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1.
Clin Pharmacol Ther ; 2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34689339

RESUMO

Information derived from routinely collected real-world data has for a long time been used to support regulatory decision making on the safety of drugs and has more recently been used to support marketing authorization submissions to regulators. There is a lack of detailed information on the use and types of this real-world evidence (RWE) as submitted to regulators. We used resources held by the European Medicines Agency (EMA) to describe the characteristics of RWE included in new marketing authorization applications (MAAs) and extensions of indication (EOIs) for already authorized products submitted to the EMA in 2018 and 2019. For MAAs, 63 of 158 products (39.9%) contained RWE with a total of 117 studies. For 31.7% of these products, the RWE submitted was derived from data collected before the planned authorization. The most common data sources were registries (60.3%) followed by hospital data (31.7%). RWE was mainly included to support safety (87.3%) and efficacy (49.2%) with cohort studies being the most frequently used study design (88.9%). For EOIs, 28 of 153 products (18.3%) contained RWE with a total of 36 studies. For 57.1% of these products, studies were conducted prior to the EOIs. RWE sources were mainly registries (35.6%) and hospital data (27.0%). RWE was typically used to support safety (82.1%) and efficacy (53.6%). Cohort studies were the most commonly used study design (87.6%). We conclude that there is widespread use of RWE to support evaluation of MAAs and EOIs submitted to the EMA and identify areas where further research is required.

2.
Hum Vaccin Immunother ; : 1-8, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34428112

RESUMO

The human rotavirus vaccine (HRV; Rotarix, GSK) is available as liquid (Liq) and lyophilized (Lyo) formulations, but only Lyo HRV is licensed in India. In this phase III, randomized, open-label trial (NCT02141204), healthy Indian infants aged 6-10 weeks received 2 doses (1 month apart) of either Liq HRV or Lyo HRV. Non-inferiority of Liq HRV compared to Lyo HRV was assessed in terms of geometric mean concentrations (GMCs) of anti-RV immunoglobulin A (IgA), 1-month post-second dose (primary objective). Reactogenicity/safety were also evaluated. Seroconversion was defined as anti-RV IgA antibody concentration ≥20 units [U]/mL in initially seronegative infants (anti-RV IgA antibody concentration <20 U/mL) or ≥2-fold increase compared with pre-vaccination concentration in initially seropositive infants. Of the 451 enrolled infants, 381 (189 in Liq HRV and 192 in Lyo HRV group) were included in the per-protocol set. The GMC ratio (Liq HRV/Lyo HRV) was 0.93 (95% confidence interval [CI]: 0.65-1.34), with the lower limit of the 95% CI reaching ≥0.5, the pre-specified statistical margin for non-inferiority. In the Liq HRV and Lyo HRV groups, 42.9% and 44.3% (baseline) and 71.4% and 73.4% (1-month post-second dose) of infants had anti-RV IgA antibody concentration ≥20 U/mL, and overall seroconversion rates were 54.5% and 50.0%. Incidences of solicited and unsolicited adverse events were similar between groups and no vaccine-related serious adverse events were reported. Liq HRV was non-inferior to Lyo HRV in terms of antibody GMCs and showed similar reactogenicity/safety profiles, supporting the use of Liq HRV in Indian infants.

3.
Pediatr Infect Dis J ; 40(6): 590-596, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33956757

RESUMO

BACKGROUND: Evidence on vaccine effectiveness (VE) may encourage vaccination and help fight the reemergence of measles and mumps in Europe. However, limited data exist on real-life effectiveness of individual measles, mumps and rubella (MMR) vaccines. This study evaluated VE of GSK's MMR vaccine ("Priorix") against measles and mumps. METHODS: This retrospective, case-control study used UK data from the Clinical Practice Research Datalink GOLD linked to the Hospital Episode Statistics database to identify children 1-13 years old diagnosed with measles or mumps from January 2006 to December 2018. Cases were matched to controls according to birth month/year and practice region. Cases were identified using clinical codes (without laboratory confirmation). "Priorix" exposure was identified using vaccine batch identifiers. Children exposed to other MMR vaccines were excluded. Adjusted VE was estimated for ≥1 vaccine dose in all children, and for 1 dose and ≥2 doses in children ≥4 years at diagnosis. RESULTS: Overall, 299 measles cases matched with 1196 controls (87.6% <4 years old), and 243 mumps cases matched with 970 controls (74.2% <4 years old) were considered. VE for ≥1 dose in all children was 78.0% (97.5% confidence interval: 67.2%-85.3%) for measles and 66.7% (48.1%-78.6%) for mumps. In children ≥4 years old, VE after 1 dose was 74.6% (-21.7% to 94.7%) for measles and 82.3% (32.7%-95.3%) for mumps, and VE after ≥2 doses was 94.4% (79.7%-98.5%) for measles and 86.5% (64.0%-94.9%) for mumps. CONCLUSIONS: "Priorix" is effective in preventing measles and mumps in real-life settings.

