MORE BULLSHIT FROM THE MHRA?

Dear Mr Fiddaman,

Thank you for your email of 10 July about Seroxat. As your request falls under the work of my division it has been passed to me for reply. You have asked a number of questions and I will answer them in the order in which you raised them.

1. GlaxoSmithKline’s recent letter to doctors points to a sixfold increase in risk of suicidal behaviour in adults taking paroxetine. The data in the UK Medicines and Healthcare Products Regulatory Authority’s expert working group report on suicide and antidepressants published in December 2004 does not mention this. When do you intend to amend it?

As it says in the foreword to the report, the conclusions of the report were a "snapshot in time, based on the evidence available to the group during the course of its work." The report will not, therefore, be amended.

2. Have directives been sent out to Universities to state that the information contained in the above report is wrong?

As I have said above, the report was based on information available to the Expert Working Group at the time and therefore we do not consider this information to be wrong. The key findings of the Group were communicated to health professionals in a letter from the CSM Chairman sent through the Chief Medical Officer’s Public Health Link. The CSM also issued advice to healthcare professionals and patients on the appropriate starting dose of paroxetine (Seroxat).

As you are aware in May 2006, prescribers in the UK were informed about the new analyses examining the risk of suicidal behaviour in Seroxat clinical trials in the adult population. These communications are not routinely sent to universities but this information would be have been sent to hospital doctors including those based in hospitals that have links with University departments.

3. When did the MHRA first become aware that Seroxat (Paroxetine) was 'unsafe' in the adult population?(Please supply copy of letter MHRA received from Glaxo SmithKline warning of dangers)

The MHRA does not consider Seroxat to be unsafe in the adult population. In 2004 the CSM advised that the balance of risks and benefits of all SSRIs in adults remained positive in their licensed indications but that clear advice was to be given in all SSRI product information in 3 areas: withdrawal reactions, dose changes, and suicidal behaviour.

In 2006 GlaxoSmithKline wrote to the MHRA informing us of the results of a new analysis examining the risk of suicidal behaviour in Seroxat clinical trials in the adult population. A copy of this letter has been provided and you may also wish to be aware that the analysis is available on the GlaxoSmithKline website (www.gsk.com). Personal information in the letter has been removed under Section 40 of the Freedom of Information Act.

The safety of paroxetine remains under close constant scrutiny by the MHRA and healthcare professionals and patients have been provided with information on the safe use of paroxetine as and when new data have arisen. This has included information issued in December 2005 about the safety of paroxetine during pregnancy and the information issued in May 2006 about the new analysis of the risk of suicidal behaviour in the adult population. The new data on the risk of suicidal behaviour in the adult population are under consideration by the MHRA, other European Regulatory Authorities, and the Food and Drug Administration in the United States of America and new prescribing advice will be issued as appropriate.

4. During the reviews for Seroxat, was the raw data examined?

During the course of the review by the Expert Working Group the full study reports from all paroxetine trials included in this review were carefully scrutinised but we did not go down to the level of individual patient data. It is normal scientific practice when synthesising evidence across multiple trials (for instance in meta-analysis) to use tabulated summaries of the results from each trial. Going down to the level of individual patient data ("IPD meta-analysis") is possible but extremely laborious.

Verification of trial data can be done in two ways: by audit, which goes back to the primary records and checks them as fully as possible at source, or by statistical approaches which look for inconsistencies in findings (e.g. between trial centres, across trials or between different evidence sources). We have powers to audit trials through Good Clinical Practice (GCP) inspections, as laid out in the European Clinical Trials Directive, and have an Enforcement group within the Agency to investigate suspected breaches of GCP. However, most of the trials of SSRIs pre-dated the GCP regulations. It would in any case be impossible to verify at source clinical observations such as suicidal ideation.

It is important to appreciate that there is strong statistical evidence of consistency of the main findings on SSRIs, using data which have not been collected by the pharmaceutical companies. The Report of Committee on Safety of Medicines Expert Working Group on the Safety of SSRIs, which was published on the MHRA website in December 2004, refers to data from the General Practice Research Database (GPRD). GPRD is the largest database of anonymised longitudinal data from primary care in the world. It captures comprehensive information on treatments and outcomes of a 5% sample of British general practices, from which both individual and practice identifiers are removed at source to preserve anonymity. The great strengths of GPRD for medicines research are (i) that it captures what is actually happening under normal conditions of practice, rather than in selected samples of patients recruited into clinical trials; (ii) there is sufficient information to adjust in the analysis for confounding factors which are liable to distort the true relationship between treatment and outcomes (e.g. selection bias, confounding by indication); (iii) the sheer size of the database gives high statistical power.

