Showing papers by "Peter C Gøtzsche published in 2010"

CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials

Abstract: Overwhelming evidence shows the quality of reporting of randomised controlled trials (RCTs) is not optimal. Without transparent reporting, readers cannot judge the reliability and validity of trial findings nor extract information for systematic reviews. Recent methodological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which are considered the gold standard for evaluating interventions because of their ability to minimise or avoid bias. A group of scientists and editors developed the CONSORT (Consolidated Standards of Reporting Trials) statement to improve the quality of reporting of RCTs. It was first published in 1996 and updated in 2001. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have endorsed the CONSORT statement. The statement facilitates critical appraisal and interpretation of RCTs. During the 2001 CONSORT revision, it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports. A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement. After an expert meeting in January 2007, the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement. This update improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition, such as selective outcome reporting bias. This explanatory and elaboration document-intended to enhance the use, understanding, and dissemination of the CONSORT statement-has also been extensively revised. It presents the meaning and rationale for each new and updated checklist item providing examples of good reporting and, where possible, references to relevant empirical studies. Several examples of flow diagrams are included. The CONSORT 2010 Statement, this revised explanatory and elaboration document, and the associated website (www.consort-statement.org) should be helpful resources to improve reporting of randomised trials.

[CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials (Chinese version)]

Abstract: Overwhelming evidence shows the quality of reporting of randomised controlled trials (RCTs) is not optimal. Without transparent reporting, readers cannot judge the reliability and validity of trial findings nor extract information for systematic reviews. Recent methodological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which are considered the gold standard for evaluating interventions because of their ability to minimise or avoid bias. A group of scientists and editors developed the CONSORT (Consolidated Standards of Reporting Trials) statement to improve the quality of reporting of RCTs. It was first published in 1996 and updated in 2001. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have endorsed the CONSORT statement. The statement facilitates critical appraisal and interpretation of RCTs. During the 2001 CONSORT revision, it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports. A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement. After an expert meeting in January 2007, the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement. This update improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition, such as selective outcome reporting bias. This explanatory and elaboration document intended to enhance the use, understanding, and dissemination of the CONSORT statement-has also been extensively revised. It presents the meaning and rationale for each new and updated checklist item providing examples of good reporting and, where possible, references to relevant empirical studies. Several examples of flow diagrams are included. The CONSORT 2010 Statement, this revised explanatory and elaboration document, and the associated website (www. consort-statement. org) should be helpful resources to improve reporting of randomised trials.

Placebo interventions for all clinical conditions.

