Case AUTH/1318/5/02 Safety of Seroxat (paroxetine)

The Code of Practice Panel has completed its consideration of the above and I am writing to advise you of the outcome.

As you will recall, you submitted a complaint on behalf of Social Audit Ltd about information supplied about Seroxat (paroxetine) by GlaxoSmithKline UK Limited. The complaint related to comments attributed to Mr Alan Chandler, Director of Corporate Media UK, in articles which appeared in The Independent, 1 October 2001, and Mental Health Today, April 2002. Social Audit referred to a previous case, Case AUTH/IFPMA/5/7/01, and asked the Authority to take both the circumstances and outcome of that case into account.

Mr Chandler replied on 17 October 2001 simultaneously stating that he was not referring to withdrawal symptoms but had been accurately quoted. He claimed he had been quoted out of context, but that this "is not the fault of the journalist as she was covering a complex situation". This contradicted his earlier statement that he had been accurately quoted, but you did not pursue this issue, as Social Audit was then engaged in another complaint (Case AUTH/IFPMA/5/7/01) against GlaxoSmithKline’s Dr David Wheadon, who had claimed that withdrawal reactions from paroxetine were ‘very rare’. Mr Chandler’s statement and response were produced at the appeal in Case AUTH/IFPMA’5/7/01 but no adjudication was involved.

You would have left it at that, had you not seen reported comments of the same general kind, attributed to Mr Chandler, reported by Catherine Jackson (Editor) in an article in Mental Health Today, April 2002: "You have a product that’s been available for over ten years and has benefited tens of millions of patients. As more patients use the product globally you are bound to get these reports of bizarre side effects", says Alan Chandler, Director of Corporate Media UK. "There is no scientific evidence that Seroxat leads to addiction and dependency. There have been one or two reports of discontinuation symptoms with abrupt cessation, which is why our data sheets reflect new advice to taper off the medication. The data sheet is a living document and as usage of the product increases the labelling reflects the current usage experience" .

Clause 7.2 Mr Chandler’s statement that "there is no scientific evidence that Seroxat leads to addiction and dependency" was not inconsistent with the SPC but was alleged to be unfair, ambiguous and misleading, all the more so as a statement directed to a lay readership. The assertion that paroxetine was not a medicine of dependence relied on (a) the lack of evidence to which EMEA/CPMP referred; and (b) a studiedly narrow and inappropriate interpretation of the definition in the I 0th edition of the International Classification of Diseases.

Since publication of the lCD-10 guidelines, the WHO (1998) had published a statement on "Selective serotonin reuptake inhibitors and withdrawal reactions", which made it clear (a) that dependence should be regarded as not an ‘on or off phenomenon, but as a condition that should be measured by degree; (b) that on existing definitions, sensibly interpreted, SSRIs could and did cause ‘dependence’; and (c) that in the last analysis, the patient’s experience with the medicine was the test of whether or not a medicine caused dependence:

Referring specifically to Mr Chandler’s comment that "there have been one or two reports of discontinuation symptoms with abrupt cessation", you referred to the published evidence cited in Social Audit’s previous complaint. Social Audit accepted the point made in the EMEA/CPMP review (1999) that "strong evidence which would allow definitive statements about the frequency of withdrawal reactions with the different SSRIs, is not available" However, investigators had consistently reported an incidence of withdrawal problems far greater than the incidence proposed by GlaxoSmithKline. Typical figures were 3/6 cases (50%) reported by Barr et a! (1994); 5/13 - 38.5% (Keuthen et a!, 1994); 10/50 - 20% (Coupland et a!, 1996); and 5/12 -41.6% (Bhuamik and Wildgust, 1996). One recent review concluded as follows:

In addition to the aforementioned study by Rosenbaum et a!, you referred to the study reported by Oehrberg et al (1995); the correspondent in the published report was identified as Dr R Judge from SmithKline Beecham Pharmaceuticals, Harlow. The investigators reported: "... only 19 patients out of 55 (34.5%) who had received paroxetine reported any adverse event on discontinuation, as compared with seven out of 52 (13.5%) on placebo. This trial was especially significant because GlaxoSmithKline indicated in response to the previous complaint (letter of 14 August 2001) that its estimate of the incidence of withdrawal reactions was substantially based on the finding that only 7 patients out of the 8,143 on its clinical trials database were reported to have experienced a withdrawal syndrome. Apart from the fact that the design of many trials on the SmithKline Beecham’s database (number unknown, but believed to be the large majority) would positively obscure evidence of the nature, incidence and severity of withdrawal - the number of patients experiencing withdrawal reactions in this one trial reported by Oehrberg et a! was over twice the number on the whole SmithKline Beecham clinical trials database. Not only was this trial excluded from the company’s database, but it also signalled an incidence of withdrawal reactions far in excess of the low levels the company implicitly claimed.

