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Industry sponsorship and research outcome: systematic review with meta-analysis
Abstract
Purpose
Clinical research is widely sponsored by drug and device companies. We investigated 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. This review is an update of a previous Cochrane review.
Methods
In this update we searched MEDLINE and Embase (2010 to February 2015), Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). We included empirical studies that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. Two assessors included papers, extracted data and assessed risk of bias. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether conclusions agreed with results.
Results
We included 27 additional papers in this update (review now includes 75 papers). Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI 1.17–1.37), no difference in harms results RR: 1.37 (95% CI 0.64–2.93) and more often favorable conclusions RR: 1.34 (95% CI 1.19–1.51) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in reporting of data and heterogeneity of results. Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI 1.05–1.50), compared with non-industry sponsored studies.
Conclusions
Drug and device studies sponsored by manufacturing companies have more favorable efficacy results and conclusions than studies sponsored by other sources.
... Chemical manufacturers have a financial stake in the production of existing chemicals and have an incentive to delay data generation to maintain or grow their market [54,56]. Early warning signals of harm are often ignored or downplayed by those with financial stakes in the outcome of any prevention activities, leading to delays in action to the detriment of public health; as demonstrated by numerous well-characterized toxicants including tobacco smoke, lead, and air pollutants [57][58][59]. For example, in 1989 EPA issued a final rule under the original TSCA to ban the use of most products containing asbestos, a naturally-occurring fiber classified as carcinogenic to humans by IARC in 1977 and 1987, and widely-used in commerce despite known health impacts in asbestos factory workers as early as 1898 [60][61][62]. ...
... It is well established that chemical industry sponsors and researchers financially supported in whole or part by the chemical industry gain from asserting that industrial chemicals are safe and sowing doubt about data to the contrary [58,115]. These findings can be used to prevent, delay, alter, or minimize regulation, and market these chemicals to increase their production and sale and such tactics have been used in various hazardous agents including but not limited to asbestos, lead, and tobacco [59,115,116]. ...
... Even when controlling for the methodological risk of bias or internal validity, instances when studies are determined to have similar biases based on evaluation of their published methods (e.g., how they conducted exposure and outcome assessment), studies with industry sponsorship or authors with a financial COI are more likely to report findings that favor the sponsor's product than those without [58,[124][125][126][127][128]. This phenomenon occurs across several research areas including tobacco, pharmaceutical, nutrition, and chemical. ...
The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a “safe” or “no-risk” level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.
... As demonstrated by myriad well-characterized toxicants including lead, air pollutants, including greenhouse gases and tobacco smoke, those with financial a stake in the manufacture, distribution and sale of hazardous agents are incentivized to ignore, downplay, distort or create confusion around the early warning signs on the harms of their products, which leads to delay regulatory action to the detriment of public health [53,54,145,146]. It has been demonstrated across pharmaceutical, tobacco, nutrition, chemical and ELF-EMF research that studies that have an industry sponsor or an author with a financial COI are more likely to produce results and conclusions that favor the sponsor's product than studies without an industry sponsor or author with a COI [52,[147][148][149][150][151]. This bias remains even when we control for the other methodological risks of bias (or internal validity) that could influence a study's results [52,147,150]. ...
... It has been demonstrated across pharmaceutical, tobacco, nutrition, chemical and ELF-EMF research that studies that have an industry sponsor or an author with a financial COI are more likely to produce results and conclusions that favor the sponsor's product than studies without an industry sponsor or author with a COI [52,[147][148][149][150][151]. This bias remains even when we control for the other methodological risks of bias (or internal validity) that could influence a study's results [52,147,150]. Industry sponsors or authors with a COI can intentionally bias the research process through various mechanisms, including how the research question is framed, through the design and conduct of a study; how the events are coded; how the study data are analyzed and the results and conclusions are reported [152][153][154][155]. For example, in a 2019 evaluation of data linking exposure to the herbicide paraquat with a potential risk of Parkinson's Disease, the U.S. EPA Office of Pesticide Programs (EPA Pesticide Office) identified a distinct difference in reported outcomes based on study sponsorship [44]. ...