4.
Pharmacoepidemiol Drug Saf ; 30(7): 843-857, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33634545

RESUMO

INTRODUCTION: Information regarding availability of electronic healthcare databases in the Asia-Pacific region is critical for planning vaccine safety assessments particularly, as COVID-19 vaccines are introduced. This study aimed to identify data sources in the region, potentially suitable for vaccine safety surveillance. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE). METHODS: Nineteen countries targeted for database reporting were identified using published country lists and review articles. Surveillance capacity was assessed using two surveys: a 9-item introductory survey and a 51-item full survey. Survey questions related to database characteristics, covariate and health outcome variables, vaccine exposure characteristics, access and governance, and dataset linkage capability. Other questions collated research/regulatory applications of the data and local publications detailing database use for research. RESULTS: Eleven databases containing vaccine-specific information were identified across 8 countries. Databases were largely national in coverage (8/11, 73%), encompassed all ages (9/11, 82%) with population size from 1.4 to 52 million persons. Vaccine exposure information varied particularly for standardized vaccine codes (5/11, 46%), brand (7/11, 64%) and manufacturer (5/11, 46%). Outcome data were integrated with vaccine data in 6 (55%) databases and available via linkage in 5 (46%) databases. Data approval processes varied, impacting on timeliness of data access. CONCLUSIONS: Variation in vaccine data availability, complexities in data access including, governance and data release approval procedures, together with requirement for data linkage for outcome information, all contribute to the challenges in building a distributed network for vaccine safety assessment in the Asia-Pacific and globally. Common data models (CDMs) may help expedite vaccine safety research across the region.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Interoperabilidade da Informação em Saúde , Farmacoepidemiologia/métodos , Vigilância de Produtos Comercializados/métodos , Ásia/epidemiologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Bases de Dados Factuais/estatística & dados numéricos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Geografia , Humanos , Cooperação Internacional , Ilhas do Pacífico/epidemiologia , Farmacoepidemiologia/organização & administração , Farmacovigilância , Vigilância de Produtos Comercializados/estatística & dados numéricos , SARS-CoV-2/imunologia
5.
Hum Vaccin Immunother ; 17(1): 269-277, 2021 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-32609045

RESUMO

The etiology of intussusception (IS), a serious gastrointestinal obstruction, remains unclear. Limited evidence suggests a role for viral infection. We investigated the risk of IS after rotavirus gastroenteritis (RV GE) in the first year of life. In this retrospective, self-controlled case series (SCCS), we assessed the risk of IS after RV GE using data from United States administrative claims databases. Incidence rate ratios (IRR) of IS were calculated for the 7- and 21-day risk periods after RV GE (main analysis) or after fracture (sensitivity analysis). A total of 290,912,068 subjects were screened; 42 presented claims for RV GE and IS, and 66 for fracture and IS. The IRRs of IS after RV GE were 79.6 (95% confidence interval, CI: 38.6-164.4) and 25.5 (95% CI: 13.2-49.2) in the 7- and 21-day risk periods. The sensitivity analysis showed an association between IS and fracture for both periods, suggesting potential confounding. Post-hoc analyses did not confirm the association between fracture and IS but suggested a potential association between RV GE and IS. A temporal association between RV GE and IS was detected using claims databases. Due to some limitations of the data sources, this association should be further investigated.


