Social Audit Ltd

P O Box 111 London NW1 8XG

Telephone/Fax 44 (0)171 586 7771

Dear Keith,

As you will know from Dr Wood, I wish to complain formally about the way in which the Medicines Agency has responded to the request for information I made in my letter to Dr Price dated 23 October 1997. As you might expect, there are several strands to this complaint, since the Agency's refusal was made on several different grounds. Dr Wood's letter of 23^rd January identified these as follows:

1. The license holder, SmithKline Beecham, claimed that the information was commercially confidential

2. The company said that disclosure would benefit their competitors

3. The MCA saw no reason to doubt these assertions

4. The MCA itself decided that disclosure would risk harming the company

5. The Agency also believed that disclosure would risk prejudicing the future supply of confidential information from the Company

6. The information had been supplied to the MCA in confidence

7. There was no risk to public health or safety sufficient to override these considerations.

8. The harm or prejudice arising from disclosure outweighed the public interest in making information available.

This complaint is not primarily addressed to either point one or two, because the Company was almost bound to resist disclosure. The substantive issue here is whether the MCA should have agreed with the Company, apparently without question, and then have decided that the company's and its own interests outweighed the public interest. Having studied the Guidance on Interpretation of Exemptions 13 and 14, I believe the MCA was mistaken in deciding that the data requested should be regarded as "sensitive" information; and/or that its disclosure would significantly benefit a competitor; and/or that disclosure would be "unwarranted" in these circumstances.

I cannot accept that the data I requested is "sensitive" information within the meaning of the 1997 Guidance. Dr Price had already informed me that the incidence of withdrawal reactions observed in the paroxetine pre-marketing trials "was less than that seen with commonly used anti-depressants". I sought further information because I wanted to check that the MCA had relied on good enough evidence to make an intelligent assessment of the incidence and severity of withdrawal reactions with this drug. I very much doubt it, but would be happy to reconsider if you felt able to give me your personal assurance that the protocols, design and execution of these studies were of a good enough scientific quality to allow the Agency to reliably conclude that withdrawal reactions from paroxetine were relatively rare.

Whether or not you are satisfied that the Agency's assessment of withdrawal reactions to paroxetine was based on an analysis of trials of good enough scientific quality, I cannot imagine why these data should be regarded as "sensitive". What possible harm could be done to the reputation of either the drug or the company by revealing the basis of the MCA assessment - in particular when the Agency concluded that paroxetine was relatively benign in relation to competing products?

As I indicated to Dr Wood, these data would be likely to be positively helpful to the company. Perhaps they would provide even something of an antidote to the abundant evidence already in the public domain which indicates that withdrawal reactions to paroxetine are much more frequently seen than with other antidepressants. Why should disclosure of this information harm the company in any way, when paroxetine has already attracted more Yellow Cards relating to suspected withdrawal symptoms than any other drug in the history of the UK medicines control system - and probably more than all of the others on the ADROIT database put together?

In these circumstances, it does not seem adequate for the MCA to explain its decision simply by pointing generally in the direction of numbered exemptions to the Code. So far, the MCA has failed to specify any harm or risk that might be done by disclosure, but I invite you to do so now. In the meantime, I do not believe there are adequate grounds for believing that any significant harm would or even could result from disclosure, if only because the damage to the license holder has already been done. It has long been recognised that withdrawal reactions are especially prominent with paroxetine. Thus, Eli Lilly & Co had decided to advertise that "Prozac helps to avoid the unpleasant symptoms of Discontinuation Syndrome", long before my request for disclosure was made. In support of this claim, the company cite six papers dating from 1995 and 1996, including one paper from the MCA (Price, 1995).

In short, within the meaning of the 1997 Guidance on Interpretation, the information requested is not of the "relevant type", nor "of value to its original possessor", would not "be useful to a competitor" and does not convey information "otherwise unattainable by them". The information requested is in no sense a "trade secret"; has no "intrinsic commercial value", and there is no reason to think its disclosure "might unreasonably disadvantage" the company. Please would you specify any reasons, if you do not agree.

I recognise that the Company would have submitted data to the MCA in the expectation of confidentiality - yet it is clear that this is not an absolute guarantee. The Company's rights in this respect are defined by s. 118 of the Medicines Act, but this specifically removes any guarantee of confidentiality "where disclosure was made in the performance of … duty". The question of "duty" arises in this case not only because the MCA is committed to make as much information available as possible, but also because of strong prima facie evidence that its original assessment of risk was wildly wrong, whether or not it was based on an effective scrutiny of trials of an adequate scientific quality. The safety implications here are profound.

Subject to what I may learn through the further request for disclosure I sent to Dr Wood yesterday, I suggest that it was open to the MCA to assert its right to disclose on these grounds, and that it failed to seek to take advantage of this option when it would have been proper to do so. Instead, the MCA appears to have accepted without question the Company's assertion that disclosure involved confidential information and of value to a competitor, for reasons which are entirely unclear.

