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The riddle of the drug regulators

Critics press for review of licensing system

Sarah Boseley, health editor
Saturday March 13, 2004
The Guardian

The resignation last night of Richard Brook, the chief executive of the mental health charity Mind, from an expert working group on antidepressants has prompted calls for a review of the system of regulating and licensing medical drugs.

Mr Brook was appointed as a lay member of the group, set up by the Committee on the Safety of Medicines last year for a thorough look at all the allegations against the antidepressant Seroxat, after years of patients' and consumer groups' concern about the side-effects of modern antidepressants. Some people say they cannot stop taking them, because withdrawal makes them feel so bad, others say the drugs have made them violent or suicidal.

On Thursday the CSM issued a warning to doctors about the appropriate dosage of Seroxat, a warning for which Mr Brook had been pressing in the light of trial data more than 14 years old which the CSM failed to consider in three successive reviews of the drug.

Mr Brook's appointment was a departure from the CSM's normal practices of drawing on a pool of scientists and drug experts who, with few exceptions, have or in the past had links with the drug companies, from shareholdings to research grants to their universities. All members have to declare their interests and either withdraw from the room or not vote when conflicts arise. Even so, there have been allegations of "institutional bias".

The suggestion is that the regulating authorities and the drug companies are too closely interrelated. Key figures not only on the CSM but also in the Medicines and Healthcare Products Regulatory Agency - the drug licensing body which it advises - have a history of consultancy, research or even employment by pharmaceutical companies. Ian Hudson, for instance, the worldwide safety director of GlaxoSmithKline (GSK) until 2001, is now director of licensing at the MHRA.

The MHRA and CSM say that they have to draw on the expertise of a relatively small pool of highly qualified individuals who inevitably have gained their experience in the industry, but critics say it would be possible to find academics who are completely independent.

One of the fiercest critics, Charles Medawar of the consumer group Social Audit, will allege in a book to be published on Tuesday, Medicines Out of Control?, that the system is dangerously secretive, riddled with conflicts of interest, and indelibly flawed by chaotic and incompetent procedures for evaluating drug benefits and risks.

"These revelations [of the Seroxat trials] provide compelling evidence of the need for transparency in drug regulation. Had the evidence from these dose-ranging studies been made publicly available the regulators' errors would have been apparent years ago," he said.

Mr Medawar believes that there may be problems with the dosage of many other drugs, not only antidepressants. Eli Lilly, he points out, conducted a study of its own SSRI (selective serotonin reuptake inhibitor) drug Prozac in both 20mg and 5mg formulations. About 53% of patients responded satisfactorily to the low dose and 64% to the higher dose. Yet the 20mg tablet was licensed for everybody. "That means 50% of people are being exposed to four times the dose they need."

Mr Medawar is one of those who are troubled by the revolving door between the drug regulators and the pharmaceutical industry. The MHRA chairman, Sir Alastair Breckenridge, resigned his position on Glaxo's scientific advisory committee to take up his previous position as chairman of the CSM, although he has usually left the room when Seroxat has been discussed.

"For many years Breckenridge had close ties with the manufacturers of Seroxat, yet he played a key role in the regulation of that drug," Mr Medawar said. While he was still on GSK's advisory board Professor Breckenridge took part in the Seroxat licensing discussions, although he did not vote.

The data at the heart of the matter showed Seroxat to be ineffective and unsafe at high doses. An estimated 17,000 patients were put on doses higher than the recommended 20mg last year, according to the Department of Health. Seroxat is made by GSK in 20mg and 30mg tablets. But higher doses are no more effective than the 20mg pill, and carry the risk of increased side-effects.

The data on the drug comes from one of the original trials carried out to establish the effect and safety of different doses before GSK applied for a licence to sell it in 1990. Patients in the trial, which was conducted in 1985-86, were started on 10, 20, 30 or 40mg doses. Many of those on the higher doses dropped out because of the side-effects.

The MHRA and CSM were given this information by the company and they licensed it for depression, with 20mg as the recommended dose.

The MHRA, it is understood, did not employ statisticians at the time of the 1990 licence approval and must therefore have relied on GSK (then SmithKline Beecham) for an explanation of the data.

David Healy, director of the North Wales department of psychological medicine of the University of Wales, who claims that there is a suicide risk for a minority of patients on SSRIs, said: "This would look like a case of the MHRA taking what the company said. It's only when they get pushed beyond a certain point that they begin to systematically check things out."

Alastair Benbow, GSK's head of European clinical psychiatry, said yesterday that GSK did not agree with the MHRA's interpretation of the early study. He said the dosage study had been carried out in a way that would not be done today and that other studies, which had started patients on 20mg and then gradually increased the dose, should have been taken into account. Gradually increasing the dose was safe and some patients would benefit from taking doses of more than 20mg a day.

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