Going PRO – clinical trials must plan to capture patient-reported outcomes

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Post authored by David Moher All participants in research are important. What patients in clinical trials tell us about treatments – patient-reported outcomes (PROs) such as quality of life and symptoms – is being used more and more to improve … Continue reading »

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PLOS ONE supports registration and reporting of all trials

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Emphasizing the fact that clinical trials can influence treatment decisions, the recent AllTrials campaign has called for all trials past and present to be registered, and the results reported. As one of the initiating organisations behind this initiative, PLOS is committed to continuously developing and adopting policies that might help rectify publication bias in the trials literature. Following in the footsteps of PLOS Medicine, this campaign has led the editorial staff at PLOS ONE to re-evaluate how we handle unregistered trials.

Previously, in line with the International Committee of Medical Journal Editors (ICMJE) policy and like several other journals, we required all clinical trials that began after July 1, 2005 to be registered prospectively (before patient recruitment) in a publicly available registry approved by the World Health Organization (WHO). To stress the need for prospective registration, papers that did not fulfill these criteria were rejected, but this potentially prevented the results of some trials from being published. Thus while we still expect prospective registration to be standard practice, as of today, we will also consider retrospectively registered clinical trials to help ensure the medical community has access to the results of these trials.

These retrospectively registered clinical trials must however meet the following criteria:

1) The trial must be registered in a WHO-approved registry before submission to the journal

2) The authors must explain the reason for late registration within the methods section of the manuscript

3) They must include a statement confirming that all ongoing or future related trials are registered

As a reminder, when determining what constitutes a clinical trial, PLOS ONE follows the WHO’s definition: “a clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.” The ICMJE further clarifies that “health-related interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events”.

The ICMJE also recommends that if scientists are unsure whether their trial meets the above definition, they should err on the side of registration.

We believe that while prospective trial registration remains the gold standard, this change in policy will be a positive step towards increased transparency and accountability and is in line with another recent initiative supported by PLOS ONE, the RIAT (Restoring Invisible and Abandoned Trials) initiative. This is also in accordance with the core values of the journal to publish all papers, including studies reporting negative results, provided they are technically sound and done to high scientific and ethical standards.

 

Image: by NHS Confederation on Flickr

PLOS’s continued commitment to transparency in trial publication

As of today, PLOS is retiring its two “Hubs”, which have respectively highlighted and brought together open-access content in two specific areas: Biodiversity and Clinical Trials. These sites were initially developed to experiment with how the open-access literature might be reorganised and filtered across journals, providing ways of enabling readers in particular fields to access material of interest to them. The Hub:Clinical Trials was dedicated to highlighting clinical trials research across the PLOS journals, as well as maintaining an archive of the original work previously published in PLOS Clinical Trials. Although the Hub will no longer exist, all unique articles originally published in PLOS Clinical Trials will continue to be openly available at http://www.plosclinicaltrials.org, as well as in PubMed Central. Trials research published in other PLOS journals will be available as usual on those journals’ sites. The decision in no way diminishes PLOS’s commitment to publishing all correctly conducted and reported clinical trials and we also intend to explore new ways of aggregating content in future. PLOS has always been committed to raising awareness about the effects of publication biases in relation to clinical trial data, and to providing ways of addressing those biases. This commitment now continues through a number of ongoing initiatives which PLOS journals continue to support.

Firstly, PLOS ONE continues its commitment to publishing the results of clinical trials research, irrespective of trial outcome. The journal’s publication criteria have always emphasised that for a paper to be published, following rigorous peer review, that work is technically sound and properly reported. In relation to clinical trials research, PLOS ONE (and other PLOS journals) requires authors to use CONSORT guidelines in reporting their study; to have prospectively registered their trial in a public, international registry such as clinicaltrials.gov; and to provide a copy of the original trial protocol as supporting information for editors, reviewers and readers to evaluate against the published report. The journal therefore provides a unique mechanism to rectify publication bias in the trials literature – a bias that has been described by the Alltrials Campaign as potentially “leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated”. Since January 2011, PLOS ONE has accepted for publication 406 articles classified as trials. Included amongst the papers published are frequent examples of well-conducted studies which fail to find “positive” effects of experimental interventions – such as this study looking at a complex intervention aimed at decreasing x-ray referrals for patients with acute low back pain; and this study evaluating the effects of an advocacy initiative aimed at reducing the risk of pedestrian injury.

Secondly, PLOS staff members continue to be involved in external initiatives which aim to address publication bias and to increase transparency in trial publication. Both Ginny Barbour (Editorial Director for Medicine at PLOS and Chief Editor, PLOS Medicine) and I have been involved in the European Medicines Agency’s Advisory Groups regarding its development of a new policy for making publicly available the original datasets  for clinical trials which underpin drug regulatory decision making in Europe. The Agency has now released its draft policy which is open for public comment. The policy makes some important statements. For example, EMA does not consider clinical trial data to be commercially confidential, and the draft policy states that the interests of public health outweigh the considerations of commercial confidentiality. The draft policy would make all summary clinical trial data and documents (where there are no concerns about patient privacy) open access, at the time of the EMA’s report of a positive, negative or withdrawal decision on a drug indication.

PLOS is an initiating organisation behind the Alltrials initiative, which it endorses. Alltrials calls for “all trials to be registered and reported”. PLOS’s declaration of support for Alltrials can be read here. As a result of recent campaigning, some forward-thinking drug companies – such as GSK and Medtronic  – have supported or developed initiatives to freely share individual patient level trial data with academic researchers for independent scrutiny.