Background
In February 2021, over one hundred scientists and policy experts participated in a web-based Workshop to discuss the ways that divergent evaluations of evidence and scientific uncertainties are used to delay timely protection of human health and the environment from exposures to hazardous agents. The Workshop arose from a previous workshop organized by the European Environment Agency (EEA) in 2008 and which also drew on case studies from the EEA reports on ‘Late Lessons from Early Warnings’ (2001, 2013). These reports documented dozens of hazardous agents including many chemicals, for which risk reduction measures were delayed for decades after scientists and others had issued early and later warnings about the harm likely to be caused by those agents.
Results
Workshop participants used recent case studies including Perfluorooctanoic acid (PFOA), Extremely Low Frequency – Electrical Magnetic Fields (ELF-EMF fields), glyphosate, and Bisphenol A (BPA) to explore myriad reasons for divergent outcomes of evaluations, which has led to delayed and inadequate protection of the public’s health. Strategies to overcome these barriers must, therefore, at a minimum include approaches that 1) Make better use of existing data and information, 2) Ensure timeliness, 3) Increase transparency, consistency and minimize bias in evidence evaluations, and 4) Minimize the influence of financial conflicts of interest.
Conclusion
The recommendations should enhance the production of “actionable evidence,” that is, reliable evaluations of the scientific evidence to support timely actions to protect health and environments from exposures to hazardous agents. The recommendations are applicable to policy and regulatory settings at the local, state, federal and international levels.
... Our bias risk assessment will be based on the Cochrane Risk of Bias tool-version 2 (RoB 2) as recommended in The Cochrane Handbook of Systematic Reviews of Interventions [41]. Moreover, we will include an assessment of for-profit bias [42]. We will judge a publication at high risk of vested interests if a trial is sponsored by the industry or if just one author has affiliation to the industry. ...
... • Trials at high risk of bias compared to trials at low risk of bias • Trials without vested interests compared to trials with unknown or known risk of vested interests [42] • Trials published before 2000 compared to trials published after 2000 • Target nucleus (e.g. subthalamic nucleus, internal globus pallidus, ventral intermedius nucleus) • Types of comparators (e.g. ...
Background
Deep brain stimulation has been used since the 1980s for neurological disorders and the USA and Europe have now approved it for Parkinson’s disease, essential tremor, dystonia, and epilepsy. Previous reviews have assessed the effects of deep brain stimulation on different neurological disorders. These reviews all had methodological limitations.
Methods
This is a protocol for a systematic review based on searches of major medical databases (e.g. MEDLINE, EMBASE, CENTRAL) and clinical trial registries. Two review authors will independently extract data and conduct risk of bias assessment. We will include published and unpublished randomised clinical trial comparing deep brain stimulation versus no intervention, usual care, sham stimulation, medical treatment, or resective surgery for Parkinson’s disease, essential tremor, dystonia, or epilepsy. The effects of deep brain stimulation will be analysed separately for each of the different diagnoses. Primary outcomes will be all-cause mortality, disease-specific symptoms, and serious adverse events. Secondary outcomes will be quality of life, depressive symptoms, executive functioning, level of functioning, and non-serious adverse events. Data will be analysed using fixed-effect and random-effects meta-analyses and Trial Sequential Analysis. Risk of bias will be assessed with the Cochrane Risk of Bias tool—version 2, an eight-step procedure to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE).
Discussion
Deep brain stimulation is increasingly being used for different neurological diseases, and the effects are unclear based on previous evidence. There is a need for a comprehensive systematic review of the current evidence. This review will provide the necessary background for weighing the benefits against the harms when assessing deep brain stimulation as intervention for individual neurological disorders.
Systematic review registration
PROSPERO 306,556.
... Since the beginning of this century, several studies have shown that clinical trials funded by the industry result in favorable outcomes for the test drug at a frequency of 4 to 20 times higher than in independent trials for the same drugs 33 . A more recent meta-analysis involving all this research confirmed a four times higher frequency of favorable results in studies promoted by the industry as well as a lower record of adverse effects 34 . ...
