Systematic reviews with financial conflicts of interest linked to favourable conclusions and lower methodological quality

Financial conflicts of interest in systematic reviews: associations with results, conclusions, and methodological quality

Abstract

Background
Financial conflicts of interest in systematic reviews (e.g. funding by drug or device companies or authors’ collaboration with such companies) may impact on how the reviews are conducted and reported.

Objectives
To investigate the degree to which financial conflicts of interest related to drug and device companies are associated with results, conclusions, and methodological quality of systematic reviews.

Search methods
We searched PubMed, Embase, and the Cochrane Methodology Register for studies published up to November 2016. We also read reference lists of included studies, searched grey literature sources, and Web of Science for studies citing the included studies.

Selection criteria
Eligible studies were studies that compared systematic reviews with and without financial conflicts of interest in order to investigate differences in results (estimated treatment effect and frequency of statistically favourable results), frequency of favourable conclusions, or measures of methodological quality of the review (e.g. as evaluated on the Oxman and Guyatt index).

Data collection and analysis
Two review authors independently determined the eligibility of studies, extracted data, and assessed risk of bias. We synthesised the results of each study relevant to each of our outcomes. For meta‐analyses, we used Mantel‐Haenszel random‐effects models to estimate risk ratios (RR) with 95% confidence intervals (CIs), with RR > 1 indicating that systematic reviews with financial conflicts of interest more frequently had statistically favourable results or favourable conclusions, and had lower methodological quality. When a quantitative synthesis was considered not meaningful, results from individual studies were summarised qualitatively.

Main results
Ten studies with a total of 995 systematic reviews of drug studies and 15 systematic reviews of device studies were included. We assessed two studies as low risk of bias and eight as high risk, primarily because of risk of confounding. The estimated treatment effect was not statistically significantly different for systematic reviews with and without financial conflicts of interest (Z‐score: 0.46, P value: 0.64; based on one study of 14 systematic reviews which had a matched design, comparing otherwise similar systematic reviews). We found no statistically significant difference in frequency of statistically favourable results for systematic reviews with and without financial conflicts of interest (RR: 0.84, 95% CI: 0.62 to 1.14; based on one study of 124 systematic reviews). An analysis adjusting for confounding due to methodological quality (i.e. score on the Oxman and Guyatt index) provided a similar result. Systematic reviews with financial conflicts of interest more often had favourable conclusions compared with systematic reviews without (RR: 1.98, 95% CI: 1.26 to 3.11; based on seven studies of 411 systematic reviews). Similar results were found in two studies with a matched design, which therefore had a reduced risk of confounding. Systematic reviews with financial conflicts of interest tended to have lower methodological quality compared with systematic reviews without financial conflicts of interest (RR for 11 dimensions of methodological quality spanned from 1.00 to 1.83). Similar results were found in analyses based on two studies with matched designs.

Authors’ conclusions
Systematic reviews with financial conflicts of interest more often have favourable conclusions and tend to have lower methodological quality than systematic reviews without financial conflicts of interest. However, it is uncertain whether financial conflicts of interest are associated with the results of systematic reviews. We suggest that patients, clinicians, developers of clinical guidelines, and planners of further research could primarily use systematic reviews without financial conflicts of interest. If only systematic reviews with financial conflicts of interest are available, we suggest that users read the review conclusions with skepticism, critically appraise the methods applied, and interpret the review results with caution.

Does a prediabetic condition increase the risk of developing (type 2) diabetes ?

Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia (‘prediabetes’)

A war on “prediabetes” has created millions of new patients and a tempting opportunity for pharma. But how real is the condition, and is it good medicine?

2018 Study Abstract

Review question
We wanted to find out whether raised blood sugar (‘prediabetes’) increases the risk of developing type 2 diabetes and how many of these people return to having normal blood sugar levels (normoglycaemia). We also investigated the difference in type 2 diabetes development in people with prediabetes compared to people with normoglycaemia.

Background
Type 2 diabetes is often diagnosed by blood sugar measurements like fasting blood glucose or glucose measurements after an oral glucose tolerance test (drinking 75 g of glucose on an empty stomach) or by measuring glycosylated haemoglobin A1c (HbA1c), a long-term marker of blood glucose levels. Type 2 diabetes can have bad effects on health in the long term (diabetic complications), like severe eye or kidney disease or diabetic feet, eventually resulting in foot ulcers.

