Thank you for your letter of 21 February. I am pleased to answer the questions you set in that letter.

Question 1

Please will you send the Committee copies of all papers relating to the EWG report tabled at the meeting of the CSM held on 25 November and full minutes relating to this agenda item.

  I am enclosing the papers which relate to the EWG (Annex A) that were tabled at the meeting of 25 November and the minutes of that meeting. Other papers were discussed under this agenda item but were not tabled. We can provide these if required.

  All data considered by the EWG was not included in the final report . . . is the MHRA intending to publish or make publicly available all the evidence on which the EWG based its conclusions?

  The report of the Expert Working Group contains the evidence which formed the basis for the conclusions of the Group. In the 18 month period of the review the Expert Working Group considered a large number of analyses and assessments of data from different sources. It was not possible to include every piece of data in the final report, which was designed to be a readable and accessible document for both health professionals and patients. Therefore the data provided in the report was that on which the key decisions were based. The MHRA will, subject to any relevant exemptions in the Freedom of Information Act, make available on request the full data and assessments considered by the EWG.

  On the subject of efficacy, the EWG's remit did not extend to re-evaluation of the efficacy of these products, although the risks were considered in the general context of the benefits. The EWG specifically looked at the balance of risks and benefits with increasing dose of SSRIs and the efficacy and safety data reviewed are included in the final report. One patient group where the lack of evidence for efficacy had a fundamental impact on the balance of risks and benefits of the products was in paediatric use. Therefore the efficacy data for children is included in the final report.

Question 2

The Agency communications strategy

  As requested, I am enclosing a copy of the MHRA Communications Review conducted by Stonehenge, the public relations firm appointed after a procurement exercise launched in late 2003.[118] The Report, entitled "A Case for Change" was presented to the Agency in April 2004. The Report also contains the Patient View Report at Annex C. I am also enclosing as requested the extracts from the minutes of the Agency and Executive Boards where this issue was discussed (Annex B). Should the Report be published with the evidence of the Committee, I would be grateful for the time to ensure that anyone named individually in the Report is happy for their name to appear. I have also removed Appendix E as this is a comparative study of the press functions of other Agencies not within the remit of this Inquiry.

  Stonehenge's report was comprehensive and extremely detailed. It provided the basis for the development of short and long term plans for our communications policy. Given the detail the Report contained, and the relatively low base from which the Agency started its work, much progress has been made.

  Recruitment of a Director of Communications started almost immediately. However, as with any senior appointment, the process and the notice period which followed the successful appointment, has meant that our new Director of Communications was only able to take up post at the end of January 2005. The new Communications Division, consisting of existing and newly recruited staff under Simon Gregor's direction will come into being on 1 April 2005. However, an internal working group set up before Mr Gregor's arrival has progressed a number of issues, including an audit of all internal and external publications, the preparation for the launch of a procurement exercise seeking advice on the "re-branding" of these documents using an agreed Agency format and livery, the recruitment of a media relations team and the development of the Agency website. The results of these activities will be visible within the next few months. For example, the Agency will be taking over responsibility for its own press and media relations in mid March (work previously carried out on our behalf by DH media centre). The new website, with considerable additional functionality, will be launched in the early Autumn of 2005. In the longer term, the Agency is planning to work with key stakeholders in raising a better awareness of risk literacy among patients and healthcare professionals.

Question 3

Increasing the patient voice in regulation

  The MHRA seeks to involve patients as stakeholders in the regulatory environment in a number of ways, including formally, through the Committee on Safety of Medicines and its sub-committees and in less formal ways across the range of its work.

  In 2004 you may be aware that the Agency consulted on the reform of the Medicines Act Advisory Bodies. The Agency's restructuring plans will include greater patient participation in the regulatory process. There will be two lay members on the on the Commission for Human Medicines and the Committees set up under section 4 of the Medicines Act. The Agency is also establishing Expert Advisory Groups to advise the Statutory Committees, and each of these will have two patient members. The lay and patient members will meet independently and regularly as a patient forum. The new committee structure will be in place for the Autumn of 2005.

