Clinical Trial Transparency

While the issue of clinical trial transparency has long been an area of controversy, the matter has certainly hit the headlines in recent months. As a result, the pharmaceutical industry stands firmly in the public gaze and effectively stands accused of promoting a bias to the publication of positive clinical data and the suppression of negative data - to the alleged detriment of consumers.

Why has this issue come to the fore now? The trigger was pulled in June 2004, when New York Attorney General Eliot Spitzer accused GlaxoSmithKline of suppressing information regarding the effectiveness and safety of Paroxetine in adolescents. Apparently spurred into action by this potentially damaging event, GSK announced it was creating the first clinical trial database to publicly disseminate information on GSK sponsored clinical trials. Other companies (including Merck and Eli Lilly) were quick to follow suit. Then in September 2004, in a co-ordinated industry response, PhRMA (The Pharmaceutical Research and Manufacturers of America) announced the launch of a voluntary clinical trials database for the publication of the results of clinical studies conducted with marketed drugs. This database is intended to involve the broad participation of PhRMA membership, although as a voluntary initiative, this is not guaranteed. Coincident with the PhRMA initiative, the International Committee of Medical Journal Editors (ICMJE) issued a statement indicating that, if a clinical study is to be considered for future publication in its member journals, then that clinical study must be listed in a public registry (at or before the onset of patient enrolment). The statement sets out to prevent selective reporting and publication bias in favour of positive results. Enter the politicians. Representative Henry Waxman and Senator Ted Kennedy have since indicated that they intend to introduce legislation mandating publication of all clinical trial results on a government website. The issue of clinical trial transparency has thus become highly charged. What does all this mean? Clearly the pharmaceutical industry is under pressure and the PhRMA initiative could be perceived as a timely response. Widespread adoption can only help to improve public image and restore trust in the industry. Importantly, rapid and successful implementation of this initiative could allow the industry to retain some control on its release of clinical data - hence the implementation date of October 1, 2004. Conversely, anything that is perceived as a delaying tactic is only likely to fuel the debate further. But even with the PhRMA initiative underway, the debate is likely to continue as the proposed database has already attracted criticism given

• The voluntary nature of industry participation
• The summary nature of the data to be made available (as opposed to full access to unpublished trials)
• The concern with self regulation given the direct involvement and potential influence of the industry in the database

The resultant conclusion is that stakeholders beyond the industry will continue to press for complete transparency. What is deemed acceptable disclosure could be a key ‘battleground’. However, it could also be argued that the PhRMA initiative is too little, too late. Based on the Paroxetine/Spitzer case, it has already been proposed that antidepressants carry a black box warning on a potential increase in suicidal ideation in children. This is a potentially significant development. It will not be difficult for some to draw the conclusion that appropriate use of antidepressants has been negatively influenced by the way the disclosure of clinical trial results has been managed. This may play into the hands of those who favour a mandatory program. Similarly, the ICMJE initiative poses a challenge for the industry. Assuming that the industry will want to continue to publish major clinical studies in prestigious peer reviewed journals, then compliance appears inevitable. That ‘interaction’ with other health stakeholders (particularly the medical profession) is an important step in influencing medical practice. However, the inevitable concern is that any move that increases transparency could have negative consequences for the pharmaceutical industry and could lead to

• Violation of IP rights with competitors gaining easier, deeper, and earlier insight on competitor activity - raising the issue of confidentiality and competitive advantage
• Fewer new products entering development if increasing transparency leads to erosion of the value of differentiating factors
• Fewer studies in potentially risky populations (potentially narrowing treatment populations)
• More rigor in the design and conduct of clinical studies (thus increasing the cost of R&D) as the industry seeks to ameliorate risk

From an overall industry perspective, the ability to shoulder the financial risk of potentially negative clinical study results rests with big pharma. Biotechs/small enterprises are increasingly unlikely to be able to bear the risks and additional cost of R&D. This could have important consequences for industry structure. Of course, moves to increase clinical trial transparency will be welcomed by other stakeholders - particularly consumers and payers given the strengthening of the body of clinical evidence which should promote better, more robust, decision making. The practice of evidence based medicine is clearly inhibited if only part of the evidence is in view. Conclusions The clear risk to the industry is that publication of negative/equivocal trial results could undermine the commercial status of a given product. Equally, failure to enter a study in registry/ database initiatives may tarnish a company and its product(s) to the extent that a given product may not be fully adopted into medical practice. Arguably, registering a clinical trial could result in some loss of competitive edge and potential loss of commercial advantage. That may become an inevitable consequence of the pressures emerging from other stakeholders. The key for the pharmaceutical industry may rest in active participation and the exertion of some influence on the final shape of these database/registry initiatives. This in turn could reduce negative impact (for the industry) while improving the image of the industry in the eyes of consumers. However, the jury is still out on how the clinical trial transparency issue will resolve. One thing is certain, as we enter the final stages of the US Presidential campaign, the issue is not going to go away - the debate will continue.