Nor could the assertion that withdrawal symptoms were very rare (<1:10,000) be reconciled with evidence from spontaneous reporting. However troublesome the interpretation of these data might be, the major confounding factor was under-reporting. Yet by September 2001, the Committee on Safety of Medicines (CSM) had received 1,242 reports of withdrawal reactions to paroxetine - a far higher number than for any other medicine on the ADROIT database. The prominence of paroxetine in the ADROIT tabulation was underlined by the analysis by Price et a! in the MCA/CSM: "withdrawal reactions with paroxetine constitute a greater proportion of reports (5.1%) than with the other SSRIs (0.06-0.9%).

The same picture emerged from the data generated by the Uppsala Monitoring Centre (27 January 2001) which had operational responsibility for the WHO’s Programme for International Drug Monitoring. A table was provided which identified medicines on the Centre’s database that had attracted most reports of withdrawal problems indicative of dependence. By a wide margin, paroxetine with 2003 reports was at the top of this list.

You objected to the statement that "there have been one or two reports of discontinuation symptoms with abrupt cessation" on the ground that GlaxoSmithKline had known for many years that the frequency of withdrawal symptoms was likely to be substantial, following studies on healthy volunteers, carried out in the I 980s: "On average about half the volunteers taking part in a group of studies specifically designed to detect withdrawal problems suffered symptoms which suggest they had become physically dependent on the drug" (Boseley, 2001). The source of this information was Dr David Healy, who had personally examined this documentation in discovery relating to a US court case. Healy (2001) reported his concerns to the MCA, indicating that the results of these studies showed "withdrawal syndromes occurred at a much higher rate than occur on benzodiazepines".

The further implication of the statement at issue was that withdrawal symptoms existed only when there was abrupt cessation of treatment. In the previous complaint, Case AUTH/IFPMA/5/7/0l, you requested the company to produce such relevant evidence as it had to support this assertion, but it did not respond. You had no problem accepting that gradual reduction of dosage might attenuate withdrawal problems, but clearly it did not abolish them. Gradual tapering of dosages had been employed in the three cases reported by Barr et a!; in four of the five cases reported by Keuthen et a!; and "the majority of cases occurred despite slowly tapered withdrawal" in the series reported by Coupland et al. Reference was also made to CADRMP, 1998; and DTB, 1999. Referring to the practice of dose tapering on cessation of treatment, one recent review concluded; "as yet there is no controlled data to recommend its effectiveness, the length of time over which it should occur or the minimum dose that one should taper to" (Haddad, 2001).

Clause 7.9 You relied on the arguments and evidence set out above and invited GlaxoSmithKline to inspect the 1000-odd spontaneous reports from SSRI users on the Social Audit website, the large majority of which related to (a) withdrawal and dependence problems with paroxetine (Paxil, Seroxat, Aropax) rather than other SSRIs; and (b) reactions that were unexpectedly severe, disabling and often intensely disturbing. The website was only one of several where users so complained. Such a volume of reports, describing severe problems of a kind that manufacturers routinely denied and of which many prescribers appeared unaware, could and should be considered "available evidence" within the meaning of the Code. You provided a selection of comments posted on the Social Audit website relating to users’ experience of dependence of paroxetine.

Clause 20.2 You relied on the arguments and evidence set out above, drawing attention also to the following supplementary information in the Code; "Particular care must be taken in responding to approaches from the media to ensure that the provisions of this clause are upheld".

Clause 2 You recognised that the Authority regarded a ruling of a breach under Clause 2 as a sign of particular censure, to be used sparingly but nevertheless requested that a breach under this provision be ruled, taking into account:

I The outcome of the previous IFPMA complaint and GlaxoSmithKline’s acceptance of that decision and "assurance that it would take all possible steps to avoid similar breaches of the IFPMA Code occurring in the future" (The remarks attributed to Mr Chandler did not suggest that steps had been taken, but you kept an open mind on this. If GlaxoSmithKline had taken any steps, you invited it to explain what had been done.)