Assuntos
Gastroenterite , Intussuscepção , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Gastroenterite/epidemiologia , Humanos , Lactente , Intussuscepção/epidemiologia , Intussuscepção/etiologia , Estudos Retrospectivos , Infecções por Rotavirus/complicações , Infecções por Rotavirus/epidemiologia , Estados Unidos/epidemiologia
6.
Br J Clin Pharmacol ; 86(6): 1034-1051, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32162368

RESUMO

The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties. PLEG is thus part of the continuum of evidence development for a medicinal product, complementing earlier evidence, facilitating further elucidation of a product's benefit/risk profile, value proposition, and/or exploring broader aspects of disease management and provision of healthcare. PLEG plays a role in regulatory decision making, not only in the European Union but also in other jurisdictions including the USA and Japan. PLEG is also relevant for downstream decision-making by health technology assessment bodies and payers. PLEG comprises studies of different designs, based on data collected in observational or experimental settings. Experience to date in the European Union has indicated a need for improvements in PLEG. Improvements in design and research efficiency of PLEG could be addressed through more systematic pursuance of Scientific Advice on PLEG with single or multiple decision makers. To date, limited information has been available on the rationale, process or timing for seeking PLEG advice from regulators or health technology assessment bodies. This article sets out to address these issues and to encourage further uptake of PLEG advice.


Assuntos
Avaliação da Tecnologia Biomédica , Coleta de Dados , União Europeia , Humanos , Japão
7.
Vaccine ; 37(23): 3006-3021, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31031030

RESUMO

Clinical and post-licensure data have demonstrated that AS03-adjuvanted inactivated split virion vaccines, many with reduced antigen content, are effective against influenza infection. The objective of this review is to provide a comprehensive assessment of the safety of trivalent seasonal, monovalent pre-pandemic and pandemic AS03-adjuvanted influenza vaccines, based on non-clinical, clinical and post-licensure data in various populations. Non-clinical studies on local tolerance, toxicology and safety pharmacology did not raise any safety concerns with AS03 administered alone or combined with various influenza antigens. Data from clinical trials with over 55,000 vaccinated subjects showed that AS03-adjuvanted influenza vaccines were generally well tolerated and displayed an acceptable safety profile, although the power to detect rare events was limited. Approximately 90 million doses of A/H1N1pdm09 pandemic influenza vaccines (Pandemrix and Arepanrix H1N1) were administered worldwide, which contributed post-licensure data to the collective safety data for AS03-adjuvanted influenza vaccines. An association between Pandemrix and narcolepsy was observed during the A/H1N1pdm09 pandemic, for which a role of a CD4 T cell mimicry sequence in the haemagglutinin protein of A/H1N1pdm09 cannot be excluded. Provided that future AS03-adjuvanted influenza vaccines do not contain this putative mimicry sequence, this extensive safety experience supports the further development and use of AS03-adjuvanted inactivated split virion candidate vaccines against seasonal and pandemic influenza infections.


Assuntos
Vacinas contra Influenza/efeitos adversos , Polissorbatos/efeitos adversos , Esqualeno/efeitos adversos , Vacinação/efeitos adversos , alfa-Tocoferol/efeitos adversos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Animais , Anticorpos Antivirais/sangue , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Testes de Inibição da Hemaglutinação , Humanos , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/administração & dosagem , Narcolepsia/etiologia , Farmacovigilância , Polissorbatos/administração & dosagem , Esqualeno/administração & dosagem , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , alfa-Tocoferol/administração & dosagem
8.
Vaccine ; 37(1): 34-40, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471957

RESUMO

INTRODUCTION: It has been suggested that some vaccines have effects beyond protection against the diseases they target, called non-specific effects (NSEs). In 2016, a systematic review by Higgins et al., commissioned by the WHO Strategic Advisory Group of Experts (SAGE) on immunization, estimated the relative risk (RR) of all-cause mortality after whole-cell Diphtheria-Tetanus-Pertussis (DTwP) vaccination to be 1.38 (95% CI: 0.92-2.08), and described these potential NSEs as inconsistent. However, the selection of studies for meta-analysis, based on their proneness to bias and confounding, was debated. OBJECTIVE: To identify study characteristics and postulated risks of bias and confounding that might have impacted the RR of all-cause mortality after DTwP vaccination in observational studies conducted in low-income countries. METHODS: Based on methodological considerations on study design and analysis, we systematically assessed all 17 DTwP studies from the Higgins et al. review for risk of selection bias, exposure and outcome misclassification, confounding and differential co-interventions. We used meta-regression to assess the impact of study characteristics and the postulated risks of bias and confounding on the RR estimates, and looked for outlying and influential risk estimates. Permutation tests were performed to control for false-positive findings. RESULTS: The overall RR of all-cause mortality after DTwP vaccination including all but one outlying and influential study was 1.32 (95% CI: 0.83-2.08). Based on uni-variable meta-regression, we found that study location (p = 0.01), studies using the landmark approach (p = 0.015) and studies at high risk of exposure misclassification (p = 0.036) were significantly associated with increased RR estimates whereas studies at high risk of selection bias (p = 0.059) showed borderline significance. The results further suggest these effect modifiers are clustered in studies conducted in West-Africa. CONCLUSION: The increased RR of all-cause mortality after DTwP might be confined to West-African countries and/or certain postulated risks of bias might have inflated these RRs.


