted independently by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies will be resolved by discussion, with involvement of a third reviewer when necessary. 5.7 Quality assessment strategy Consideration of study quality will include the following factors: 1. Timing, duration and location of the study 2. Method of randomisation 3. Adequacy of allocation concealment 4. Blinding, including adequacy of method for creating and maintaining blinding 5. Numbers of participants randomised, excluded and lost to follow up. 6. Reporting of intention-to-treat analysis 7. Methods for handling missing data 8. Appropriateness of statistical analysis Protocol 09/07/2008 6

8 5.8 Methods of analysis/synthesis Data will be tabulated and discussed in a narrative review. Where appropriate, metaanalysis will be employed to obtain pooled estimates of the effect on relevant outcomes based on intention to treat analyses. Heterogeneity will be explored through consideration of the study populations, methods and interventions, and, in statistical terms, using the χ 2 test for heterogeneity and meta-regression techniques where appropriate. 5.9 Methods for estimating qualify of life Utility data will be sought from the literature. The time horizon for modelling will be a patient s lifetime in order to adequately reflect the impact of mortality on the costeffectiveness of prevention. The perspective will be that of the National Health Services and Personal Social Services (NHS/PSS). Both costs and QALYs will be discounted at 3.5%. 6 Report methods for synthesising evidence of cost-effectiveness 6.1 Identifying and systematically reviewing published cost-effectiveness studies Studies on costs, quality of life, cost effectiveness and modelling will be identified from the following sources: Bibliographic databases: MEDLINE (Ovid); EMBASE (Ovid); Cochrane Library (NHS EED and DARE); Office of Health Economics HEED database, and the most recent issue of the Office of Health Economics Evaluations Database Industry submissions Internet sites of national economic units Standard approaches to applying inclusion/exclusion criteria will be employed. Quality assessment for economic evaluations and cost-effectiveness analyses will be done using standard criteria. 2, 3 Papers may be excluded at this stage based on quality assessment. Justification for the exclusion of papers will be presented. The papers that remain in the review will be summarised on the basis of key items of information, including: 2 Drummond et al. Methods for the economic evaluation of health care programmes. 2nd edition. Oxford: Oxford Medical Publications, Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al. Review of guidelines for good practice in decision-analytic modelling in health technology assessment. Health Technol Assess 2004;8(36) Protocol 09/07/2008 7

9 Details of the study characteristics such as form of economic analysis, comparators, perspective, time horizon and modelling used. Details of the effectiveness and cost parameters such as: effectiveness data; health state valuations; resource use data; unit cost data; price year; discounting assumptions, and productivity costs. Details of the results and sensitivity analysis. 6.2 Evaluation of costs and cost effectiveness In order to explore the effectiveness and cost-effectiveness of palivizumab, and depending on the results of our literature reviews, we may build on existing decisionanalytic models or develop our own model. This choice will depend on the quality and adequacy of structure for our purposes of previously published models. The comparator will be no prophylactic treatment. Evidence on quality of life will be sought but it is likely that a cost-utility analysis will not be possible due to the lack of utility data for this population. These data restrictions are likely to require us to use alternative outcome measures such as standard effectiveness measures (life years gained). The perspective for the model will be NHS/PSS. The time horizon for the reference case analysis will be lifetime. Both costs and benefits will be discounted at 3.5%. Depending on the evidence available, sensitivity analysis will explore the effects of changing key parameters such as the probability of hospitalisation, rates of mortality and costs of morbidity. Probabilistic sensitivity analysis will be undertaken if appropriate given the form of the model used and the resources available. 7 Expertise in this TAR team 7.1 TAR Centre The West Midlands Health Technology Assessment Collaboration (WMHTAC) is an organisation involving several universities and academic groups who collaboratively produce health technology assessments and systematic reviews. Most of our members are based in the Department of Public health & Epidemiology, University of Birmingham, however other members are drawn from a wide field of expertise including economists and mathematical modellers from the Health Economics Facility, University of Birmingham, and pharmacists and methodologists from the Department of Medicines Management, Keele University. We produce systematic reviews and economic evaluations for the National Health Service Research & Development Health Technology Assessment programme (NCCHTA), the National Institute for Health and Clinical Excellence (NICE), and for the health service in the West Midlands. WMHTAC also undertakes methodological research on health Protocol 09/07/2008 8

