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Ms S Wark, Post-Licensing Division
Medicines and Healthcare products Regulatory Agency
Market Towers, 1 Nine Elms Lane
London SW8 5NQ

26 April 2006


Dear Ms Wark,

Thank you for your letter of 7 April, reference FOI 06038, nee 06007 - Seroxat/Placebo suicides. There were several aspects of your letter that left me unhappy, and I would now like to request a formal review, along with some further requests for information.

2(a) In my letter of 17 February, I questioned Dr Williams’ assertion (13 February) that, "the MHRA has had no reason to question the investigation of these cases by the MAH" – those cases being the three suicides on placebo in the paroxetine trials. Dr Williams wrote that "The Expert Working Group and the CPMP considered that this question had been adequately addressed", and your letter (7 April) also deferred to the judgment of those two bodies, hinting at careful and weighty decisions, "in the context of a detailed review of data from a number of different sources". Please supply me with any minute or other documentation giving evidence that either of these bodies ever specifically considered this issue and/or made any decision not to request all available data on the three placebo suicides from GlaxoSmithKline.

Right now, my radar registers only yards of flannel but, if you have the evidence, I would be happy to recalibrate, if not apologise. Meanwhile, I’m strongly inclined to think there is no such evidence, that any such ‘decision’ was entirely by default, and that the Agency never requested those bodies to consider the issue. My question was not about the authority for inaction, but about the rationale for not investigating when the reported results were both completely anomalous and central to the issues under consideration in an 18-month investigation. The Agency’s posture seems all the more incredible when you tell me that the MHRA is now considering over one million pages of evidence on the paediatric use of paroxetine, with a view to possible prosecution – simultaneously asking me to accept that the Agency had no need to request a couple of pages of raw data on the three placebo suicides.

2 (b) I specifically asked for "date(s), relevant references, and outline conclusions" of any audit(s) "designed to establish the completeness and veracity of any company’s (or companies’) summaries of clinical trial data, in relation to the raw data on which they were based." You mentioned the current investigation of paroxetine clinical trials, and otherwise referred only to "a significant number of GCP inspections … since 1997". Please would you let me know how many GCP inspections have been carried out since 1997, indicating what proportion were conducted either [a] on a voluntary basis – i.e. effectively by invitation from the MAH; and [b] otherwise (i.e. in the course of routine law enforcement activity). Please would you also let me know – on the basis of all such investigations - if the MHRA is generally satisfied that companies’ summaries of clinical trial data can routinely be relied on to give a true and fair view of the raw data on which they are based. Please also refer me to any available documentation that might support the Agency’s view.

4(a) The response to this question is not in any sense an answer to it. It simply recites the names of other ‘competent’ authorities, seeking to maintain the pretence that the MHRA played no part in guiding, if not manipulating, their conclusions. I am requesting a review in order to get a straight answer to my original question: what was the justification for including this case as a "placebo suicide" when death occurred after the 30-day cut-off point, and when the investigator "considered his death to be unrelated to trial therapy"? This poor man had been recruited to this clinical trial (057) specifically because he had a recent episode and history of suicidal behaviour. During the trial period he made four attempts at suicide, finally succeeding at the fifth attempt, 33 days after completion of the study. My conclusions would be: [a] this man was terribly let down; [b] members of the relevant ethical committee should be searching their souls; [c] the MHRA and all those expert committees had no good reason to consider his death in any evaluation of paroxetine; and [d] his death offers no evidence whatever of the benefits of paroxetine.

5(a) In my request of 17 February, I invited Dr Williams to respond to the question: "Do you not agree that it would be very unusual to subject a patient to ECT before some drug treatment had been tried – especially when the patient was under supervision in a controlled clinical drug trial?" This referred to the man who committed suicide in study 29060/627 for post-traumatic stress disorder. The response I got from you seemed unacceptably coy: "I am not in a position to comment on what would or would not be usual care in this situation". It was open to you to seek advice from your medically qualified colleagues’, but you failed or chose not to do so. I was not inviting personal comment from you; I was requesting a response an Agency that persists in claiming that it deserves public trust. I have yet to receive a meaningful response and therefore make this more specific information request: was the MHRA aware on 7 April 2006, the date of your reply to my letter of 17 February: [a] that this patient had been withdrawn from the study on 1st March 1999; [b] that the patient was treated for acute depression with clotiapine, oxazepam and fluoxetine prior to electro-convulsive therapy on 15 March 1999; before taking his own life on 18 March?

5(b) Your response indicated that the MHRA was satisfied with the "case narrative" on patient 627.605.01012 in study 29060/627 for post-traumatic stress disorder, on the grounds that "further details in relation to a single case would not alter the findings of the Expert Group’s review". That is nowhere near the point. My letter of 17 February to Dr Williams emphatically alerted you to the deficiency of the manufacturer’s "summary data", and to the need to examine the raw data. As things stand, either the MHRA has gone to disgraceful lengths to try to deceive us, or the MHRA did not receive from the MAH all relevant information on this case. I have attached to this letter, such details as I have of the three so-called ‘placebo suicides’ involved in paroxetine clinical trials. Please indicate: [a] whether or not all of the information contained in this attachment about each of these three ‘placebo suicide’ cases was held by the MHRA before 7 April 2006; [b] whether the summaries of data held by the MHRA before that date faithfully summarised all the evidence in the records attached; [c] if not, specifically what relevant data in the enclosed attachments were not previously known to the MHRA; and [d] whether or not the MHRA will be making representations to the MAH in relation to data they failed to supply.

6. You wrote that you had no additional information on the third placebo suicide (Study 29060/785) other than that provided in my letter. Since I provided virtually no information – other than the fact that the death and cause of death appeared to be wholly unverified, and based only on a phone call from the brother of the deceased – I question Dr William’s assertion that, "The level of detail provided in these cases is similar to that which would be expected in clinical trial adverse events." Heaven help us if this is representative of the investigations on which the MHRA relies.

In the course of the Expert Working Group enquiry, the MAH was asked to provide "the narrative of the case reports for the suicides that occurred during clinical trials and an expert report discussing these cases". Please supply copies of the narrative of these three case reports, plus the complete expert report.

7. The MHRA’s decision not to disclose the patient numbers, on the grounds that this "could potentially lead to the identification of patients" seems to be self-serving nonsense. If this were so, the whole numbering system universally employed to protect patient identity would fall apart. Some narrative details might indeed confirm the identity of (in this case) a deceased patient; numbers alone could not possibly do so.

Without prejudice to this complaint and to these further requests for information, I hope this letter conveys my continuing concern that the MHRA has far to go in proving itself as a serious democratic endeavour and as any champion of integrity in science.

Yours sincerely,
Charles Medawar