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Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports.

ABSTRACT: OBJECTIVE:To assess the benefits and harms of the human papillomavirus (HPV) vaccines. DATA SOURCES:Clinical study reports obtained from the European Medicines Agency and GlaxoSmithKline from 2014 to 2017. ELIGIBILITY CRITERIA:Randomised trials that compared an HPV vaccine with a placebo or active comparator in healthy participants of all ages. APPRAISAL AND SYNTHESIS:Two researchers extracted data and judged risk of bias with the Cochrane tool (version 2011). Risk ratio (RR) estimates were pooled using random-effects meta-analysis. OUTCOMES:Clinically relevant outcomes in intention to treat populations-including HPV-related cancer precursors irrespective of involved HPV types, treatment procedures and serious and general harms. RESULTS:Twenty-four of 50 eligible clinical study reports were obtained with 58,412 pages of 22 trials and 2 follow-up studies including 95,670 participants: 79,102 females and 16,568 males age 8-72; 393,194 person-years; and 49?months mean weighted follow-up. We judged all 24 studies to be at high risk of bias. Serious harms were incompletely reported for 72% of participants (68,610/95,670). Nearly all control participants received active comparators (48,289/48,595, 99%). No clinical study report included complete case report forms. At 4 years follow-up, the HPV vaccines reduced HPV-related carcinoma in situ (367 in the HPV vaccine group vs. 490 in the comparator group, RR 0.73 [95% confidence interval, CI, 0.53 to 1.00], number needed to vaccinate [NNV] 387, P?=?0.05, I2 =?67%) and HPV-related treatment procedures (1018 vs. 1416, RR 0.71 [95% CI 0.63 to 0.80], NNV 75, P?

SUBMITTER: Jorgensen L

PROVIDER: S-EPMC7047375 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports.

Jørgensen Lars L Gøtzsche Peter C PC Jefferson Tom T

Systematic reviews 20200228 1

<h4>Objective</h4>To assess the benefits and harms of the human papillomavirus (HPV) vaccines.<h4>Data sources</h4>Clinical study reports obtained from the European Medicines Agency and GlaxoSmithKline from 2014 to 2017.<h4>Eligibility criteria</h4>Randomised trials that compared an HPV vaccine with a placebo or active comparator in healthy participants of all ages.<h4>Appraisal and synthesis</h4>Two researchers extracted data and judged risk of bias with the Cochrane tool (version 2011). Risk r ...[more]

PMID: 32106879

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Project description:BACKGROUND:No study has looked at differences of pooled estimates-such as meta-analyses-of corresponding study documents of the same intervention. In this study, we compared meta-analyses of human papillomavirus (HPV) vaccine trial data from clinical study reports with trial data from corresponding trial register entries and journal publications. METHODS:We obtained clinical study reports from the European Medicines Agency and GlaxoSmithKline, corresponding trial register entries from ClinicalTrials.gov and corresponding journal publications via the Cochrane Collaboration's Central Register of Controlled Trials, Google Scholar and PubMed. Two researchers extracted data. We compared reporting of trial design aspects and 20 prespecified benefit and harm outcomes extracted from each study document type. Risk ratios were calculated with the random effects inverse variance method. RESULTS:We included study documents from 22 randomized clinical trials and 2 follow-up studies with 95,670 healthy participants and non-HPV vaccine comparators (placebo, HPV vaccine adjuvants and hepatitis vaccines). We obtained 24 clinical study reports, 24 corresponding trial register entries and 23 corresponding journal publications; the median number of pages was 1351 (range 357 to 11,456), 32 (range 11 to 167) and 11 (range 7 to 83), respectively. All 24 (100%) clinical study reports, no (0%) trial register entries and 9 (39%) journal publications reported on all six major design-related biases defined by the Cochrane Handbook version 2011. The clinical study reports reported more inclusion criteria (mean 7.0 vs. 5.8 [trial register entries] and 4.0 [journal publications]) and exclusion criteria (mean 17.8 vs. 11.7 and 5.0) but fewer primary outcomes (mean 1.6 vs. 3.5 and 1.2) and secondary outcomes (mean 8.8 vs. 13.0 and 3.2) than the trial register entries. Results were posted for 19 trial register entries (79%). Compared to the clinical study reports, the trial register entries and journal publications contained 3% and 44% of the seven assessed benefit data points (6879 vs. 230 and 3015) and 38% and 31% of the 13 assessed harm data points (167,550 vs. 64,143 and 51,899). No meta-analysis estimate differed significantly when we compared pooled risk ratio estimates of corresponding study document data as ratios of relative risk. CONCLUSION:There were no significant differences in the meta-analysis estimates of the assessed outcomes from corresponding study documents. The clinical study reports were the superior study documents in terms of the quantity and the quality of the data they contained and should be used as primary data sources in systematic reviews. SYSTEMATIC REVIEW REGISTRATION:The protocol for our comparison is registered on PROSPERO as an addendum to our systematic review of the benefits and harms of the HPV vaccines: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20180320.pdf: CRD42017056093. Our systematic review protocol was registered on PROSPERO on January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews on January 2018: https://doi.org/10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published on September 2018: https://doi.org/10.1136/bmj.k3694.