Finally, PLOS journals (specifically PLOS Medicine and PLOS ONE) have recently declared support for a creative new approach for getting unreported trial results into the published literature. Both journals have stated that they will support the RIAT initiative, a proposal whereby authors independent of the original triallists or sponsors could revive unreported trials and independently publish their findings based on documents obtained through public-domain documents, such as via freedom of information requests.

These and other initiatives are beginning to change the trials landscape, but there is still a very long way to go before the public can be reassured that the findings of all trials will be made immediately available in an unbiased way to inform clinical decision making. PLOS editors will continue to support efforts aimed at ensuring the full and honest reporting of the results of all trials.

My competing interests: I have contributed to one of the advisory groups of the European Medicines Agency in relation to publication and access to clinical trial data. I have also acted as a contributor to meetings of groups aiming to develop consensus statements for improved reporting of research, such as the development of the CONSORT guideline for patient-reported outcomes (I’ve received subsidy for travel expenses for such meetings). I am on the advisory group for Current Controlled Trials.

PLOS ONE welcomes RIAT (Restoring Invisible and Abandoned Trials) Initiative

 Last week BMJ published an article proposing a new initiative aimed at solving an age-old problem in medical publishing: that of the perennial failure of investigators and sponsors to publish all of the results of all their trials, accurately and transparently. The BMJ paper ups the ante and invites independent, “restorative authors” to step in and take charge of unpublished or misreported trials. It’s not so much “publish and be damned” as “publish or be published”. Restorative authors can now use as their data source the documentation from a trial (often many thousands of pages of protocols, clinical study reports, and individual patient datasets or analysed datasets) obtained through freedom of information requests. The RIAT proposers (Peter Doshi, Kay Dickersin, David Healy, S Swaroop Vedula and Tom Jefferson) describe in their table 1 the many documents and datasets they have already obtained for a large number of trials, and which they’re willing to share. Doshi et al invite collaborators to their enterprise:

We call on others to join us, to contribute trial documents they have obtained from public sources that need publishing or republishing, and to help us with the writing. We need volunteers to act in place of those who should have but did not make trial reports visible and accessible.”

Understanding the world of trial documents.

Understanding the world of trial documents.

Image credit: Doshi et al, BMJ 2013;346:f2865 (Copyright CC BY-NC 3.0)

The initiative has already garnered support from our sister journal PLOS Medicine, which has co-signed an editorial announcing that they “commit to publishing restorative clinical trial submissions”. A detailed blog by PLOS Medicine editors discusses some of the hurdles that might need to be overcome for journals to publish restored trials by independent authors. For example, many “restored trials” may not have been originally registered in public trial registries, and restorative authors may have limited ability to establish whether the trials they are restoring were ethically conducted. Generally journals will only publish the results of trials which were publicly registered, and for which authors can take responsibility for ethical oversight and provide assurance to editors that their trial was carried out ethically. The PLOS Medicine editors invite feedback via their blog on these, and other issues.

The RIAT initiative is entirely concordant with PLOS ONE’s editorial aims and mission, which seeks to publish the results of all correctly reported, scientifically sound studies, irrespective of impact or the direction of results. PLOS ONE’s publication criteria do not discriminate against “negative results”, and the journal welcomes submission of re-analyses or replications of prior work, as well as analyses based on publicly available datasets. We do require that authors adhere to study-type-specific community standards for reporting, such as the CONSORT guidelines for reporting randomized trials (which has been adapted by the RIAT authors into a specific modification, the “RIATAR” tool for documenting the RIAT process).

Consequently, PLOS ONE now invites RIAT authors to consider submitting their “restored” trial reports to PLOS ONE for publication. These papers will be considered in the context of our existing publication criteria and editorial policies, although the editors are actively considering how the specific issues noted above in relation to trial registration and ethical integrity might best be interpreted. We ask RIAT authors to clearly identify when submitting (ideally in their cover letter) that they are responding to the RIAT initiative and are submitting a RIAT study. Authors should show that they have given the original triallists and sponsors an opportunity to publish their own study. They should do this by stating in their article methods section when they contacted the original triallists and sponsors, and by what date no response had been received. (If original triallists/sponsors have indicated they wish to restore their own trial, the RIAT proposal allows a “grace” period of a year, in which they should be allowed to publish without being scooped). We will also check Rapid Responses to the BMJ article to find out whether sponsors intend to restore their own trial. We also suggest that RIAT authors ensure they fully describe the methods that they have used to conduct RIAT, including the approaches to obtaining the datasets from the original trial, to reanalyze those data and through which they have come to their conclusions. This is particularly important if the trial has already been reported by the original triallists, and if RIAT authors are drawing different inferences based on a different approach to analysis. RIAT authors should take care to distinguish responsibility for the work they have done (in obtaining public data and conducting their reanalysis) from the work done by the original triallists (the conduct of the original trial), thereby establishing what authorship means in the context of a RIAT study.

Finally, the PLOS ONE editors have noted that PLOS ONE study is included in the list of clinical study reports amassed by the RIAT group (see Table 1, “Novartis FLUAD study, cited as reference 103 in the BMJ paper. PLOS ONE reference is given below). PLOS ONE is committed to correcting the publication record where necessary and therefore we will be in touch with the RIAT group to find out whether they can share with us any information on why this study is included in their list, and for what reasons a correction of the record may be needed. Quite separate from this, we also welcome any submission to PLOS ONE of a reanalysis of this trial from restorative authors, based on the clinical study reports that the RIAT group have obtained.

Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, et al. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS One 2009;4:e4384

My conflict of interest declaration: I saw an earlier version of the RIAT article while it underwent peer review for BMJ, and provided some comments as part of the peer review process.