The social sciences have integrated the analytical and normative practices of bioethics. However, with some exceptions, the proposals have been epistemically limited to the methodological scope and strictly directed to biomedical care practices. Taking some data on the strategies of production of new drugs by the pharmaceutical industry, this essay intends to demonstrate the possible contributions of the social studies of science and technology to a theoretical-methodological foundation of bioethical analyzes around global health issues, such as the production and distribution of technologies. We conclude that at least three types of analyzes would benefit from this proximity: analyzes of the epistemological integrity of the health sciences; ethical-political analyzes around the access and security of new and old health technologies; and ethical-philosophical analyzes of harmful attitudes of the scientific community and health professionals in relation to health care.
... However, studies in which any author reported a COI had a significantly higher RCR and journal IF than non-conflicted studies. COI can influence how studies are designed, conducted, analyzed, and reported, and both author financial COIs and commercial funding have been demonstrated to be associated with more frequent reporting of statistically significant results and favorable study conclusions [30,31]. The specific influence of COIs in the orthopedic literature, and even more specifically in the arthroplasty literature, has not been consistent. ...
Background:
The use of new total joint arthroplasty technologies, including patient-specific implants/instrumentation (PSI), computer-assisted (CA), and robotic-assisted (RA) techniques, is increasing. There is an ongoing debate regarding the value provided and potential concerns about conflicts of interest (COI).
Methods:
PRISMA guidelines were followed. PubMed, MEDLINE, and Web of Science databases were searched for total hip and knee arthroplasties, unicompartmental knee arthroplasties (UKA), PSI, CA, and RA. Bibliometric data, financial COI, clinical/functional scores, and patient-reported outcomes were assessed.
Results:
Eighty-seven studies were evaluated, with 35 (40.2%) including at least one author reporting COI, and 13 (14.9%) disclosing industry funding. COI and industry funding had no significant effects on outcomes (P = 0.682, P = 0.447), and there were no significant effects of conflicts or funding on level of evidence (P = 0.508, P = 0.826). Studies in which author(s) disclosed COI had significantly higher relative citation ratio (RCR) and impact factor (IF) than those without (P < 0.001, P = 0.032). Subanalysis demonstrated RA and PSI studies were more likely to report COI or industry funding (P = 0.045). RA (OR = 6.31, 95% CI: 1.61-24.68) and UKA (OR = 9.14, 95% CI: 1.43-58.53) had higher odds of reporting favorable outcomes than PSI.
Conclusions:
Author COIs (about 40%) may be lower than previously reported in orthopedic technologies/techniques reviews. Studies utilizing RA and PSI were more likely to report COI, while RA and UKA studies were more likely to report favorable outcomes than PSI. No statistically significant association between the presence of COIs and/or industry funding and the frequency of favorable outcomes or study level of evidence was found.
Level of evidence:
Level V Systematic Review.
... However, only 23.5% of the included SRs disclosed the funding sources of their primary studies. As industry sponsorship of treatment studies may lead to a more favorable result and biased conclusion [18], readers cannot judge whether financial interests might influence the conclusions of primary studies as well as the SR itself if funding sources of primary studies were not reported. Improvement towards the methodological quality of SRs on AD treatments can be made by declaring conflicts of interest and revealing funding sources of primary studies. ...
Background
Carefully conducted systematic reviews (SRs) can provide reliable evidence on the effectiveness of treatment strategies for Alzheimer’s disease (AD). Nevertheless, the reliability of SR results can be limited by methodological flaws. This cross-sectional study aimed to examine the methodological quality of SRs on AD treatments, along with potentially relevant factors.
Methods
To identify eligible SRs on AD treatments, four databases including the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, and PsycINFO were searched. The Assessing the Methodological Quality of Systematic Reviews 2 instrument was used for quality appraisal of SRs. Multivariable regression analyses were used to examine factors related to methodological quality.
Results
A total of 102 SRs were appraised. Four (3.90%) SRs were considered as high quality; 14 (13.7%), 48 (47.1%), and 36 (35.3%) were as moderate, low, and critically low quality, respectively. The following significant methodological limitations were identified: only 22.5% of SRs registered protocols a priori, 6.9% discussed the rationales of chosen study designs, 21.6% gave a list of excluded studies with reasons, and 23.5% documented funding sources of primary studies. Cochrane SRs (adjusted odds ratio (AOR): 31.9, 95% confidence interval (CI): 3.81–266.9) and SRs of pharmacological treatments (AOR: 3.96, 95%CI: 1.27–12.3) were related to the higher overall methodological quality of SRs.
