The four-year investigation by the Medicines and Healthcare products Regulatory Agency (MHRA), billed as the largest of its kind in the UK, ended with a whimper as the agency decided not to proceed to a criminal prosecution of GSK for breaching drug safety legislation. Government prosecutors had informed the MHRA there was no realistic prospect of a conviction in the case. The key sticking point was that the legislation in force when GSK conducted paediatric trials with Seroxat and, as was claimed, failed to report an emerging picture of heightened suicidiality in patients under 18 years of age was "not sufficiently strong or comprehensive as to require companies to inform the regulator of safety information when the drug was being used for, or tested outside, its licensed indications", the agency explained. Allegations of data suppression over Seroxat and an increased risk of suicidal tendencies go back several years now; nor are they confined to the UK. Before New York attorney general and governor Eliot Spitzer's recent fall from grace, one of his high-profile sallies against the pharmaceutical industry was to sue GSK for withholding negative information from clinical trials of paroxetine (branded as Paxil in the US) in children and adolescents. In August 2004, the UK company settled the case for $2.5m (€1.6m) in damages, without admitting any wrongdoing, and committed to public disclosure of any clinical trial data in the future. In the meantime, the MHRA was conducting its own investigation. Launched in October 2003, this sought to establish whether GSK had delayed releasing data from clinical trials, conducted over an eight-year period, that suggested an increased risk of suicidal behaviour in patients under 18 years given Seroxat, an antidepressant in the selective serotonin re-uptake inhibitor (SSRI) class. Concerns had been building about an association between Seroxat and suicidal behaviour in adults since the early 1990s. Withdrawal symptoms were another focus of scrutiny. But the issue of suicidiality in children and adolescents only emerged unexpectedly at a meeting with GSK in May 2003, before the first session of a new Committee on Safety of Medicines Expert Working Group on the SSRIs. On examining the full paediatric trial data later that month, including GSK's meta-analysis that gave the signal on suicidiality, the MHRA considered the association serious enough to send out a 'Dear Doctor' letter in June 2003 advising that Seroxat should not be used off-label to treat depression in the under-18s. The full dataset also failed to demonstrate that Seroxat was effective in the treatment of depressive illness in children and adolescents, the MHRA noted. AS GSK pointed out, the UK labelling stated at the time that use of Seroxat in children "is not recommended, as safety and efficacy have not been established in this population". Yet an estimated 7,000-8,000 under-18s were being treated with the drug in the UK, according to the MHRA. What concerned the agency in particular was the time lapse between GSK completing some of the clinical trials included in the meta-analysis and communicating the information about suicidal behaviour to the agency. Moreover, GSK chose to do this in a briefing document on a prospective application for a paediatric extension to the existing UK indications for Seroxat. "Applications to extend indications take some time to prepare, are not routinely reviewed by the pharmacovigilance group within the Agency and are not an appropriate mechanism for informing a regulatory authority of a new risk:benefit concern," the MHRA commented. For its part, GSK is adamant that it only became aware of the increased risk of suicidal behaviour after it analysed the pooled clinical data from nine paediatric studies with Seroxat. "No suicides were reported in any of the nine paediatric trials conducted by GSK," the company stated. "When reviewed individually, none of these trials were considered by GSK or independent investigators to show a clinically meaningful increase in the rate of suicidal thinking or attempted suicide." As had been confirmed by the MHRA in its conclusions, "it was only when all the data became available, at the end of the research programme, and were analysed together was an increased rate of suicidal thinking or attempted suicide revealed in those paediatric patients taking Seroxat," the company added. "GSK brought this analysis to the attention of the regulatory authorities, including in the UK." The company says it rejects any suggestion that it withheld information on Seroxat, "as results from its paediatrics studies were documented and submitted to regulators in accordance with regulatory requirements. Results were also presented publicly, published in scientific journals and have been made available on GSK's website". Whether or not GSK's actions were negligent or even calculating, the MHRA is determined not to take its failure to prosecute lying down. That the agency was