  As you also will be aware, in 2003 Ministers commissioned an independent review of access to the Yellow Card Scheme Scheme, which looked in particular at transparency issues. This publication is also available on the MHRAs website and gives examples of some important early warnings of new ADRs identified through the yellow card scheme. In May 2004, the Review concluded that there should be greater access to Yellow Card data to ensure the full potential of the data was realised, and proposed a system for facilitating this. Of particular note, is the fact that recommendation in the report on direct patient reporting to the Scheme was accepted immediately and, after piloting several different options, launched a direct patient reporting scheme in January this year.

  The MHRA has been proactive in ensuring that leaflets, labels and packaging meet patients' needs for clear and authoritative information, especially in the recent Review of EU legislation. Labelling of medicines will have to include the name, strength and pharmaceutical form in Braille and changes to the order of the information in the PIL will be required. The Review importantly introduces a requirement for user testing which should help to ensure improvements to the PIL to make them more understandable for patients. Guidance on user testing is being developed by the MHRA, supported by advice from a CSM Working Group on Patient Information. The Group is also advising on possible revisions to the European Guideline on Readability. This will all involve patient consultation and be of direct benefit to patients.

  In addition, the Agency is seeking to be more transparent in its working ways of working. The Agency now publishes details of all complaints received about medicines advertising and the outcome of its investigations as well as being more open about how such decisions are made. This transparency in decision making has also extended to drug safety issues where the Agency has released previously unpublished data. The MHRA has published summaries of clinical trial data to support key communications on drug safety when it has been in the public interest to do so. Summaries of clinical trial data have been released in respect of SSRIs used in children as well as for anti-psychotics (risperidone) used in the treatment of dementia. A full and open consultation process is also carried out before a decision to re-classify a medicine (from Prescription Only to a Pharmacy or General Sales List medicine). Patient groups and charities are included on this consultation list.

Question 4

Connections with Smithkline Beecham

  From 1987 until the end of 1992, my advice was sought at irregular intervals by Beecham Pharmaceuticals, later to become Smith Kline Beecham, on general issues in the field of clinical pharmacology. My advice was not sought on specific drugs and did not involve discussion on Seroxat. From 1992 until 1997, I sat on a formal committee of Smith Kline Beecham which met regularly to discuss broad scientific areas of drug development. Specific products were not discussed. At the meeting of SCOP on 24 February 1998 there was a general discussion of SSRIs which led to a decision to set up a review of the adverse effects of the drug class of SSRIs and I felt it appropriate to chair that meeting. At the meetings on 24 September and 22 October, there was discussion about specific SSRIs, including Seroxat and it was not appropriate to take part in these discussions, in spite of the fact that I had left the Scientific Advisory Committee of Smith Kline Beecham. My actions were taken in consultation with the then Chairman of the Committee on Safety of Medicines and were fully in line with the procedures in place at the time.

Question 5

At Q797, you expressed the view that "when a patient starts to take SSRIs, there is a period of time before the benefit takes place and in that time . . . the patient is at a great risk of suicide." . . . The Committee has not been able to identify any such interpretation in the EWG final report.

  My response to that question was not meant to imply that there was no possibility of an adverse effect of treatment increasing the risk of suicidal behaviour. The EWG considered these issues very carefully and was unable to reach a firm conclusion as to whether the increased risk of suicidal behaviour seen particularly in early treatment was due to the antidepressant treatment, the underlying disease, or part of the early recovery of depressive illness.

  Turning to Professor Healy's analysis of events on withdrawal of paroxetine, the advice of the EWG was sought on the calculations and conclusions drawn by Professor Healy from the tables previously supplied to them. The Group considered this an extremely important issue. Other analyses and data sets considered by the EWG had not indicated an increase in suicidal events on withdrawal of Seroxat in adults, although an increase in suicidal thoughts and self-harm was seen in paediatric clinical trials on withdrawal of Seroxat. The EWG advised that certain limitations of the data, as presented by Professor Healy, had to be taken into account. In particular, the analysis did not take into account differences in the at-risk period and follow up between the populations on Seroxat and placebo. This is important when focussing attention on small periods of time at the end of clinical trials because by this time follow up may differ substantially between groups. In addition the denominator figures used in the calculations pertain to those randomised to start treatment and were not necessarily corrected for the immediate post-treatment phase. Furthermore, patients are unblinded to treatment in the follow-up phase, which may well affect the results.