Abstract: Background Placebo interventions are often claimed to substantially improve patient-reported and observer-reported outcomes in many clinical conditions, but most reports on effects of placebos are based on studies that have not randomised patients to placebo or no treatment Two previous versions of this review from 2001 and 2004 found that placebo interventions in general did not have clinically important effects, but that there were possible beneficial effects on patient-reported outcomes, especially pain Since then several relevant trials have been published Objectives Our primary aims were to assess the effect of placebo interventions in general across all clinical conditions, and to investigate the effects of placebo interventions on specific clinical conditions Our secondary aims were to assess whether the effect of placebo treatments differed for patient-reported and observer-reported outcomes, and to explore other reasons for variations in effect Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 4, 2007), MEDLINE (1966 to March 2008), EMBASE (1980 to March 2008), PsycINFO (1887 to March 2008) and Biological Abstracts (1986 to March 2008) We contacted experts on placebo research, and read references in the included trials Selection criteria We included randomised placebo trials with a no-treatment control group investigating any health problem Data collection and analysis Two authors independently assessed trial quality and extracted data We contacted study authors for additional information Trials with binary data were summarised using relative risk (a value of less than 1 indicates a beneficial effect of placebo), and trials with continuous outcomes were summarised using standardised mean difference (a negative value indicates a beneficial effect of placebo) Main results Outcome data were available in 202 out of 234 included trials, investigating 60 clinical conditions We regarded the risk of bias as low in only 16 trials (8%), five of which had binary outcomes In 44 studies with binary outcomes (6041 patients), there was moderate heterogeneity (P < 0001; I2 45%) but no clear difference in effects between small and large trials (symmetrical funnel plot) The overall pooled effect of placebo was a relative risk of 093 (95% confidence interval (CI) 088 to 099) The pooled relative risk for patient-reported outcomes was 093 (95% CI 086 to 100) and for observer-reported outcomes 093 (95% CI 085 to 102) We found no statistically significant effect of placebo interventions in four clinical conditions that had been investigated in three trials or more: pain, nausea, smoking, and depression, but confidence intervals were wide The effect on pain varied considerably, even among trials with low risk of bias In 158 trials with continuous outcomes (10,525 patients), there was moderate heterogeneity (P < 0001; I2 42%), and considerable variation in effects between small and large trials (asymmetrical funnel plot) It is therefore a questionable procedure to pool all the trials, and we did so mainly as a basis for exploring causes for heterogeneity We found an overall effect of placebo treatments, standardised mean difference (SMD) -023 (95% CI -028 to -017) The SMD for patient-reported outcomes was -026 (95% CI -032 to -019), and for observer-reported outcomes, SMD -013 (95% CI -024 to -002) We found an effect on pain, SMD -028 (95% CI -036 to -019)); nausea, SMD -025 (-046 to -004)), asthma (-035 (-070 to -001)), and phobia (SMD -063 (95% CI -117 to -008)) The effect on pain was very variable, also among trials with low risk of bias Four similarly-designed acupuncture trials conducted by an overlapping group of authors reported large effects (SMD -068 (-085 to -050)) whereas three other pain trials reported low or no effect (SMD -013 (-028 to 003)) The pooled effect on nausea was small, but consistent The effects on phobia and asthma were very uncertain due to high risk of bias There was no statistically significant effect of placebo interventions in the seven other clinical conditions investigated in three trials or more: smoking, dementia, depression, obesity, hypertension, insomnia and anxiety, but confidence intervals were wide Meta-regression analyses showed that larger effects of placebo interventions were associated with physical placebo interventions (eg sham acupuncture), patient-involved outcomes (patient-reported outcomes and observer-reported outcomes involving patient cooperation), small trials, and trials with the explicit purpose of studying placebo Larger effects of placebo were also found in trials that did not inform patients about the possible placebo intervention Authors' conclusions We did not find that placebo interventions have important clinical effects in general However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed

Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review

Abstract: Objective To study how composite outcomes, which have combined several components into a single measure, are defined, reported, and interpreted. Design Systematic review of parallel group randomised clinical trials published in 2008 reporting a binary composite outcome. Two independent observers extracted the data using a standardised data sheet, and two other observers, blinded to the results, selected the most important component. Results Of 40 included trials, 29 (73%) were about cardiovascular topics and 24 (60%) were entirely or partly industry funded. Composite outcomes had a median of three components (range 2–9). Death or cardiovascular death was the most important component in 33 trials (83%). Only one trial provided a good rationale for the choice of components. We judged that the components were not of similar importance in 28 trials (70%); in 20 of these, death was combined with hospital admission. Other major problems were change in the definition of the composite outcome between the abstract, methods, and results sections (13 trials); missing, ambiguous, or uninterpretable data (9 trials); and post hoc construction of composite outcomes (4 trials). Only 24 trials (60%) provided reliable estimates for both the composite and its components, and only six trials (15%) had components of similar, or possibly similar, clinical importance and provided reliable estimates. In 11 of 16 trials with a statistically significant composite, the abstract conclusion falsely implied that the effect applied also to the most important component. Conclusions The use of composite outcomes in trials is problematic. Components are often unreasonably combined, inconsistently defined, and inadequately reported. These problems will leave many readers confused, often with an exaggerated perception of how well interventions work.

Breast cancer mortality in organised mammography screening in Denmark: comparative study

