Seroxat Litigation - Report of the Committee on Safety of Medicines Expert Working Group on SSRI Antidepressants, 2004 - ‘Suicidal Behaviour in association with SSRI’

The previous and following excerpt of the Committee on Safety of Medicines (CSM) Expert Working Group (EWG) report “On the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants” published December 2004 shows that the issue of withdrawal, dependence, suicidal and aggressive behaviour in associated with SSRI fluoxetine (Prozac) was under review with some gravity by the UK Medicine Control Agency (MCA) and CSM from 1990, referenced in MCA / CSM 'Current Problems in Pharmacovigilance', June 1992.

The review widened encompassing newer SSRI drugs when approved and licensed, close monitoring of spontaneous adverse drug reports (ADRs) lead to “a UK exercise in 1998 -2000 to develop harmonised safety information for all SSRIs”, acknowledging that all drugs in the class induced similar ADRs and side effects, and Dr David Healy’s 1999 publication ‘A Failure to Warn’ raised the level of concern in the issue of suicide and introduced SSRI induced akathisia - the now acknowledged precursor to suicidal ideation and action.

Dr David Healy was in correspondence with the MCA by November 4th 1999 about the suicide issue and voicing concerns about the number of SSRIs being prescribed to children and adolescence,

“Both of these points, it seems to me, must be of concern to you. The issues are quite different to any problems that were ever raised in relation to benzodiazepine or SSRI dependence, where there is considerable ambiguity involved in deciding what constitutes dependence.  In this case there are very clear internal company documents and a pattern of behaviour, possibly stemming from legal advice, that is inconsistent with prescription only arrangements.

Based on RCT evidence from a number of companies, epidemiological studies and other sources, at a conservative estimate I believe one person per week has killed themselves in the UK for every week that Prozac has been available over and above the number that would have done so if the same patients had been left untreated and one person per day has attempted suicide with unknown consequences for their future risk of suicide.  I would be happy to go through this evidence with you, if this would help and indeed I would be happy to have the error of my ways pointed out if anyone can see a problem with my figures or logic.

Against the background outlined above, I feet particularly impelled to act as I am doing now in writing to you having been the convenor and author of a report on childhood psychopharmacology for the British Association for Psychopharmacology, which supported the prescription of psychotropic drugs to children and teenagers in appropriate circumstances and with appropriate monitoring.  This document has not led directly to increased rates -of prescribing of SSRIs to adolescents in this country but it has done nothing to put a brake on what has been a dramatic increase in' recent years. Unfortunately, I now find my in-tray filling with files on teenagers committing suicide within a week or two of commencing Prozac. It is this that makes the problem difficult to walk away from.”

one of his most cited studies “Emergence of antidepressant induced suicidality” was published March 1st 2000 in the International Journal of Psychiatry in Clinical Practice, Volume 6, Number 1.

In June 2000, although the CSM concluded it was “impossible to answer the question of whether SSRIs caused suicidal behaviour in a small subpopulation of patients”, they advised updating all SSRI and antidepressant patient information leaflets (PILs) adding “a warning that suicidal thoughts may occur or increase in the early stages of treatment”.  In 2000 the UK SSRI suicide assessment was also presented to the EU Pharmacovigilance Working Party (PhVWP), where all members agreed with the scientific conclusions.

The CSM reviewed the suicidal behaviour, aggression and akathisia issue, December 2001, concluding the possibility of this affecting “a small high-risk population could not be ruled out”, and advised the risk of akathisia occurring be added to all SSRI Summaries of Product Characteristics (SPC).  The UK assessment report was discussed at the PhVWP which agreed, but considered further discussion was required to clarify definition of the term akathisia.

November 21st 2002, Dr David Healy presented research relating to suicidal behaviour, including reanalysis of studies on fluoxetine, to a group of CSM and external experts who concluded, no change in regulatory position in relation to suicide issue, but advised changes to UK Seroxat PIL to clarify withdrawal reactions – also recommended a suicidal behaviour study using the General Practice Research Database (GPRD) and reanalysis of fluoxetine clinical trial data.  Further expert group meeting planned for March 2003.

By March 17th 2003 the planned CSM meeting was intercepted, the expert group was dissolved.

The ‘expert group’ was dissolved following the November 21st 2002 meeting due to objections raised by Seroxat Litigation Lead Lawyer Mark Harvey and Seroxat User Groups (SUG) against two members of the panel Dr Michael Donaghy, a reader in clinical neurology from Oxford University, and David Nutt, professor of psychopharmacology at Bristol University who both disclosed holding shares in Glaxo Smith Kline (GSK) - the formation of a new CSM Expert Working Group was agreed by the end of January 2003.

Mark Harvey and the reported by Hugh James Solicitors and their Media and PR company GoodRelations, 4000 SUG group members were said to be “unhappy” that the CSM review panel had not agreed an undertaking to consider the groups evidence of side effects they said they have suffered - although it had invited representatives of the group to the planned meeting, whilst excluding representation of patients taking other SSRI SNRI class drugs.