  The EWG considered that, although inconclusive, the data supported the need for close monitoring of patients during taper and withdrawal of Seroxat, which was a key recommendation of the EWG. In order to fully clarify this issue the EWG advised that a large placebo controlled double-blind randomised trial of withdrawal events would be required.

  You have asked for the best estimate of the proportion of SSRIs prescribed for mild and mild-moderate depression. As part of the EWG review of the safety of SSRIs, the MHRA commissioned a study using the General Practice Research Database (GPRD). The aim of the study was to investigate whether there was an association between antidepressants and self harm in patients with first time treated depression. As part of this study two psychiatrists carried out a classification of the depression diagnoses entered by the GPs into mild, moderate and severe depression. It should be noted that patients with severe recurrent depression are likely to be under-represented in this dataset as it considers first time treated depression and is based in primary care. Furthermore, the classification was carried out without seeing the patients and therefore relies on the way that GPs use the coding system for entering diagnoses into GPRD which is known to be variable.

  In this study, approximately 95% of patients with first time treated depression had diagnoses consistent with mild or moderate depression. This proportion was the same across SSRIs, TCAs and other antidepressants with no suggestion that SSRIs were preferentially prescribed in mild depression. This information is available on the website of the British Medical Journal as supplementary material to the published GPRD study (Martinez et al BMJ 2005;330:389).

Question 6

At Q798, you were asked if the MHRA/CSM statement, that SSRIs were effective medicines in the treatment of depression, required some qualification, in view of the lack of evidence of efficacy of the products in treating mild depression. Would you address this point . . .? Could you specifically advise the Committee why no restriction on the use of SSRIs was proposed in the Summary of Product Characteristics?

  SSRIs are indicated for treatment of depressive illness. It is for the individual practitioner, informed by clinical guidelines, to consider whether the risks and benefits of treatment are appropriate for an individual. The recent NICE guidance on treatment of depression concludes that antidepressants are not recommended for the initial treatment of mild depression, because the risk-benefit ratio is poor. However the guidance states that the use of antidepressants should be considered in patients with mild depression that is persisting after other interventions. The currently licensed indications reflect the patient population studied in clinical trials and allow for the individual prescribing judgement necessary in each case.

Question 7

In relation to paroxetine withdrawal reactions, you wrote in your letter of 4 February that, "the MHRA has never indicated that withdrawal was rare . . ." the Committee would wish to know if the statement in your letter applies also to the MCA. Specifically, the Committee invites you to comment on the 1996 paper published by MCA/CSM staff that concluded "overall, symptoms due to stopping an SSRI are rare . . .".

  You ask whether the statement "the MHRA has never indicated that withdrawal was rare" also applies to the MCA in the light of the paper by Price et al published in the British Journal of Clinical Pharmacology in 1986. I can confirm that this is the case. The conclusions of this paper were based purely on spontaneous reporting, a data source which has limitations for the assessment of incidence of an adverse reaction and particularly so for withdrawal reactions. Neither the MCA nor the MHRA considered spontaneous reporting alone a sufficiently robust data set to form regulatory decisions or prescribing advice on the incidence of withdrawal reactions.

  You have asked that I comment on your observations relating to the incidence of withdrawal reactions. My comments on each observation are provided below as numbered in your letter.

Lack of evidence for a taper regimen

    (a)  We fully accept that clinical trial data for Seroxat do not provide direct evidence that gradual withdrawal of an SSRI will reduce the incidence of withdrawal symptoms.

    (b)  The recommendation that the dose should be tapered gradually at the end of treatment is based largely on the knowledge of the pharmacology of these products and detailed descriptions of tapering regimen described in individual case reports from patients and prescribers. In addition, the clinical trial data for venlafaxine and sertraline provide some evidence to suggest that tapering of dose may be beneficial.

Failure to warn about incidence of withdrawal reactions

    (c)  At the time of licensing, data from 222 patients withdrawn abruptly from Seroxat did suggest that some patients experienced events on withdrawal. This information was included in the product information for Seroxat from the time of licensing. The data sheet stated that "As with many psychoactive substances it may be prudent to discontinue therapy gradually because of the possibility of discontinuation symptoms such as disturbed sleep, irritability and dizziness."