Abstract: Objective To determine whether the previously observed 25% reduction in breast cancer mortality in Copenhagen following the introduction of mammography screening was indeed due to screening, by using an additional screening region and five years additional follow-up. Design We used Poisson regression analyses adjusted for changes in age distribution to compare the annual percentage change in breast cancer mortality in areas where screening was used with the change in areas where it was not used during 10 years before screening was introduced and for 10 years after screening was in practice (starting five years after introduction of screening). Setting Copenhagen, where mammography screening started in 1991, and Funen county, where screening was introduced in 1993. The rest of Denmark (about 80% of the population) served as an unscreened control group. Participants All Danish women recorded in the Cause of Death Register and Statistics Denmark for 1971-2006. Main outcome measure Annual percentage change in breast cancer mortality in regions offering mammography screening and those not offering screening. Results In women who could benefit from screening (ages 55-74 years), we found a mortality decline of 1% per year in the screening areas (relative risk (RR) 0.99, 95% confidence interval (CI) 0.96 to 1.01) during the 10 year period when screening could have had an effect (1997-2006). In women of the same age in the non-screening areas, there was a decline of 2% in mortality per year (RR 0.98, 95% CI 0.97 to 0.99) in the same 10 year period. In women who were too young to benefit from screening (ages 35-55 years), breast cancer mortality during 1997-2006 declined 5% per year (RR 0.95, CI 0.92 to 0.98) in the screened areas and 6% per year (RR 0.94, CI 0.92 to 0.95) in the non-screened areas. For the older age groups (75-84 years), there was little change in breast cancer mortality over time in both screened and non-screened areas. Trends were less clear during the 10 year period before screening was introduced, with a possible increase in mortality in women aged less than 75 years in the non-screened regions. Conclusions We were unable to find an effect of the Danish screening programme on breast cancer mortality. The reductions in breast cancer mortality we observed in screening regions were similar or less than those in non-screened areas and in age groups too young to benefit from screening, and are more likely explained by changes in risk factors and improved treatment than by screening mammography.

Conflicts of interest at medical journals: the influence of industry-supported randomised trials on journal impact factors and revenue - cohort study.

Abstract: Background Transparency in reporting of conflict of interest is an increasingly important aspect of publication in medical journals. Publication of large industry-supported trials may generate many citations and journal income through reprint sales and thereby be a source of conflicts of interest for journals. We investigated industry-supported trials' influence on journal impact factors and revenue. Methods and Findings We sampled six major medical journals (Annals of Internal Medicine, Archives of Internal Medicine, BMJ, JAMA, The Lancet, and New England Journal of Medicine [NEJM]). For each journal, we identified randomised trials published in 1996–1997 and 2005–2006 using PubMed, and categorized the type of financial support. Using Web of Science, we investigated citations of industry-supported trials and the influence on journal impact factors over a ten-year period. We contacted journal editors and retrieved tax information on income from industry sources. The proportion of trials with sole industry support varied between journals, from 7% in BMJ to 32% in NEJM in 2005–2006. Industry-supported trials were more frequently cited than trials with other types of support, and omitting them from the impact factor calculation decreased journal impact factors. The decrease varied considerably between journals, with 1% for BMJ to 15% for NEJM in 2007. For the two journals disclosing data, income from the sales of reprints contributed to 3% and 41% of the total income for BMJ and The Lancet in 2005–2006. Conclusions Publication of industry-supported trials was associated with an increase in journal impact factors. Sales of reprints may provide a substantial income. We suggest that journals disclose financial information in the same way that they require them from their authors, so that readers can assess the potential effect of different types of papers on journals' revenue and impact. Please see later in the article for the Editors' Summary

The benefits and harms of screening for cancer with a focus on breast screening.

Abstract: The balance between benefits and harms is delicate for cancer screening programs. By attending screening with mammography some women will avoid dying from breast cancer or receive less aggressive treatment. But many more women will be overdiagnosed, receive needless treatment, have a false-positive result, or live more years as a patient with breast cancer. Systematic reviews of the randomized trials have shown that for every 2000 women invited for mammography screening throughout 10 years, only 1 will have her life prolonged. In addition, 10 healthy women will be overdiagnosed with breast cancer and will be treated unnecessarily. Furthermore, more than 200 women will experience substantial psychosocial distress for months because of false-positive findings. Regular breast self-examination does not reduce breast cancer mortality, but doubles the number of biopsies, and it therefore cannot be recommended. The effects of routine clinical breast examination are unknown, but considering the results of the breast self-examination trials, it is likely that it is harmful. The effects of screening for breast cancer with thermography, ultrasound or magnetic resonance imaging are unknown. It is not clear whether screening with mammography does more good than harm. Women invited to screening should be informed according to the best available evidence, data should be reported in absolute numbers, and benefits and harms should be reported using the same denominator so that they can be readily compared.

