SSRIs

Introduction

Seroxat belongs to a group of drugs called SSRIs (Selective serotonin reuptake inhibitors) and was licensed by the MHRA as an anti-depressant in 1990. Ever since, some patients have complained that the drug, which is manufactured by GlaxoSmithKline (GSK), elicits suicidal thoughts. This, along with the regulator’s suspicion that users suffer the risk of dependence followed by severe withdrawal symptoms, led to an inquiry in May 2003. The MHRA set up an Expert Working Group (EWG) for one of its committees, the CSM, to examine the drug. One of the lay members of the group left soon after the investigation began. The other, Richard Brook from the mental health charity MIND, resigned in protest halfway through the review, claiming there was an influence of the drug industry on regulation. ‘We have got to be very careful because the pharmaceutical companies will sue us if we get this wrong; they will take us to court and take us through legal processes.’ Brook later told BBC’s Panorama: ‘I have little confidence that the drugs they’re licensing day by day are being licensed in a way I would feel appropriate and what’s even more concerning I have very little confidence in drugs that have been licensed in the past.’

In 2004, the CSM released its report after an eighteen month enquiry. The 235-page manuscript revealed that Seroxat was ‘ineffective and unsafe at high doses.’ Data from trials carried out by GSK in the eighties, even before Seroxat was licensed, showed that patients on high doses had to drop out of the trials because of side-effects. Despite receiving this information, the MHRA and CSM went on to licence the drug with 20 mg as the recommended dose. The regulator claimed it did not work with statisticians at the time and would have relied on GSK for an explanation of the data. Steve Spain of the pharmaceutical and chemical giant Ciba-Geigy assures us that ‘we [they] are the data experts. We can handle the science,’ but based on the EWG’s findings on Seroxat, it is unreasonable to expect the public to trust the data that companies interpret and present to the regulators. It is also unreasonable to expect us to trust our regulators, when they are simply gathering rather than regulating the information handed to them.

The Health Select Committee (HSC) took the Seroxat case into account in 2005, when it reported on the influence of the UK pharmaceutical industry. It highlighted several problems with the licensing process of drugs in general, and considered:

• The significance of intensive drug promotion and PR management in shaping perceptions of drug benefit and risk.
• The pervasiveness of conflicts of interest of all kinds, and their significance as factors that affect the quality of drug prescribing.
• The need for greater transparency of data and clarity in regulatory warnings and communications.

While the HSC was presenting its findings, the MHRA was carrying out an investigation into the withholding of information by the manufacturers of Seroxat. In 2008, the four-year inquiry by the regulator revealed that a pharmaceutical giant had put its profits before the public’s right to know about the risks of one of its controversial anti-depressants.

Three years after legislation was included in Labour’s manifesto compelling the drug industry to publish its results of clinical trials, the public and indeed the government finally discovered that GSK delayed informing the regulatory authorities that Seroxat increased the likelihood of suicide among teenagers. Three years after one of the government’s own committees recommended that the clinical trials register be maintained by an independent body and the results of all clinical trials data containing full trials information be put on the register at launch as a condition of the marketing licence,we finally found out that GSK failed to notify the MHRA about controversial clinical trial results.

GSK had been aware since 1998 that there was a higher risk of suicidal behaviour among under-eighteens using Seroxat rather than a placebo and that the controversial drug was ineffective in dealing with depressive illness in children. GSK not only failed to inform its regulator of the findings, but it sent out an internal document informing its employees to ‘effectively manage the dissemination of these data in order to minimise any potential negative effect.’ For ten years the company has financially benefited from selling a drug which may have killed hundreds if not thousands of its young patients. ‘Nine clinical trials by GSK, conducted between 1994 and 2002, found the drug was not effective treating depression in children. In trials, 3.4 per cent of children on the drug experienced mood changes, tried to harm themselves or thought of committing suicide, compared with 1.2 percent on placebo pills.’