10 technology assessment, and provides training in systematic reviews and health technology assessment. 7.2 Team members contributions Dr Amanda Burls is a Consultant in Public Health and Director of WMHTAC and will act as Senior Reviewer, taking overall responsibility for project management and the quality of the final report. Dr Carole Cummins has been involved with systematic reviews conducted by WMHTAC since 1998, and is currently Senior Lecturer in paediatric clinical trials based at the Institute of Child Health, University of Birmingham. She will be the lead reviewer on this project and will take the lead role in study selection, data extraction and meta-analysis. She will draft the final report, incorporating contributions from other members of the team as appropriate. Sue Bayliss is an Information Specialist for WMHTAC and ARIF (the Aggressive Research Intelligence Facility) both based at the University of Birmingham and has provided information support for a number of reviews conducted by WMHTAC. She will provide information support for literature searching and retrieval for this project. Dr Emma Frew is a Lecturer in Health Economics based at the Health Services Management Centre at the University of Birmingham and has provided health economics and modelling input to a number of reports conducted by WMHTAC. She will take the lead on health economics and decision analytic modelling for this report. Josie Sandercock is a Medical Statistician and Honorary Research Fellow at the University of Birmingham and has acted as senior reviewer and/or statistical adviser on a number of reports conducted by WMHTAC. She has compiled the protocol and will provide statistical advice for this report. 8 Competing interests of authors None 9 Timetable/milestones Submission of protocol: 1st September 2006 Submission of final report: to be confirmed Protocol 09/07/2008 9

11 10 Appendices 10.1 Draft search strategy Database: Ovid MEDLINE(R) <1966 to June Week > (Reviews) 1 exp Respiratory Syncytial Virus, Human/ or rsv.mp. 2 respiratory syncytial virus.mp. 3 bronchiolitis.mp. or exp Bronchiolitis, Viral/ 4 or/1-3 5 palivizumab.mp. 6 monoclonal antibod$.mp. 7 exp Antibodies, Monoclonal/ 8 synagis.mp. 9 exp Immunotherapy/ or immunoprophylaxis.mp. 10 or/ and (systematic adj review$).tw. 13 (data adj synthesis).tw. 14 (published adj studies).ab. 15 (data adj extraction).ab. 16 meta-analysis/ 17 meta-analysis.ti. 18 comment.pt. 19 letter.pt. 20 editorial.pt. 21 animal/ 22 human/ not (21 and 22) not (18 or 19 or 20 or 23) 25 or/ and Database: Ovid MEDLINE(R) <1966 to June Week > (RCTs) 1 exp Respiratory Syncytial Virus, Human/ or rsv.mp. 2 respiratory syncytial virus.mp. 3 bronchiolitis.mp. or exp Bronchiolitis, Viral/ 4 or/1-3 5 palivizumab.mp. 6 monoclonal antibod$.mp. 7 exp Antibodies, Monoclonal/ 8 synagis.mp. 9 exp Immunotherapy/ or immunoprophylaxis.mp. Protocol 09/07/

12 10 or/ and randomized controlled trial.pt. 13 controlled clinical trial.pt. 14 randomized controlled trials.sh. 15 random allocation.sh. 16 double blind method.sh. 17 single-blind method.sh. 18 or/ (animals not human).sh not clinical trial.pt. 22 exp clinical trials/ 23 (clin$ adj25 trial$).ti,ab. 24 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 25 placebos.sh. 26 placebo$.ti,ab. 27 random$.ti,ab. 28 research design.sh. 29 or/ not not comparative study.sh. 33 exp evaluation studies/ 34 follow up studies.sh. 35 prospective studies.sh. 36 (control$ or prospectiv$ or volunteer$).ti,ab. 37 or/ not not (20 or 31) or 31 or and limit 41 to yr=" " Database: EMBASE <1980 to 2006 Week 27> (Reviews) 1 exp Respiratory Syncytial Pneumovirus/ or rsv.mp. or exp Bronchiolitis/ 2 bronchiolitis.mp. 3 respiratory syncytial virus.mp. 4 or/1-3 5 palivizumab.mp. or exp PALIVIZUMAB/ 6 exp Monoclonal Antibody/ or monoclonal antibod$.mp. 7 synagis.mp. 8 immunoprophylaxis.mp. or exp IMMUNOPROPHYLAXIS/ Protocol 09/07/

13 9 or/ and 9 11 "meta-analysis"/ 12 metaanalys$.ti,ab. 13 meta-analys$.ti,ab. 14 meta analys$.ti,ab. 15 cochrane.ti,ab,de. 16 (review$ or overview$).ti,ab. 17 (synthes$ adj3 (literature$ or research$ or study or studies or data)).mp. 18 pooled analy$.ti,ab. 19 (systematic$ adj2 review$).ti,ab. 20 or/ and or and Database: Cochrane Library 2006 Issue 2 (CDSR, CENTRAL) (Reviews and RCTs) #1 respiratory next syncytial #2 rsv #3 bronchiolitis #4 MeSH descriptor Bronchiolitis, Viral, this term only #5 MeSH descriptor Respiratory Syncytial Virus, Human, this term only #6 (#1 OR #2 OR #3 OR #4 OR #5) #7 immunoprophylaxis #8 monoclonal next antibod* #9 MeSH descriptor Antibodies, Monoclonal explode all trees #10 palivizumab #11 (#7 OR #8 OR #9 OR #10) #12 (#6 AND #11) Protocol 09/07/