Assuntos
Viés , Países em Desenvolvimento/estatística & dados numéricos , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Imunização/efeitos adversos , África Ocidental , Criança , Pré-Escolar , Difteria/prevenção & controle , Vacina contra Difteria e Tétano/administração & dosagem , Humanos , Lactente , Mortalidade , Estudos Observacionais como Assunto , Análise de Regressão , Tétano/prevenção & controle , Coqueluche/prevenção & controle
9.
Vaccine ; 35(23): 3041-3049, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28465097

RESUMO

Post-authorisation safety studies (PASS) of vaccines assess or quantify the risk of adverse events following immunisation that were not identified or could not be estimated pre-licensure. The aim of this perspective paper is to describe the authors' experience in the design and conduct of twelve PASS that contributed to the evaluation of the benefit-risk of vaccines in real-world settings. We describe challenges and learnings from selected PASS of rotavirus, malaria, influenza, human papillomavirus and measles-mumps-rubella-varicella vaccines that assessed or identified potential or theoretical risks, which may lead to changes to risk management plans and/or to label updates. Study settings include the use of large healthcare databases and de novo data collection. PASS methodology is influenced by the background incidence of the outcome of interest, vaccine uptake, availability and quality of data sources, identification of the at-risk population and of suitable comparators, availability of validated case definitions, and the frequent need for case ascertainment in large databases. Challenges include the requirement for valid exposure and outcome data, identification of, and access to, adequate data sources, and mitigating limitations including bias and confounding. Assessing feasibility is becoming a key step to confirm that study objectives can be met in a timely manner. PASS provide critical information for regulators, public health agencies, vaccine manufacturers and ultimately, individuals. Collaborative approaches and synergistic efforts between vaccine manufacturers and key stakeholders, such as regulatory and public health agencies, are needed to facilitate access to data, and to drive optimal study design and implementation, with the aim of generating robust evidence.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Indústria Farmacêutica/legislação & jurisprudência , Tecnologia Farmacêutica/legislação & jurisprudência , Vacinas/efeitos adversos , Vacina contra Varicela/efeitos adversos , Humanos , Vacinas contra Influenza/efeitos adversos , Vacinas Antimaláricas/efeitos adversos , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Vacinas contra Papillomavirus/efeitos adversos , Medição de Risco , Vacinas contra Rotavirus/efeitos adversos , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/organização & administração , Vacinação , Vacinas/administração & dosagem , Vacinas Atenuadas , Vacinas Combinadas/efeitos adversos
10.
Drug Saf ; 40(8): 693-702, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28417321

RESUMO

INTRODUCTION: We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines. METHODS: Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored. RESULTS: Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients. The regulatory commitment to evaluate the signal through a stepwise investigation was closed in 2014. CONCLUSION: Lessons learned highlight the importance of investigating plausible biological mechanisms between vaccines and potentially associated adverse outcomes, and the importance of selecting appropriate study settings and designs for safety signal investigations.


Assuntos
Rejeição de Enxerto/induzido quimicamente , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Farmacoepidemiologia/métodos , Adolescente , Adulto , Idoso , Animais , Combinação de Medicamentos , Feminino , Rejeição de Enxerto/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polissorbatos/efeitos adversos , Vigilância de Produtos Comercializados/métodos , Esqualeno/efeitos adversos , Esqualeno/imunologia , Adulto Jovem , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/imunologia
11.
Pharmacoepidemiol Drug Saf ; 25(12): 1397-1406, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27601179

