|Department of Health|
|MEDICINES CONTROL AGENCY|
|Market Towers 1 Nine Elms Lane London SW8 5NQ|
|TEL: 020 7273 0400|
|FAX: 020 7273 0675||.Our Ref: OG 02/49|
|16 January 2003|
Dear Mr Medawar,
CSM ad hoc expert group on safety of SSRIs
Thank you for your further letter of 25 November 2002. I am sorry that you feel the need to make a formal complaint that you were not invited to the ad hoc expert meeting on the safety of SSRIs on 21 November. As I explained to Dr Healy and Professor Herxheimer it was a scientific meeting set up with the principal objective of exploring the data of concern to Dr Healy.
I will answer the questions in your letter in turn.
1. Spelling mistakes in website message in response to the Panorama programme.
A pre-final draft of the message on Seroxat prepared in response to the Panorama programme was mistakenly put on the MCA website. Once the error was noticed the draft was replaced with the final copy. While it is regrettable that this error was made, we have not assigned individual responsibility and no action has been taken against any individuals. Staff within the agency who deal with issues that are of media interest often work under a great deal of pressure and we have to recognise that mistakes will occasionally occur. We are satisfied that we have appropriate clearance procedures in place for all documents that are being released to the public.
2. There have been isolated reports of more serious symptoms on withdrawal...
We do not consider that this statement is misleading. I explained the reasons for this in my previous letter.
3. Is the MCA saying that reports of severe withdrawal are not serious?
As explained in my previous letter, severity relates to the intensity of a reaction, which in itself may or may not be serious. Therefore some severe reactions will be serious in a regulatory sense and some will not.
4. Does the MCA accept that paroxetine is associated with a characteristic withdrawal syndrome?
There is no regulatory requirement for MCA to denote whether the collection of symptoms commonly seen on withdrawal of paroxetine or other SSRIs constitute a characteristic withdrawal syndrome. There are some symptoms which occur more commonly on withdrawal of paroxetine and other SSRIs than others.
5. Does the MCA believe that the majority of Yellow Cards for paroxetine report something other than a withdrawal syndrome?
The majority of reporters use the term withdrawal reactions.
6. In the MCA paper, WHAT IS A SERIOUS REACTION, examples of serious reactions include withdrawal syndrome. Is there any difference between this withdrawal syndrome and the withdrawal syndrome seen with paroxetine?
This paper is a guide for reporters as to the reactions which we would consider fall within the regulatory criteria for a serious reaction that is they are potentially fatal, life threatening, disabling, incapacitating, result in or prolong hospitalisation or are otherwise medically significant and therefore would encourage reporters to report. On the ADROIT database, the terms withdrawal reactions and withdrawal syndrome are flagged as serious this means that reports which are received citing these terms are given a higher priority than non-serious reactions and are reviewed on a weekly basis. Therefore, whether we call symptoms on stopping SSRIs or other drugs a withdrawal syndrome or a withdrawal reaction, we consider that these are potentially serious reactions and should be reported, even if the symptoms reported in association with the withdrawal reaction do not in themselves fall into the category of serious.
7.Does the MCA/CSM accept that failure to recognise withdrawal reactions for what they are would be a significant factor in underreporting of withdrawal reactions to SSRIs and what if any evidence do they have of the extent of this problem?
There is variable underreporting associated with all adverse reactions and we would fully accept that there is likely to be a greater level of underreporting associated with symptoms on stopping medication due to failure to recognise these symptoms as associated with the drug. We do not at present have data that would allow us to accurately calculate the extent of underreporting of withdrawal reactions.
8. Does the MCA/CSM accept 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?
We have no way of determining this since these are matters relating to clinical management.
9. Does the MCA/CSM accept that the widely held professional belief that SSRIs do not cause dependence (unlike benzodiazepines) contributes to this problem?
We consider that it is important that health professionals are aware that SSRIs cause withdrawal reactions to allow them to advise and to manage their patients appropriately. Greater awareness of withdrawal reactions would enable prescribers to distinguish them from relapse of the condition and treat their patient accordingly.
10. Does the MCA/CSM accept that withdrawal reactions to SSRIs are commonly treated by prescribing more of the same drug, or another of the same kind of drug?