Raised blood glucose levels (hyperglycaemia), which are above normal ranges but below the limit of diagnosing type 2 diabetes, indicate prediabetes, or intermediate hyperglycaemia. The way prediabetes is defined has important effects on public health because some physicians treat people with prediabetes with medications that can be harmful. For example, reducing the threshold for defining impaired fasting glucose (after an overnight fast) from 6.1 mmol/L or 110 mg/dL to 5.6 mmol/L or 100 mg/dL, as done by the American Diabetes Association (ADA), dramatically increased the number of people diagnosed with prediabetes worldwide.

Study characteristics
We searched for observational studies (studies where no intervention takes place but people are observed over prolonged periods of time) that investigated how many people with prediabetes at the beginning of the study developed type 2 diabetes. We also evaluated studies comparing people with prediabetes to people with normoglycaemia. Prediabetes was defined by different blood glucose measurements.

We found 103 studies, monitoring people over 1 to 24 years. More than 250,000 participants began the studies. In 41 studies the participants were of Australian, European or North American origin, in 7 studies participants were primarily of Latin American origin and in 50 studies participants were of Asian or Middle Eastern origin. Three studies had American Indians as participants, and one study each invited people from Mauritius and Nauru. Six studies included children, adolescents or both as participants.

This evidence is up to date as of 26 February 2018.

Key results
Generally, the development of new type 2 diabetes (diabetes incidence) in people with prediabetes increased over time. However, many participants also reverted from prediabetes back to normal blood glucose levels. Compared to people with normoglycaemia, those with prediabetes (any definition) showed an increased risk of developing type 2 diabetes, but results showed wide differences and depended on how prediabetes was measured. There were no clear differences with regard to several regions in the world or different populations. Because people with prediabetes may develop diabetes but may also change back to normoglycaemia almost any time, doctors should be careful about treating prediabetes because we are not sure whether this will result in more benefit than harm, especially when done on a global scale affecting many people worldwide.

Certainty of the evidence
The certainty of the evidence for overall prognosis was moderate because results varied widely. The certainty of evidence for studies comparing prediabetic with normoglycaemic people was low because the results were not precise and varied widely. In our included observational studies the researchers often did not investigate well enough whether factors like physical inactivity, age or increased body weight also influenced the development of type 2 diabetes, thus making the relationship between prediabetes and the development of type 2 diabetes less clear.

Authors’ conclusions:
Overall prognosis of people with IH worsened over time. T2DM cumulative incidence generally increased over the course of follow-up but varied with IH definition. Regression from IH to normoglycaemia decreased over time but was observed even after 11 years of follow-up. The risk of developing T2DM when comparing IH with normoglycaemia at baseline varied by IH definition. Taking into consideration the uncertainty of the available evidence, as well as the fluctuating stages of normoglycaemia, IH and T2DM, which may transition from one stage to another in both directions even after years of follow-up, practitioners should be careful about the potential implications of any active intervention for people ‘diagnosed’ with IH.

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Cochrane HPV vaccine review not found to be ‘Trusted Evidence’

The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias

In May 2018, the Cochrane Collaboration published its review of the human papillomavirus (HPV) vaccines. The review primarily assessed the vaccines’ effect on precursors to cervical cancer. Cochrane has high standards for its reviews; however, there were important limitations in its HPV vaccine review, which we address in this paper.

Key findings

  • The Cochrane human papillomavirus (HPV) vaccine review missed nearly half of the eligible trials
  • No included trial in the Cochrane review used a placebo comparator
  • The included HPV vaccine trials used composite surrogate outcomes for cervical cancer
  • The Cochrane review incompletely assessed serious and systemic adverse events
  • The Cochrane review did not assess HPV vaccine-related safety signals
  • Industry trial funding and other conflicts of interest
  • Cochrane’s public relations of the review were uncritical

Conclusion

Part of the Cochrane Collaboration’s motto is ‘Trusted evidence’. We do not find the Cochrane HPV vaccine review to be ‘Trusted evidence’, as it was influenced by reporting bias and biased trial designs. We believe that the Cochrane review does not meet the standards for Cochrane reviews or the needs of the citizens or healthcare providers that consult Cochrane reviews to make ‘Informed decisions’, which also is part of Cochrane’s motto. We recommend that authors of Cochrane reviews make every effort to identify all trials and their limitations and conduct reviews accordingly.

Read the author’s full paper on The BMJ.