RESUMO

PURPOSE: Investigational and marketed vaccines are increasingly evaluated, and manufacturers are required to put in place mechanisms to monitor long-term benefit-risk profiles. However, generating such evidence in real-world settings remains challenging, especially when rare adverse events are assessed. Planning of an appropriate study design is key to conducting a valid study. The aim of this paper is to illustrate how feasibility assessments support the generation of robust pharmacoepidemiological data. METHODS: Following an initiative launched by the International Society for Pharmacoepidemiology in May 2014, a working group including members of the private and public sectors, was formed to assess the value of conducting feasibility assessments as a necessary step before embarking on larger-scale post-licensure studies. Based on five real-life examples of feasibility assessments, lessons learned and recommendations were issued by the working group to support scientific reasoning and decision making when designing pharmacoepidemiologic vaccine studies. RESULTS: The working group developed a toolbox to provide a pragmatic approach to conducting feasibility assessments. The toolbox contains two main components: the scientific feasibility and the operational feasibility. Both components comprise a series of specific questions aimed at overcoming methodological and operational challenges. CONCLUSIONS: A feasibility assessment should be formalized as a necessary step prior to the actual start of any pharmacoepidemiologic study. It should remain a technical evaluation and not a hypothesis testing. The feasibility assessment report may facilitate communication with regulatory agencies toward improving the quality of study protocols and supporting the endorsement of study objectives and methods addressing regulatory commitments. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.


Assuntos
Farmacoepidemiologia/métodos , Projetos de Pesquisa , Vacinas/administração & dosagem , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Estudos de Viabilidade , Humanos , Agências Internacionais , Fatores de Tempo , Vacinas/efeitos adversos
12.
Vaccine ; 34(31): 3598-606, 2016 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-27216760

RESUMO

BACKGROUND: Annual seasonal influenza vaccination is recommended for transplant recipients. No formal pharmacoepidemiology study has been published on the association between solid organ transplant (SOT) rejection and vaccination with seasonal trivalent inactivated influenza vaccines (TIIVs). METHODS: The risk of SOT (liver, kidney, lung, heart or pancreas) rejection after TIIV vaccination was assessed using a self-controlled case-series method (NCT01715792). SOT recipients in England with transplant rejection were selected from the Clinical Practice Research Datalink and linked Hospital Episode Statistics inpatient data. The study period (September 2006 to August 2009) encompassed three consecutive influenza seasons. We calculated the relative incidence (RI) of SOT rejection between the 30- and 60-day post-vaccination risk periods and the control periods (any follow-up period excluding risk periods), using a Poisson regression model. RESULTS: In seasons 2006/07, 2007/08, 2008/09 and pooled seasons, 132, 136, 168 and 375 subjects, respectively, experienced at least one transplant rejection; approximately half (45%-51%) of these subjects had received a TIIV. For season 2006/07, the RI of rejection of any organ, adjusted for time since transplantation, was 0.74 (95% CI: 0.24-2.28) and 0.58 (95% CI: 0.24-1.38) during the 30-day and 60-day risk periods, respectively. Corresponding RIs for season 2007/08 were 1.21 (95% CI: 0.55-2.64) and 1.31 (95% CI: 0.69-2.48); for season 2008/09, 0.99 (95% CI: 0.43-2.28) and 0.64 (95% CI: 0.31-1.33); and for pooled seasons 1.01 (95% CI: 0.58-1.76) and 0.88 (95% CI: 0.56-1.38). The results of a separate analysis of kidney rejections and analyses that took into account additional potential confounders were consistent with those of the main analyses, with 95% CIs including 1 and upper limits below 3. CONCLUSION: This study provides reassuring evidence of the safety profile of TIIVs in SOT recipients, thus supporting current recommendations to vaccinate this risk group annually.


Assuntos
Rejeição de Enxerto/epidemiologia , Vacinas contra Influenza/administração & dosagem , Transplantados , Vacinação/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Inglaterra , Feminino , Humanos , Lactente , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
13.
PLoS One ; 11(2): e0149289, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26901063

RESUMO

BACKGROUND: An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies. METHODS: We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible. RESULTS: Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72-28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49-15.1) and the French odds ratio of 5.43 (95% CI: 2.6-10.08) to 1.85 (2.5th-97.5th percentile: 0.85-4.08). CONCLUSION: We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Narcolepsia/epidemiologia , Pandemias , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Finlândia/epidemiologia , França/epidemiologia , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/epidemiologia , Masculino , Narcolepsia/induzido quimicamente , Suécia/epidemiologia
14.
BMJ Open ; 6(1): e009264, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26823177

