The chief executive of Mind, the mental health charity, last night
resigned from a high profile review of modern antidepressant drugs,
accusing the British medicines regulatory body of negligence. 

Richard Brook had a unique position as a lay member of the expert
working group on the class of antidepressants which includes Seroxat and
Prozac. 
 

His resignation came in protest at what he considered a cover-up by the
regulators, after months of pressure on him not to reveal the review's
findings that Seroxat has for years been prescribed by doctors in an
unsafe dose and that the regulators had the evidence in their possession
for more than 10 years. 
 

Mr Brook's resignation sheds a rare light on the workings of the
secretive drug regulation agency and its advisers, and will heighten
public concern over their relationships with the pharmaceutical
manufacturers. 
 

The expert group drew the attention of the government's advisory
Committee on Safety of Medicines to the dosage issue in October. Mr
Brook, who had been invited to represent patient interests because of
concerns that the CSM is too close to the pharmaceutical industry,
pressed for the findings on dosage to be put into the public domain. 
 

Mr Brook warned the CSM and the Medicines and Healthcare Products
Regulatory Agency, which licenses drugs on the advice of the CSM, last
week that he felt he had no choice but to go public because of the risks
to patients. He was warned in a letter last Monday from the MHRA that he
could risk prosecution under the Medicines Act 1968, which protects the
commercial confidentiality of information from drug trials. 
 

But Lord Warner, the health minister, to whom Mr Brook had expressed his
concerns, intervened, and on Thursday the CSM put out a "reminder" to
all doctors that they should prescribe Seroxat only at the recommended
dose, which is 20mg. Last year 17,000 people were put on a higher dose
by their doctors, running the risk of increased side-effects, which some
have alleged include agitation and thoughts of violence and suicide. 
 

In his letter of resignation to Kent Woods, chief executive of the MHRA,
Mr Brook said although he was pleased the information was now in the
public domain he was unhappy that the announcement had stopped short of
acknowledging that the crucial dosage data had been in the possession of
the MHRA since 1990. 
 

"The nature of the announcement fails to make public the fact that the
clinical trial data you issued was available to the regulator for over a
decade," he wrote. 
 

"Despite four major regulatory reviews during this period and
considerable consumer reporting and disquiet, the Committee on Safety of
Medicines failed either to identify or communicate these key facts. As
far as I am aware, the MHRA has not seen fit to acknowledge or address
what in my view appears to be extreme negligence." 
 

He regretted the fact that consumers would now be without a voice in the
review, but wrote: "I believe my continuation on the expert working
group without a frank and open admission of these important facts has
become impossible. Consumers are entitled to full information both about
medicines and how the regulator operates." 
 

The warning letter to him on Monday had made it clear to him that he
could not carry on, he said. Mr Brook said it was unclear why the MHRA
had not acted earlier to ensure nobody was on too high a dose. 
 

"Either they didn't understand the full implications of the available
medical data at the time or, worse, that data was fully understood and
they failed to act. Either way it amounts to extreme negligence and a
clear dereliction of the MHRA's duty to safeguard the wellbeing of the
British public." 
 

Mind is calling for an independent review of the workings of drug
regulation with patient representation at its heart. They were backed by
Charles Medawar of the consumer group Social Audit. 
 

"Richard Brook's brave resignation is enormously significant, and the
loss of the one independent consumer figurehead now calls into question
the whole credibility of the CSM's review," he said. 
 

"It is alarming that Brook was put under such pressure, and typical of
the regulators to try to gag him - and then produce a statement that is
profoundly misleading by omission. "Brook holds a public position of
considerable importance, and the Department of Health is the major
sponsor of MIND. 
 

"Brook's resignation pretty much mandates a formal parliamentary
investigation of the UK medicines control system. 
 

"The drug regulators have made a series of bad errors; it is completely
unacceptable that they should be now allowed to investigate their own
mistakes."

The riddle of the drug regulators 
http://society.guardian.co.uk/mentalhealth/story/0,8150,1168505,00.html
Critics press for review of licensing system 

Sarah Boseley, health editor
Saturday March 13, 2004
The Guardian <http://www.guardian.co.uk>  

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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