AllTrials (sometimes called All Trials or AllTrials.net) is a project advocating that clinical research adopt the principles of open research. The project summarizes itself as "All trials registered, all results reported": that is, all clinical trials should be listed in a clinical trials registry, and their results should always be shared as open data.
At the center of the organisation is a petition signed by over 85,000 individuals and 599 organisations (as of August 2015):
Thousands of clinical trials have not reported their results; some have not even been registered.
Information on what was done and what was found in these trials could be lost forever to doctors and researchers, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated.
All trials past and present should be registered, and the full methods and the results reported.
We call on governments, regulators and research bodies to implement measures to achieve this.
Ben Goldacre, author of Bad Science and Bad Pharma , is a founder of the campaign and its most public spokesperson. In 2016, he participated in the launch of the OpenTrials database. [1]
AllTrials is an international initiative of Bad Science, BMJ , Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative, PLOS and Sense about Science and is being led in the US by Sense about Science USA, Dartmouth's Geisel School of Medicine and the Dartmouth Institute for Health Policy & Clinical Practice. [2]
The project is a reaction to under-reporting of research. [3] [4] [5] [6]
A substantial proportion (estimates range from one-third to one-half) of medical research goes unpublished. [7] It has also been shown that negative findings are less likely to be published than positive ones, even in the absence of conflicts of interest.[ citation needed ]
Much medical research is done by the pharmaceutical industry, which have a conflict of interest reporting results which may hurt sales of their products. [8] There is a measurable funding bias in reporting; studies have shown that published drug studies funded by pharmaceutical companies are much more likely to support the use of the tested drug than studies with other funding. Industry-funded trials are also less likely to be published. [7] [9]
If the statistical methods used to analyse the trial are not chosen before the study it started, there is a danger that researchers will intentionally or unintentionally pick the method that gives the results they expect, or which gives the most significant results. This makes the analysis statistically invalid .
Not publishing trials which fail to find a clear effect exposes trial volunteers to pointless risk [10] and wastes research effort (as the same trial is repeated over and over). It also biases the medical literature, making it report effects where none exist (since, given enough trials, eventually one will find a difference by pure chance). [11]
Pre-trial registration makes non-publication and changes in analysis methods obvious to medical reviewers. It also enables authors of meta-studies to track down and analyse missing data. Finally, it lets doctors and patients know when a trial is looking for volunteers. [10]
There are other sources of bias, such as the conditions sometimes attached to funding by funding agencies with a financial interest in the trial's outcome. Medical researchers may be asked to agree to allow the funding agency to censor results. Some funding agencies may also refuse to give the medical researcher access to the raw data, giving them only the finished analysis, or even a draft paper, and asking them to put their name to it. This is not acceptable academic practice, and some academic journals require that authors sign a statement that they have not entered into such agreements. [8] [9]
Ben Goldacre, a physician and spokesperson for the campaign, would like to address the systematic flaws in clinical research which cause data to be lost after it is gathered. [12] [13] [14] [15] [16] [17] [18]
The campaign has been widely covered, and supported, in the academic press. The British Medical Journal and PLOS are founding members. Nature [19] and The Lancet [20] both published supportive articles in January 2014.
There has also been mainstream media coverage. [21]
There has been criticism from the Pharmaceutical Research and Manufacturers of America (PhRMA), with senior vice-president Matt Bennett saying that trial data disclosure measures which AllTrials has recommended to the European Medicines Agency "could risk patient privacy, lead to fewer clinical trials, and result in fewer new medicines to meet patient needs and improve health.". [22]
AllTrials have published a detailed statement [23] of exactly what they want to see published, which states "The AllTrials campaign is not calling for individual patient data to be made publicly available".
A 2012 editorial published by senior regulators from the European Medicines agency [24] largely agreed with AllTrials, saying "We consider it neither desirable nor realistic to maintain the status quo of limited availability of regulatory trials data". They were also of the opinion that adequate standards for protection of personal data could be written. However, they warned that third party reanalysis was neither a guarantee of quality nor of lack of conflict of interest, which, in the worst case, could lead to negative public health consequences.[ citation needed ]
They suggested that reanalyses should therefore be subject to the same regulations as sponsor analyses, such as registering analysis plans. They argued against completely unrestricted access to data, but in favor of broader access. [24] AllTrials is not calling for completely unrestricted access to raw data, [23] so the scope of disagreements is limited to what restrictions should be in place.