Inconsistent reporting of surrogate outcomes in randomised clinical trials: cohort study

Abstract: Objective To assess if authors of randomised clinical trials convey the fact that they have used surrogate outcomes and discussed their validity. Design Cohort study. Setting Six major general medical journals. Participants Randomised clinical trials published in 2005 and 2006 that used a surrogate as a primary outcome. Results Of 626 published randomised clinical trials, 109 (17%) used a surrogate as a primary outcome. Of these trials, 62 (57%, 95% confidence interval 47% to 67%) clearly reported that the primary outcome was a surrogate. Only 38 (35%, 26% to 45%) also discussed the validity of the surrogate. Conclusion Only about one third of authors of randomised clinical trials that used a surrogate as a primary outcome reported adequately on the surrogate. Better reporting is needed.

Adequacy of authors’ replies to criticism raised in electronic letters to the editor: cohort study

Abstract: Objective To investigate whether substantive criticism in electronic letters to the editor, defined as a problem that could invalidate the research or reduce its reliability, is adequately addressed by the authors. Design Cohort study. SettingBMJ between October 2005 and September 2007. Inclusion criteria Research papers generating substantive criticism in the rapid responses section on bmj.com. Main outcome measures Severity of criticism (minor, moderate, or major) as judged by two editors and extent to which the criticism was addressed by authors (fully, partly, or not) as judged by two editors and the critics. Results A substantive criticism was raised against 105 of 350 (30%, 95% confidence interval 25% to 35%) included research papers, and of these the authors had responded to 47 (45%, 35% to 54%). The severity of the criticism was the same in those papers as in the 58 without author replies (mean score 2.2 in both groups, P=0.72). For the 47 criticisms with replies, there was no relation between the severity of the criticism and the adequacy of the reply, neither as judged by the editors (P=0.88 and P=0.95, respectively) nor by the critics (P=0.83; response rate 85%). However, the critics were much more critical of the replies than the editors (average score 2.3 v 1.4, P Conclusions Authors are reluctant to respond to criticisms of their work, although they are not less likely to respond when criticisms are severe. Editors should ensure that authors take relevant criticism seriously and respond adequately to it.

Breast cancer awareness month. Still awaiting screening facts.

Abstract: On 19 February 2009 we wrote a letter in the Times calling for the leaflet, Breast Screening: the Facts , to be rewritten because none of the invitations for screening told the truth about its harms and benefits.1 Two days later the Times reported that the national …

Who evaluates public health programmes? A review of the NHS Breast Screening Programme

Abstract: Breast screening with mammography was introduced in the UK in 1988, and the Annual Review 2008 from the NHS Breast Cancer Screening Programme (NHS BSP) summarizes the 20-year experience. Twenty years is a long time and it seems reasonable to ask what might be expected from such a review from a public health institution. First and foremost, one would expect to see an analysis that shows that screening has lowered breast cancer mortality in the UK. Secondly, one would wish to see a comparison of this benefit with a quantification of the most important harms, as this would allow the readers to judge for themselves whether the programme has been worth its large cost. If the screening programme had lived up to the expected mortality reduction that was the basis for its introduction, it should have been easy for the NHS Breast Cancer Screening Programme to demonstrate this for the politicians and other interested parties. This is not what the 26-page publication does, however. It celebrates 20 years of breast screening, as one of the headlines says. As with all good birthdays, it is the qualities of the celebrated that are mentioned, not the shortcomings. In line with the positive framing, the first sentence in the Review refers to the 20th anniversary as a ‘momentous occasion’. The Review exaggerates the benefit, omits the harms, and looks like propaganda aimed at persuasion. It comes wrapped in a beautiful layout that would pride any marketing department if it had been a sales brochure for a drug (Figure 1). The first words on the cover page are: ‘Saving lives through screening’, and the symbolism is strong. Most of the cover space is taken up by a picture of a delicate rose in the distinctive pink colour that has become iconic for the fight against breast cancer. The rose is transparent, symbolizing the scientific illumination and radiological technique through which the programme operates.

Intravenous alpha-1 antitrypsin augmentation therapy: systematic review.