RESUMO

OBJECTIVE: To assess the risk of solid organ transplant (SOT) rejection after vaccination with the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine Pandemrix. DESIGN: Self-controlled case series (SCCS) in the UK Clinical Practice Research Datalink (CPRD) and its linked component of the Hospital Episodes Statistics (HES) inpatient database. Analyses were conducted using the SCCS method for censored, perturbed or curtailed post-event exposure. PARTICIPANTS: Of the 184 transplant recipients having experienced at least one SOT rejection (liver, kidney, lung, heart or pancreas) during the study period from 1 October 2009 to 31 October 2010, 91 participants were included in the main analysis, of which 71 had been exposed to Pandemrix. MAIN OUTCOME MEASURES: Occurrence of SOT rejection during risk (30 and 60 days after any Pandemrix dose) and control periods. Covariates in the CPRD included time since transplantation, seasonal influenza vaccination, bacterial and viral infections, previous SOT rejections and malignancies. RESULTS: The relative incidence (RI) of rejection of any one of the five transplanted organs, adjusted for time since transplantation, was 1.05 (95% CI 0.52 to 2.14) and 0.80 (95% CI 0.42 to 1.50) within 30 and 60 days after vaccination, respectively. Similar estimates were observed for rejection of a kidney only, the most commonly transplanted organ (RI within 30 days after vaccination: 0.85 (95% CI 0.38 to 1.90)). Across various models and sensitivity analyses, RI estimates remained stable and within a consistent range around 1.0. CONCLUSIONS: These results suggest a reassuring safety profile for Pandemrix with regard to the risk of rejection in SOT recipients in England and contribute to inform the benefit-risk of AS03-adjuvanted pandemic influenza vaccines in transplanted patients in the event of future pandemics. TRIAL REGISTRATION NUMBER: NCT01715792.


Assuntos
Rejeição de Enxerto , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Medição de Risco , Vacinação , Humanos , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo , Reino Unido , Vacinação/efeitos adversos
15.
Hum Vaccin Immunother ; 12(1): 187-93, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26379011

RESUMO

A link between Pandemrix™ (AS03-adjuvanted H1N1 pandemic influenza vaccine, GSK Vaccines, Belgium) and narcolepsy was first suspected in 2010 in Sweden and Finland following a number of reports in children and adolescents. Initial scepticism about the reported association faded as additional countries reported similar findings, leading several regulatory authorities to restrict the use of Pandemrix™. The authors acknowledge that currently available data suggest an increased risk of narcolepsy following vaccination with Pandemrix™; however, from an epidemiologist's perspective, significant methodological limitations of the studies have not been fully addressed and raise questions about the reported risk estimates. We review the most important biases and confounders that potentially occurred in 12 European studies of the observed association between Pandemrix™ and narcolepsy, and call for further analyses and debate.


Assuntos
Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Narcolepsia/induzido quimicamente , Narcolepsia/epidemiologia , Métodos Epidemiológicos , Europa (Continente)/epidemiologia , Humanos
16.
Hum Vaccin Immunother ; 10(10): 2942-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25483467