This article is missing information about the substance of the disagreement.(August 2015) |
The campaign is an initiative of Sense about Science, [25] Centre for Evidence Based Medicine, The Dartmouth Institute for Health Policy and Clinical Practice, [26] James Lind Alliance, Cochrane Collaboration, [27] [28] BMJ Group, PLOS, [29] and Bad Science. The petition statement of AllTrials has been signed by organizations including Wellcome Trust, [30] British Library, Medical Research Council (UK), British Heart Foundation, Institute for Quality and Efficiency in Health Care, National Institute for Health and Care Excellence, BioMed Central, [31] National Physicians Alliance, Royal Society of Medicine, Health Research Authority, American Medical Student Association, GlaxoSmithKline, [32] and others.
As of May 2017, The AllTrials petition has been signed by 90,282 people and 721 organisations. [33] In October 2016, AllTrials published a road map detailing steps that various types of organisations can take to get more trials registered and more results reported. [34]
85 investors with >€3.5 trillion (£2.45trn; $3.83trn) of investments have supported AllTrials (as of July 2015), with Peter van der Werf of RobecoSAM saying: "We deem this to be a financially material factor and encourage all companies to gain credibility regarding their approach to clinical trial transparency by signing up to the AllTrials principles.". [35] The Laura and John Arnold Foundation provided early and ongoing financial support. [36]
The original policy of the Coalition for Epidemic Preparedness Innovations required that funded parties pre-register any trials in a clinical trials registry, publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy. In May 2018 the CEPI proposed changing the policy to remove these provisions. [37] The policy was changed by the CEPI in December 2018. [38] [39]
The European Federation of Pharmaceutical Industries and Associations and Pharmaceutical Research and Manufacturers of America have expressed interest in lobbying against the campaign. [40] Campaign supporters criticized Hoffmann-La Roche's plans to be more open but not to the extent requested by AllTrials. [41] [42]
A placebo is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets, inert injections, sham surgery, and other procedures.
Cochrane is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes 53 review groups that are based at research institutions worldwide. Cochrane has approximately 30,000 volunteer experts from around the world.
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.
In published academic research, publication bias occurs when the outcome of an experiment or research study biases the decision to publish or otherwise distribute it. Publishing only results that show a significant finding disturbs the balance of findings in favor of positive results. The study of publication bias is an important topic in metascience.
The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceuticals for use as medications to be administered to patients, with the aim to mitigate symptoms or disease conditions, vaccinate them, or alleviate symptoms of disease or surgical or disease condition. Pharmaceutical companies may deal in generic or brand medications and medical devices. They are subject to a variety of laws and regulations that govern the patenting, testing, safety, efficacy using drug testing and marketing of drugs. The global pharmaceuticals market produced treatments worth $1,228.45 billion in 2020 and showed a compound annual growth rate (CAGR) of 1.8%.
Ben Michael Goldacre is a British physician, academic and science writer. He is the first Bennett Professor of Evidence-Based Medicine and director of the Bennett Institute for Applied Data Science at the University of Oxford. He is a founder of the AllTrials campaign and OpenTrials to require open science practices in clinical trials.
Doxazosin, sold under the brand names Cardura among others, is a medication used to treat symptoms of benign prostatic hyperplasia and hypertension. For high blood pressure, it is a less preferred option. It is taken by mouth.
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Good clinical practice (GCP) is an international quality standard, which governments can then transpose into regulations for clinical trials involving human subjects. GCP follows the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and enforces tight guidelines on ethical aspects of clinical research.
PLOS Medicine is a peer-reviewed weekly medical journal covering the full spectrum of the medical sciences. It began operation on October 19, 2004, as the second journal of the Public Library of Science (PLOS), a non-profit open access publisher. All content in PLOS Medicine is published under the Creative Commons "by-attribution" license. To fund the journal, the publication's business model requires in most cases that authors pay publication fees. The journal was published online and in a printed format until 2005 and is now only published online. The journal's acting chief editor is Clare Stone, who replaced the previous chief editor, Larry Peiperl, in 2018.
In epidemiology, reporting bias is defined as "selective revealing or suppression of information" by subjects. In artificial intelligence research, the term reporting bias is used to refer to people's tendency to under-report all the information available.
Sense about Science is a United Kingdom charitable organization that promotes the public understanding of science. Sense about Science was founded in 2002 by Lord Taverne, Bridget Ogilvie and others to promote respect for scientific evidence and good science. It was established as a charitable trust in 2003, with 14 trustees, an advisory council and a small office staff. Tracey Brown has been the director since 2002.