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Révision (Cochrane) du vaccin HPV : incomplète et avec de nombreux biais ?

Rien ne justifie de recommander le vaccin Gardasil contre les papillomavirus

Cochrane – Une institution indépendante de l’industrie pharmaceutique, a récemment blanchi les vaccins recommandés pour prévenir le cancer du col de l’utérus, controversés depuis dix ans. Des voix qui contestent solidement l’efficacité de cette vaccination mettent aujourd’hui leurs données à la disposition du public et des médias.

Avec ses collègues (Dr Jean-Pierre Spinosa, gynécologue, et Serena Tinari, journaliste d’investigation), Catherine Riva considère que Cochrane devrait rétracter cette revue et tout reprendre depuis le début. Mais l’organisation est restée sourde aux doléances qu’ils lui ont adressées suite à la publication de la revue. Son refus d’entrer en matière est la goutte de trop qui les amène aujourd’hui à tout rendre public. Le 10 décembre, leur analyse critique de la revue Cochrane sur les vaccins anti-HPV était dévoilée sur le British Medical Journal  L’ensemble des données et des tableaux à l’appui de leurs conclusions ainsi que leurs six ans de correspondance avec Cochrane sont désormais en accès libre.

LisezRien ne justifie de recommander le vaccin Gardasil contre les papillomavirus” sur parismatch.

Lessons learnt on transparency, scientific process and publication ethics

The short story of a long journey to get into the public domain unpublished data, methodological flaws and bias of the Cochrane HPV vaccines review

Abstract

Cochrane meta-analyses are considered the gold standard to assess public health interventions’ benefits and risks. Cochrane reviews shall apply evidence-based medicine (EBM) methodology on the best available evidence; they shall adhere to strict ethical guidelines as authors of Cochrane reviews are supposed to not have bias, nor conflicts of interest. Our 6 years’ documented case on the Cochrane human papillomavirus (HPV) vaccines review demonstrates that Cochrane guidelines can fail. According to EBM standards, such relevant methodological and ethical flaws void Cochrane positive conclusions on HPV vaccines efficacy.

Cochrane published a review of the human papillomavirus (HPV) vaccines on 9 May 2018. On 4 June, we submitted a detailed analysis of this review as a comment via the Cochrane website.

Our comment highlights serious methodological flaws in the review:

  • (A) studies’ quality not properly assessed;

  • (B) post hoc subgroup analyses presented as randomised controlled trial results;

  • (C) reporting bias not acknowledged;

  • (D) selective reporting not taken into consideration;

  • (E) biased trial designs;

  • (F) unpublished data not included;

  • (G) conflict of interests (COI) in the authors’ group;

  • (H) n=7 studies on Gardasil included, n=18 for Cervarix—the latter not being marketed in the USA anymore.

… continue reading on The BMJ, by Catherine Riva, December 2018.

visit re-check ref hpv-vaccination.

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Why prescription drugs are now the third leading cause of death and the pharmaceutical manufacturers dominance of mental healthcare

James Moore interviews Professor Peter Gøtzsche, Nordic Cochrane Centre Director, 2017

James Moore was keen to talk to Prof. Peter Gøtzsche about his background in research, his views on antidepressant prescribing and how pharmaceutical manufacturers have influenced mental healthcare.

Overview

  • Professor Gøtzsche’s background in clinical trials within the Pharmaceutical industry.
  • How the pharmaceutical manufacturers were manipulating clinical trial data for their own gain.
  • How drug manufacturers have denied for more than 20 years that benzodiazepines and antidepressant drugs cause dependance.
  • How the UK drug regulator (MHRA) also denied this in 2003 at the same time that the World Heath Organisation reported that 3 antidepressants were in the top 30 list of drugs that create dependance.
  • That surveys of patients show that between 50% and 66% of those taking antidepressants experience dependance.
  • The similarities between the pharmaceutical industry and the tobacco industry.
  • That stopping an antidepressant suddenly can be very dangerous.
  • How prescription drugs have become the third leading cause of death behind heart disease and cancer.
  • How pharmaceutical manufacturers have used their power and influence to the detriment of patient safety.
  • That the best science shows that there is no doubt that psychiatric drugs have killed millions of people over the years.
  • How psychotherapy is shown to reduce the risk of suicide but instead we prescribe pills that increase the suicide risk for all ages of patients.
  • That the chemical imbalance lie is still being propagated amongst psychiatrists even thought here is no scientific evidence whatsoever so support it.
  • How psychiatric drugs should be used for acute/emergency situations only.
  • That the medication centred approach of psychiatry does more harm than good.
  • How patients should avoid psychiatric drugs unless they are used for a very short time or that the patient really feels that they need them.
  • That when you look at the randomised controlled trials, there is a large risk of bias in these trials and that antidepressant efficacy has been overstated.
  • That the Cochrane Collaboration undertook the most rigorous meta analysis ever undertaken of 131 trials involving 27,422 patients taking SSRI’s, this analysis showed that antidepressants do not have any meaningful effects and their harms outweigh any benefits there might be.