RESUMO

Clinical trials have shown that AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines are highly immunogenic, although with an increased reactogenicity profile relative to non-adjuvanted vaccines in terms of the incidence of common injection site and systemic adverse events (AEs). We evaluated pooled safety data from 22,521 adults who had received an AS03-adjuvanted H5N1 or A(H1N1)pdm09 influenza or control vaccine with the purpose to identify medically-attended AEs (MAEs), including subsets of serious AEs (SAEs), potentially immune-mediated diseases (pIMDs), and AEs of special interest (AESI), and to explore a potential association of these AEs with the administration of an AS03-adjuvanted influenza vaccine. For participants who had received an AS03-adjuvanted vaccine, the relative risks (RRs) for experiencing a MAE or a SAE compared to control group (participants who had received a non-adjuvanted vaccine or saline placebo) were 1.0 (95% confidence interval [CI]: 0.9; 1.1) and 1.1 (95% CI: 0.9; 1.4), respectively. The overall RRs for experiencing an AESI or a pIMD (AS03-adjuvanted vaccine/control) were 1.2 (95% CI: 0.9; 1.6) and 1.7 (95% CI: 0.8; 3.8), respectively. Thirty-8 participants in the AS03-adjuvanted vaccine group had a pIMD reported after vaccine administration, yielding an incidence rate (IR) of 351.9 (95% CI: 249.1; 483.1) per 100,000 person-years. The estimated IRs in the AS03-adjuvanted vaccine group were greater than the literature reported rates for: facial paresis/VIIth nerve paralysis, celiac disease, thrombocytopenia and ulcerative colitis. These results do not support an association between AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines and the AEs collected in the trials included in the analysis.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Vírus da Influenza A Subtipo H1N1/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/uso terapêutico , Polissorbatos/efeitos adversos , Esqualeno/efeitos adversos , alfa-Tocoferol/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Combinação de Medicamentos , Feminino , Humanos , Vacinas contra Influenza/efeitos adversos , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Polissorbatos/uso terapêutico , Risco , Esqualeno/uso terapêutico , Vacinação , Adulto Jovem , alfa-Tocoferol/uso terapêutico
17.
BMJ Open ; 4(3): e004546, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24607562

RESUMO

INTRODUCTION: The aetiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) remains incompletely understood and strategies for treatment and prevention have not altered significantly for many years. Improved understanding of the role of respiratory pathogens in acute exacerbations of COPD (AECOPD) is required and the use of molecular microbiological techniques may lead to insights into host-pathogen interactions and the development of more targeted therapeutic approaches. METHODS AND ANALYSES: Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) is a longitudinal epidemiological study to assess how changes in the COPD airway microbiome contribute to the incidence and severity of AECOPD. Patients with COPD aged 40-85 are followed monthly for 2 years, and reviewed within 72 h of onset of symptoms of AECOPD. Exacerbations are detected using daily electronic diary cards. Blood, sputum, nasopharyngeal and urine samples are collected at prespecified timepoints. Molecular diagnostic and typing techniques are used to describe the dynamics of airway infection during AECOPD and stable disease, and associations with clinical outcome. This study aims to refine the case definition of AECOPD to reflect the possible microbiological aetiology. AERIS will assess the impact of AECOPD on health-related quality of life and healthcare resource utilisation, and the possible interactions between nutritional status, infection and immune responses. ETHICS AND DISSEMINATION: AERIS is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and has been approved by the institutional ethics and review board. All participants must provide written informed consent. The results obtained will be disseminated at international medical conferences and in peer-reviewed publications. DISCUSSION: Few other studies have addressed the complexity of the microbiological and systemic components of COPD or employed real-time electronic tracking of symptoms to identify AECOPD and potential aetiological triggers. RESULTS: Results of AERIS will increase our understanding of the contribution of pathogens to AECOPD, potentially leading to new targeted therapeutic and preventative interventions. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01360398.


Assuntos
Doença Pulmonar Obstrutiva Crônica/microbiologia , Infecções Respiratórias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos Clínicos , Progressão da Doença , Feminino , Serviços de Saúde/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Técnicas Microbiológicas , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Estado Nutricional , Estudos Prospectivos , Qualidade de Vida , Projetos de Pesquisa , Reino Unido
18.
BMC Public Health ; 13: 1065, 2013 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-24215264