Three recent epidemiological analyses of GPRD examining the relationships between antidepressant treatment and adverse outcomes. The first, by Professor Hershel Jick and colleagues of Boston University, USA, was published in the Journal of the American Medical Association and the second, commissioned by MHRA, has been published in the BMJ. The third was commissioned by Glaxo Smithkline. The three used slightly different study designs and different time periods but their findings are consistent.

The association between SSRI use and suicidal behaviour/ideation (not suicide) which was seen in the pooled analysis of the placebo-controlled trials in children and adolescents was also present in the analysis of GPRD for patients £ 18 years. The concordance between totally different data sets, analysed by very different methodologies, is striking. Furthermore, the GPRD analysis for anti-depressant treated adults shows clearly that those treated with SSRIs were at no greater risk of suicidal behaviour than matched patients treated with tricyclic antidepressants (TCAs). (Both SSRI and TCA treated patients showed a higher rate of non-fatal self harm in the early weeks after the start of treatment, but this appears to reflect the course of the illness around the time of medical presentation rather than any effect attributable to the medicine prescribed. Hence the advice for close monitoring of all patients in the early phase of treatment).

It should be apparent from this that the conclusions of the Expert Working Group are robust.

5. Subsequent calls from myself and my colleagues (under the Freedom of Information Act (FOIA) has resulted in the MHRA stating that "all 'available' data was examined" - Could you please elaborate on what exactly the data was?

In 2004 the Expert Working Group considered clinical trial data, epidemiological studies, published literature, data from the General Practice Research database (GPRD) and spontaneous adverse drug reaction reports, including patient reports. The data considered by the Expert Working Group during the course of its review are clearly outlined in the Group’s report published on the MHRA website in December 2004.

If you have a query about this letter, please contact me. If you are unhappy with our decision to withhold certain information, you may ask for it to be reviewed. That review will be undertaken by a senior member of the Agency who has not previously been involved in your request. If you wish to pursue that option please write to the Communications Directorate, 10th Floor, Medicines and Healthcare products Regulatory Agency, at the above address quoting reference 06/230. After that, if you remain dissatisfied, you may appeal to the Information Commissioner at

The Information Commissioner’s Office
Wycliffe House
Water Lane
Wilmslow

Yours sincerely,
Stephen Fawbert
Freedom of Information Coordinator
Vigilance and Risk Management of Medicines Division
MHRA


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My initial thoughts to this is that it is yet another reason why the MHRA are not competent enough to scrutinise the medicines that we, the British public, take.

Answer to question 1 I put to them kind of sums the MHRA up

Here we have a publication, the UK Medicines and Healthcare Products Regulatory Authority’s expert working group report on suicide and antidepressants published in December 2004, that the MHRA will not amend despite having evidence that the data within is false. Since 2004 the MHRA have recieved evidence that Seroxat can cause suicide/aggression in the adult population - yet they will NOT amend the findings. This publication is no doubt a guidance for GP's, Healthcare workers and more worringly students training in the field of Healthcare - not to mention the public who wish to read it.

The tired out phrase of 'We examined the data that was available at that time' is nothing more than a 'cover our arse' statement.

To put it in laymans terms let's pretend that chocolate giant, Cadbury's, found out that one of their products caused severe vommiting. A statement in the national press would no doubt ensue and the said product would be removed from shelves. Any advertising campaign would surely be amended would it not? TV & Radio adverts amended along with posters etc.

So back to the MHRA and a product that they have on numerous occasions gave the all clear. Seroxat. The MHRA have evidence in their possession that Seroxat is a dangerous drug. The previous report does not suggest this - so, what do they decide to do?

Nothing!

The Chief Executive Officer of the MHRA, Prof. Kent Woods, may not be the head of a leading confectionary company. Thank goodness he is not.

Do YOU have faith in the MHRA?


Robert Fiddaman