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Dr June Raine, Director
Post-Licensing Division
Medicines Control Agency
Market Towers, 1 Nine Elms Lane
London SW8 5NQ

25 November 2002

       Dear Dr Raine,

CSM ad hoc group on safety of SSRIs

Thank you for your letter of 21 October in which you declined to invite me to the meeting on 21 November. Having watched the MCA/CSM floundering on this issue for the past five years, and causing much distress to many patients in the process, the Agency’s response did not surprise me. You were wrong to presume I had nothing to add to the information I sent, but perhaps it was expecting too much to think the MCA might wish "to ensure mutual understanding" with me of the kind you say you sought with Dr. David Healy.

Apropos of this, I was not at all amused to hear from Dr Healy that you told him that the real reason you refused both his and my request that I attend that meeting was that I was "not a scientist". Dr Herxheimer tells me you said the same to him. I am now writing to advise you that I shall be making a formal complaint about my exclusion from this meeting and matters arising. To prepare this, I need to raise a number of questions. I should be grateful for your response within the time limits specified in the relevant Code.

1. What is the MCA’s explanation for posting on its website the "important safety message" on the Panorama programme on Seroxat a text in which over 1% of the words had been incorrectly spelled (televison styages psycological syptoms aboput suidcide)?

[a] What investigations were carried out into this lapse?

[b] How many people were judged at least partly responsible?

[c] What were the ranks of those deemed specifically responsible?

[d] What action, if any, was taken against any person(s) held responsible?

[e] What steps have been taken to prevent recurrence?

I would appreciate any further information you can give by way of reassurance that the MCA’s working conditions, organisation and methods are sufficient to prevent any such mistakes arising on other important safety issues.

2. Will the MCA now withdraw the false and misleading statement, "There have been isolated reports of more serious symptoms on withdrawal," in its Response to Panorama? The seemingly patronising quibble in your letter of 13 November is yet another example of the MCA playing with words until their meaning is lost. Why can’t the Agency use words whose definition is rooted in public understanding?

[a] Is the MCA saying that reports of "severe" withdrawal aren’t "serious"?

[b] Does the MCA accept that paroxetine is associated with a characteristic "withdrawal syndrome"?

[c] Does the MCA believe that the majority of Yellow Cards for paroxetine report something other than a "withdrawal syndrome"? If not, what is the MCA’s estimate of the proportion of Cards that do, and on what is it based?

[d] In the MCA paper, WHAT IS A SERIOUS REACTION, examples of "serious reactions" include "withdrawal syndrome." It there any difference between this "withdrawal syndrome" and the "withdrawal syndrome" seen with paroxetine? If so, what is it?

The MCA/CSM has received many more Yellow Cards reporting severe withdrawal reactions to SSRIs than for any other class of drug, also many more reports of severe withdrawal reactions to paroxetine – the subject of the Panorama programme – than for any other medicinal drug. The Agency knows that only a small fraction of recognised ADRs are reported and should also be aware that significant numbers of withdrawal reactions are not recognised, but mistakenly attributed to relapse – exactly what happened with benzodiazepines. Do the MCA/CSM accept:

[e] that failure to recognise withdrawal reactions for what they are would be a significant factor in under-reporting of withdrawal reactions to SSRIs – and what if any evidence do they have of the extent of this problem?

[f] that patients are commonly advised that the problems they experience when trying to stop taking SSRIs give evidence of ‘relapse’ - when the actual cause is withdrawal reactions?

[g] that the widely-held professional belief that SSRIs do not cause dependence (unlike ‘therapeutic dependence’ seen with benzodiazepines) contributes to this problem?

[h] that withdrawal reactions to SSRIs are commonly treated by prescribing more of the same drug, or another drug of the same kind?

[i] that for any or all of the above reasons, it is improper and misleading to estimate the frequency of adverse drug effects – in this case, "isolated" – on levels of spontaneous reporting?

[j] that many patients are caused much distress when advised that they are not suffering from withdrawal symptoms, but that something is wrong with them?

