1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 WHO Statement on Improving Availability and Transparency of Observational Studies on Influenza Vaccine Effectiveness Draft Version 9 June 2017 WHO vaccine policy recommendations are the result of rigorous scientific review. Careful evidence review is needed to evaluate and interpret the magnitude of vaccine effect, any variability due to geography or subpopulations vaccinated, any limitations due to study design and conduct, or other factors that are important for assessing the public health value of vaccination [1, 2]. Policy making requires expert interpretation of data, relying on both comprehensive data availability and transparency [1]. Thus, the underreporting or misreporting of biomedical research undermines the WHO policy making process [3-7]. WHO is actively engaged in multiple initiatives to promote research availability and transparency. In 2005, WHO called for the registration of all clinical trials [8], and in 2015 WHO issued a formal position that results from all clinical trials should be reported within 12 months of study completion [9, 10]. In a 2017 joint statement on public disclosure of results from clinical trials, several research funding agencies affirmed the WHO position that the prospective registration and timely public disclosure of results from all clinical trials are of critical scientific and ethical importance [11]. While the joint statement focused on clinical trials, it also stressed that issues of transparency, reduction of waste, and reporting bias are important for other types of research, including observational studies. The joint statement called for the development of transparency frameworks for these other types of research. Public health decision making regarding influenza vaccines is increasingly informed by observational studies. Influenza viruses are constantly mutating, necessitating annual reformulation of influenza vaccines and annual revaccination of individuals at risk. Vaccine performance can vary widely from year-to-year, depending on the degree of match between vaccine viruses and circulating viruses, age and comorbidities of the persons being vaccinated, and the specific vaccine product being used. Influenza vaccines are mainly used in high-income countries [12, 13], where placebo controlled trials are generally considered unethical due to recommendations for routine vaccine use, either in the entire population or in specific high-risk groups. Observational influenza vaccine effectiveness studies guide decisions regarding influenza vaccine strain composition [14], vaccine licensure [15], vaccine recommendations [16-18], and investment [19]. Thus, it is in the best interest of public health that influenza vaccine effectiveness data be comprehensively available and transparent to facilitate critical appraisal by decision makers. In February 2017, the WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) discussed the interpretation of influenza vaccine research for 1
41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 the purposes of WHO policy decisions [20]. IVIR-AC noted the increasing reliance of WHO on observational influenza vaccine effectiveness studies and acknowledged a compelling need to insure the quality and comparability of such studies and to optimize their interpretation for policy making. It is in this context that WHO advises all individuals and groups conducting influenza vaccine effectiveness research to ensure data availability and transparency. The following should be done to facilitate this effort: Study registration and protocol availability Before a study is initiated, it should be registered in a publicly available, free-toaccess, searchable registry complying with WHO s international agreed standards. 1 Any changes to the study details or analysis plans should be updated. At the time of study registration, study protocols should be made publicly available on free-to-access, searchable websites or on existing data custodial websites [21] with the location noted in the registry. If these websites are not used, the results should be posted on a free-to-access, publicly available, searchable institutional website of the Regulatory Sponsor, Funder, or Principal Investigator. Reporting timeframes A manuscript including the main findings of studies should be submitted for publication in a peer reviewed biomedical journal within 12 months of study completion with an open access mechanism, unless there is a specific reason why open access cannot be used, or otherwise made available publicly at most within 24 months of study completion. Key results should be made publicly available within 12 months of study completion by posting to the results section of the study registry. 2 Where a registry is used without a results section available, the results should be posted on a free-to-access, publicly available, searchable institutional website of the Regulatory Sponsor, Funder or Principal Investigator. Registry identifier code/number in publication The registry identifier code/number should be included in all study publications and abstracts to facilitate linking of study-related publications and registry site records. 1 As of 9 June 2017, clinicaltrials.gov and ISRCTN allow registration of observational studies. 2 Key results refer to the Results items from the STROBE statement checklist and include descriptive data, outcome data, and main results. 2
