Peter C Gøtzsche’s research while affiliated with Rigshospitalet and other places

Our analysis suggests that well-monitored warfarin might be equally good, or even better, for atrial fibrillation depending on the DOAC and outcome. Our analysis warrants granular investigations based on the COMBINE AF (A Collaboration between Multiple institutions to Better Investigate Non-vitamin K antagonist oral anticoagulant use in Atrial Fibrillation) data set to establish which anticoagulant to use and in which setting. New analyses should be conducted with predefined TTR thresholds and transparently reported.

Background A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. This is an update of a review previously updated 2013 and originally published 2001. Objectives To assess the effect of screening for breast cancer with mammography on mortality and morbidity. Search methods For this 2023 update, we searched PubMed, CENTRAL, the Cochrane Breast Cancer Group Specialised Register, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov up to 28 February 2023. Selection criteria Randomised clinical trials (RCTs) comparing mammographic screening with no mammographic screening. Data collection and analysis Two authors independently extracted data. Study authors were contacted for additional information. Our main outcomes of interest were deaths due to breast cancer, any cancer, and due to any cause, and harms measured as overdiagnosis, number of mastectomies, lumpectomies, use of radiotherapy and of chemotherapy. Certainty of evidence was assessed with GRADE. Main results Eight eligible trials from Europe and North America that compared women offered screening mammography with women not offered screening were included. We excluded a trial because the randomisation failed to produce comparable groups. The eligible trials included 600,000 women in the age range 39 to 74 years. The trials with adequate randomisation did not show a benefit in terms of a reduction in breast cancer mortality at 13 years (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02; 33 vs 30 deaths from breast cancer per 10,000 women; 3 RCTs; 292,153 participants). The findings at 24 years were similar to those at 13 years. Our certainty in both estimates was downgraded 1 level to 'low' due to changes in technology and treatment (indirectness) and due to imprecision. The trials with suboptimal randomisation showed a reduction in breast cancer mortality at 13 years with an RR of 0.75 (95% CI 0.67 to 0.83; 4 RCTs; 306,937 participants; very low certainty evidence). In women below age 50 years, the results from adequately randomised trials did not show a reduction in breast cancer mortality at 13 years of follow-up (RR 0.87, CI 0.73 to 1.03; 28 vs 24 deaths from breast cancer per 10,000 women; 3 RCTs; 218,697 participants, low certainty evidence), nor for women at least 50 years (RR 0.94, CI 0.77 to 1.15; 53 vs 50 deaths from breast cancer per 10,000 women; 2 RCTs; 74,261 participants, low certainty evidence). Only one trial included women aged 70 years and above and could not provide a reliable effect estimate.We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of the risk of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on total cancer mortality, including breast cancer, (RR 1.00, 95% CI 0.96 to 1.04; 288 vs 288 cancer deaths per 10,000 women; 3 RCTs; 292,954 participants; moderate certainty evidence; the follow-up was 10.5 years for Canada, 9 years for Malmo and 23 years for the UK age trial). All-cause mortality was not reduced (RR 0.98, 95% CI 0.94 to 1.03 after 7 years; RR 0.99, 95% CI 0.95 to 1.03 after 13 years; 324 vs 328 deaths per 10,000 women; and RR 1.01, 95% CI 0.99 to 1.04 after 24 years; 773 vs 765 deaths per 10,000 women; 2 RCTs; 250,671 participants; moderate certainty evidence) in the adequately randomised trials. There were more lumpectomies and mastectomies combined in the screened groups, likely reflecting overtreatment (RR 1.31, 95% CI 1.22 to 1.42; 164 vs 214 operations per 10,000 women; 2 RCTs; 132,321 participants; moderate certainty evidence), as were the number of mastectomies alone (RR 1.20, 95% CI 1.08 to 1.32; 122 vs 102 per 10,000 women; 2 RCTs; 132,321; moderate certainty evidence). The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy (data for each outcome available from only one adequately randomised trial; low certainty evidence). Breast screening increased the number of breast cancer diagnoses (overdiagnosis)(RR 1.25, CI 1.18 to 1.34, 142 vs 113 diagnoses at 7 to 9 years of follow-up; 3 RCTs, 292,979 participants; moderate certainty evidence) in trials that did not screen the control group after the intervention phase. Authors' conclusions Because of substantial changes in screening technology, treatment, and breast cancer awareness since the trials were done, the estimates from the trials are uncertain in today's setting. As breast cancer mortality is an unreliable outcome that is biased in favour of screening, it is noteworthy that screening did not reduce total cancer mortality or total mortality. Breast screening does not meet the criteria that population screening should be based on rigorously performed randomised trials that show that the benefits outweigh the harms. No studies have been completed in low income countries and one small study from Colombia has yet to provide data on long term outcomes. Women, clinicians and policy makers should consider the trade-offs and the uncertainties carefully when they decide whether or not to attend or support breast screening programmes.

