8 May 1998

Dear Charles,

Thank you for your letter of 14 March.

I should make it clear at the outset that I have not taken "the greatest exception" to the numerous questions you have raised with me, and the Medicines Control Agency, so much as the innuendos you have made concerning the integrity of past and present members of the CSM. You spoke, for example, at the Kings Fund of possible conflicts of interest of Committee members and in the same breath reminded the audience of the Poggiolini affair. By inference, therefore, you appear to be suggesting that the CSM has motives other than those of the public interest when it gives its advice to the Licensing Authority. You chose your words with extreme care and you are therefore in the luxurious position (of which I am sure you are aware) of being able to question the integrity of CSM members without fear of retribution. You will now perhaps understand why I am angry at your approach, and why I would be delighted for you to make a referral to the Committee on Standards in Public Life. The fact that you have so far failed to do so speaks volumes.

The first two pages of your letter contain eleven bullet points that you describe as facts but which are mainly assertions, personal interpretations of data and judgements relating to a range of issues. You have, previously, been engaged in voluminous correspondence with various members of the staff of the Medicines Control Agency on many of these matters. They have responded to you with the greatest courtesy, despite the intemperate tone of some of your letters, and given you all the information that is possible for them to provide. I concur, completely, with the statements and conclusions in these letters concerning the question of withdrawal reactions with SSRIs. I, indeed, go further:-

1) I do not accept your opinion that the conclusions of the Montgomery & Dunbar paper are invalid because the authors discounted the possibility of withdrawal symptoms, and because they would have therefore interpreted withdrawal symptoms as relapse. In the Methods section it is stated that the principal outcome was withdrawal from the study because of the reappearance of depression (as supported by various criteria). You may be unaware that, in most cases, symptoms associated with paroxetine withdrawal are clearly distinguishable from those of the underlying illness. The study was a randomised double-blind controlled trial which provides good evidence for the efficacy of paroxetine in preventing relapse and recurrence of depression over the period of the study.

2) You persist in confusing withdrawal reactions with dependency despite the differences being pointed out to you. It is, frankly, difficult to sustain a discussion with you when you persistently appear to confuse, or misuse, scientific terminology

3) I have tried on many occasions in the past to explain the difficulties in assessing "yellow card" reports in a quantitative manner. These discussions have been and remain a dialogue of the deaf. In the case of withdrawal reactions to paroxetine you suggest that the MCA/CSM's estimate of frequency is of the order of at least 100 times lower than that found by other investigators. I assume that you are referring to the paper by Price et al in the British Journal of Clinical Pharmacology. This is only one approach to estimating frequency and, as the authors acknowledge, there is considerable scope for under-estimation because of under-reporting. You also attach great significance to the numbers of reports of withdrawal symptoms with paroxetine compared with other drugs. Such comparisons are invariably difficult to interpret and can never be taken at face value.

3) I am sure you have seen the Editorial in the British Medical Journal on "Antidepressant discontinuation reactions" by Drs Haddad and others (1998; 316:1105-5). This, by authors completely independent of the MAC/CSM, fails to support your contention.

I am glad you agree that experience of drug development and clinical trials is a valuable experience for members to bring to the CSM. Your remark, however, that "companies also play a major part in deciding who gets to the top" is bizarre. If you mean that companies decide who will get research grants and, hence, who will be promoted by their institutions then you are so wide of the mark as to lack any credibility. Without going into laborious detail the fact of the matter is that Universities tend to promote those individuals who bring in those research grants that maximise their Research Assessment Exercise ratings. This means research council and peer-reviewed charity grants; research income from pharmaceutical companies is virtually ignored.

You ask for certain information relating to the CSM be provided to you under the Open Government Code. This was discussed at the last meeting of the Committee. Members decided that I should not provide you with answers to the questions you pose. If you wish to take the matter further then I suggest you write to the MCA.

You ask whether the Committee has a "policy on what to do if it makes a serious mistake involving public health and safety". The CSM does not have any policy on such an issue. If, having given its advice, further information becomes available that casts doubt on a product's quality, efficacy or safety then the CSM may advise changes to the product literature or (occasionally) suspension or revocation of the product license. I know of no instance where the Committee has revisited an issue, without additional data or information, and revised its advice to the Licensing Authority.

Yours sincerely,

Professor M D Rawlins


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