Clinical trials with negative results – to publish or not to publish?

publications

A “finding” – what does it mean?

In a clinical trial language a finding is usually referred to a numerical result of an analysis for a specific outcome, for example a relative risk (1). In proper understanding of research it is crucial to have some additional background information consisting of four key elements: methodological context, population context, a result for each outcome and interpretation (1). It has to be known how the trial was conducted and what was the hypothesis, to whom the results of the trial can be applied, what were the results for each outcome, and what are probable answers to the questions asked (1).

Where a “finding” can be found?

According to World Medical Association’s statement of principles for medical research involving people, every investigator running a clinical trial should register it and report its results (2). It is crucial for keeping medical information up to date (2).  There are several platforms provided for registration of clinical trials and reporting their results. To register a trial, the details should be submitted directly to any of the Primary Registries of the WHO Registry Network or an International Committee of Medical Journal Editors (ICMJE) approved registry. List of registries is available on the WHO website on International Clinical Trials Registry Platform (ICTRP) (3). It is only necessary for a trial to be registered once (in one registry) (3). The world’s largest register is clinicaltrials.gov which accepts registration from anywhere in the world (2). Although the registration of clinical trial is highly recommended immediately when the clinical trial begins, in some cases it is possible to register a trial retrospectively.

Publish or not publish?

Researchers who decide to embark on a clinical trial commit themselves to report the findings in accordance with ethical principles (1). However, it has been estimated that half of all completed clinical trials are never published in academic journals (4). Additionally, it is twice more likely to publish a trial with positive results than others (4). The problem of not publishing the results of clinical studies applies to industry trials, non-industry trials, international trials, trials at all stages of drug development, and to clinical trials of all sizes (4). When results are published, they are not always complete, what may lead to potentially biased view of the trial and its results (1).

Selective reporting of the results impacts informed health-care decisions of both healthcare practitioners and patients (1). A process leading to more transparent reporting of findings of clinical studies has already begun (1). The value of making clinical trial results publicly available, whether they are positive or negative, is more than of purely administrative benefit. It is not only ethical but also practical, because it helps avoid duplicating studies (1). Additionally, knowledge of specific finding has a great influence on people trying to choose between alternative interventions (1). Not publishing results, both positive and negative, can lead to serious consequences such as bad treatment decisions and missed opportunities for good medicine (2). In the United States, the public disclosure of clinical trial results is required by the US FDA Amendment Act 2007 (2). It puts study sponsors under an obligation of posting results of the trial on clinicaltrial.gov within a year of the completion of the trial. This obligation refers to all trials with at least one site in the US (2). In European Union, a similar tendency is observed.  Posting results of clinical trials on EudraCT is mandatory since the 21st July, 2014 (8). Study sponsors are obliged to post results within 6 or 12 months since the end of their trials, depending on the type of the trial concerned (8). For trials that ended before July 21st, 2014, sponsors will have to post results retrospectively (8).

A negative result?

In the context of clinical trials the concept of “negative” result is often misnomer (5). A trial with negative results is often a study that for various reasons fails to show effectiveness in a certain indication or use (5). A negative result is rarely understood as an unexpected or unwanted harm for patients from the drug or medical device being tested (5). There are different reasons for failure of the trial, including insufficient statistical power of the study, inappropriate choice of route, dose or frequency of administration of the study drug (5). Negative result of a study can be caused by lack of effectiveness of the drug investigated (5). To substitute the term “negative” result, it would be more appropriate to use the word “unsuccessful” or “inconclusive” (5). Perception of the term “negative” applied to clinical trials is often inappropriately pejorative (5). A negative result of a trial is not always a proof of any actual harm. It may serve as a clue in which direction future trials should turn to look for potential benefits (5). Additionally, blocking the publication of a “negative” result could be a way in which pharmaceutical companies try to exaggerate the benefits of their products (5). Most clinical trials that are “negative” or inconclusive are also less attractive to journal editors, reviewers and medical practitioners (5). It has been observed that negative results do not make riveting reading (6). Chris Williams, M.D., coordinator of the Cochrane Cancer Network, Oxford, England said that “there is a strong link between failure to publish and a study being negative” (6). The initiative has been undertaken to create a journal that will accept publication based on the quality of clinical trial instead the newsworthiness of the results (6). It is considered to become a source for meta-analysis and overall view to what happened to disappearing trials (6). This open-access journal is called “Journal of Negative Results in Biomedicine”. (6).

Publishing “negative” results of clinical trials, even those with properly planned methodology and execution, is a reminder that understanding limitations of clinical trials is essential to discover which therapies simply work and which do not (5). The publication of the results can be enhanced, for example through ensuring at the very beginning of the trial, in the contracts, that results will be published regardless of whether they are satisfactory (4). Additionally, Ethical Committees or Health Research Authorities could commit to insisting on publishing the results of clinical trials and to checking that no study results are being withheld (4).

Summary

Publishing negative results of clinical trials with background information opens an opportunity to avoid possible mistakes in designing other prospective trials.  It creates a basis for modifications of trial design that leads to new answers and new possibilities in medicine. Publishing the results is simply being fair with patients who participated in the research, experienced inconvenience and sometimes risk, in the belief that their participation will improve understanding of which treatment works best (4). There are strong arguments for publishing “negative” results of clinical trials as well as positive, because what is negative now, can bring future success.

References

(1)D Ghersi et al. 2008. Reporting the findings of clinical trials: a discussion paper. Biulettin of The World Health Organization. 86(6): 492-493

(2)http://www.alltrials.net//wp-content/uploads/2013/09/What-does-all-trials-registered-and-reported-mean.pdf

(3)http://www.who.int/ictrp/trial_reg/en/

(4) http://www.alltrials.net/wp-content/uploads/2013/01/Missing-trials-briefing-note.pdf

(5)http://www.forbes.com/sites/henrymiller/2013/04/03/what-we-learn-can-learn-from-negative-clinical-trials/

(6)http://www.jnrbm.com/about

(7) http://www.alltrials.net//wp-content/uploads/2013/01/letter-to-EMA-from-clinical-trial-participants-2013-Jan-18.pdf

(8) http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/06/news_detail_002127.jsp&mid=WC0b01ac058004d5c1

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