Aims We have previously described the European Medicines Agency’s (EMA) and the US Food and Drug Administration’s guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3 years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. Methods We submitted Freedom of Information requests in February 2020 to access EMA’s lists of committee members (and their declared conflicts of interest) involved in drafting the 13 ‘Clinical efficacy and safety’ guidelines available on EMA’s website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e. defined as any financial industry relationship). It is a follow-up paper to our first report ( http://doi.org/10.1017/S2045796021000147 ). Results After 2 years and 9 months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%–44% declared any interests and we judged 14%–18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. Conclusions After almost 3 years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the ‘Clinical efficacy and safety’ guidelines and to not remove conflicts of interest declarations after 1 year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Background: Depression drugs can be difficult to come off due to withdrawal symptoms. Gradual tapering with tapering support is needed to help patients withdraw safely. Objective: To review the withdrawal success rates, using any intervention, and the effects on relapse/recurrence rates, symptom severity, quality of life, and withdrawal symptoms. Methods: Systematic review based on PubMed and Embase searches (last search 4 October 2022) of randomised trials with one or more treatment arms aimed at helping patients withdraw from a depression drug, regardless of indication for treatment. We calculated the mean and median success rates and the risk difference of depressive relapse when discontinuing or continuing depression drugs. Results: We included 13 studies (2085 participants). Three compared two withdrawal interventions and ten compared drug discontinuation vs. continuation. The success rates varied hugely between the trials (9% to 80%), with a weighted mean of 47% (95% confidence interval 38% to 57%) and a median of 50% (interquartile range 29% to 65%). A meta-regression showed that the length of taper was highly predictive for the risk of relapse (P = 0.00001). All the studies we reviewed confounded withdrawal symptoms with relapse; did not use hyperbolic tapering; withdrew the depression drug too fast in a linear fashion; and stopped it entirely when receptor occupancy was still high. Conclusion: The true proportion of patients on depression drugs who can stop safely without relapse is likely considerably higher than the 50% we found.

We believe that the NHS has a clinical and moral obligation to help those who have been harmed by taking their medication as prescribed. Panorama has revealed the scale of the problem and the horrendous impact it has had on so many people’s lives. To help mitigate these impacts, we therefore urgently call upon the UK government to fund and implement withdrawal support services, including a national helpline.

The current paradigm in psychiatry is that psychosis should be treated with neuroleptics as first-line therapy. Neuroleptics should not be used at all. Randomised trials have shown that they kill many patients and do not have clinically relevant effects but cause permanent brain damage in most patients treated long-term and prevent them from coming back to a more normal life. If an acutely disturbed patient feels that a drug is needed, benzodiazepines work faster than neuroleptics, are much less toxic, and are also what virtually all patients prefer if asked. Psychiatry seems to be the only area in society where the law is systematically being violated all over the world. We need to respect the patients’ rights and the law, which will also lead to better outcomes.KeywordsPsychosisPsychiatryPsychiatric drugs

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper.