/pdf/european-evidence-based-consensus-on-the-prevention-2i61racmdl.pdf

European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease.

Background
Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical industry sponsored studies are more often favorable to the sponsor’s product compared with studies with other sources of sponsorship. This review is an update using more stringent methodology and also investigating sponsorship of device studies.

Objectives
To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship.

Search methods
We searched MEDLINE (1948 to September 2010), EMBASE (1980 to September 2010), the Cochrane Methodology Register (Issue 4, 2010) and Web of Science (August 2011). In addition, we searched reference lists of included papers, previous systematic reviews and author files.

Selection criteria
Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions.

Data collection and analysis
Two assessors identified potentially relevant papers, and a decision about final inclusion was made by all authors. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals).

Main results
Forty-eight papers were included. Industry sponsored studies more often had favorable efficacy results, risk ratio (RR): 1.32 (95% confidence interval (CI): 1.21 to 1.44), harms results RR: 1.87 (95% CI: 1.54 to 2.27) and conclusions RR: 1.31 (95% CI: 1.20 to 1.44) compared with non-industry sponsored studies. Ten papers reported on sponsorship and effect size, but could not be pooled due to differences in their reporting of data. The results were heterogeneous; five papers found larger effect sizes in industry sponsored studies compared with non-industry sponsored studies and five papers did not find a difference in effect size. Only two papers (including 120 device studies) reported separate data for devices and we did not find a difference between drug and device studies on the association between sponsorship and conclusions (test for interaction, P = 0.23). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment and follow-up. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.32 (95% CI: 1.05 to 1.65), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.84 (95% CI: 0.70 to 1.01).

Authors' conclusions
Sponsorship of drug and device studies by the manufacturing company leads to more favorable results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.

/pdf/industry-sponsorship-and-research-outcome-1zaeyoxoy7.pdf

Industry sponsorship and research outcome

Background
Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America.

Objectives
Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults.

Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010).

Selection criteria
Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms.

Data collection and analysis
Two review authors independently assessed trial quality and extracted data.

Main results
We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barre Syndrome per million vaccinations. The harms evidence base is limited.

Authors' conclusions
Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission.

WARNING:
This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.

Vaccines for preventing influenza in healthy adults

Tick-borne encephalitis

Context Previous studies indicate that the interpretation of trial results can be distorted by authors of published reports. Objective To identify the nature and frequency of distorted presentation or “spin” (ie, specific reporting strategies, whatever their motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results) in published reports of randomized controlled trials (RCTs) with statistically nonsignificant results for primary outcomes. Data Sources March 2007 search of MEDLINE via PubMed using the Cochrane Highly Sensitive Search Strategy to identify reports of RCTs published in December 2006. Study Selection Articles were included if they were parallel-group RCTs with a clearly identified primary outcome showing statistically nonsignificant results (ie, P ≥ .05). Data Extraction Two readers appraised each selected article using a pretested, standardized data abstraction form developed in a pilot test. Results From the 616 published reports of RCTs examined, 72 were eligible and appraised. The title was reported with spin in 13 articles (18.0%; 95% confidence interval [CI], 10.0%-28.9%). Spin was identified in the Results and Conclusions sections of the abstracts of 27 (37.5%; 95% CI, 26.4%-49.7%) and 42 (58.3%; 95% CI, 46.1%-69.8%) reports, respectively, with the conclusions of 17 (23.6%; 95% CI, 14.4%-35.1%) focusing only on treatment effectiveness. Spin was identified in the main-text Results, Discussion, and Conclusions sections of 21 (29.2%; 95% CI, 19.0%-41.1%), 31 (43.1%; 95% CI, 31.4%-55.3%), and 36 (50.0%; 95% CI, 38.0%-62.0%) reports, respectively. More than 40% of the reports had spin in at least 2 of these sections in the main text. Conclusion In this representative sample of RCTs published in 2006 with statistically nonsignificant primary outcomes, the reporting and interpretation of findings was frequently inconsistent with the results.

/pdf/reporting-and-interpretation-of-randomized-controlled-trials-293878lmqx.pdf

Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes.

Measles, mumps and rubella (MMR) are three very dangerous infectious diseases which cause severe morbidity, disability and death in low-income countries.
Based on the evidence provided by three cohort studies (3104 participants), vaccination with one dose of MMR vaccine is at least 95% effective in preventing clinical measles among preschool children; in schoolchildren and adolescents at least one dose of MMR vaccine was 98% effective in preventing laboratory-confirmed measles cases; one or two MMR doses were respectively 92% and 95% effective in preventing secondary measles cases.
At least one dose of MMR vaccine is effective in preventing clinical mumps among children and adolescents when prepared with Jeryl Lynn strains (vaccine effectiveness = 69% to 81%, one cohort and one case-control study, 1656 participants), as well as when prepared with Urabe strain (vaccine effectiveness = 70% to 75%, one cohort and one case-control study, 1964 participants). Effectiveness against laboratory-confirmed mumps in children and adolescents was estimated to be between 64% to 66% for one and 83% to 88% for two doses of Jeryl Lynn MMR (two case-control studies, 1664 participants) and 87% for Urabe-containing MMR (one cohort study, 48 participants). Vaccination with Urabe MMR confers protection against secondary mumps infection (vaccine effectiveness = 73%, one cohort study, 147 participants).
We identified no studies assessing the effectiveness of MMR vaccine against clinical or laboratory-confirmed rubella.
Results from two very large case series studies involving about 1,500,000 children who were given the MMR vaccine containing Urabe or Leningrad-Zagreb strains show this vaccine to be associated with aseptic meningitis; whereas administration of the vaccine containing Moraten, Jeryl Lynn, Wistar RA, RIT 4385 strains is associated with febrile convulsion in children aged below five years (one person-time cohort study, 537,171 participants; two self controlled case series studies, 1001 participants). The MMR vaccine could also be associated with idiopathic thrombocytopaenic purpura (two case-controls, 2450 participants, one self controlled case series, 63 participants).
We could assess no significant association between MMR immunisation and the following conditions: autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, or bacterial or viral infections. The methodological quality of many of the included studies made it difficult to generalise their results.