Conclusion
Methodological quality of SRs on AD treatments is unsatisfactory, especially among non-Cochrane SRs and SRs of non-pharmacological interventions. Improvement in the following methodological domains requires particular attention due to poor performance: registering and publishing protocols a priori, justifying study design selection, providing a list of excluded studies, and reporting funding sources of primary studies.
Everybody eats, and what we eat – or do not – affects the brain and mind. There is significant general, applied, academic, and industry interest about nutrition and the brain, yet there is much misinformation and no single reliable guide. Diet Impacts on Brain and Mind provides a comprehensive account of this emerging multi-disciplinary science, exploring the acute and chronic impacts of human diet on the brain and mind. It has a primarily human focus and is broad in scope, covering wide-ranging topics like brain development, whole diets, specific nutrients, research methodology, and food as a drug. It is written in an accessible format and is of interest to undergraduate and graduate students studying nutritional neuroscience and related disciplines, healthcare professionals with an applied interest, industry researchers seeking topic overviews, and interested general readers.
What differentiates scientific research from non-scientific inquiry? Philosophers addressing this question have typically been inspired by the exalted social place and intellectual achievements of science. They have hence tended to point to some epistemic virtue or methodological feature of science that sets it apart. Our discussion on the other hand is motivated by the case of commercial research, which we argue is distinct from (and often epistemically inferior to) academic research. We consider a deflationary view in which science refers to whatever is regarded as epistemically successful, but find that this does not leave room for the important notion of scientific error and fails to capture distinctive social elements of science. This leads us to the view that a demarcation criterion should be a widely upheld social norm without immediate epistemic connotations. Our tentative answer is the communist norm, which calls on scientists to share their work widely for public scrutiny and evaluation.
Background
Among people with a diagnosis of borderline personality disorder (BPD) who are engaged in clinical care, prescription rates of psychotropic medications are high, despite the fact that medication use is off‐label as a treatment for BPD. Nevertheless, people with BPD often receive several psychotropic drugs at a time for sustained periods.
Objectives
To assess the effects of pharmacological treatment for people with BPD.
Search methods
For this update, we searched CENTRAL, MEDLINE, Embase, 14 other databases and four trials registers up to February 2022. We contacted researchers working in the field to ask for additional data from published and unpublished trials, and handsearched relevant journals. We did not restrict the search by year of publication, language or type of publication.
Selection criteria
Randomised controlled trials comparing pharmacological treatment to placebo, other pharmacologic treatments or a combination of pharmacologic treatments in people of all ages with a formal diagnosis of BPD. The primary outcomes were BPD symptom severity, self‐harm, suicide‐related outcomes, and psychosocial functioning. Secondary outcomes were individual BPD symptoms, depression, attrition and adverse events.
Data collection and analysis
At least two review authors independently selected trials, extracted data, assessed risk of bias using Cochrane's risk of bias tool and assessed the certainty of the evidence using the GRADE approach. We performed data analysis using Review Manager 5 and quantified the statistical reliability of the data using Trial Sequential Analysis.
Main results
We included 46 randomised controlled trials (2769 participants) in this review, 45 of which were eligible for quantitative analysis and comprised 2752 participants with BPD in total. This is 18 more trials than the 2010 review on this topic. Participants were predominantly female except for one trial that included men only. The mean age ranged from 16.2 to 39.7 years across the included trials. Twenty‐nine different types of medications compared to placebo or other medications were included in the analyses. Seventeen trials were funded or partially funded by the pharmaceutical industry, 10 were funded by universities or research foundations, eight received no funding, and 11 had unclear funding.
For all reported effect sizes, negative effect estimates indicate beneficial effects by active medication. Compared with placebo, no difference in effects were observed on any of the primary outcomes at the end of treatment for any medication.