77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 Results reporting Reports should adhere to STROBE consensus guidance for observational research [22], when applicable. As with all observational studies, reports of observational influenza vaccine effectiveness studies should include sufficient details on the study participants, data collection, and analyses to enable readers to judge the validity of the study. Sharing of individual participants data The benefit of sharing research data and the facilitation of research through greater access to primary datasets is a principle which WHO sees as important. WHO is actively engaged with multiple initiatives related to data sharing, and WHO supports sharing of health research datasets whenever appropriate. WHO encourages researchers to deposit anonymized study datasets in a publicly available, free-toaccess, searchable website within 12 months of study completion unless there is a specific reason why this should not be done. 3
92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 References 1. World Health Organization. Guidance for the Development of Evidence-Based Vaccination Related Recommendations. Available at: http://www.who.int/immunization/sage/guidelines_development_recommendation s.pdf. Accessed 10 March 2017. 2. Duclos P, Durrheim DN, Reingold AL, Bhutta ZA, Vannice K, Rees H. Developing evidence-based immunization recommendations and GRADE. Vaccine 2012; 31(1): 12-9. 3. Miller JE, Korn D, Ross JS. Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012. BMJ open 2015; 5(11): e009758. 4. Saito H, Gill CJ. How frequently do the results from completed US clinical trials enter the public domain?--a statistical analysis of the ClinicalTrials.gov database. PloS one 2014; 9(7): e101826. 5. Manzoli L, Flacco ME, D'Addario M, et al. Non-publication and delayed publication of randomized trials on vaccines: survey. BMJ (Clinical research ed) 2014; 348: g3058. 6. Jones CW, Handler L, Crowell KE, Keil LG, Weaver MA, Platts-Mills TF. Nonpublication of large randomized clinical trials: cross sectional analysis. BMJ (Clinical research ed) 2013; 347: f6104. 7. Chen R, Desai NR, Ross JS, et al. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers. BMJ (Clinical research ed) 2016; 352: i637. 8. World Health Organization. International Clinical Trials Registry Platform (ICTRP). 9. Moorthy VS, Karam G, Vannice KS, Kieny MP. Rationale for WHO's new position calling for prompt reporting and public disclosure of interventional clinical trial results. PLoS medicine 2015; 12(4): e1001819. 10. World Health Organization. WHO Statement on Public Disclosure of Clinical Trial Results. Available at: http://www.who.int/ictrp/results/reporting/en/. Accessed 16 March 2017. 11. Joint statement on public disclosure of results from clinical trials. Available at: http://who.int/ictrp/results/ictrp_jointstatement_2017.pdf. Accessed 25 May 2017. 12. Ortiz JR, Perut M, Dumolard L, et al. A global review of national influenza immunization policies: Analysis of the 2014 WHO/UNICEF Joint Reporting Form on immunization. Vaccine 2016; 34(45): 5400-5. 13. Palache A, Oriol-Mathieu V, Fino M, Xydia-Charmanta M. Seasonal influenza vaccine dose distribution in 195 countries (2004-2013): Little progress in estimated global vaccination coverage. Vaccine 2015; 33(42): 5598-605. 14. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2016-2017 northern hemisphere influenza season. Available at: http://www.who.int/influenza/vaccines/virus/recommendations/201602_recomme ndation.pdf. Accessed 9 March 2017. 15. Wijnans L, Voordouw B. A review of the changes to the licensing of influenza vaccines in Europe. Influenza and other respiratory viruses 2016; 10(1): 2-8. 4
136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 16. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports 2016; 65(5): 1-54. 17. World Health Organization. Vaccines against influenza WHO position paper - November 2012. Wkly Epidemiol Rec 2012; 87(47): 461-76. 18. Centers for Disease Control and Prevention. ACIP votes down use of LAIV for 2016-2017 flu season. Available at: http://www.cdc.gov/media/releases/2016/s0622-laivflu.html. Accessed 7 March 2017. 19. Global Alliance for Vaccines and Immunisation (GAVI). Final Vaccine Investment Strategy Analysis 2013: Maternal Influenza. Geneva, Switzerland: Global Alliance for Vaccines and Immunisation (GAVI), 2013. 20. Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC): summary of conclusions and recommendations, 1-2 February 2017 meeting. Wkly Epidemiol Rec 2017; 92(15): 181-8. 21. Tudur Smith C, Hopkins C, Sydes MR, et al. How should individual participant data (IPD) from publicly funded clinical trials be shared? BMC medicine 2015; 13: 298. 22. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61(4): 344-9. 5