Emma Veitch's blog

FDA's "Good" Reprint Practices Now Policy

Emma Veitch — Mon, 26 Jan 2009 08:54:45 -0800

Quick update on the FDA's draft policy regarding promotion of off-label drug use, which Gavin blogged about last July. Despite widespread negative publicity in the blogosphere along with opposition from health organisations and consumer advocates, the proposals have now been released as formal guidance from the agency. Essentially this policy now means that drug companies can promote off-label drug use by circulating reprints of journal articles describing those uses to doctors. Providing the FDA's guidance is followed, FDA does not see the activity as "establishing intent that the product be used for an unapproved new use..." We know, for all the reasons described in Gavin's blog (and in a recent PLoS Medicine article), that promoting off-label use is potentially harmful to patients. (Note also this week Eli Lilly has been reported in BMJ as settling "the largest individual corporate fine in history", in relation to off-label promotion of olanzapine). Despite this, the policy is described as only "guidance", with the document stating that "FDA's guidance documents do not establish legally enforceable rights or responsibilities". I, and presumably others, are left wondering how it will be possible for the agency to enforce pharmaceutical promotion in the future.

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Data access and the NHS - more research versus patient privacy?

Emma Veitch — Wed, 19 Nov 2008 10:00:51 -0800

The Guardian's front page story from a couple of days ago ("NHS medical research plan threatens patient privacy") looks like it has generated some healthy and opinionated responses from readers, but the government consultation that led up to it has now closed. The story here is that the proposed UK National Health Service constitution - enshrining the principles and values of the NHS - contained, buried amongst other important stuff on issues such as access to services, quality of care, and informed choice, a crucial nugget which could change the way that medical researchers get access to patients' data.

The Constitution Handbook says (p24): "...Therefore, the NHS will do all it can to give patients, from every part of England, with any illness or disease, a right to know about research that is of particular relevance to them and, if they choose, to take part in approved medical research that is appropriate for them. Patients can therefore expect that a health professional or a research professional who owes the same duty of confidentiality as a health professional may use care records, in confidence, to identify whether they are suitable to participate in approved clinical trials..."

According to the Guardian, Harry Cayton, the new chairman of the National Information Governance Board for Health and Social Care, has billed the proposal as "ethically unacceptable".

It's not obvious from the Handbook how it would be decided which researchers, and which research projects, could directly get access to medical records. It's also not stated whether researchers involved in commercially funded projects (eg, trials funded by drug companies) would be able to screen databases and directly contact patients. As some respondents have argued, the current system of recruiting patients may result in bias for some types of research. But if the proposals are to go ahead, it would be crucial to develop a secure framework to establish which research questions are in the greatest public interest and most in need of a broader approach to recruitment. This does seem to have been recognised by the National Health Service's own Patient Information Advisory Group, which has advised that the proposal be removed until fuller discussion has taken place.

Clearly, with centralised and (virtually) universal computerised medical records, the UK has enormous potential to strengthen its medical research culture; but I'd be interested to hear whether similar proposals are being developed in other countries, and what public reaction is developing.

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UK sets out guidance on research misconduct

Emma Veitch — Tue, 16 Sep 2008 10:06:49 -0700

The US has its Office of Research Integrity (ORI), and many Nordic countries (for example, Denmark, Norway, and Sweden) have national bodies that respond to cases of scientific misconduct; but the UK, and very many other countries, have nothing similar. Now the UK Research Integrity Office (UKRIO) has released guidance about what to do in cases of suspected research misconduct for "all organisations engaged in research using funds from funders such as the Research Councils and other government bodies, as well as from charities, overseas funding bodies and the commercial sector". A PDF copy of the guidance can be downloaded here (PDF file).

The UKRIO's definition of misconduct is broader than that outlined by ORI, covering misrepresentation of data or interests and failure to follow accepted procedures in carrying out various aspects of research, as well as the key three areas ORI considers important (fabrication, falsification, and plagiarism). Although the guidance outlines standard procedures that universities should follow when faced with allegations of misconduct, UKRIO has no power to investigate or impose sanctions (unlike ORI or some other national bodies).

As highlighted in a recent Times Higher Education article, it'll be interesting to see what impact the guidance has and whether self-regulation by universities and other research bodies really is the answer to investigating misconduct. The model followed here is similar to that used by COPE (the Committee on Publication Ethics), which offers guidance and support to editors on handling ethical breaches in publication practice, but which cannot itself take action.

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To IRB or not to IRB?

Emma Veitch — Tue, 29 Jul 2008 09:46:58 -0700

The Committee on Publication Ethics (COPE), of which PLoS Medicine, and other PLoS journals, are members, has recently released guidance for editors on the thorny topic of "research, audit and service evaluations". This guidance aims to help editors decide how to handle their journal's requirement for ethical review in relation to these types of studies. As outlined by COPE, most journals require that for any research involving human subjects, the study has been approved by a properly constituted ethics committee.