We accept that withdrawal reactions to SSRIs are treated by restarting the drug in question, or another of the same kind of drug sometimes. We have no way of estimating how frequently this occurs in general clinical practice.
11. Does the MCA/CSM accept that for any or all of the above reasons, it is improper and misleading to estimate the frequency of adverse drug effects from the levels of spontaneous reporting?
We would fully accept that spontaneous reporting cannot be used to calculate the incidence of adverse reactions.
12. Does the MCA/CSM accept that many patients are caused much distress when advised that they are not suffering from withdrawal symptoms, but that something is wrong with them?
It is not possible for us to comment on the feelings of individual patients, however we would fully accept that the increased recognition of the occurrence of withdrawal reactions associated with SSRIs is important for patients and prescribers.
13. Please indicate what proportion of the cases submitted in the letter of Vt June would be regarded as not serious but severe.
Of the 43 cases submitted with your letter of 1 June, 12 describe symptoms on withdrawal that are not flagged as serious on the ADROIT medical dictionary. In 22 of the reports, at least one symptom on withdrawal is flagged as serious on the ADROIT medical dictionary. In 9 of the reports specific symptoms are not listed and therefore a judgement cannot be made. All of the reports seem to describe reactions that are severe.
14. Please supply a list of the people who attended the meeting of 21 November.
A list of attendees is attached.
15. You ask what correspondence we supplied to the expert group.
We provided to the expert group your letters of 1 June, 2 August, 4 August, 12 October and the letter that you placed on your website on 20 July 2002.
16. Please confirm that the three items below were discussed at the meeting.
I can confirm that the following items were discussed at the meeting of 21 November:
Statement about the absence of potential to cause addiction in the Seroxat PIL
Patient reports from the Social Audit website
Dependence is to be discussed further at the next meeting of the expert group.
17. Please explain why these items were not discussed during the part of the meeting when Dr Healy and Professor Herxheimer were present.
As explained previously, Dr Healy was invited specifically to present his research on the question of suicidality to the relevant CSM experts to ensure mutual understanding of these data. Dr Healy presented his views on the question of suicidality and also referred to the issue of dependence. The meeting specifically sought the views of Dr Healy and Professor Herxheimer on communications with patients.
18. You ask whether the MCA in any way disagreed with the extract from the WHO bulletin Drug Information (1998,12,3,136-138).
It is not the remit of the MCA or CSM to endorse definitions of dependence or other clinical conditions. In our evaluation of withdrawal reactions associated with SSRIs we have previously used the internationally agreed definitions of dependence. Where it is particularly important that there is clarity about the meanings of different terms is in the communication of drug safety issues. The utility of such definitions in communication with the public and prescribers is an issue that you have raised on a number of occasions and one which the expert group considered important and to which we will be giving further consideration.
19. You ask a number of questions in relation to the reference to statements that Seroxat does not cause addiction in the Seroxat PIL.
This relates to the question above and is one of the aspects of the product information that is under review.
20. You ask whether we regard comments posted on the Social Audit website from paroxetine users as significant evidence.
We would certainly regard reports of adverse reactions from patients as evidence and as mentioned previously asked the expert group to consider these reports at the meeting of 21 November.
21. You have asked for a copy of the assessments of the issues raised in your correspondence, a copy of the agenda of the meeting and any minute relating to the 3 key issues that you have raised.
I attach a copy of the agenda for the meeting of 21 November. In relation to the papers and the minutes of the meeting, exemption 10 of the Code of Practice on access to Open Government Information applies. This information cannot be released. It remains confidential and publication would be premature whilst the issues are still under consideration. However I will arrange for the relevant documents to be sent to you once regulatory action is complete.
22. You ask whether we were aware of the existence of the paper, Terminology in reporting abuse-related adverse drug reactions, discussed at September 2002 at the 33rd meeting of theWHO Expert Committee on Drug Dependence.
At 21 November we were not aware of the existence of this draft report. We now have a copy and will certainly take this into account in our future discussions about terminology.
