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International Clinical Trials

Clinical Trial Reporting: Examination in Progress

Helena Korjonen of the National Heart Forum looks at current practice in registering and publishing clinical trials

The average cost of researching and developing a new chemical or biological entity stood at €1,059 million ($1,513 million) in 2007, and the expenditure for R&D in Europe was estimated at €26,000 million ($37,145 million) in the same year (1). There are around 107,000 individuals working in pharmaceutical R&D in the EU, and the pharmaceutical industry funds thousands more researchers in university and healthcare centres (1).

Law, regulations and guidelines surrounding the clinical trial industry change rapidly, and it is difficult for individuals to keep up with these and whom they affect. Countries have different legal requirements with regards to public registration of clinical trials and different levels of public disclosure of information.

Over the past few years, progress has been made in the public registration of clinical trials, in particular with the push by the International Committee of Medical Journal Editors (ICMJE), stating that trials must be registered if the sponsor intends to publish the results in one of their peer-reviewed biomedical journals (2). In 2000, Clinicaltrials.gov was set up, and is managed by the US National Institutes of Health and the National Library of Medicine. It has emerged as one of the leading Clinical Trial Registers (CTRs), together with clinicalstudyresults.org, for disclosing results. From 1st May 2004, in line with the new EU Clinical Trial Directive 2001/20/EC (3), sponsors in the EU must, by law, register trials on the European Union Drug Regulatory Authorities Clinical Database (EudraCT) before recruitment of subjects for a trial begins. EudraCT is managed by the European Medicines Evaluation Agency (EMEA), and is only accessible by the competent authorities and the EMEA, although pressures for public access continue.

Finding trial information can be confusing as there is a vast number of registers available – both CTRs managed independently and those managed by sponsors themselves. Controversy surrounding the issue of what data should be provided at the time of registration also exists, and in particular the reluctance of sponsors in providing what they define as confidential or sensitive trial information for fear of losing commercial advantage (4,5). Following advice from PhRMA in June 2004 (6), pharmaceutical companies started setting up their own CTRs, meaning that trial information has become dispersed across many sites and the type of information given varies from site to site, including duplication occurring across many CTRs (7,8).

PhRMA made recommendations to its members to disclose study results within 12 months of study completion (9), and this has become law in the state of Maine, US (10). In October 2007, the ICMJE updated its statement to include the disclosure of results, allowing abstracts to be released prior to the final results being published (11).

In May 2007, the WHO announced their International Clinical Trial Registration Platform (ICTRP) for searching across a network of CTRs, thus reducing the need to search single registers separately (12). They have undoubtedly taken charge of setting the standard for CTRs for the future. At present, there is no standard format for trial registers.

OBJECTIVES, OUTCOME AND SAMPLE SIZE

The aim of the survey was to examine current perceptions and practices of registering clinical trials using CTRs, and the dissemination of the results of trials using different methods. The target audience was clinical research professionals involved in managing clinical trials, such as clinical research associates, administrators and project managers. The main research objective was to find out whether they feel confident in their understanding of trial registration and the dissemination of results. Although the sample was small (n=98) (see Figure 1), the results give an indication of individuals’ understanding of clinical trial registration and publication of results.

MATERIALS AND METHODS

Methods and Filters

Ethical approval for this survey was sought, but not required, from University College London. The survey was deployed using Zoomerang on the web. The internet gives the opportunity to conduct surveys more efficiently and effectively than traditional print methods. However, using only a webbased survey does create risks, in particular the self-selection of respondents, which may result in a sample that does not represent the targeted population, and we must assume that not everyone has access to a computer or the web, which could reduce the potential sample (13,14).

Relevant professional bodies were asked to distribute information about the survey via email, their website and through their newsletter or magazine. These were: Pharmaceutical Information & Pharmacovigilance Association (PIPA) (15), European Medical Writer’s Association (EMWA) (16) and The Institute of Clinical Research (ICR) (17). Non-members were also able to access the survey via links on the internet. The survey software recognised IP addresses for those completing the survey, barring an IP address from entering the survey again once submitted.

In total, these organisations had a potential 7,113 members exposed to the survey (EMWA – 860 members; PIPA – 727 members; and ICR – 5,526 members). The survey was announced in ICR’s CRfocus, in EMWA’s Write Stuff, and in PIPA’s Pipeline. The survey was launched on 20th August 2007 and closed 7th October 2007. The survey had 938 visits, with a total of 468 responses which consisted of 159 partial responses and 309 complete responses. Incomplete responses from individuals who abandoned the survey were eliminated. Responses from outside the EU were also filtered out in order to analyse EU opinion. Another filter asked individuals to declare if they work with publishing clinical trial results and only those who responded ‘yes’ to this question were retained for analysis. Ninety-eight responses were from the EU and therefore eligible for analysis (see Figure 1 for responses and filters).