However, for some types of studies and in some countries, ethical approval is not required (or, may not even be possible). For example, the
US Department of Health and Human Services exempts research from review if it involves studying existing data or specimens, providing data is anonymised and delinked from the participant it originated from; exemptions also apply for five other major categories of research. In the UK, the National Research Ethics Service issues its own guidelines to help people to work out whether what they are planning to do is research (which requires ethical review) versus audit or service evaluation (which don't).

The PLoS Medicine editors recently discussed the COPE guidance. That guidance suggests that editors think about four key components, quite apart from the "box-ticking" exercise of checking that ethical review and informed consent have been obtained. Those four areas are: 1) scientific validity; 2) minimisation of harm; 3) whether benefits outweigh harms; and to 4) the need to seek clarification from authors or ethics committees regarding local laws and regulations, as necessary.

At PLoS Medicine, our journal policy is that "All research involving humans and animals must have been approved by the authors’ institutional review board or equivalent committee...". We do however recognise that many studies may be exempt from ethical review, and therefore our overriding approach is that authors describe clearly in their paper how ethical oversight for the study was obtained, and how the informed consent of participants was handled. This means that reviewers, and readers, will be able to judge for themselves whether the protection of human participants in the study was appropriate.

At the same time, we recognise that "journals should not automatically defer to ethics committees", as Kamran Abbasi and Iona Heath have pointed out in a BMJ editorial, and we consider the key areas outlined by COPE as part of our editorial review process. If we do have concerns regarding the protection of human participants in a study, irrespective of whether that study was approved by an ethics committee (or exempt from ethical review), the editors reserve the right to follow up, under the guidance of our advisory group on publication ethics, as necessary.

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Prying into protocols

Emma Veitch — Tue, 22 Jul 2008 09:00:47 -0700

Just spotted an interesting letter in last week's Lancet discussing selective reporting of clinical trials. This may sound like something you've heard many times before (eg here) but in the Lancet letter the authors describe what happenned to trials for which the original protocols were posted on Lancet's own website.

Evidence regarding selective reporting has been around for a while (eg the 2004 study mentioned above pulled out a set of protocols approved by Danish ethics committees, and matched them up with corresponding results publications. The authors showed that 62% of trials had "at least 1 primary outcome that was changed, introduced, or omitted"). However, at the moment very few trial protocols are ever published; the decision to publish or not is entirely voluntary, and very few journals offer the service. The Lancet offers protocol review - although the page is a bit hard to find), as do many of the BioMed Central journals.

In their letter to the Lancet, Al-Marzouki and colleagues describe how, for the set of trials they examined, unreported or switched primary and secondary outcomes were common, with no explanation for why outcomes were included, left out, or changed between the original plan and final report. What's amazing here is that this phenomenon occurs despite the fact that the protocol has been made public at an early stage, entirely voluntarily, and that triallists are presumably aware that as a result their eventual papers might be compared against the original analysis plans.

PLoS Medicine doesn't offer protocol review, but we do require authors to send us copies of the trial protocol when they submit their papers. We, our reviewers and academic editors find it's an incredibly tough job to compare submitted trial reports against protocols, but do occasionally find discrepancies. Al-Marzouki and colleagues suggest that a universal standard for protocols might simplify the process - but we're not there yet. The Good Clinical Practice guidelines provide a format - but only for trials done by drug or device companies to gain regulatory approval. Sadly it seems that in order to carry out a thorough scientific evaluation of a submitted trial, someone -- either an editor, reviewer, or careful reader -- has to .... actually read through the entire protocol... plus the report of course. Surely technology can give us something better than this?

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Your input on how clinical trials should be reported - public consultations at WHO and ClinicalTrials.gov soon to close

Emma Veitch — Mon, 16 Jun 2008 08:09:55 -0700

In the US, a new law will very soon require sponsors of clinical trials to start submitting data on the results of completed trials into an expanded version of the registry website clinicaltrials.gov.

Interested parties only have two days left to submit comments on a draft version of the results database - go to the website at http://prsinfo.clinicaltrials.gov/rrs-mockup-intro.html to see the current draft and give your feedback.

The World Health Organization also wants to hear public feedback on their proposal that “the findings of all clinical trials must be made publicly available”. The survey is only open until June 27th.

The PLoS Medicine editors have commented on both consultations - don't let policies develop on important questions relating to access to clinical trials data without first having your say!

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Children's medicines matter

Emma Veitch — Fri, 07 Dec 2007 06:45:37 -0800

Editors spend so much of every day with their heads thoroughly immersed, indeed swimming, in research papers, that it can be heartening to hear about initiatives that aim to prioritise the studies that really will make a difference. Yesterday I happenned to drop in to a press conference that was being held to launch the World Health Organization's new initiative, "Make Medicines Child Size".

This initiative takes as its starting point the huge, and global, gap between the need for children's medicines and their availability. Howard Zucker, Assistant Director-General of the WHO, highlighted the surprising and shocking fact that, in the developed world, 50% of children take medicines that have have either only been tested on adults, or are not authorized for use in children at all. WHO has already made important steps towards framing the extent of this problem, by releasing a model list of essential medicines for children (PDF 371kb) and by identifying a set of key priority research targets. The three most important research priorites, according to WHO, include research targetted towards second-line treatments for TB; studies aimed at developing medicines for TB/HIV coinfection; and drug development for neglected diseases such as schistosomiasis and filariasis.