RESUMO

BACKGROUND: Data on the psychosocial burden of human papillomavirus (HPV)-related diseases other than cervical cancer are scarce. The objectives of this study were to measure and compare the psychosocial burden and the impact on health-related quality of life (HRQoL) of HPV-related lower genital tract diseases and genital warts (GW) using several generic and disease-specific instruments. METHODS: Overall, 842 individuals with normal cervical cytology (n = 241), borderline nuclear abnormalities and/or mild dyskaryosis (n = 23), cervical intraepithelial neoplasia (CIN)1 (n = 84), CIN2/3 (n = 203), vulval intraepithelial neoplasia (VIN)2/3 (n = 43), GW (n = 186) and a history of GW (non-current) (n = 62) were included. The generic European Quality of Life Index Version 5D (EQ-5D) questionnaire was completed by patients with GW and VIN2/3. Sexual functioning was evaluated using the Change in Sexual Functioning Questionnaire (CSFQ). Psychosocial impact was measured in women using the HPV Impact Profile (HIP) questionnaire. HRQoL was assessed using a GW-specific questionnaire, the Cuestionario Especifico en Condilomas Acuminados (CECA) (completed by patients with GW and history of GW). For each instrument, scores were compared between groups using the Student's t-test. In addition, utility loss due to GW and VIN2/3 was evaluated by comparing mean EQ-5D scores weighted by age and sex with the UK general population normal values. RESULTS: A significant psychosocial impact was found in women diagnosed with HPV-related genital diseases, particularly in those with GW. The health state of younger adults with GW was significantly impaired compared with UK normal values (mean EQ-5D index score 0.86 vs 0.94, p < 0.001 for 18-24-year-olds; 0.87 vs 0.93, p = 0.030 for 25-34-year-olds). VIN2/3 was found to have a significant negative impact on sexual functioning, and women with VIN2/3 had a highly impaired health state compared with women in the UK general population (weighted mean EQ-5D index score 0.72 vs 0.89, p < 0.001; weighted mean Visual Analogue Scale score 62 vs 85, p < 0.001). CONCLUSIONS: HPV-related lower genital tract lesions and GW significantly impair psychosocial wellbeing and HRQoL. The psychosocial aspects of HPV-related diseases need to be considered when evaluating the potential benefit of HPV vaccination.


Assuntos
Adaptação Psicológica , Condiloma Acuminado/psicologia , Infecções por Papillomavirus/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Testes Psicológicos , Psicologia , Fatores Socioeconômicos , Inquéritos e Questionários , Reino Unido/epidemiologia , Adulto Jovem
19.
Vaccine ; 28(30): 4719-30, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20451636

RESUMO

GARDASIL has been shown to reduce the incidence of pre-cancerous cervical, vulvar, and vaginal lesions, and external genital warts causally related to HPV6/11/16/18. Because of its expected public health benefit on reduction of cervical cancer and other HPV-related diseases, this vaccine has been rapidly implemented in the routine vaccination programs of several countries. It is therefore essential to assess its impact and safety through post-licensure surveillance programs. Here, we present a summary of 16 post-licensure safety and impact studies across 20 countries. These studies address general safety, including autoimmune disorders, long-term effectiveness, and type replacement. A summary of the surveillance efforts of the Unites States Centers for Disease Control and Prevention can be found in the accompanying article by Markowitz et al.


Assuntos
Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Atitude do Pessoal de Saúde , Criança , Ensaios Clínicos como Assunto , Condiloma Acuminado/epidemiologia , Condiloma Acuminado/prevenção & controle , Indústria Farmacêutica , Europa (Continente) , Feminino , França , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18 , Humanos , Licenciamento , Programas de Assistência Gerenciada , Infecções por Papillomavirus/epidemiologia , Vacinas contra Papillomavirus/efeitos adversos , Aceitação pelo Paciente de Cuidados de Saúde , Vigilância de Produtos Comercializados , Sistema de Registros , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Adulto Jovem
20.
Int J Epidemiol ; 38(6): 1497-511, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19720726

RESUMO

BACKGROUND: Whereas the International Agency for Research on Cancer (IARC) Monograph concluded that the evidence for the relationship between cigarette smoking and liver cancer is sufficient, the US Surgeon General's report summarized the data as suggestive but not sufficient. METHODS: A meta-analysis of previous epidemiologic studies may help to clarify the potential association. We identified 38 cohort studies and 58 case-control studies in a systematic literature search for studies on liver cancer and cigarette smoking. The meta-relative risk (mRR) of liver cancer and dose-response trends were calculated. Tests for heterogeneity, publication bias assessment and influence analyses were performed. RESULTS: Compared with never smokers, the adjusted mRR was 1.51 [95% confidence interval (CI) 1.37-1.67] for current smokers and 1.12 (95% CI 0.78-1.60) for former smokers. The increased liver cancer risk among current smokers appeared to be consistent in strata of different regions, study designs, study sample sizes and publication periods. CONCLUSION: The results of our meta-analysis show that tobacco smoking is associated with liver cancer development, which supports the conclusion by the IARC Monograph. This conclusion has an important public health message for areas with high smoking prevalence and high liver cancer incidence such as China.


Assuntos
Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Saúde Pública , Fumar/efeitos adversos , Ásia/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Razão de Chances , Prevalência , Fatores de Risco , Estados Unidos/epidemiologia
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