23. WHO data
The attendees of the meeting of 21 November were not specifically provided with the information that three SSRIs are among the top 30 drugs for which drug dependence has ever been reported to the WHO. The main focus was UK spontaneous reporting data, although some WHO data were provided. The UK contribute to the WHO database and the two data sets are fairly consistent. We at the MCA are aware that paroxetine is associated with the highest number of reports for withdrawal reactions.
24. You ask whether the MCA/CSM accepts the following propositions. I am unable at this stage to give a CSM position on these issues but have responded below:The notion that withdrawal is unrelated to dependence is inconsistent with the ICD-10 diagnostic guidelines.Based on common sense, one would consider that an uncomfortable withdrawal syndrome will increase the risk of dependence.
ICD-10 defines a dependence syndrome as follows:
A cluster of behavioural, cognitive and physiological phenomena that develop after repeated substance use that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.
Therefore we would agree that from the definition above, withdrawal reactions may be a feature of dependence, but dependence may occur without withdrawal reactions.
It would seem reasonable that the more severe the withdrawal symptoms, the more likely it will be that the patient will require a longer taper period or in some situation to restart the drug in question.
Unless studies indicate the contrary, it is highly unlikely that a serious withdrawal syndrome will not lead to drug dependence?
Without specific expertise in this area I am unable to speculate on this likelihood however the definition from ICD-10 implies that withdrawal reactions alone are no sufficient or necessary for a diagnosis of dependence.
25. You question the choice of the Chair of the meeting on 21 November 2002.
We consider Professor Mackay an appropriate choice for chair of this meeting given his knowledge, skills and experience both in clinical psychiatry, academic research and in medicines regulation. As we have stated in previous correspondence in relation to your suggestion that the study by Price et al (1996) should be withdrawn, any decision to withdraw the paper is one for the authors and not for the MCA/CSM.
I hope you find these responses helpful. If you are unhappy with our decision not to release all the information you requested, you may ask for it to be reviewed. A senior member of the Agency who has not previously been involved in your request will undertake the review. If you wish to pursue that option please write to me. After that if you are still unhappy, you may ask a Member of Parliament to make a complaint on your behalf to the Ombudsman (known officially as the Parliamentary Commissioner for Administration) who may decide to conduct his own investigation.
Yours sincerely DR J M RAINE, Director, Post-Licensing Division
CLICK HERE TO READ ON
List of attendees at the meeting of 21 November
Chairman: Professor Angus Mackay Physician Superintendant/Director of mental health Services Lomond and Argyll, Scotland.
Dr Michael J Donaghy Reader in Clinical Neurology, Oxford University and Consultant Neurologist, Radcliffe Infirmary, Oxford
Professor David Nutt Professor of Psychopharmacology, Bristol University
Professor David G Cunningham Owens Professor of Psychiatry, Edinburgh University
Dr Patricia Wilkie PhD Lay Representative
Dr David Baldwin Senior Lecturer in Psychiatry, University of Southampton.
Professor Stephen Evans (Medical statistics and Epidemiology), London School of Hygiene and Tropical Medicine
Dr Anna Higgitt Senior Policy Adviser - Mental Health Services - Department of Health
Dr June Raine Director, Post Licensing Division Medicines Control Agency
Ms Sarah Wark Risk assessment unit manager Pharmacovigilance
Dr Lesley Wise Statistician/Epidemiologist Team Leader Pharmacoepidemiology Research team Dr Cheryl Key Risk assessment unit team leader, Pharmacovigilance
Ms Lesley Curwen Scientific Assessor, Pharmacovigilance
Dr Sue Morris Senior scientific assessor, Pharmacovigilance
Dr Camilla Parikh Medical assessor Pharmacovigilance
David Daley Communications Directorate
AD HOC EXPERT MEETING ON SAFETY OF SSRIs
Meeting to be held at 2pm, Thursday 21st November 2002, CR1 19th Floor, Market Towers
1. Chairmans introduction
2. Remit of the Group
3. Declaration of interests
4. SSRIs and Suicidality (Paper provided) Dr C Key
5. Presentation by Dr David Healy
6. SSRIs and withdrawal reactions and dependence (Paper provided) Ms L Curwen
7. Review of Product information (Paper provided)