GSK did not pass this information on to its regulator when planning to apply for approval to use the drug to treat children. The manufacturer broke the law and should have been promptly punished. The extent of punishment was put forward to a member of an MHRA committee. When asked if there are enough sanctions in place to stop distortions and the holding back of information by the regulator and industry officials, he replied: ‘I think so. If the companies are withholding information, this would be seen as a criminal act and these actions will be viewed through criminal law. In cases in the USA, chief executives were sent to prison. They may have been withholding and falsifying information. These were criminal acts which were putting patients’ lives at risk.'

However, if this is the case in America, it does not seem to be true in the United Kingdom. GSK will not face criminal prosecutions, because the legislation in the area is insufficiently clear on whether and when drugs companies should inform regulators. The government maintains that it cannot compel the industry to publish trial data. A spokesperson for the Department of Health said: ‘The government has consistently supported open access to information about research when the findings could affect decisions about treatment or health outcomes. We planned to support the principle of mandatory registration of clinical trials in the UK, but legal advice stated this would be illegal under EU law.’ In the UK, it is compulsory for manufacturers to report adverse reactions in clinical trials, but only if trials are carried out on home soil. ‘Only one of the nine GSK trials of Seroxat in children was conducted in the UK and breach of this obligation was not a criminal effect.’ Billions of pounds and several years after extensive and expensive enquiries into the controversial drug, GSK walks away innocently. This should never have been the case.

Seroxat: Why GSK and the MHRA should be held accountable

*Delaying the inevitable

‘Manufacturers have become addicted to a system fraught with delay, because delay has served them so well. With large budgets and long tenures, corporate executives can wait out and wear down regulatory agencies, where rapid turnover at the top assures that no high-ranking decision maker stays on a single issue for too long.’ This practice of delaying the exposure of the truth is evident in the Seroxat case. Alasdair Brekenridge, the head of the MHRA, illustrated this practice perfectly when he was questioned in the House of Commons in January 2005 after the EWG’s report was made public. He quoted from the regulator’s information sheet on Seroxat, which was published when the drug was first licensed in 1990: ‘As with many psychoactive medicines, it may be advisable to discontinue therapy gradually as abrupt discontinuation may lead to symptoms, such as dizziness, sensory disturbances, sleep disturbances, agitation or anxiety, nausea, sweating and confusion.' The issue of withdrawal and suicidal tendencies in users was addressed again in 1993 in the regulator’s journal Current Problems in Pharmacovigilance, before a further article was published on the matter in 2000. The EWG investigated the matter again in 2003. . It was raised in the HSC’s report The Influence of the Pharmaceutical industry in 2005 and in a subsequent investigation which was disclosed in 2008. These issues have been inspected and re-inspected for eighteen years and there are still unanswered questions.

*Vested interests

‘Most common...are misinterpretations or distortions of scientific work – essentially, the spinning of science. The fragrant twisting of research findings to humour a particularly political view violates the integrity of science by treating its conclusions as mere political fodder, rather than useful information to be considered in its full context.’ Dr Richard Brook of MIND resigned from the EWG, citing reasons which are also reflected in Chris Mooney’s book The Republican War of Science. The committee that formed the working group went against its normal practice to appoint him in the first place, as its standard routine is to ‘...draw[ing] on a pool of scientists and drug experts who, with few exceptions, have or in the past had links with drug companies, from shareholdings to research grants to their universities.’

The question of whether people with vested interests in pharmaceutical companies should serve on these committees was put to a member of the MHRA, who replied: ‘The short is answer is that there are virtually no experts who don’t have some interests with drug companies. We work in pharmacy. There are studentships – post-graduates who may get from five to one hundred thousand pounds from companies – not necessarily to work on a product specifically. Many members of the MHRA do consultancies for companies – that’s where they make their money. But they are obliged to declare their interests.'