Compared with placebo, medication may have little to no effect on BPD symptom severity, although the evidence is of very low certainty (antipsychotics: SMD ‐0.18, 95% confidence interval (CI) ‐0.45 to 0.08; 8 trials, 951 participants; antidepressants: SMD −0.27, 95% CI −0.65 to 1.18; 2 trials, 87 participants; mood stabilisers: SMD −0.07, 95% CI −0.43 to 0.57; 4 trials, 265 participants).
The evidence is very uncertain about the effect of medication compared with placebo on self‐harm, indicating little to no effect (antipsychotics: RR 0.66, 95% CI 0.15 to 2.84; 2 trials, 76 participants; antidepressants: MD 0.45 points on the Overt Aggression Scale‐Modified‐Self‐Injury item (0‐5 points), 95% CI −10.55 to 11.45; 1 trial, 20 participants; mood stabilisers: RR 1.08, 95% CI 0.79 to 1.48; 1 trial, 276 participants).
The evidence is also very uncertain about the effect of medication compared with placebo on suicide‐related outcomes, with little to no effect (antipsychotics: SMD 0.05, 95 % CI −0.18 to 0.29; 7 trials, 854 participants; antidepressants: SMD −0.26, 95% CI −1.62 to 1.09; 2 trials, 45 participants; mood stabilisers: SMD −0.36, 95% CI −1.96 to 1.25; 2 trials, 44 participants).
Very low‐certainty evidence shows little to no difference between medication and placebo on psychosocial functioning (antipsychotics: SMD −0.16, 95% CI −0.33 to 0.00; 7 trials, 904 participants; antidepressants: SMD −0.25, 95% CI ‐0.57 to 0.06; 4 trials, 161 participants; mood stabilisers: SMD −0.01, 95% CI ‐0.28 to 0.26; 2 trials, 214 participants).
Low‐certainty evidence suggests that antipsychotics may slightly reduce interpersonal problems (SMD −0.21, 95% CI −0.34 to ‐0.08; 8 trials, 907 participants), and that mood stabilisers may result in a reduction in this outcome (SMD −0.58, 95% CI ‐1.14 to ‐0.02; 4 trials, 300 participants). Antidepressants may have little to no effect on interpersonal problems, but the corresponding evidence is very uncertain (SMD −0.07, 95% CI ‐0.69 to 0.55; 2 trials, 119 participants).
The evidence is very uncertain about dropout rates compared with placebo by antipsychotics (RR 1.11, 95% CI 0.89 to 1.38; 13 trials, 1216 participants). Low‐certainty evidence suggests there may be no difference in dropout rates between antidepressants (RR 1.07, 95% CI 0.65 to 1.76; 6 trials, 289 participants) and mood stabilisers (RR 0.89, 95% CI 0.69 to 1.15; 9 trials, 530 participants), compared to placebo.
Reporting on adverse events was poor and mostly non‐standardised. The available evidence on non‐serious adverse events was of very low certainty for antipsychotics (RR 1.07, 95% CI 0.90 to 1.29; 5 trials, 814 participants) and mood stabilisers (RR 0.84, 95% CI 0.70 to 1.01; 1 trial, 276 participants). For antidepressants, no data on adverse events were identified.
Authors' conclusions
This review included 18 more trials than the 2010 version, so larger meta‐analyses with more statistical power were feasible. We found mostly very low‐certainty evidence that medication may result in no difference in any primary outcome. The rest of the secondary outcomes were inconclusive. Very limited data were available for serious adverse events. The review supports the continued understanding that no pharmacological therapy seems effective in specifically treating BPD pathology. More research is needed to understand the underlying pathophysiologic mechanisms of BPD better. Also, more trials including comorbidities such as trauma‐related disorders, major depression, substance use disorders, or eating disorders are needed. Additionally, more focus should be put on male and adolescent samples.
Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
To map the current status of head-to-head comparative randomized evidence and to assess whether funding may impact on trial design and results.
From a 50% random sample of the randomized controlled trials (RCTs) published in journals indexed in PubMed during 2011, we selected the trials with ≥100 participants, evaluating the efficacy and safety of drugs, biologics, and medical devices through a head-to-head comparison.