2 The evidence provided of an established pattern of unacceptable behaviour.

3 That misleading statements were made to a lay rather than professional audience.

4 Mr Chandler’s seniority in the company

5 The damaging consequences of such statements for patients and prescribers alike

In relation to this last point, the users’ comments provided were representative of recurrent themes: many prescribers were not aware of the significance of withdrawal and dependence problems (Young and Currie, 1997); users were not often warned about the possibility of withdrawal effects and dependence; prescribers were often unaware of the risks of mistaking withdrawal symptoms for ‘relapse’ and sometimes reluctant to accept patients’ accounts of withdrawal symptoms, causing considerable distress; patients unable to discontinue medicines were obliged to resume taking them, much against their free will; withdrawal effects might be extremely distressing and disabling; and withdrawal and post-withdrawal effects were reported to be worse than the condition for which the medicine was prescribed.

Discontinuation symptoms, also referred to as withdrawal symptoms, comprised a diverse range of symptoms, but did not in themselves indicate dependence (Haddad, 1998 and Haddad, 2001). Dependence was a syndrome and diagnosis required several other features such as tolerance, inability to control medicine use, primacy of medicine taking behaviour, and continued use despite harmful consequences (Haddad et a! 1998). Dependence was often used synonymously with the term addiction. In 2000, following a comprehensive review, the EMENCPMP released a position paper on "Selective Serotonin Uptake Inhibitors (SSRIs) and Dependency/Withdrawal reaction". A copy was provided. It endorsed the conclusions of the April 1998 CSM review that had not identified evidence that SSRIs were medicines of dependence, but that the product information for all SSRIs should contain appropriate warnings about well-recognised withdrawal reactions. They noted that following the request of the European Commission that the CPMP considered this issue, further evaluation of the clinical evidence relating to dependence associated with SSRIs was carried out by France and Germany, and that no evidence that SSRIs were medicines of dependence was found. Based on this and other evidence, the CPMP concluded that the available clinical evidence did not suggest that the SSRIs caused dependence. With respect to discontinuation or withdrawal, it recommended that the key elements of withdrawal reaction statements in the SPCs should be harmonised throughout the European Union and recommended the following, among other things:

A statement that although withdrawal reactions might occur on stopping therapy, the available preclinical and clinical evidence did not suggest that SSRIs caused dependence.

A list of symptoms reported in association with withdrawal reactions for that product.

A statement that the majority of withdrawal reactions were mild and self-limiting.

Advice that prescribers should consider gradual dose reduction when stopping treatment.

In accordance with the recommendations of the CPMP, the Seroxat SPC stated under Section 4.8 (undesirable effects) "In common with other SSRIs, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. Dizziness, sensory disturbance (eg parasthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt discontinuation of Seroxat. They are usually mild, self-limiting and symptomatic treatment is seldom warranted. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when antidepressive treatment is no longer required, gradual discontinuation by dose tapering be carried out." In accordance with these principles, the relevant sections of the briefing document approved for use in October 2001 were as follows:

"Addiction

• Seroxat unlike, for example, smoking or alcohol is not addictive. There are well-defined international criteria for drug dependency and addiction and Seroxat is clearly shown as being neither addictive nor causing dependence.

Discontinuation

• Abrupt stopping of any antidepressant can result in a small number of patients experiencing discontinuation symptoms.

• These symptoms - such as dizziness - are generally mild, short-lasting and self-limiting.

• As recommended by The British National Formulary (BNF) and the EMEA, the likelihood of these symptoms is minimised by gradually tapering the daily dose.

• Seroxat’s high volume of usage compared to other SSRIs means that clinicians might perceive these symptoms occur more frequently witt~, Seroxat. It is important to remember that this is a class effect and can occur with all SSRIs.

• The Seroxat SmPC states "In common with other SSRIs, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. 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 mild, self-limiting and symptomatic treatment is seldom warranted. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when antidepressive treatment is no longer required, gradual discontinuation by dose tapering be carried out".

GlaxoSmithKline stated that the comments reported in Mental Health Today (April 2002) were, "You have a product that’s been available for over 10 years and has benefited tens of millions patients. As more patients use the product globally you are bound to get these reports of bizarre side effects", says Alan Chandler, director of Corporate Media UK. "There is no scientific evidence that Seroxat leads to addiction and dependency. There have been one or two reports of discontinuation symptoms with abrupt cessation, which is why our data sheets reflect new advice to taper off the medication. The data sheet is a living document and as usage of the product increases the labelling reflects the current usage experience" ".

There were two specific parts of this statement that the complainant discussed. Firstly, "there is no scientific evidence that Seroxat leads to addiction and dependency". Secondly, "there have been one or two reports of discontinuation symptoms with abrupt cessation".