Clearly, these advances cannot happen overnight. Hans Hogerzeil emphasised the need for additional funding for the research and development efforts that WHO has identified. The pharmaceutical industry can be incentivised (as for example, certain legal changes in the US have done), but cannot be expected to deliver solutions to every one of these challenges. Encouragingly, Nathalie Seigneuret (European Medicines Agency) noted that funding will be available from the European Union's Framework Programme 7 budget for certain trials which drug companies are unlikely to deliver.

And finally, a theme emphasised by several speakers was the importance of improving access to medicines. In many instances, drug regulatory systems will need to be changed to ensure that evidence relating to drug efficacy and safety can be used globally to allow countries to import the drugs that are needed.

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Quackbusters

Emma Veitch — Fri, 16 Nov 2007 02:50:16 -0800

Editors rarely have much to delight them on cold Friday mornings in Cambridgeshire so here at PLoS-UK HQ there was a frisson of excitement over Ben Goldacre's latest blog. It seems faintly ridiculous that around 50 years after the first properly randomized trials were done (and please don't quote me on specifics here, because I'm not a trials historian - check out the James Lind Library if you want more precision), anyone has to defend the importance of scientific rigour, appropriate controls, and dispassionate appraisal of all the available evidence. And yet with respect to the practice of homeopathy, someone has to go to the trouble of laying out the basic principles of evidence-based medicine: just read the blog to find out why.

Ben also talks about publication bias. We have no idea whether this is a more serious problem for homeopathy trials than for other types of study, but it has been estimated that around the results from around half of all trials never make it into the literature. As pointed out in the blog, clinical trial registries are a crucial way of addressing this problem. The essential idea behind registries is that 20 basic pieces of information about every trial get deposited into a publicly-accessible database before any patients are recruited. Then, when a trial has been completed, everyone can match up the results with the original plan for the study, and it will also be obvious if a trial (or specific outcomes from a trial) have not been reported.

As I've said probably far too many times, registries are a crucial step forwards, but ultimately don't go far enough. We also need a way to ensure that the results are eventually reported. This is an area within which the World Health Organization's group which developed the International Clinical Trials Registry Platform has been investigating international norms and standards. At PLoS we are also committed to publishing the results of all correctly conducted and reported trials, irrespective of outcome, within PLoS ONE, and making these available via our Clinical Trials Hub. And, of course, PLoS Medicine publishes rigorously conducted trials which the editors think will significantly advance clinical management or public health policy.

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Who cares about trials registration?

Emma Veitch — Wed, 31 Oct 2007 09:23:55 -0700

A paper recently appeared in Trials (an open-access journal published by BioMed Central) looking at whether investigators carrying out trials are aware of and agree with current international standards on trials registration. Encouragingly, the majority of investigators in the survey supported registration of all 20 items in the dataset recommended by the World Health Organization, although it is disappointing that even a tiny number of indviduals were opposed to upfront registration of any data at all!

Our experience at PLoS Medicine and PLoS ONE has been that in general, although most researchers are aware of the need for trials registration, we still receive a disturbingly large number of submissions reporting trials which were not registered before participants were enrolled. We don't want bias to creep into the evidence base relating to benefits and harms of interventions, so it's essential that investigators register their trials at the earliest possible stage. This will also ensure that researchers don't experience problems trying to publish their results later on.

Contact us, or comment via this blog, if you have any questions about the trials registration policy at PLoS Medicine or the other PLoS journals (more information is available via our Author Guidelines).

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PLoS Hub for Clinical Trials now launched - take a spin

Emma Veitch — Fri, 28 Sep 2007 11:44:11 -0700

The PLoS Hub for Clinical Trials is live today - completing the merger of PLoS Clinical Trials with PLoS ONE. Our goal in developing Hubs is to provide a place where you, the researcher or reader, can easily reach relevant PLoS content and build on it. Think of the Hub as a gateway directly connecting you to articles that you are likely to be interested in; you can sign up to get email alerts of the most recent additions directly from the Hub.

Articles included in the Hub are published on the Topaz platform, which means that you can use the tools we've developed for annotating, discussing, and rating articles for every paper included in the Hub. These features are available on content previously published in PLoS Clinical Trials and on PLoS ONE, and papers from the soon-to-be launched PLoS Neglected Tropical Diseases. Ultimately we hope that the Hub will grow into a great resource for clinical triallists.

PLoS is as committed as ever to publishing the results of all clinical trials, regardless of outcome, and to making this information freely and publicly available; find out more about how you can submit your trials research to PLoS journals.

If you are interested in the results, conduct and design of trials, check out the Hub, try out the commenting and rating tools, and send us your feedback: what do you want to see, and be able to do, in the Hub? This is just the beginning, and we plan to add further Hubs for specific subject areas, as well as cool new community features. Visit, come back, and comment!

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