angry and frustrated at the outcome of the case was clear from the tone of a letter sent to GSK's chief executive officer (CEO), Dr Jean-Pierre Garnier, by MHRA CEO Professor Kent Woods. Noting that the agency would be pressing for changes in both EU and national law "to make it absolutely clear that pharmaceutical companies have a legal responsibility to inform the regulator of any information that changes the benefit: risk profile of their products, regardless of whether the information relates to a licensed indication", Professor Woods commented: "Such a course of action should be unnecessary in an industry which relies so heavily on public trust and aspires to high ethical standards". "I would have thought it self-evident that such information should be made available promptly to the regulator in order that action can be taken to protect public health," he added. "However, that moral responsibility now needs to be insisted upon by the unambiguous force of the law." As the MHRA observed, the legislative framework has changed since GSK disclosed its findings from the Seroxat meta-analysis in May 2003. For example, the implementation of the European Union's clinical trial Directive (2001/20/EC) made the failure to report adverse events from clinical trials a criminal offence. But neither the Directive nor the corresponding UK regulations applied to trials conducted outside the European Economic Area, the agency noted. Most of GSK's paediatric studies with Seroxat were carried out in the US. Amendments to the core EU pharmaceutical Directive, 2001/83/EC - which took effect from October 2005 - have clarified the obligation of product sponsors to report relevant safety information from clinical trials with drugs outside their normal conditions of use. When this provision was incorporated into UK law, it included an obligation to supply any such information promptly. "Therefore, the law has been strengthened to an extent, but not yet fully," the MHRA pointed out. In addition, the European Commission is consulting on proposals to reinforce the EU's system for monitoring drug safety. The MHRA has proposed that "the EU should take this opportunity to introduce a number of additional changes" as part of this process, with a view to ensuring "there remains no room for doubt in industry's and regulators' minds about the obligations of Marketing Authorisation Holders under EU and UK legislation to report information of relevance to the risk and benefit of medicines on the market". In particular, the MHRA wants to see "absolute clarity in the legislation as to the information that must be supplied to the regulator, regardless of its source (e.g., inside and outside the EU, arising as a result of any use including use outside the terms of the marketing authorisation, use in any clinical trials, as well as use as defined in the marketing authorisation"). The agency is also looking for "clear time scales within which such information must be supplied and sanctions for failing to comply with the legislation". On the UK front, the MHRA has sent out letters to the Association of the British Pharmaceutical Industry (ABPI), the BioIndustry Association, the British Generic Manufacturers Association and the Proprietary Association of Great Britain, informing these groups that parallel proposals to amend national law will shortly go out for consultation. The agency was backed up by the UK government. Minister for public health Dawn Primarolo noted that the Seroxat investigation had "revealed weaknesses in EU legislation as it stood at the time, in terms of what safety information drugs companies were legally obliged to provide to the regulators. I have therefore asked that immediate steps are taken as follows: to secure a strengthening of the law in this area through changes to the EU Directive and, in the meantime, amending the law as it applies in the UK". The ABPI said it welcomed "the introduction of any new legislation that provides further genuine protection for the patient, without simply adding unnecessary bureaucracy". All the same, the association pointed out, industry was "already required by legislation to undertake ongoing monitoring of its medicines both during development and after launch". For all its insistence that it had acted "properly and responsibly" over the Seroxat paediatric data, GSK gave a hint of contrition - or at least diplomacy. "Whilst there are substantive and rigorous requirements in place regarding disclosure of clinical trial data, it is clear that there is a need and benefit to strengthen the confidence of decision-makers and the general public that all pharmaceutical industry clinical trial data are disclosed promptly and transparently," commented Dr Alistair Benbow, medical director for GSK Europe. "GSK is committed to working with the Government, appropriate regulatory authorities and other pharmaceutical companies to take whatever action is necessary to improve legislation and policy in this area."