Sources

Long-term use of ADHD drugs impair fertility in mammals

Impaired reproduction after exposure to ADHD drugs : Nordic Cochrane Centre systematic review of animal studies

Researchers from the Nordic Cochrane Centre have reviewed animal studies for effects of long-term use of drugs against Attention Deficit Hyperactivity Disorder (ADHD). The findings show that long-term use may impair the reproductive system, with some studies showing delayed sexual maturation. There were a total of 17 studies available, published between 1975 and 2016, where 13 were rat trials.

2017 Study Abstract

BACKGROUND
Few studies have reported on long-term harms caused by ADHD drugs but they are known to impair growth.

OBJECTIVE
To assess whether ADHD drugs impair reproduction in mammals.

METHODS
Systematic review of reproduction in studies of animals treated with ADHD drugs.

DATA SOURCES
PubMed, Biosis and EMBASE.

RESULTS
We included 17 studies. The studies were generally of poor quality or poorly reported. Two studies reported the use of one of three advised randomisation methods. Fifteen studies used placebo which suggested blinding. On clonidine, the ability to produce offspring was reduced for male rats, which approached two females each. In one study, 10 treated rats produced no offspring while all four controls did. In another study, 10 treated rats impregnated nine females while 10 controls impregnated 16. On methylphenidate, vaginal opening was delayed in two studies (in one, the mean difference was 4.0 days, 95% CI 2.5 to 5.6, and number of estrous cycles was halved; in the other, the minimum delay was 6 days), while in two other studies no difference occurred. Generally, the impairments improved after a drug-free period and were less pronounced when treatment started later in life.

CONCLUSION
ADHD drugs impair the reproduction in animals.

Sources, More Information

  • Impaired reproduction after exposure to ADHD drugs: Systematic review of animal studies, IOS Press, International Journal of Risk & Safety in Medicine, vol. 29, no. 1-2, pp. 107-124, DOI: 10.3233/JRS-170743, 2 September 2017.
  • New systematic review links long-term use of ADHD drugs to impaired fertility in mammals, Cochrane Nordic, Oct 11 2017.
  • Featured image The Cochrane Collaboration on Facebook.

What are systematic reviews?

Cochrane: Trusted evidence. Informed decisions. Better health

Published on 27 Jan 2016 by Cochrane.

This video explains why systematic reviews are important and how they are done. This includes an explanation of how the effects of interventions are compared in order to provide evidence.

Cochrane exists so that healthcare decisions get better.

During the past 20 years, Cochrane has helped to transform the way health decisions are made.

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The Cochrane Collaboration: Medicine’s Best-Kept Secret

By Alan Cassels, Foreward by Sir Iain Chalmers, 2015

The-Cochrane-Collaboration book cover omage
To celebrate its 20th anniversary, writer and professional medical skeptic Alan Cassels was selected to draw back the curtains on the Cochrane Collaboration. His extensive interviews of Cochranites allowed him to document their achievements, resulting in a book that its leadership ultimately refused to publish.

” In the complex, ever-evolving realm of modern medicine, how can you even begin to understand what’s hocus-pocus and what really works? Best-selling author and researcher Alan Cassels answers with a single word: Cochrane.

Though largely unknown to the public, the Cochrane Collaboration is made up of more than 30,000 medical researchers and consumer representatives from more than 100 countries – unbiased experts and investigators who parse the science of modern health care and delve deep into the evidence (or lack thereof) to determine what works and what doesn’t.

In this frank, factual and entertaining volume, Cassels draws from more than 160 interviews to shed light on this international cadre of medical truth-seekers whose rigorous work helps prevent medical misjudgement, reduce unnecessary suffering, preserve lives and circumvent the squandering of billions of dollars. “

More books from Alan Cassels