  In responding to this point it may be helpful if I provide a brief description of the paper published by Price et al in the British Journal of Clinical Pharmacology in 1996. It was a comparison of spontaneous reporting data for four SSRIs. The paper was not intended to be a review of all available data sources and did not include any clinical trial data. It did not reflect any agreed position of the MCA or CSM and was not a document on which regulatory decisions were based.

  The paper by Price et al clearly describes the biases and confounding variables which influence the interpretation of spontaneous reporting data. The authors highlighted data which suggested that paroxetine was associated with a higher frequency of reporting of withdrawal reactions than other SSRIs. Further information on the nature of withdrawal reactions with paroxetine was specifically sought through a retrospective survey of doctors who had reported such reactions through the Yellow Card scheme. In relation to severity, the paper includes the following information "21% of reactions were said to be mild, 58% moderately severe, and 21% severe."

  The review which was considered by SCOP and CSM in 1998 looked at all sources of data for all the SSRIs and related antidepressants, including unpublished clinical trial data. From review of all available data the CSM concluded that "to date, studies had not been carried out of an appropriate design to allow an estimation of frequency of withdrawal reactions". As a result of this review the CSM advised that product information for all SSRIs and related antidepressants should contain warnings about withdrawal reactions. The CSM further advised that any reference to withdrawal reactions being "rare" should be removed from the product information for SSRIs (it was present in the product information for fluvoxamine and sertraline only). This review did not contradict the data on paroxetine which was available at the time of licensing—the paper included these data and resulted in strengthened warnings in product information on the basis of accumulating post-marketing data.

  The estimate of withdrawal reactions added to paroxetine product information in 2003 was based on more recent trials which included a taper phase during which events on withdrawal were systematically recorded. These trials indicated that 25% of patients experienced symptoms on stopping treatment and 15% of those experienced symptoms described as severe. In the same trials, 15% of patients experienced symptoms on stopping placebo and 9% of those experienced symptoms described as severe. The most common events reported in clinical trials as occurring on stopping both paroxetine and placebo were similar and included dizziness, nausea, insomnia, anxiety and headache.

Doubts about evidence for efficacy of paroxetine in relapse prevention

    (d)  In responding to this point I would like to draw your attention to a systematic review which looked at evidence for efficacy of antidepressants in relapse prevention in 31 randomised trials (including that by Montgomery and Dunbar) and was published in The Lancet in 2003 (Geddes et al, Lancet 2003; 361:653-51). The authors took into account the possibility that withdrawal effects associated with stopping active treatment could inflate the effectiveness of the active treatment in prevention of relapse. However their review did not identify an excess of cases of "relapse" within a month after discontinuation, which argued against this possibility.

  The recent NICE guidance on treatment of depression concludes that responders to medication, who have had multiple relapse, should stay on medication to avoid relapse, with appropriate re-evaluation of treatment taking into account their individual risk factors.

Question 8

At Q800, you stated, in relation to paroxetine, that, "There was additional, clear information for the patients". The first reference to withdrawal symptoms appeared in the patient information leaflet five years after the introduction of Seroxat. The 1996-97 Seroxat patient information leaflet stated that withdrawal symptoms were "unusual". Please could you clarify and explain the basis on which withdrawal symptoms were described as "unusual".

  There was no requirement for a medicine to have a patient information leaflet when Seroxat was first licensed. At that time the warning about withdrawal reactions was in the information for prescribers.

  The first patient information leaflet for Seroxat after patient information leaflets became a requirement stated, "Some people find that if they suddenly stop taking these tablets, they feel dizzy, shaky, sick, anxious, confused or have tingling sensations. They may also have difficulty sleeping and vivid dreams when they do sleep. But these symptoms are unusual and generally disappear after a few days. To avoid these symptoms, your doctor may tell you to take smaller doses or to spread doses further apart before you stop taking the tablets altogether".

  This wording was considered generally to reflect the wording in the summary of product characteristics at the time which stated that "Symptoms including dizziness, sensory disturbance (eg paraesthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt discontinuation of `Seroxat'. They are usually self-limiting and symptomatic treatment is seldom warranted. No particular patient group appears to be at higher risk of these symptoms; it is therefore recommended that when antidepressive treatment is no longer required, gradual discontinuation by dose-tapering or alternate day dosing be considered". The word "unusual" has no specific regulatory meaning.

2 March 2005