Please would you also indicate – with examples if you wish – your rough estimate of the proportion of cases (submitted with my letter to Dr Jones of 1st June) that should be regarded as not ‘serious’, but only ‘severe’

3. Please supply a list of the people who attended the meeting on 21 November, indicating their affiliation to the MCA or CSM. In your letter of 13 September, you wrote: "we will ensure that all your correspondence is provided to experts at this meeting." Please will you confirm that our full correspondence was [a] provided to all those attending the meeting on behalf of the MCA/CSM; and [b] that in particular the three items below were discussed at this meeting. Please also explain, [c] why these issues were not discussed during that part of meeting when Drs Healy and Herxheimer were present, given their eminence and expertise on, inter alia, SSRI dependence and patient communication issues, respectively?

4. As promised in your letter of 3 July, please will you now answer questions 4, 7 and 8 in my letter to Dr Jones of 1st June. These were as follows:

[a] Please let me know if the MCA in any way disagrees (and if so why?) with the following assessment of published in the WHO bulletin, Drug Information (1998, 12, 3, 136-138): "There is obviously some confusion about the concept of dependence ... The simplest definition of drug dependence given by WHO is 'a need for repeated doses of the drug to feel good or to avoid feeling bad' (WHO, Lexicon of alcohol and drug terms, 1994). When the patient needs to take repeated doses of the drug to avoid bad feelings caused by withdrawal reactions, the person is dependent on the drug. Those who have difficulty coming off the drug even with the help of tapered discontinuation should be regarded as dependent, unless a relapse into depression is the reason for their inability to stop the antidepressant medication. In general, all unpleasant withdrawal reactions have a certain potential to induce dependence and this risk may vary from person to person. Dependence will not occur if the withdrawal symptoms are so mild that all patients can easily tolerate them. With increasing severity, the likelihood of withdrawal reactions leading to dependence also increases. Although reporting rates of SSRI withdrawal are low in comparison with prescribed doses, it is prudent to recommend the monitoring of patient withdrawal symptoms even when SSRIs are prescribed at modest doses."

[b] Is it not the case that the strong and assured denial of any addiction problem in the current Patient Information Leaflet for Seroxat are [i] at best, meaningless since the word ‘addiction’ means entirely different things to the writer and reader; [ii] otherwise stunningly unhelpful and obviously misleading to users; [iii] likely to compound an already serious situation which causes many users much distress; and [iv] indicative of a drug regulatory system whose views on this matter are pretty much indistinguishable from those of the companies they regulate?

[c] Please will you let me know if you regard comments posted on the Social Audit website from paroxetine users as significant and admissible ‘evidence’ within the meaning of that word suggested by the EMEA recommendation on SSRI withdrawal that, "any evidence, which will emerge or will be produced should continue to be evaluated"? If so, how do you evaluate them? If not, please explain. (As your reply will be posted on our website and read by many users, it would be helpful if you were to explain why you would regard them as less significant than the lack of "scientific" evidence on which your approved warnings rely.)

5. Please provide a copy of any assessment of the issues I raised in our correspondence since June that was provided by the MCA to (all or some) those attending the meeting on 21 November. I appreciate you may want to ‘redact’ them; I hope you will feel able not to leave them gutted for meaning. Please will you also provide, on the same basis, a copy of both the agenda of that meeting and any minute relating to any discussion of the three key issues – items 4[a], 4[b] and 4[c] above

6. At 21 November, was the MCA aware of the existence of the paper, Terminology in reporting abuse-related adverse drug reactions, discussed in September 2002 at the 33rd meeting of the WHO Expert Committee on Drug Dependence? If so, were any of the issues raised by ECDD communicated to those attending the meeting on 21 November?

7. At 21 November, were the MCA/CSM meeting participants aware [a] that three SSRIs are among the top 30 drugs for which "drug dependence" has ever been reported to WHO’s Monitoring Centre at Uppsala? Were the MCA/CSM also aware, [b] that the UMC database has recorded more "withdrawal syndrome" reports for paroxetine than for any other drug in the world? Does the MCA/CSM accept the following propositions and if not, why not:

[c] The notion that withdrawal is unrelated to dependence in inconsistent with the ICD-10 diagnostic guidelines

[d] Based on common sense, one would consider that uncomfortable withdrawal syndrome will increase the risk of dependence

[e] Unless studies indicate the contrary, it is highly unlikely that serious withdrawal syndrome will not lead to drug dependence?