RESULTS

 Table 1: List of respondents' affiliations  
  n=
 Medical communications agency 1
 Charity/university 9
 Freelance/consultant 12
 National health service 9
 Industry 61
 Other 6
 Total 98

 Table 2: List of respondents' job functions 
n=
 Medical writer 11
 Medic/scientist/researcher 11
 Product manager 1
 CRA*/project manager 16
 CR**/clinical manager/director 37
 Statistician/data manager 2
 Regulatory/quality 2
 Nurse/pharmacist 2
 Admin/support role 4
 Operations/process 3
 Other 9
 Total 98

*   Clinical research associate
** Clinical research

 

Demographic Data

Out of 98 responses, 63 per cent (n=61) were from industry (see Table 1). (When ‘industry’ is stated, this is a term encompassing pharmaceutical companies, contract research organisations (CROs) or device companies.) Thirty-nine per cent (n=37) of respondents were clinical research managers or directors, although a wide variety of roles were represented (see Table 2). Finally, 69.4 per cent (n=68) respondents have acted as authors or medical writers in the past 12 months.

Confidence in Clinical Trial Registration and Publishing Results

Respondents were asked to rate their understanding of current practices of registering clinical trials and publishing the results. Only 6 per cent (n=6) of respondents rated themselves as highly confident, but 47 per cent (n=46) were reasonably confident and 38 per cent (n=37) were mildly confident (see Figure 2, page 96). Nine per cent (n=9) stated that they were not at all confident. The least confident respondents worked in the national health service.

Publication Policies

Seventy-two and a half per cent (n=71) of respondents said that their organisation had a publication policy, leaving 17.5 per cent (n=17) that did not have a policy and 10 per cent (n=10) that did not know. Seventy per cent (n=7/10) of those who did not know if they had a publication policy worked in industry.

Registration in a CTR

When asked about the last trial they were involved in, 60.2 per cent (n=59) stated that it was registered in a CTR, and 15.3 per cent (n=15) stated that they did not know, leaving 24.5 per cent (n=24) that said that the trial was not registered. Clinicaltrials.gov was the most used CTR by 71 per cent (n=69) of respondents (23). While 60.2 per cent (n=59) of respondents said that the sponsor did not have its own CTR available to the public online, 22.45 per cent (n=22) stated that they did.

Dissemination of Results

Fifty-six per cent (n=55) of respondents said that the sponsor did not have its own website for posting clinical trial results; 30.6 per cent (n=30) of respondents stated that they had their own website; 45.9 per cent (n=45) of respondents said that the sponsor did not use any publicly accessible site for posting trial results; and 38.8 per cent (n=38) did not know. Only 13.3 per cent (n=13) of respondents provided a response to which website was used to post clinical trial results to. Clinicalstudyresults.org was mentioned by 3.1 per cent (n=3) of respondents (24).

Releasing Research Results Early

There are many definitions of what is meant by releasing research results early: results that are released before the end of a study (for example at a conference or as interim results), before a trial is published, or perhaps because a trial is closed down early for whatever reason. In the last trial that respondents were involved with, 31.6 per cent (n=31) of respondents said that they released research results early by a poster at a conference and 31.6 per cent (n= 31) said that they did not release results early (see Figure 3).

Respondents were able to agree or disagree to statements with regards to releasing research results early: 21.4 per cent (n=21) strongly disagreed with ‘I don’t agree with releasing results prior to publication in a peer-reviewed journal’ and 31.6 per cent (n=31) strongly agreed with ‘Published results by themselves are meaningless without analysis’. Forty-eight per cent (n=47) disagreed and 52 per cent (n=51) agreed with the statement that ‘Releasing research results early is a positive development’.

Releasing Unfavourable Results

Unfavourable results refer to those which did not meet the expected positive outcome. In a recent trial showing unfavourable results, 35.7 per cent (n=35) of respondents said that they published the results in a peer-reviewed journal (see Figure 4). Five per cent (n=16) of respondents who said that they did not release unfavourable results said that the main reason for this was that it was not company policy to publish unfavourable results.

Methods of Publishing used when Disseminating Results

The main method used to disseminate research results by 81.6 per cent (n=80) of respondents was to publish them in a peer-reviewed journal. This was followed by 74.5 per cent (n=73) who present results through conference abstracts or posters. Then, 62.2 per cent (n=61) disseminate through conference presentations, 45.9 per cent (n=45) published in top medical journals, and 42.8 per cent (n=42) of respondents used their own websites for dissemination (see Table 3). Only 19.4 per cent (n=19) respondents chose open access (OA) journals, and when prompted ‘why not?’, 21.4 per cent (n=21) responded that it was not considered to have the same impact as a paper or electronic subscription journal, and 28.6 per cent (n=28) of respondents said that they did not know enough about open access journals to choose this method.