Peter Christian Gøtzsche is a Danish physician, medical researcher, and former leader of the Nordic Cochrane Center at Rigshospitalet in Copenhagen, Denmark. He is a co-founder of the Cochrane Collaboration and has written numerous reviews for the organization. His membership in Cochrane was terminated by its Governing Board of Trustees on 25 September 2018.
Bad Science, written by Ben Goldacre, criticises certain physicians and the media for a lack of critical thinking and misunderstanding of evidence and statistics which is detrimental to the public understanding of science. Goldacre explains basic scientific principles to demonstrate the importance of robust research methods, experimental design, and analysis to make informed judgements and conclusions of evidence-based medicine. Bad Science is described as an engaging and inspirational book, written in simple language and occasional humour, to effectively explain academic concepts to the reader.
Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients is a book by the British physician and academic Ben Goldacre about the pharmaceutical industry, its relationship with the medical profession, and the extent to which it controls academic research into its own products. It was published in the UK in September 2012 by the Fourth Estate imprint of HarperCollins, and in the United States in February 2013 by Faber and Faber.
Big Pharma conspiracy theories are conspiracy theories which claim that the medical community in general and pharmaceutical companies in particular, especially large corporations, operate for sinister purposes and against the public good, that they conceal effective treatments, or even cause and worsen a wide range of diseases for the purpose of profitability, or for other nefarious reasons. Some theories have included the claim that natural alternative remedies to health problems are being suppressed, the claim that drugs for the treatment of HIV/AIDS are ineffective and harmful, the claim that a cure for all cancers has been discovered but hidden from the public, claims that COVID-19 vaccines are ineffective, and that alternative cures are available for COVID-19. In each case the conspiracy theorists have blamed pharmaceutical companies' search for profits. A range of authors have shown these claims to be false, though some of these authors nevertheless maintain that other criticisms of the pharmaceutical industry are legitimate.
Study 329 was a clinical trial which was conducted in North America from 1994 to 1998 to study the efficacy of paroxetine, an SSRI anti-depressant, in treating 12- to 18-year-olds diagnosed with major depressive disorder. Led by Martin Keller, then professor of psychiatry at Brown University, and funded by the British pharmaceutical company SmithKline Beecham—known since 2000 as GlaxoSmithKline (GSK)—the study compared paroxetine with imipramine, a tricyclic antidepressant, and placebo. SmithKline Beecham had released paroxetine in 1991, marketing it as Paxil in North America and Seroxat in the UK. The drug attracted sales of $11.7 billion in the United States alone from 1997 to 2006, including $2.12 billion in 2002, the year before it lost its patent.
The Centre for Evidence-Based Medicine (CEBM), based in the Nuffield Department of Primary Care Health Sciences at the University of Oxford, is an academic-led centre dedicated to the practice, teaching, and dissemination of high quality evidence-based medicine to improve healthcare in everyday clinical practice. CEBM was founded by David Sackett in 1995. It was subsequently directed by Brian Haynes and Paul Glasziou. Since 2010 it has been led by Professor Carl Heneghan, a clinical epidemiologist and general practitioner.
Conflicts of interest (COIs) often arise in academic publishing. Such conflicts may cause wrongdoing and make it more likely. Ethical standards in academic publishing exist to avoid and deal with conflicts of interest, and the field continues to develop new standards. Standards vary between journals and are unevenly applied. According to the International Committee of Medical Journal Editors, "[a]uthors have a responsibility to evaluate the integrity, history, practices and reputation of the journals to which they submit manuscripts".
The Lancet MMR autism fraud centered on the publication in February 1998 of a fraudulent research paper titled "Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children" in The Lancet. The paper, authored by now discredited and deregistered Andrew Wakefield, and listing twelve coauthors, falsely claimed non-existent, causative links between the MMR vaccine, colitis, and autism. The fraud was exposed in a lengthy Sunday Times investigation by reporter Brian Deer, resulting in the paper's retraction in February 2010 and Wakefield being struck off the UK medical register three months later. Wakefield reportedly stood to earn up to $43 million per year selling diagnostic kits for a non-existent syndrome he claimed to have discovered. He also held a patent to a rival vaccine at the time, and he had been employed by a lawyer representing parents in lawsuits against vaccine producers.
Drug companies on CEPI's scientific advisory panel, including Johnson & Johnson, Pfizer, and Japan's Takeda, pushed back. CEPI mostly capitulated in a December 2018 two-page declaration in which it jettisoned specifics but gave lip service to its founding mission of "equitable access to these vaccines for affected populations during outbreaks."