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[e-drug] UK Drug Regulatory Agency Accused of Cover-Up

E-DRUG: UK Drug Regulatory Agency Accused of Cover-Up
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[This might become as important as the Softenon case, which started drug
regulation in most European countries. Long story but very important for the
way how we handle drug regulation and safety.  WB]

Dear Members of E-Drug,

On Saturday, the UK Guardian published an article on the controversy
following the resignation of a member of one of the UK drug regulatory
agency's expert committees. The consumer representative resigned after a
behind-the-scenes struggle on SSRI antidepressant safety and efficacy
data from clinical trials and reports by physicians and patients.

The themes involved in the controversy echo those taken up and expanded
upon in a new book by Charles Medawar and Prof. Anita Hardon to be
released next week. The book "Medicines out of control? Antidepressants
and the conspiracy of goodwill" warns about how public health suffers
from many regulatory systems' secrecy, conflicts of interest and flawed
decisions about benefit and risk.

More information about the book will follow this coming week. Below an
article from the Alliance for Human Research Protection and the article
in the Guardian from Saturday. Reprinted here under fair use.

Best wishes,

Lisa Hayes
On behalf of Health Action International Europe
Amsterdam

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Subject: Drug Safety Regulatory Agency Accused of Cover-Up_Guardian
3-13-04


ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting openness and full disclosure
http://www.ahrp.org

When push came to shove, the British Medicines and Healthcare Products
Regulatory Agency (MHRA, equivalent to the FDA) put the interests of a drug
company ahead of the public health interest. Following a
behind-the-scenes-struggle, Mr. Richard Brook, Executive Director of
MIND, resigned from an expert workgroup of the Committee on Safety in
Medicine reviewing SSRI antidepressant safety and efficacy data from
clinical trials and reports by physicians and patients.  Brook, the panel's
only consumer advocate, charged the committee and the MHRA with a cover-up
in its efforts to conceal the severity of the drug-related problems.

The panel's review of the original Paxil / Seroxat data found that
regulators have known since 1990 that higher than recommended doses
20mg) caused severe adverse side effects leading many patients testing the
drug to drop out. Yet, neither physicians prescribing Paxil nor the public
was informed about the potential hazards posed by higher doses. Regulators
in Britain, Canada, and the US failed to protect the public health by
requiring GlaxoSmithKline to put prominent warnings on the drug's label. As
a result, ill-informed doctors prescribe Paxil / Seroxat and other
antidepressants at unsafe higher doses than recommended, leading to
preventable harm and deaths.

The evidence shows that regulators in the UK and the US have known about the
risks for patients, but have tacitly aided and abetted manufacturers who
concealed vital safety information from prescribing physicians and the
public for over a decade.

When it became apparent that the UK committee would cover-up the evidence of
dose related harmful drug effects, Brook warned the CSM and MHRA that "he
felt he had no choice but to go public [with the evidence] because of the
risks to patients." The Guardian reports that Brook "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."

The unraveling antidepressant saga both in the UK and the US provides a
window into the secret world in which drug manufacturers and
government regulators interact behind closed doors.  This secret
intermingling is undermining the safety of patients who take prescribed
drugs because physicians who prescribe the drugs are kept uninformed about
the known and potential dangers posed by these and probably other drugs. For
some patients SSRIs can trigger violent and suicidal behavior.

The Guardian reports: "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."

Cozy relationships between FDA officials and drug company officials are even
more pervasive at the FDA because the financial stakes are so much greater.
For example, the chief counsel for the FDA, Daniel Troy, filed an Amicus
Curiae brief in 2003 with a US court siding with Pfizer, the manufacturer of
the SSRI antidepressant, Zoloft. The issue was the company's failure to warn
about suicidal risks of Zoloft. Troy argued that FDA would not permit Pfizer
to put a warning on the Zoloft label about evidence suggesting a link
between the drug and increased suicide risk, because that would be
"misbranding the drug."

That Amicus Curiae brief is part of Congressional testimony submitted by the
Alliance for Human Research Protection to the Senate Health,
Education,  Labor & Pension Committee hearing on Suicide Prevention and
Youth: Saving Lives, March 2, 2004, and will be posted on the committee's
website.

The Guardian reports that failure to warn physicians about prescribing a
higher than 20mg recommended dose of Paxil / Seroxat, has resulted in about
17,000 patients [in the UK]- out of an estimated 500,000 on the drug - to be
started on higher doses than recommended last year. Experts informed AHRP
that the equivalent estimates for the US would be between 250,000 and
500,000 (out of 3 million) Americans who would have been prescribed too high
a dose. For estimates of US consumption of SSRI antidepressants, see a
letter submitted by Dr. David Healy, foremost expert on the effects of
antidepressants to the FDA at the request of Dr. Robert Temple, FDA
Director  of the Office of Drug Evaluation I at:
http://www.ahrp.org/risks/healy/FDA0204.html

On Thursday, March 11, a mildly phrased alert issued to UK physicians by the
CSM appears to be  a direct result of Mr. Brook's warning to the committee.
The CSM alert informs physicians that higher doses of Paxil / Seroxat were
no more effective than the recommended 20mg dose, but that higher doses
cause more adverse effects.  See:
http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/parox
etine_11304.htm

MIND, the largest nonprofit mental health agency in the UK, 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.

The following links lead to additional Guardian reports Saturday March 13,
2004:

Drug safety agency accused of cover-up Sarah Boseley, health editor
http://politics.guardian.co.uk/publicservices/story/0,11032,1168613,00.html

http://politics.guardian.co.uk/publicservices/story/0,11032,1168584,00.html

A secretive system Editorial

Contact: Vera Hassner Sharav
Tel: 212-595-8974
e-mail: veracare@ahrp.org

 ~~~~~~~~~~

http://politics.guardian.co.uk/publicservices/story/0,11032,1168586,00.html

The Riddle of the Drug Regulators
Critics press for review of licensing system

Sarah Boseley, health editor
Saturday March 13, 2004

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 19
85-86, 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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