Abstract: We reviewed the benefits and harms of augmentation therapy with alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. We searched for randomised trials comparing augmentation therapy with placebo or no treatment in PubMed and ClinicalTrials (7 January 2010). Two trials were included with a total of 140 patients. The trials ran for two to three years. Mortality data were not reported. There was no information on harms in the first trial; in the second trial, serious adverse events were reported in ten of 38 patients in the drug group and in 18 of 39 patients in the placebo group. Annual number of exacerbations and quality of life were reported in the second trial and were similar in the two groups. The meta-analyses showed that forced expiratory volume in one second deteriorated a little more in the drug group than in the placebo group (difference -20 ml per year; 95% confidence interval -41 to 1; p = 0.06). For carbon monoxide diffusion, the difference was -0.06 mmol/min./kPa per year (95% confidence interval -0.17 to 0.05; p = 0.31). Lung density measured by computed tomography deteriorated a little less in the drug group than in the placebo group (difference 1.14 g/l; 95% confidence interval 0.14 to 2.14; p = 0.03) over the total course of the trials. Augmentation therapy with alpha-1 antitrypsin cannot be recommended in view of the lack of evidence of clinical benefit and the cost of treatment.

Breast screening: why estimates differ by a factor of 20-25.

Abstract: Duffy et al. estimated that between 2 and 2.5 lives are saved for every overdiagnosed case, which is 20–25 times more favourable than the estimate from the Cochrane review of the randomized trials. They used a 38% reduction in breast cancer mortality from the Two-County trial, which is 2.5 times higher than the estimate based on all the trials. They also used UK data but contradict themselves. They consider the mortality stable in the unscreened age groups, but also report a significant 18% decline in breast cancer mortality in women aged under 50 years. The decline in the age group 50–69 years was 27%, and by using an unclear method described in a footnote, they concluded that screening conferred a further 28% mortality reduction. This disagrees starkly with data from Cancer Research UK: women aged 40–49 (who were never invited to screening) had the same decline in mortality (44%) as those aged 50–64. The graphs are misleading. Data for women below 50 years were lumped together, but as deaths from breast cancer before age 30 are extremely rare (12 cases in 2008), the graph is close to the x axis, which conceals the huge decline in mortality in young women. Data from the age group 50–64 years were combined with 65–69 years, although screening of older women did not start before 2001, which conceals that breast cancer mortality in the age group 50–64 years began to decline before the UK programme started in 1988. Duffy et al. substantially underestimate overdiagnosis. Firstly, they excluded carcinoma in situ, which was not stated in their paper. One of us asked Duffy on national radio whether he only included invasive cancer, which he confirmed. Secondly, they used an unverified model with incorrect assumptions. It is wrong to assume that essentially all incidence increase with screening represents earlier diagnosis. Thirdly, they adjusted for a compensatory decline in breast cancer incidence in women no longer screened, which did not exist for the years they examined. More updated numbers show an abrupt increase when screening was extended to the age group 65–70 years in 2001 (Figure 1 below), which is far bigger than any possible recent compensatory decline. We estimated 57% overdiagnosis in England and Wales. Duffy et al. estimated that only 12% of cancers are overdiagnosed. Duffy et al. say they estimated the benefit directly from empirical data and looked at women actually screened, which they consider partly explains the disagreement with us

Unbalanced reporting of benefits and harms in abstracts on rofecoxib

Abstract: Purpose It was predicted from the mechanism of action that, compared to older non-steroidal anti-inflammatory drugs, rofecoxib (Vioxx) would reduce gastrointestinal bleeding, but also that it would increase the occurrence of cardiovascular thrombosis. From the patient’s point of view, both effects are important and should be investigated and reported similarly. We studied how they have been reported over time.

Sponsorship of Medical Textbooks by Drug or Device Companies

Abstract: Background: To study whether medical textbooks are sponsored by drug or device companies, and if so, whether they have tried to influence their contents. Methods : Cross-sectional study of the medical textbooks written in Danish for graduate clinical courses at the University of Copenhagen and anonymous web-based survey of editors. For sponsored books, we also contacted the authors. Results : Eleven of 71 medical textbooks (15%) were sponsored. We contacted 11 editors, and for 8 books that had authors that were not editors, we also contacted one author. Ten editors and 5 authors replied. One editor was contacted 5 times by the various sponsors concerning the content of specific chapters and in another case the sponsor had the content of a chapter changed regarding its own drug. Two of the authors noted that they did not know that the book was sponsored. Conclusions : Sponsorship of medical textbooks was not uncommon and may lead to lack of academic freedom. Medical students may be particularly vulnerable to commercial influences, as they have had little or no training in commercial biases and generally believe what they read in textbooks.

Sleep apnoea: from person to patient, and back again

Abstract: The frustrations of the treatment offered for sleep apnoea made “being a patient” difficult