/pdf/vaccines-for-measles-mumps-and-rubella-in-children-2p4onoiytk.pdf

Vaccines for measles, mumps and rubella in children

Cochrane Review: Vaccines for measles, mumps and rubella in children Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C. Vaccines for measles, mumps and rubella in children. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD004407. DOI: 10.1002/14651858.CD004407.pub3



This companion piece to the review, “Vaccines for measles, mumps and rubella in children,” contains the following pieces: 



The abstract of the review




A commentary from one or more of the review authors, explaining why the review team felt the review was an important one to produce




A commentary from Joan Robinson, Editor-in-chief, outlining the review's findings




A review of clinical practice guidelines from the American Academy of Pediatrics, the Canadian Paediatric Society and the National Institute for Health and Care Excellence (NICE), United Kingdom




Some other recently published references on this topic

Cochrane in context: Vaccines for measles, mumps and rubella in children

Background
Tick-borne encephalitis (TBE) is a disease of the central nervous system caused by a tick-borne viral infection. TBE can lead to severe neurological syndromes such as meningitis, meningoencephalitis, and meningoencephalomyelitis, which can result in death. There is no treatment, and prevention with the vaccine is the only intervention currently available.

Objectives
To evaluate vaccines for preventing TBE in terms of effectiveness and adverse effects.

Search methods
In June 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE, EMBASE, LILACS, and mRCT. We also checked reference lists of articles.

Selection criteria
Randomized and quasi-randomized controlled trials comparing TBE vaccines against placebo, control vaccines, no intervention, or a different dose or schedule of the intervention vaccine.

Data collection and analysis
Two authors applied the inclusion criteria, extracted data, and assessed each trial's risk of bias. We could not combine the included trials in a meta-analysis because of differences in comparisons and outcomes.

Main results
Eleven trials (corresponding to 10 papers) involving 8184 participants (6586 adults and 1598 children) were included. Different versions of three types of TBE vaccines were tested (IPVE, FSME-IMMUN, and Encepur); out of which only three (Encepur children, Encepur Adults, and FSME-IMMUN "new") are currently licensed. No trials reported on cases of clinical TBE, but all reported on antibody titre (seroconversion). All the vaccines gave seroconversion rates of over 87%. Systemic and local adverse effects were common; none were severe or life threatening.

Authors' conclusions
Tick-borne encephalitis vaccines appear to be highly immunogenic, but the relationship between seroconversion and clinical protection has not been established. Although adverse effects were commonly reported, none were serious or life threatening.

Vaccines for preventing tick‐borne encephalitis

Background Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012. Objectives To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019). Selection criteria We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age. Data collection and analysis Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE. Main results We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella, using a vaccine with the BRD2 strain which is only used in China, is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.

Vaccines for measles, mumps, rubella, and varicella in children

Objective To explore the relation between study concordance, take home message, funding, and dissemination of comparative studies assessing the effects of influenza vaccines.

Design Systematic review without meta-analysis.

Data extraction Search of the Cochrane Library, PubMed, Embase, and the web, without language restriction, for any studies comparing the effects of influenza vaccines against placebo or no intervention. Abstraction and assessment of quality of methods were carried out.

Data synthesis We identified 259 primary studies (274 datasets). Higher quality studies were significantly more likely to show concordance between data presented and conclusions (odds ratio 16.35, 95% confidence interval 4.24 to 63.04) and less likely to favour effectiveness of vaccines (0.04, 0.02 to 0.09). Government funded studies were less likely to have conclusions favouring the vaccines (0.45, 0.26 to 0.90). A higher mean journal impact factor was associated with complete or partial industry funding compared with government or private funding and no funding (differences between means 5.04). Study size was not associated with concordance, content of take home message, funding, and study quality. Higher citation index factor was associated with partial or complete industry funding. This was sensitive to the exclusion from the analysis of studies with undeclared funding.

Conclusion Publication in prestigious journals is associated with partial or total industry funding, and this association is not explained by study quality or size.

https://www.bmj.com/content/bmj/338/bmj.b354.full.pdf

Maria Grazia Debalini

Papers

Vaccines for measles, mumps and rubella in children

Cochrane in context: Vaccines for measles, mumps and rubella in children

Vaccines for preventing tick‐borne encephalitis

Vaccines for measles, mumps, rubella, and varicella in children

Relation of study quality, concordance, take home message, funding, and impact in studies of influenza vaccines: systematic review