In which I suggest a preprint archive for clinical trials

The ArXiv preprint archive for research articles in physics, mathematics, computer science and related disciplines was initiated by Paul Ginsparg in 1991. ArXiv enables the rapid dissemination of research articles prior to peer review, and it quickly became very successful in this. ArXiv has not made the peer-reviewed journal obsolete, but rather provides a service that traditional journals – and that also includes Open Access journals – can’t provide. By 1998, more than 90% of all peer-reviewed papers published in high-energy physics first appeared on ArXiv. Nature Precedings was started in 2007 to provide similar services for research in biology, medicine (except clinical trials), chemistry and earth sciences. In addition, many preprints are also hosted in institutional repositories.

The research that I am doing is clinical research, trying to improve the treatment of patients with cancer. Most clinical trials are drug trials, but there are also surgical interventions, trials with medical devices, etc. Clinical trials are a special kind of research, and I have talked about some aspects in a previous post. Registration of clinical trials before the first patient is treated – providing key information from the trial protocol – is now required in many countries, including the United States and the European Union. The U.S. database of registered clinical trials (Clinicaltrials.gov) is publicly available, and the EU is working on doing the same with their EudraCT database. The International Committee of Medical Journal Editors (ICMJE), and in consequence many medical journals, also requires clinical trial registration. Since September 2008 the U.S. Food and Drug Administration (FDA) also requires all clinical trials registered at Clinicaltrials.gov to provide key results within 12 months after the last patient has finished treatment.

From Basic Discoveries to Patient Treatment

Flickr image by myelinrepairfoundation.

The results of clinical trials are rarely first reported in a peer-reviewed journal, but rather are usually first presented at a conference – in the case of important practice-changing clinical trials often before an audience of thousands of people. The conference abstracts are also an important source of information, even though they don’t provide the space for more detailed information, including tables and figures. Many societies publish conference abstract in their society journals, but bibliographic databases such as PubMed probably don’t cover all conference abstracts reporting clinical trial results.

The peer-reviewed paper is usually published months or even years after the conference presentation. This not only allows for more mature data – e.g. survival information – but also critical review and discussion of the data. The publication of the peer-reviewed paper is not the first time the medical community learns about the results of a clinical trial, or draws conclusions for their own research or clinical practice. To take a recent example from a clinical trial in cancer: the results of the TROPIC trial of cabazitaxel chemotherapy in hormone-refractory metastatic prostate cancer (Clinicaltrials.gov NCT00417079) were first reported at the ASCO Genitourinary Cancers Symposium March 5 (and there was a press release a day earlier). Capazitaxel was approved by the FDA on June 17, and I treated the first patient with the drug in September. The peer-reviewed paper was published in The Lancet October 2.

I would like to suggest that we need a preprint archive for clinical trial research papers. The preprints should be uploaded at the time of journal submission, or shortly after the conference presentation. The preprint server should add some structure to the preprints, e.g. linking to both the clinical trials registry (Clinicaltrials.gov, EudraCT, and others) and the published paper. The preprint should fulfill the requirement for reporting results set by the FDA. Articles in the preprint archive should be freely available, and should ideally provide the main results as downloadable datasets. The preprint server will only work if medical journals – and ideally the ICMJE – have a clear policy allowing prior publication as preprint.

This post was inspired by discussions with Salvatore Mele and Ivan Oransky. And it is my first contribution to the Open Access Week that starts on Monday.

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10 Responses to In which I suggest a preprint archive for clinical trials

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  2. Chris Rusbridge says:

    This does sound like a good idea. I think it faces an uphill struggle however.

    ArXiV built on a long-established practice of circulating paper pre-prints in HEP, since publication lead times were so long. This meant that ArXiV was only a change in technology, not a change in culture. There was (I think) a similar culture of working papers in Economics, which led to the early RePEc system. Attempts to introduce a similar system in other disciplines have not been nearly as successful.

    I don’t know if Clinical Trials has a similar tradition to draw on. Whether or not it has, I guess there are likely to be concerns that publishing clinical trial “results” that have not been peer-reviewed will allow platforms for the less rigorous “medical approaches” to put up papers that could be misleading. In ArXiV this was never a problem at the start (there was a prior stage of “peer review” before anyone got a physics grant, anyway), but more lately as it has grown, I think there have been systems put in place to detect the more egregiously blatant non-science articles.