His argument suggests that people who work both for the industry and the regulator are impartial. However, ‘science is a social process, thus, despite the shared norms about objectivity and truth, a population of scientists can be influenced by the values of private funders, who can especially influence interpretations that are not cut and dry. Where there is a wriggle room in science, it will tend to shift toward the sponsor’s interests.’ Davidson also insinuates that the declaration of interests by these individuals is enough to ensure transparency in the licensing process of drugs. However, ‘disclosure of interests does not satisfy the principles unless efforts are made to prohibit certain relationships. Faculty members who are principles or officers in a company or who have substantial equity interest in a company should be prohibited from engaging in research sponsored by that company. Nothing less will ensure that a firewall exists between a principle stakeholder of the knowledge and the investigator.’

This absence of this firewall in the case of Seroxat allowed a former, prominent GSK employee to sit on a committee which made decisions on the antidepressant. The MHRA chairman, Sir Alastair Breckenridge, left GSK’s scientific advisory committee to take a position he used to assume as chairman of the CSM. Apparently, he left the room whenever Seroxat was being discussed and did not vote during licensing meetings, but as CSM chairman, he still had a key role in the regulation of that drug. Another example is that of Ian Hudson, the worldwide safety director of GSK until 2001, who is now director of licensing at the MHRA. The disclosure of their interests ‘simply provides a rationalisation for continuing to create more serious conflicts.’

*The small print

One of the shortfalls of the EWG’s investigation centres around the Summary of Product Characteristics (SPC). This crucial two-page document ‘is the small print in the implied contract between drug manufacturers and the regulator…It formally defines what a drug should be used for, spells out the approved drug dosages and identifies known and suspected hazards.’ It serves as a set of rules for manufacturers, ‘is part of the product licence and legally determines what drugs should be used for, and how manufacturers may and may not promote them.’

The fact that pharmaceutical companies usually write their own SPCs is a concern in itself, but it is remarkable that the GSK was asked to supply and evaluate the main information that notified the EWG review. Furthermore, the EWG mainly ignored the raw data and relied on the clinical summaries the companies had arranged. Here was the perfect opportunity for the group to scrutinize and question various inconsistencies and grave oversights in the licensing process of the antidepressant. Instead it trusted the information supplied to it by the companies and ‘advice’ presented to it from the CSM, which essentially undermined its existence as a review group. ‘The immediate point is that the CSM appears to be either impotent or oblivious to the limitations of the regulatory process, including the seamy side of the relationship between companies and regulators.’ Alternatively, it may be just be incompetent.

When interviewed, a member of the MHRA explained that the regulator gets both raw data and summaries when licensing drugs, but they usually consider the latter. ‘About twenty years ago, they [members of the MHRA] said that the raw data and paper information for one application stood as high as the Eifel Tower. That was the detailed information. But equally, there are lots of summaries of the information and so we have licensing assessors sifting through the information. They look through the summaries to begin with. They may or may not look at the raw data – they may be satisfied with the summaries.' So presumably, even if GSK had supplied every clinical trial including those which did not give positive results (which it failed to do), chances are the CSM may not have even noticed at the time.

With regards to the use of Seroxat in adults, the EWG seemed to assume efficacy predominantly on the grounds that not treating depression may be more hazardous than doing so. The review group did not directly assess antidepressant efficacy in adults, and with the exception of minor changes to the small print warnings in the drug’s SPC, ‘manufacturers will be able to promote SSRIs exactly as they do now – notably with ‘disease awareness campaigns, orchestrated by PR agencies who target the ‘authoritative third parties’ who communicate with you and me.’

Doctors across the UK continue to prescribe Seroxat and other antidepressants as they were before the review, but drug companies have covered themselves should a legal battle ensue in the future. Buried in the new SPC, is an exclusion clause which states: ‘Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs.’ Also included in the small print: ‘Furthermore, there is evidence that in a small group of people, antidepressants may increase the risk of suicidal thoughts and self-harm.’ The EWG also stated that if cannot rule out the possibility that the antidepressant either benefits or harms patients, and it admits that it has a limited understanding of the experts and authorities and the data they supply. It seems that the report did little to assess the safety of SSRIs, but rather highlighted the inadequacy of the present system of drug control.

