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FEATURES << Impact of legislation and reporting standards on publication planning
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Impact of legislation and reporting standards on publication planning
Published 11 November 2008, written by Andrew Berrie and Sarah Bartlett
What has led us to this point?
The publication planning landscape has changed dramatically over the past 10 years. We have moved from an arena largely free of restriction and regulation to one that has come under intense and sustained scrutiny from several sources – legislators, journal editors, medical societies, commentators and even mainstream newspapers. Today, many Pharma companies have publication policies and procedures in place to routinely register clinical trial protocols, and some have ensured that summaries of past trial results (published or not) are publicly available on their own registries.
It was back in 1997 that things started to change, as the US Food and Drug Administration (FDA) implemented its Drug Modernization Act, known as FDAMA, a wide-reaching piece of US legislation that touched on a number of topics related to the regulation of drugs, devices and biological products. Section 113 of FDAMA essentially outlined the beginning of http://clinicaltrials.gov/, a publicly available website established and run by the US National Institutes of Health (NIH). The initial objective for the website was to register all clinical trials testing FDA-regulated drugs for efficacy in serious or life-threatening diseases or conditions. This was not for disclosure or transparency purposes but to provide patients and doctors with better information sources about important trials.
If we fast forward to 2005, the International Committee of Medical Journal Editors (ICMJE, www.icmje.org) made registration of clinical trials (other than Phase I) in a publicly accessible database a prerequisite for subsequent publication in their journals.
The ICMJE is just a small and select group of journal editors but it is highly influential, including the editors of major general medical journals such as JAMA, N Engl J Med, Lancet and BMJ. So while this requirement currently only concerns a few of the highest ‘tier’ of general medical journals, the ICMJE has recommended that all medical journal editors adopt a similar policy, and several journals have now followed their lead.
This policy was designed to increase the transparency of clinical research following a number of high-profile newspaper and journal articles asserting that some pharmaceutical companies were actively withholding clinical data or seeking to selectively publish positive clinical trials. This view arose because trials were essentially being conducted ‘behind closed doors’ – only pharmaceutical companies, individual investigators and regulatory authorities knew about them. Making trial information publically accessible before completion would mean the outcomes of ‘negative’ or ‘failed’ studies could not be buried.
Two years later, in 2007, the ICMJE expanded the scope of its guidelines to include Phase I trials (with a deadline of 1 July 2008 for registration). Meanwhile, in September 2007, the FDA amended its Modernization Act with the Amendments Act (FDAAA), such that the requirement for registration included “all applicable clinical trials” (FDAAA Public Law 110-85, section 801) – though Phase I trials were still excluded from this amendment. [More details here].
However, FDAAA went beyond clinical trial registration and mandated that results be disclosed over the next 2-3 years in a publicly accessible database. According to FDAAA, the results of studies from Phase II onwards for pharmaceutical/biological drugs and devices approved by the FDA must be registered within 12 months of the estimated or actual trial completion date (whichever is earlier). This applies to any Phase II, III or IV studies that were initiated after 27 September 2007 or were ongoing as of 26 December 2007. Delays in submitting results may be granted for certain reasons but not generally for journal submission.
What does all this mean for publication planners?
Things could get more difficult for publication planners due to two aspects: what is deemed prior publication and the related issue of speed of publication.
FDAAA stipulates that demographics, as well as primary and secondary outcomes, should be reported. In fact, the information required to be posted is considerably extensive, including tables of demographic and baseline characteristics (shown for each treatment arm within the study), plus the patient ‘flow’, tables of primary and secondary outcomes (again by treatment arm) and tests of statistical significance.
Until now, brief reports of fewer than 500 words, such as abstracts or press releases, have not been considered by journals to constitute prior publication, which would jeopardise publishing the full manuscript. But as the FDA now wants much more information – and will impose a $10,000-a-day fine for noncompliant companies – the dynamics are changing.
Will journals be interested in publishing a manuscript when the full demographics and absolute values of primary end points (with accompanying p values) are already widely accessible? Happily, the answer appears to be ‘yes’. The BMJ stated earlier this year (Groves T. Mandatory disclosure of trial results for drugs and devices. BMJ 2008;336:170) that it would not consider results deposition as prior publication and other journals are following suit.
Of course, let’s not forget that journal impact factors are strengthened by papers reporting randomised clinical trials, so it’s not in the journals’ best interests to preclude papers where results have simply been disclosed according to the format and deadline required by law. However, they probably will expect more interpretation, commentary and discussion of the results. [More details here].
Also, for publication planners, journal lead-times will undoubtedly become an even more critical factor in journal selection if a publication is to be available before the FDA’s 12-month post-completion deadline. Planners need to ensure the option to update the ‘estimated’ trial completion date is exercised, as this will permit them the full 12 months’ allowance to maximise the likelihood of journal publication prior to the results being posted. Industry review processes also need to be examined and streamlined to ensure that these don’t unwittingly delay the process further.
On the plus side, one major bonus of the clinical trials register for publication planners is the help it gives in building competitor awareness, in terms of timing of pivotal trials, end points, comparators, formulations, combinations and so on. It will also improve the information available for individuals wishing to conduct systematic reviews.
What next?
The practicality of how a pharmaceutical company might ensure the posting of results for totally independent trials of their approved products still appears to be under review. Another question that remains unanswered is the ability to post results on long-term follow-up – in particular, disease areas (such as oncology and cardiovascular disease) where these are often as important, if not more so, than earlier findings.
We will need to see whether deposition of trial data will actually help achieve the objective of balance and transparency. One could envisage a scenario where negative and uninteresting trials are reported solely in the registry, while those with more positive outcomes are published in full.
However, with confidence in the integrity of Pharma being at one of its lowest points, this legislation should help increase public trust. Previously, there hasn’t been confidence that all clinical data have been disclosed and FDAAA should achieve that aim, even if it isn’t all in a peer-reviewed format.
About the authors
Andrew Berrie is Chief Operations Officer at Complete Medical Group and Sarah Bartlett is Head of Editorial and Scientific Services at Complete Medical Communications
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Feedback: Do you have any comments about this article? Contact the Publisher, Peter Llewellyn.
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