8. Was it appropriate that the meeting on 21 November should be chaired by one of the co-authors of the 1996 paper – which the MCA/CSM has repeatedly refused to withdraw – that concluded that "overall, symptoms due to stopping an SSRI are rare" and that reported withdrawal reactions "do not appear to be severe" (sic); and that "there was no evidence of habituation" and that withdrawal symptoms are "relatively mild and do not have features of a physical drug dependency syndrome"? Has Dr Mackay subsequently published any statement by way of modifying these views?

9. I find it impossible to reconcile the reason you gave to Drs Healy and Herxheimer for excluding me from the 21 November meeting ("not a scientist") with the reason you gave me ("We consider the data that you have provided speaks for itself and you have made your position on these issues very clear"). Please explain. For the record, I consider I have been grossly frustrated by the MCA/CSM over the past five years – endlessly encouraged not to make my position clear – and above all on this occasion. If the data I have provided over the years - and might have provided at that meeting - had sunk in, there would be nothing like the abundant evidence there now is of the MCA/CSM’s incompetence and insensitivity on this issue.

10. I may not have formal qualifications as a scientist but at least I behave like one. Fifteen years ago, a major drug company also sought to shut me out of the action – in my view, with considerably more justification than the MCA/CSM did on this occasion. The company lost its case in the Court of Appeal and I shall be happy to rely on their Lordship’s unanimous finding in support of my forthcoming complaint, that this exclusion had little or nothing to do with the public interest. I enclose a short summary of the relevant law report (Independent, 23 January 1987):

"At an early stage two years ago, it appeared to the plaintiffs’ solicitors that the problem of assembling and organising the documentation and co-ordinating the expert advice and evidence would be uniquely difficult, because the subject-matter was highly technical, involving medical and scientific specialities of many different kinds and because the extent of the documentation would demand computerisation if particular documents were ever to be available as and when required. His Lordship said that it was thought the documents would number about 1.2 million.

"In these circumstances the plaintiffs’ solicitors considered that they needed the assistance of someone capable of (a) acting as a co-ordinator and interpreter in their dealings with the medical experts, (b) undertaking research to identify relevant experts and to uncover supporting evidence in scientific publications, (c) analyse a mass of evidence given in similar proceedings in the United States and (d) computerise all this material, together with the material which would become available on discovery. They found such a man …

"In considering the risk to the defendants, His Lordship said that the defendants’ fears that there would be a breach of confidence because Mr Medawar was an "investigative journalist," were unfounded. His Lordship doubted whether Mr Medawar was to be regarded as a journalist in any ordinary way. He was a writer on medical and scientific subjects with a specialist interest in the pharmaceutical industry. He might be an unwelcome critic, but there was no evidence that he was a fanatic or that he would breach the duty of confidentiality ..." (The Independent, 23 January 1987)

I would not expect you to comment on this, though you should know that I have received no payment of any kind from solicitors involved in SSRI litigation, and have made a point of avoiding such involvement. You might also want to ponder that I attended relevant parts of the last two meetings of the ECDD at the invitation of WHO. However, I would want to consider the MCA/CSM response on the above questions before framing the complaint I wish to pursue. As it relates to the MCA’s alleged failure to even begin to come to grips with serious (sic) drug safety problems that I first warned of in 1994, there is some urgency in this and I would appreciate a prompt response.

I expect you will passing a copy of this letter to Mr Alder, though I’m afraid he’s not in my good books either. I hold him responsible for excluding me also from the MCA’s recent consultation on ‘disease awareness’ campaigns – pretty cool in view of our long correspondence on the subject throughout 2000. I was, incidentally, recently reminded of his skills at a public meeting – at which I suggested that the main obstacle to consumer understanding of drug benefits and risks was not lack of commercially-sponsored drug and disease information, but the mad levels of secrecy in the drug registration/regulation process that so closely unite the industry and the MCA/CSM. You may be interested to know that a retired senior DoH official took up this point: the gist of what she said was that the secrecy was indeed pretty mad, but that this was down to the MCA, rather than the DoH. She exemplified her frustrations saying that, if you call the MCA and ask if today is Tuesday, they hum and hah and say they will let you know. Only if you call them on Friday, will the MCA reluctantly confirm, yes, it might well have been Tuesday, three days ago.

I look forward to hearing from you in the near future – in particular your response to question 4 above, which I raised six months ago.

Yours sincerely,
Charles Medawar

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List of correspondence with MCA/CSM