Table 3: Methods of publishing used for dissemination of results 
  n= 
 Blog/wiki 1
 Online discussion groups 2
 Repository 5
 Newspapers/magazines 6
 Advertising 9
 Website (external) 13
 Reprints of journal articles 18
 Open access journal 19
 Promotional material 19
 Standard letter sent out to physicians 25
 Meetings, conferences, exhibitions 40
 Press release 41
 Website (own) 42
 One of the top medical journals 45
 Conference presentation 61
 Conference abstract/poster 73
 Other peer-reviewed journal 80

Awareness of Publication Guidelines

The awareness of publication guidelines varied amongst respondents: 76.5 per cent (n=75) of respondents scored the ICMJE guidelines with the highest awareness. The guidelines that respondents have used and find useful are seen in Figure 5.

DISCUSSION

There are many arguments relating to whether research results should be disclosed. The Declaration of Helsinki (18), which underpins medical research, states that the results (including negative results) should be published and made available publicly. The ICH GCP guidelines which remain the main guidelines for the ethical conduct of clinical trials, state that organisations must have a publication policy in place (19). Revealing results so that other researchers are aware of studies that have taken place also ensures that there is not unnecessary duplication of research, and that data can be shared. The underreporting of trials is a form of scientific misconduct (20). Also, evidence-based decision-making can become biased due to the lack of available results from trials that have a bearing on treatment decisions.

The results indicate that respondents are not aware of the sponsors’ actions with regards to trial registration, or that the sponsor does not follow current guidelines with regard to trial registration. As previously mentioned, Clinicaltrials.gov (21) was the most commonly used CTR for trial registration. The ISRCTN (22) CTR followed.

Two concerns arose from the analysis. The first is that the results indicate that many of the respondents were not aware of the sponsors’ actions with regard to the dissemination of results. The second concern is that the sponsors are not disseminating results using CTRs or other publicly accessible sites for posting trial results (such as studyresults.org). However, it seems that sponsors are using their own websites to disseminate trial results. This is confirmed by a statement by PhRMA recommending that pharmaceutical companies disclose their results (9) and a number of global pharmaceutical propriety CTRs exist for example GSK Clinical Study Register (23) and Eli Lilly and Company Clinical Trial Register (24). There was an indication that the sponsor had policies on various processes such as publication policies, releasing research results early and the release of unfavourable results, but some respondents were unaware of such policies.

The results show that the respondents were not clear about the currently available publication guidelines on the preparation of publishing. Few guidelines had actually been used by respondents, but these included the ICMJE (25) Uniform Requirements, Good Publication Practice for Pharmaceutical Companies (26) guidelines and the CONSORT statement (27). These three guidelines were also rated as the ‘most useful’ to ‘very useful’. It is possible that the respondents who were not aware of any guidelines rarely get involved in writing publications.

Respondents were asked to select methods used to disseminate the results of a trial. The peer-reviewed journal remains at the top of the list of methods used for releasing the final results, even though there has been discussion about the role of the peer-reviewed journal not being the right vehicle for releasing results (28) and it is known that not all results will be published in a peer-reviewed journal (29). Surprisingly, electronic methods still featured low on the list for methods used by respondents. During the time of this survey, the ICMJE has set guidelines with regard to the publication of results, such as encouraging abstracts to be submitted to conferences or a website (11), which may change the way in which results are disseminated.

There were a number of limitations to this study, which hopefully future studies will overcome. This was an English language web-based survey, which may have caused a coverage and language bias. An additional problem may have been that a number of respondents did not have knowledge of certain aspects of clinical trial registration and publishing results to be able to answer all the questions.

CONCLUSION

This survey provided an insight into the personal understanding of current guidelines and regulations of trial registration of those working in clinical research, but more studies are needed. Although these individuals are highly or reasonably confident in the current practices of clinical trial registration, there is still a small number that do not feel confident, and these individuals tend to work mainly in the health service. The role of the WHO, the ICMJE and many others in setting standards and guidelines in trial registration and public disclosure of results is encouraging and will improve clinical trial reporting.

Note: Thanks to Dr Ian Rowlands, UCL Centre for Publishing, DIS, University College London, Supervisor of the research project, for offering advice on study design and statistical methods.

References

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Helena Korjonen is the Associate Director, Information Services, at the National Heart Forum (NHF), a charitable alliance working to reduce the risk of preventable chronic diseases. A qualified information professional, Helena is also working towards her PhD on the topic of ‘The process of dissemination of clinical trial information’ at the Department of Information Studies at London’s UCL. Prior to this, Helena has worked in the pharmaceutical industry and at a professional body for clinical research professionals. Her research interests are the social web, publishing methods and digital preservation.
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