    Have you thought about how such safeguards might be put in place for clinical trials pre-prints?

  3. Martin Fenner says:

    Chris, I completely agree that this idea will face an uphill struggle – mainly because conference organizers and journal publishers might not be interested in preprints of clinical trials.

    But I tried to emphasize in the blog post that there is a long-established practice in clinical medicine to report and discuss clinical trials before the peer-reviewed publication. And because the registration and conduct of clinical trials is so regulated, I don’t see a real danger of reporting of less rigorous research. The much bigger danger in clinical medicine is publication bias, i.e. to only publish clinical trials with “positive” results. A preprint archive would be a good platform for “negative” trials.

    We should also not forget that the peer-reviewed paper in clinical medicine is often not the last word on the subject. We often need confirmatory studies and a meta-analysis (think Cochrane Collaboration) before clinical practice is changed.

  4. antipodean says:

    There is a journal for this already Controlled Clinical Trials. Plus a reasonably detailed trial description must be published online anyway.

  5. Martin Fenner says:

    As I understand it, Controlled Clinical Trials (now called Contemporary Clinical Trials) is a journal about clinical trial methodology. A preprint archive is not an alternative to a traditional journal, but an intermediary step in the publication process.

    The trial results provided in abstracts or at the Clinicaltrials.gov website are really just the basic information. A paper in a preprint archive could contain much more detailed information.

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  7. F1000 Posters (http://f1000posters.com) (a conflict of interest statement here: I run this repository) is like a preprint service in that we take posters and more recently presentation slides that have been presented at national and international conferences in biology and medicine – and it is open access. We do have a few submissions that are smaller clinical trials and to one of the points of Chris Rusbridge, we make it clear on every single submission that the work may not have been peer reviewed so the general public etc are clear. One of the problems is that some of the key journals (most notably NEJM) consider deposition of the poster in a repository such as ours as prior publication and while this is the case, it will clearly hinder the online release of this information before the journal article is published. The other issue is that many of these societies (ASCO being a case in point) do have their own poster/presentation repositories and may take the copyright of the poster/slides as a result, preventing their more wider release elsewhere. ASCO charge you to access these documents, while many societies put them behind a member-only wall.

  8. Rebecca, thank you for the info about F1000 Posters. It would be really helpful if more journals would not consider the public release of a poster prepublication. Posters in the larger society meetings are shown to thousands of people. It is understandable that societies want to have the copyright for the posters, but that makes the wide distribution of posters so much more difficult.

    F1000 Posters is using a Creative Commons license, but that license is unfortunately Creative Commons Attribution Non-Commercial. This license makes it difficult to also upload them to a conference website, as a conference is usually a commercial activity. How do you handle this situation?

  9. The Creative Commons Non-Commercial licence only affects what someone else can do with the work if they access it via F1000 Posters and they rely on the Creative Commons Non-Commercial licence to permit its use. As the author retains the copyright of the poster, they are free to licence or assign copyright of that poster to anyone else they choose (as long as the assignment does not result in the rights granted to F1000 already in existence being terminated, or any licence is not an exclusive arrangement). Hence, depositing with F1000 Posters should have no detrimental impact on the author also depositing with a society or conference.

    Although I agree that it is perhaps not surprising that some societies like to take copyright of the posters, I would argue that doing so is not in line with the purposes of a society which is to support its members’ best interests. In taking such copyright, it means that should the authors decide to write up the work for submission to a journal and wish to re-use any of the figures from the poster (which they often do), the journal now has to get permission for the reuse of the figure(s) from the society (i.e. Reproduced with kind permission from society repository X); I suspect most journals would be less than happy with this if they realised that they may well be currently breaking copyright by publishing some of these articles.

  10. Martin Fenner says:

    Rebecca, thank you for the clarification. I agree with what you say in the last paragraph about copyright for figures, and I have briefly talked about this in a presentation last year. For me Creative Commons licenses are not only about free access, the right to reuse is at least as important.