With regard to the first part, GlaxoSmithKline concurred with you that this comment was consistent with the Seroxat SPC, and clearly also with the briefing document enclosed. The relevant sections of this briefing document approved for use in December 2001 and used since then stated:

"Discontinuation

• Stopping any antidepressant can result in some patients experiencing discontinuation symptoms. The most common of these symptoms may include dizziness, sensory disturbances, agitation, anxiety, nausea and sweating. In most cases these symptoms are mild to moderate in nature and self-limiting.
• As recommended by the BNF and the EMEA the likelihood of discontinuation symptoms is minimised by gradually tapering the daily dose.
• Discontinuation symptoms are completely different to addiction or dependence. Haddad and Young, BMJ 1998, stated "Discontinuation symptoms do not in themselves indicate drug dependence. Dependence is a syndrome, and diagnosis requires several other features, such as tolerance, inability to control drug use, primacy of drug taking behaviour, and continued use despite harmful consequences. Antidepressants are not associated with fhese features and are not drugs of dependence".
• The Seroxat summary of product characteristics (SPC) states that "In common with other SSRIs, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. 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 mild, self-limiting and symptomatic treatment was seldom warranted. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when antidepressive treatment is no longer required, gradual discontinuation by dose tapering be carried out".

Addition/Dependence

• Seroxat is not addictive. There are well-defined international criteria for drug dependency and addiction and Seroxat is clearly shown as being neither addictive nor causing dependence.
• The European Regulatory Body, the CPMP, have recently completed (April 2000) a thorough review of safety data collected following the discontinuation of all SSRIs and other newer serotonergic antidepressant medications. The Medicines Control Agency (MCA) and CPMP had concluded that SSRIs did not cause dependency/addiction.
• There has been no reliable scientific evidence from either preclinical studies, long term clinical trials or clinical experience, to suggest that Seroxat is addictive, shows dependence or is a drug of abuse."

All these statements were supported by published data and the Seroxat SPC. As stated above, GlaxoSmithKline believed that the EMEAICPMP position paper on SSRIs and Dependency/Withdrawal Reactions (2000) provided a comprehensive and clear recommendations that were incorporated within the Seroxat SPC and hence into its briefing document.

GlaxoSmithKline stated that the anecdotal reports of adverse events by users of paroxetine from the Social Audit website had been reported to the company’s clinical safety department as part of its standard adverse event reporting procedure. However, it believed that Social Audit’s website was not a source of valid and reliable data, presenting many potential biases and containing unverified data. GlaxoSmithKline did not believe it should be considered ‘available evidence’ within the meaning of the Code. GlaxoSmithKline hoped that Social Audit advised any patients reporting adverse events that their treating physicians should be notified in order that they could complete appropriate yellow card reporting of their symptoms to the CSM.

With regard to the specific comment attributed to Mr Chandler that "There have been one or two reports of discontinuation symptoms with abrupt cessation", the position of GlaxoSmithKline with respect to discontinuation of Seroxat was clearly enunciated in the relevant briefing document (December 2001) given above. GlaxoSmithKline acknowledged that the statement attributed to Mr Chandler by Mental Health Today was not consistent with this briefing document. This statement was attributed to Mr Chandler as part of a ‘long conversation with Catherine Jackson initiated by media interest in changes to the product data sheet and patient leaflet for the antidepressant Seroxat’ (letter to you, 3 May 2002). Mr Chandler explained in his letter to you that he could not remember the precise details of the conversation with the journalist, but that if detailed figures had been required, referral to an appropriate medical expert in the company would have been made.

In summary, the statement "there have been one or two reports of discontinuation symptoms with abrupt cessation" attributed to Mr Chandler was not consistent with the briefing document. However, the information in its briefing document was consistent with the Seroxat SPC and published data, being a factual and balanced document, which underwent the required internal approval process.

As no transcripts were available, there was difficulty in ascertaining exactly what was said in the conversation between Mr Chandler and the journalists. Nevertheless, the statement in the Independent (October 2001) referring to paroxetine and other SSRIs, as made by Mr Chandler (see letter of 17 October 2001) was consistent with the SPC and briefing document and GlaxoSmithKline did not believe this statement had led to a breach of the Code. The comment reported in Mental Health Today (April 2002) of "There is no scientific evidence that Seroxat leads to addiction and dependency" was consistent with the briefing document and the Seroxat SPC. As such, GlaxoSmithKline did not accept that a breach of Clauses 3.2, 7.2, 7.9 and 20.2 of the Code had occurred, with respect to that specific comment. However, the comment "There have been one or two reports of discontinuation symptoms with abrupt cessation" was not consistent with either the appropriate briefing document (December 2001) nor the Seroxat SPC.

Hence GlaxoSmithKline accepted that, if the statement was made by Mr Chandler, a breach of Clauses 3.2, 7.2, 7.9 and 20.2 of the Code had occurred with respect to this specific comment.