Project description:To determine benefits and harms of arthroscopic knee surgery involving partial meniscectomy, debridement, or both for middle aged or older patients with knee pain and degenerative knee disease.Systematic review and meta-analysis.Pain and physical function.Systematic searches for benefits and harms were carried out in Medline, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2014. Only studies published in 2000 or later were included for harms.Randomised controlled trials assessing benefit of arthroscopic surgery involving partial meniscectomy, debridement, or both for patients with or without radiographic signs of osteoarthritis were included. For harms, cohort studies, register based studies, and case series were also allowed.The search identified nine trials assessing the benefits of knee arthroscopic surgery in middle aged and older patients with knee pain and degenerative knee disease. The main analysis, combining the primary endpoints of the individual trials from three to 24 months postoperatively, showed a small difference in favour of interventions including arthroscopic surgery compared with control treatments for pain (effect size 0.14, 95% confidence interval 0.03 to 0.26). This difference corresponds to a benefit of 2.4 (95% confidence interval 0.4 to 4.3) mm on a 0-100?mm visual analogue scale. When analysed over time of follow-up, interventions including arthroscopy showed a small benefit of 3-5?mm for pain at three and six months but not later up to 24 months. No significant benefit on physical function was found (effect size 0.09, -0.05 to 0.24). Nine studies reporting on harms were identified. Harms included symptomatic deep venous thrombosis (4.13 (95% confidence interval 1.78 to 9.60) events per 1000 procedures), pulmonary embolism, infection, and death.The small inconsequential benefit seen from interventions that include arthroscopy for the degenerative knee is limited in time and absent at one to two years after surgery. Knee arthroscopy is associated with harms. Taken together, these findings do not support the practise of arthroscopic surgery for middle aged or older patients with knee pain with or without signs of osteoarthritis.PROSPERO CRD42014009145.

Project description:BackgroundCurrent prophylactic vaccines against human papillomavirus (HPV) target two oncogenic types (16 and 18) that contribute to 70% of cervical cancer cases worldwide. Our objective was to quantify the range of additional benefits conferred by second-generation HPV prophylactic vaccines that are expected to expand protection to five additional oncogenic types (31, 33, 45, 52 and 58).MethodsA microsimulation model of HPV and cervical cancer calibrated to epidemiological data from two countries (Kenya and Uganda) was used to estimate reductions in lifetime risk of cervical cancer from the second-generation HPV vaccines. We explored the independent and joint impact of uncertain factors (i.e., distribution of HPV types, co-infection with multiple HPV types, and unidentifiable HPV types in cancer) and vaccine properties (i.e., cross-protection against non-targeted HPV types), compared against currently-available vaccines.ResultsAssuming complete uptake of the second-generation vaccine, reductions in lifetime cancer risk were 86.3% in Kenya and 91.8% in Uganda, representing an absolute increase in cervical cancer reduction of 26.1% in Kenya and 17.9% in Uganda, compared with complete uptake of current vaccines. The range of added benefits was 19.6% to 29.1% in Kenya and 14.0% to 19.5% in Uganda, depending on assumptions of cancers attributable to multiple HPV infections and unidentifiable HPV types. These effects were blunted in both countries when assuming vaccine cross-protection with both the current and second-generation vaccines.ConclusionSecond-generation HPV vaccines that protect against additional oncogenic HPV types have the potential to improve cervical cancer prevention. Co-infection with multiple HPV infections and unidentifiable HPV types can influence vaccine effectiveness, but the magnitude of effect may be moderated by vaccine cross-protective effects. These benefits must be weighed against the cost of the vaccines in future analyses.

Project description:ObjectiveTo determine benefits and harms of arthroscopic knee surgery involving partial meniscectomy, debridement, or both for middle aged or older patients with knee pain and degenerative knee disease.DesignSystematic review and meta-analysis.Main outcome measuresPain and physical function.Data sourcesSystematic searches for benefits and harms were carried out in Medline, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2014. Only studies published in 2000 or later were included for harms.Eligibility criteria for selecting studiesRandomised controlled trials assessing benefit of arthroscopic surgery involving partial meniscectomy, debridement, or both for patients with or without radiographic signs of osteoarthritis were included. For harms, cohort studies, register based studies, and case series were also allowed.ResultsThe search identified nine trials assessing the benefits of knee arthroscopic surgery in middle aged and older patients with knee pain and degenerative knee disease. The main analysis, combining the primary endpoints of the individual trials from three to 24 months postoperatively, showed a small difference in favour of interventions including arthroscopic surgery compared with control treatments for pain (effect size 0.14, 95% confidence interval 0.03 to 0.26). This difference corresponds to a benefit of 2.4 (95% confidence interval 0.4 to 4.3) mm on a 0-100 mm visual analogue scale. When analysed over time of follow-up, interventions including arthroscopy showed a small benefit of 3-5 mm for pain at three and six months but not later up to 24 months. No significant benefit on physical function was found (effect size 0.09, -0.05 to 0.24). Nine studies reporting on harms were identified. Harms included symptomatic deep venous thrombosis (4.13 (95% confidence interval 1.78 to 9.60) events per 1000 procedures), pulmonary embolism, infection, and death.ConclusionsThe small inconsequential benefit seen from interventions that include arthroscopy for the degenerative knee is limited in time and absent at one to two years after surgery. Knee arthroscopy is associated with harms. Taken together, these findings do not support the practise of arthroscopic surgery for middle aged or older patients with knee pain with or without signs of osteoarthritis.Systematic review registrationPROSPERO CRD42014009145.

Project description:BackgroundSchizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries).MethodsWe searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556.ResultsOf the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference - 5.83, 95% CI - 10.79 to - 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (- 6.01, 95% CI - 8.7 to - 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (- 7.89, 95% CI - 12.1 to - 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity.ConclusionIPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.

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Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports.

Publications

Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports.

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