*Peer review

‘Without a doubt, peer review – the rigorous vetting of unpublished research by independent, qualified experts – represents a cornerstone of modern science. Academics’ reputation hinge of the ability to get their work through peer review an into leading journals; university presses employ peer review to decide which books to publish; and federal agencies like the National Institutes of Health use peer review to weigh the merits of applications for federal research grants.’ According to Charles Medawar of the consumer group Social Audit, the EWG report was never intended for peer review as it is incomplete; its authorship is uncertain; key source data are unavailable; and bias is unacknowledged.

Independent experts have since carried out research into the selective reporting of Seroxat drug trials in adolescents. Their work, which was published in the International Journal of Risk and Safety in Medicine in 2008, was rejected by the British Medical Journal on sole grounds that legal peer review would be too expensive. As a result, the public at large remains unaware of the damaging report entitled Clinical Trials and Drug Promotion: Selective Reporting of Study 329, which analysed documents obtained during litigation. It found that there was no significant efficacy difference between Seroxat and placebo on the two primary outcomes or six secondary outcomes in the original protocol; and it established that the drug was negative for efficacy and positive for harm. Claims that the drug was ‘generally well tolerated and effective’ arose from selective reporting of the 15 per cent of outcomes that were positive and selective under reporting of the other efficacy and serious adverse effect findings.

*Incompetence vs Negligence

What is particularly prevalent in the case of Seroxat is that the Director of the Post-Licensing Division at the MHRA, Dr June Raine, whose responsibilities include all issues that relate to medicines once they are authorised for use on the market, still assumes this position despite doing nothing to get the antidepressant withdrawn. She was made aware of the possible dangers of the drug in 2000 by Professor David Healy, the Director of the North Wales Department of Psychological Medicine at the University of Wales College of Medicine. Healy got in touch again in 2001 when he served as an expert witness in the Schell/ Tobin case. Don Schell was a passive family man who had been prescribed antidepressants. Whist on them, he shot dead his wife Rita, his daughter Deb and baby Alyssa before turning the gun on himself. Father and husband to the deceased Tim Tobin and other family members sued GSK and won a historic victory, with the jury awarding them the equivalent of 4.7 million pounds in June 2001. The Wyoming court in America ruled that Seroxat had contributed to the wrongful and violent deaths of Don and Rita Schell and Deborah and Alyssa Tobin and that SmithKline Beecham (GSK) had been responsible for failures to test and warn.

Healy sent a letter to Raine in 2001, warning the regulator that GSK had been found ‘...guilty on several accounts including the count that Paroxetine (Seroxat) can cause suicidality...’ (appendix 8). According to Healy: ‘Volunteers who had participated in the programme went on to suicidal acts. The relationship between their intake of paroxetine and later suicidal acts is a matter about which neither you nor SmithKline Beecham should be sanguine. These studies were for the most part done on company employees. None of the studies bar the missing ones were done by investigators with a background in psychiatry. The investigators were general physicians with a primary interest in gastrointestinal problems who could not have been expected to detect mental problems of this sort that have concerned me [him] and I [he] would have thought should concern you.'

Healy passed this information on to the correct MHRA official, but Raine did nothing about this at the time. And even when it was revealed that these claims were in fact true and GSK had tried to hide them from the public, Raine held on to her position.

Interestingly, Dr Hudson who worked for SmithKline Beecham and GSK when it changed name, was a witness for the manufacturer during the Shell/Tobin case. The same Dr Hudson is now employed by the MHRA as the CHMP (Committee for Human Medicinal Products) delegate for the UK.: a perfect example of the revolving door between the industry and its regulators. Dr Hudson had broad responsibilities across GSK’s portfolio when employed by the company, but had particular involvement with Seroxat and Avandia.The latter is a controversial diabetes drug which, according to documents obtained through the Freedom of Information Act, could cause patients to die of heart attacks.