In March 2008, a four-year investigation into whether Glaxosmithkline had withheld negative information about the effects of Seroxat on under-18s ended with a decision that there was insufficient evidence to mount a successful prosecution. Special Children reports

Tim Whattler was just 17 when he hanged himself in February 2006. It wasn’t his first attempt. Diagnosed with Asperger’s syndrome and ADHD he had spent much of his short life in a variety of psychiatric units or being cared for by his parents at home. Their story, which appeared in the Telegraph last July, is an unsettling one. Typically, as part of Tim’s treatment he had been prescribed anti-depressants. These included Seroxat (a brand name for paroxetine), which he had been prescribed in his teens. There was no suggestion at the time of his death that Seroxat was to blame, but one wonders whether his parents would have ever have agreed to him taking it if they knew then what we know now.

Safety under scrutiny
In March of this year the outcome of a four-year investigation by the Medicines and Healthcare products Regulatory Agency (MHRA) into Glaxosmithkline and its antidepressant drug Seroxat came to a conclusion. The investigation focused on whether GSK had failed to inform the MHRA of information it had on the safety of Seroxat in under-18s in a timely manner. The investigation was undertaken with a view to a potential criminal prosecution for breach of drug safety legislation. It was the largest investigation of its kind in the UK, and included the scrutiny of over one million pages of evidence.

The decision taken by government prosecutors, based on the investigation findings and legal advice, was that there was no realistic prospect of a conviction, and that the case should therefore not proceed to criminal prosecution. The reason given was that the legislation in force at the time 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 (in this case, use in children when it was licensed only for adults).

Trialling Seroxat for children

Seroxat is part of a group of medicines known as selective serotonin re-uptake inhibitors (SSRIs), which have been used in the treatment of depressive illness and anxiety disorders since the late 1980s. Their use had been authorised in the late 1980s and early 1990s on the basis of data showing a positive balance of benefits and risks in the adult population. No antidepressants were specifically authorised at that time for the treatment of depression in children and adolescents, because until the mid-1990s clinical trials to investigate the safety and effectiveness of medicines in children were not encouraged. As a result Seroxat’s packaging at the time stated: ‘The use of Seroxat in children is not recommended as safety and efficacy have not been established in this population.’ What we now know, however, is that between April 1994 and September 2002 SmithKline Beecham plc and subsequently GSK conducted a programme of nine clinical trials into the paediatric use of Seroxat. The first two of these trials, completed towards the end of 1998, failed to show that Seroxat was effective but the company made no change to the statement on the packaging. During 1999, 32,000 Seroxat prescriptions were issued to children in the UK. A further seven trials were conducted, the last of which concluded on 16 September 2002. None of these trials demonstrated efficacy for Seroxat in treating a major depressive disorder in children.

Making headlines
Throughout this period concerns were expressed about the safety of SSRIs. This intensified in October 2002 when Panorama screened ‘Secrets of Seroxat’. Sixty-five thousand people called the BBC helpline and 1,300 people emailed the programme. In response to the controversy, the MHRA convened an ad hoc meeting of relevant experts to consider the latest data relating to SSRIs in general and Seroxat in particular. In preparation for the meeting it held a meeting with GSK at which it asked about the status of clinical trials in children. The company provided an overview and said it was planning to submit an application for paediatric indications for Seroxat. GSK raised no concerns about lack of efficacy or adverse reactions in the clinical trials in the paediatric population at that meeting.

The ad hoc group met in late November and made recommendations to the Committee on Safety of Medicines (CSM). These concerned the risks and benefits in adults ‘as there had not been a strong signal of a safety issue in children’. However, in February 2003 the CSM decided to establish an expert working group to further investigate the safety of SSRIs. Its first meeting was scheduled for late May but before it met a second Panorama programme—‘Emails from the Edge’, based on the response to its first programme—was broadcast. In the same month, 94 MPs signed an early day motion (EDM 238) tabled by Parmjit Dhanda MP calling on the Department of Health to look into the labelling and availability of the drug.

The issue comes to light
Two days before the expert working group meeting, the MHRA held a second meeting with GSK to ensure, among other things, that all of the data that GSK held that was relevant to safety of Seroxat had been supplied. It was at this meeting that GSK handed out copies of a briefing document purporting to support its application to extend indications for Seroxat to include use in children. While doing so, GSK drew the Agency’s attention to a safety issue which it had identified in its paediatric clinical trials: an increased rate of events relating to suicidal behaviour among paediatric patients with major depressive disorder treated with Seroxat. As the subsequent MHRA report states: ‘The significance of the data provided in the GSK briefing document was that they represented robust evidence from controlled studies of a causal association between an SSRI and suicidal behaviour.’

Change of approach

At the time, there were an estimated 7–8,000 under-18s being treated with Seroxat in the UK. Once informed of this data the CSM ‘advised that there should be prompt communication to UK health professionals’. A letter went out in June advising that Seroxat should not be used in the treatment of depressive illness in under-18s. Because of concerns about the way in which the risks had come to light, the matter was then referred to the MHRA’s enforcement group, triggering the subsequent four-year investigation. Following its failure to secure a prosecution of GSK the MHRA has proposed the EU system for monitoring the safety of medicines should be strengthened. As its report states:

‘The aim will be to ensure that as a result of this exercise 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.’

Health minister Dawn Primarolo has said that new legislation will be in place by the end of the year.

Response from Mind

Paul Farmer, chief executive of Mind, said: ‘Mind welcomes news that the government is to increase drug companies’ responsibility to pass on clinical trials information. We look forward to discussions with ministers to ensure that patients’ interests are best served. We hope that the legislation will pass quickly through parliament; this is far too important to be delayed any longer.

‘There can be no excuses from the pharmaceutical industry. The public must be able to have trust and confidence in the medicines they are taking. We need to be sure that the tragedies associated with Seroxat can never happen again. The best way to achieve this is for drug companies to publish all clinical trials data, making it available for scrutiny and review, and to inform prescribing decisions.’