In relation to point five above, I have no difficulty accepting that the Company would have been displeased if the MCA had disclosed and, yes, this probably would have led at least to threats of a restricted supply of information in future. On the other hand, I cannot accept that this exemption was intended to provide the complete justification for non-disclosure, if a company objects to it. It is clearly essential to draw the line somewhere with a sweeping rule like this because, if you don't, you more or less invite companies to get heavy-handed. If you don't stand up to this when appropriate to do so, you end up capitulating every time.

I suggest disclosure would have proper in this case for several other reasons, which come to Dr Wood's point: "We considered there was no risks to public health or safety sufficient to override these reasons". This indicated to me either that the MCA has failed to understand the real nature of the risk outlined in my paper and/or that it has entirely prejudged the issue - notwithstanding the commitment you gave to thoroughly investigate the evidence it provides.

It is now clear that the MCA/CSM has hugely under-estimated the incidence of withdrawal reactions from SSRIs; it also be shown that the Agencies reached thoroughly misleading conclusions because the methodologies and analyses used were inappropriate and unsound. It is therefore all the more incumbent on the MCA to disclose, to set the record straight. Dr Wood did give a little ground in her letter, acknowledging that withdrawal symptoms with SSRIs "may not be as rare as suggested in our original paper", but such an admission is quite inadequate in the light of the available evidence. The fact is that the MCA/CSM are still clinging to the idea that withdrawal symptoms are rare, when they evidently are not.

I repeat my request that the MCA withdraws the 1996 paper by Price et al., referred to in previous correspondence, on the grounds that its conclusions are unsafe and that it actively promotes the risk of dependence. I invite you to compare its conclusions about the incidence of withdrawal symptoms, for example, with the following extract from the Washingtonian article to which I referred you last month. In this, the author reviewed, inter alia, the venlafaxine licensing application submitted to the FDA:

1. "It appears the reports represent genuine withdrawal reactions, but the low frequency of reporting per thousand prescriptions together with the published comparative studies [1-3, 11] suggest that, overall, symptoms due to stopping an SSRI are rare. The absolute risk of a withdrawal reaction with any of the SSRIs may be so low that differences are undetectable except through spontaneous reporting where drug exposure is high. The withdrawal symptoms observed do not appear to be severe." (Price at al., 1996)

2. "The investigators who were testing Effexor observed that 'clusters of symptoms sometimes occurred at or shortly after the discontinuation of Effexor treatment'. As a result, Wyeth-Ayerst did a survey of all the patients in the clinical trial's testing program. Overall, 35 per cent of the Effexor patients experienced withdrawal symptoms ranging from a flulike syndrome to insomnia, nausea, nervousness and loss of energy.

"In five patients, Wyeth-Ayerst reported, withdrawal symptoms were so severe and prolonged that medical treatment was required. Two patients could not be withdrawn from the drug, and treatment was resumed. One patient was hospitalised. Two others had to be treated with another antidepressant. These five cases suggest a risk of severe addiction in some patients." (Moore TJ, 1997)

Perhaps most important, the MCA's failure to appreciate that withdrawal symptoms with paroxetine are in fact commonplace also clearly implies that it has badly miscalculated the long-term effectiveness of the drug. Specifically, the MCA has approved the following data sheet claim: "Long-term treatment with Seroxat has shown that antidepressant efficacy is maintained for periods of at least one year."

However, the best evidence for that claim came from a trial which carefully selected patients who had previously done well on the study drug, and which specifically excluded those who had done well on placebo. As the trial design took no account of the possibility of withdrawal reactions, any untoward effects on discontinuation were automatically counted as signs of relapse - and therefore of the effectiveness of the active drug. One author was employed by SmithKline Beecham; the other had extensive personal interests in this and several other companies manufacturing SSRI antidepressants, and was also a member of the CSM. (Montgomery & Dunbar, 1993)

The implications of this are obviously worrying and this mistake, in itself, has important safety implications. However, as I emphasise in my paper, the nub of the safety problem is not so much to do with the sometimes very unpleasant effects of withdrawal, but with the many people who become habitual users because they cannot face withdrawal. That is what I call "dependence" and what I think the public generally understands it to mean. The risks involved might be so much the greater because so little is known about the long term unwanted effects of using SSRIs, albeit enough to give grounds for concern.

In these circumstances, I cannot possibly accept Dr Wood's assurance that there are no significant safety issues here, and that that the manufacturers' interests outweigh the public interest in disclosure.

The more I get involved with this issue, the more I am inclined to think that this complaint goes to the heart of UK medicines control policy, not to mention standards of conduct in public life (Neill Committee, 1998). I hope you will treat this complaint accordingly.

Yours sincerely,

Charles Medawar

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	List of MCA/CSM Correspondence