Finally, GlaxoSmithKline had fully accepted the previous IFPMA ruling and Mr Chandler had been fully compliant with all of Social Audit’s regular requests, with appropriate written responses within adequate timelines. GlaxoSmithKline took this very seriously and it denied that a breach of Clause 2 of the Code had occurred.

The amendment to the SPC was approved by the MCA in June 2001 and included in packs on the market from July 2001. Following the recommendations of the CPMP the SPC was supplemented to include the following additional statement "In common with other selective serotonin reuptake inhibitors, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence". This amendment was approved in conjunction with a number of other changes to the Seroxat SPC. These changes were a result of a company review of Seroxat and a review of the SSRIs by the MCA.

The dates on the briefing documents of 6 September and 19 December corresponded to the final ABPI approval dates and these documents were therefore available for use from those dates onwards. Consequently the briefing document available in October for use in responding verbally to media enquiries was the version approved on 6 September.

Panel Ruling The Panel noted the reference to Case AUTH/IFPMN5/7/0l which concerned Social Audit and GlaxoSmithKline. That case had been considered under the IFPMA Code and related to statements made by Dr David Wheadon who at the time worked for SmithKline Beecham. The Authority dealt with the matter under the Constitution and Procedure for the Authority. Dr Wheadon had stated that with reference to discontinuation syndrome, that what had been seen in terms of anecdotal reports was that it happened very rarely. The US product information described the frequency of withdrawal syndrome as a rare event. The statement was considered to be misleading in breach of the IFPMA Code. IFPMA agreed with the opinion of the Code of Practice Appeal Board that there was a breach of the IFPMA Code (Sections 1.3 and 1.7). The requisite undertaking had been received and the report for the case was made public by the IFPMA in January 2002.

The Panel was concerned that there were two quotations from an employee of GlaxoSmithKline that Seroxat did not cause withdrawal symptoms. These being "There’s no reliable scientific evidence to show they cause withdrawal symptoms or dependency" in The Independent, 10 October 2001, and "There is no scientific evidence that Seroxat leads to addiction and dependency. There have been one or two reports of discontinuation symptoms with abrupt cessation . . ." in Mental Health Today, April 2002.

The Seroxat SPC (Section 4.8) stated:

"In common with other selective serotonin reuptake inhibitors, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. Dizziness, sensory disturbance (eg paraesthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt withdrawal of Seroxat. They are usually mild, self-limiting and symptomatic treatment is seldom warranted. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when antidepressive treatment is no longer required, gradual discontinuation by dose-tapering be carried our.

Given the circumstances GlaxoSmithKline needed to be extremely careful about references to withdrawal symptoms/discontinuation symptoms. The company itself referred to the position as complex.

Complaints about items in the media were judged upon the material and comments provided by the company to the journalist. The Panel noted that there was no contemporaneous evidence or record of the conversations between the journalists and Mr Chandler. The company submitted that Mr Chandler could not remember the precise details of the conversation with the journalist at Mental Health Today. It might be that the journalists had misquoted Mr Chandler. II so it did not appear that this had been followed up by GlaxoSmithKline. The Panel queried whether it was likely that two journalists would misquote with similar effect. If Mr Chandler had been quoted accurately, the statements were inconsistent with the Seroxat SPC and GlaxoSmithKline’s briefing documents. The company must ensure that material and comments were not inconsistent with the SPC. No written materials had been supplied to the journalists. Such documentation might have avoided the problems. Companies would be well advised to back up oral interviews with written material and to keep good records as to what was said.

On the evidence before the Panel it was not possible to determine precisely what had been said in such circumstances it had no option other than to rule no breach of Clauses 2, 3.2, 7.2, 7.9 and 20.2 of the Code.

As the Code of Practice Panel has ruled no breaches of Clauses 2, 3.2, 7.2, 7.9 and 20.2 of the Code, you are entitled to appeal against any or all of these rulings to the Code of Practice Appeal Board if you have reasons for so doing. The Appeal Board includes independent members and a membership list is enclosed. Notice of appeal must be received within ten working days of receipt of notification and must be accompanied by reasons for the appeal. Your notice of appeal would therefore be due by Tuesday, 6 August. If prior commitments make it impossible for you to meet this deadline, please let us know as soon as possible so that alternative arrangements can be made.

If there is an appeal both parties will be entitled to appear or be represented before the Appeal Board.

In accordance with Paragraph 7.2 of the Constitution and Procedure, I enclose a copy of GlaxoSmithKline’s response to the complaint.