We analyzed 319 trials. Overall, 238,386 of the 289,718 randomized subjects (82.3%) were included in the 182 trials funded by companies. Of the 182 industry-sponsored trials, only 23 had two industry sponsors and only three involved truly antagonistic comparisons. Industry-sponsored trials were larger, more commonly registered, used more frequently noninferiority/equivalence designs, had higher citation impact, and were more likely to have "favorable" results (superiority or noninferiority/equivalence for the experimental treatment) than nonindustry-sponsored trials. Industry funding [odds ratio (OR) 2.8; 95% confidence interval (CI): 1.6, 4.7] and noninferiority/equivalence designs (OR 3.2; 95% CI: 1.5, 6.6), but not sample size, were strongly associated with "favorable" findings. Fifty-five of the 57 (96.5%) industry-funded noninferiority/equivalence trials got desirable "favorable" results.
The literature of head-to-head RCTs is dominated by the industry. Industry-sponsored comparative assessments systematically yield favorable results for the sponsors, even more so when noninferiority designs are involved.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Objective To explore the risk of industry sponsorship bias in a systematically identified set of placebo controlled and active comparator trials of statins.
Design Systematic review and network meta-analysis.
Eligibility Open label and double blind randomised controlled trials comparing one statin with another at any dose or with control (placebo, diet, or usual care) for adults with, or at risk of developing, cardiovascular disease. Only trials that lasted longer than four weeks with more than 50 participants per trial arm were included. Two investigators assessed study eligibility.
Data sources Bibliographic databases and reference lists of relevant articles published between 1 January 1985 and 10 March 2013.
Data extraction One investigator extracted data and another confirmed accuracy.
Main outcome measure Mean absolute change from baseline concentration of low density lipoprotein (LDL) cholesterol.
Data synthesis Study level outcomes from randomised trials were combined using random effects network meta-analyses.
Results We included 183 randomised controlled trials of statins, 103 of which were two-armed or multi-armed active comparator trials. When all of the existing randomised evidence was synthesised in network meta-analyses, there were clear differences in the LDL cholesterol lowering effects of individual statins at different doses. In general, higher doses resulted in higher reductions in baseline LDL cholesterol levels. Of a total of 146 industry sponsored trials, 64 were placebo controlled (43.8%). The corresponding number for the non-industry sponsored trials was 16 (43.2%). Of the 35 unique comparisons available in 37 non-industry sponsored trials, 31 were also available in industry sponsored trials. There were no systematic differences in magnitude between the LDL cholesterol lowering effects of individual statins observed in industry sponsored versus non-industry sponsored trials. In industry sponsored trials, the mean change from baseline LDL cholesterol level was on average 1.77 mg/dL (95% credible interval −11.12 to 7.66) lower than the change observed in non-industry sponsored trials. There was no detectable inconsistency in the evidence network.
Conclusions Our analysis shows that the findings obtained from industry sponsored statin trials seem similar in magnitude as those in non-industry sources. There are actual differences in the effectiveness of individual statins at various doses that explain previously observed discrepancies between industry and non-industry sponsored trials.
Introduction:
Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events.
Areas covered:
In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed.
Expert opinion:
The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient's metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart 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. A similar association between sponsorship and outcomes have been found for device studies, but the body of evidence is not as strong as for sponsorship of drug studies. This review is an update of a previous Cochrane review and includes empirical studies on the association between sponsorship and research outcome.
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:
In this update we searched MEDLINE (2010 to February 2015), Embase (2010 to February 2015), the Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). 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 screened abstracts and identified and included relevant papers. 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 (CIs)).
Main results:
Twenty-seven new papers were included in this update and in total the review contains 75 included papers. Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI: 1.17 to 1.37) (25 papers) (moderate quality evidence), similar harms results RR: 1.37 (95% CI: 0.64 to 2.93) (four papers) (very low quality evidence) and more often favorable conclusions RR: 1.34 (95% CI: 1.19 to 1.51) (29 papers) (low quality evidence) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in their reporting of data and the results were heterogeneous. We did not find a difference between drug and device studies in the association between sponsorship and conclusions (test for interaction, P = 0.98) (four papers). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI: 1.05 to 1.50) (13 papers), 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: 0.83 (95% CI: 0.70 to 0.98) (six papers).
Authors' conclusions:
Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy 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.
Background:
Clinical trial registries are in widespread use to promote transparency around trials and their results.
Objective:
To describe characteristics of drug trials listed in ClinicalTrials.gov and examine whether the funding source of these trials is associated with favorable published outcomes.
Design:
An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006.
Setting:
ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999.
Measurements:
Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations.
Results:
Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization-funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization-funded trials without industry contributions (P = 0.005 across groups).
Limitations:
The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting.
Conclusion:
In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources.
Primary funding source:
National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health.
Meta-analyses may become biased if the reported data in the individual
trials are biased and if overlap among trials cannot be identified. We describe
the unanticipated problems we encountered in collecting data for a meta-analysis
comparing a new antifungal agent, fluconazole, with amphotericin B in patients
with cancer complicated by neutropenia. In 3 large trials that comprised 43%
of the patients identified for the meta-analysis, results for amphotericin
B were combined with results for nystatin in a "polyene" group. Because nystatin
is recognized as an ineffective drug in these circumstances, this approach
creates a bias in favor of fluconazole. Furthermore, 79% of the patients were
randomized to receive oral amphotericin B, which is poorly absorbed and not
an established treatment, in contrast to intravenous amphotericin B, which
was administered in 4 of 5 placebo-controlled trials, or 86% of patients.
It was unclear whether there was overlap among the "polyene" trials, and it
is possible that results from single-center trials were included in multicenter
trial reports. We were unable to obtain information to clarify these issues
from the trial authors or the manufacturer of fluconazole. Two of 11 responding
authors replied that the data were with the drug manufacturer and two indicated
that they did not have access to their data because of change of affiliation.
In the meta-analyses, fluconazole and amphotericin B (mostly given orally)
had similar effects (13 trials), whereas nystatin was no better than placebo
(3 trials). Since individual trials are rarely conclusive, investigators,
institutions, and pharmaceutical companies should provide essential details
about their work to ensure that meta-analyses can accurately reflect the studies
conducted and that patients will realize maximum benefits from treatments.
We recommend that investigators keep copies of their trial data to help facilitate
accurate and unbiased meta-analyses.
Medical research is a prerequisite of clinical advances, while health service research supports improved delivery, access, and cost. Few previous analyses have compared the United States with other developed countries.
To quantify total public and private investment and personnel (economic inputs) and to evaluate resulting patents, publications, drug and device approvals, and value created (economic outputs).
Publicly available data from 1994 to 2012 were compiled showing trends in US and international research funding, productivity, and disease burden by source and industry type. Patents and publications (1981-2011) were evaluated using citation rates and impact factors.
(1) Reduced science investment: Total US funding increased 6% per year (1994-2004), but rate of growth declined to 0.8% per year (2004-2012), reaching $117 billion (4.5%) of total health care expenditures. Private sources increased from 46% (1994) to 58% (2012). Industry reduced early-stage research, favoring medical devices, bioengineered drugs, and late-stage clinical trials, particularly for cancer and rare diseases. National Insitutes of Health allocations correlate imperfectly with disease burden, with cancer and HIV/AIDS receiving disproportionate support. (2) Underfunding of service innovation: Health services research receives $5.0 billion (0.3% of total health care expenditures) or only 1/20th of science funding. Private insurers ranked last (0.04% of revenue) and health systems 19th (0.1% of revenue) among 22 industries in their investment in innovation. An increment of $8 billion to $15 billion yearly would occur if service firms were to reach median research and development funding. (3) Globalization: US government research funding declined from 57% (2004) to 50% (2012) of the global total, as did that of US companies (50% to 41%), with the total US (public plus private) share of global research funding declining from 57% to 44%. Asia, particularly China, tripled investment from $2.6 billion (2004) to $9.7 billion (2012) preferentially for education and personnel. The US share of life science patents declined from 57% (1981) to 51% (2011), as did those considered most valuable, from 73% (1981) to 59% (2011).
New investment is required if the clinical value of past scientific discoveries and opportunities to improve care are to be fully realized. Sources could include repatriation of foreign capital, new innovation bonds, administrative savings, patent pools, and public-private risk sharing collaborations. Given international trends, the United States will relinquish its historical international lead in the next decade unless such measures are undertaken.