Although according to watchdog organization Social Audit Charles Medawar’s February 26th 2003 complaint letter to the Rt Hon Frank Dobson PC MP, House of Commons and The Guardian health editor Sarah Bosely’s March 17th 2003 article – Charles Medawar was also “unhappy” about the choice of chairman, Angus Mackay, director of mental health services in Lomond and Argyle, Scotland, one signatory to the CSM 1996 paper which concluded SSRI withdrawal symptoms were rare, relatively mild and not meeting the World Health Organization (WHO) dependency criteria,

and drew attention to inconsistencies in CSM member Professor David Nutt’s personal interest disclosures, that according to the CSM website he had listed current personal interests in two other companies that make SSRIs Lundbeck: Citalopram Cipramil Celexa, Escitalopram Cipralex Lexapro and Wyeth, Pfizer: Venlafaxine Efexor Effexor, Medawar made no reference to three others which he disclosed at the November 21st 2002 meeting, Pfizer: Sertraline Lustral Zoloft, Eli Lilly: Fluoxetine Prozac Sarafem - Duloxetine Cymbalta Yentreve, and Solvay.

It was also revealed that in the minutes of the CSM November 2002 meeting another expert witness, Dr David Baldwin, now Reader in Psychiatry in the Clinical Neuroscience Division, University of Southampton School of Medicine declared a personal interest in Lundbeck, manufacturers of the drugs Escitalopram (Cipralex Lexapro) and Citalopram (Cipramil Celexa), now UK’s most prescribed SSRI

however, it appears that Mark Harvey and the SUG group members lodged no objections to his or Angus Mackay's involvement with the expert group.

It was later discovered Dr Baldwin had connections with five other companies all manufactures of SSRIs - Bristol-Myers Squibb (it’s SSRI Serzone Nefazodone was taken off market April 2004, for causing liver damage in dozens of patients, and linked to the deaths of 20 people), Wyeth (Venlafaxine Efexor Effexor), Eli Lilly (Fluoxetine Prozac Sarafem, Duloxetine Yentreve) , Organon (Merck Sharp & Dohme Limited: Mirtazapine Zispin), Pharmacia (owned by Pfizer Inc. Sertraline Lustral Zoloft) and SmithKline Beecham (Paroxetine Seroxat Paxil).

The Medicines and Healthcare products Regulatory Agency report “MHRA Investigation into Glaxosmithkline/Seroxat” published March 6th 2008, outlines the situation with regard prescribing antidepressants to children and adolescents, and the efforts of the CSM in gaining information from SmithKline Beecham plc (SKB), subsequently GSK .

October 13th 2002 the first BBC Panorama Shelley Jofre Seroxat program aired - at this point no antidepressants were specifically authorised (licensed) for treatment of depression in children and adolescents, until the mid-1990 clinical trials to investigate the safety and effectiveness of medicines in children were not encouraged. All drugs, including Seroxat, unlicensed or studied for use in children carry the following standard statement in the SPC in relation to use, the warning reads

“Children: The use of [drug name] in children is not recommended as safety and efficacy have not been established in this population”.

In preparation for the November 21st 2002 ad hoc expert group meeting into the safety of SSRIs and in the wake of the first BBC Panorama Seroxat program, the CSM called a meeting with GSK on November 14th 2002 with the focus of implementing further changes required to the Seroxat product information in relation to withdrawal.  At this meeting the agency - obviously aware that GSK had carried out trials in the use of Seroxat in the paediatric population - asked about the status of clinical trials in children.

GSK provided an overview with regard the nine paediatric studies carried out between April 1994 and September 2002, declaring their proposal to submit a license application for the use of Seroxat for paediatric indications in late June 2003, although they did not raise concern about the lack of efficacy or adverse reactions; until licence was sought for paediatric use there was no requirement to submit paediatric study results.

The November 21st 2002 ad hoc CSM meeting with MHRA representatives and independent experts including Dr David Healy was planned to discuss issues relating to the SSRI drug class withdrawal reactions, although suicide and related events were also discussed, and recommendations made in relation to available safety data on adult use – as until this point the safe use in the paediatric population had not been officially raised.

January 2003, by this time the two members of the expert group panel had been singled out and the panel was under threat of a judicial review by the Seroxat Litigation lead lawyer Mark Harvey of Hugh James Solicitors. The MHRA presented recommendations to the CSM and they agreed further work on the SSRI issues was required, they formally agreed to establish a new Expert Working Group to Investigate the Safety of SSRIs in February 2003, the CSM expert group meeting planned for March 2003 was abandoned.

On February 28th 2003 - pre-empting the planned March 2003 CSM expert group meeting - GSK voluntarily sent the MHRA an update on clinical trial data in relation to suicidal behaviour, the submission included two sets of data analyses, both dated October 25th 2002.  The submission included both adult and paediatric study data, but did not differentiate between the two – as the paediatric participant numbers were far less than the adults, their data and the relevance of the evident safety signal was lost in final evaluation.

Unfortunately, the enforced delay and formation of the new and ‘acceptable’ Expert Working Group to Investigate the Safety of SSRIs postponed the requested clarification and separation of GSK’s information until May 21st 2003, at a second meeting the CSM called with them in advance of the planned first new Expert Working Group meeting on May 23rd 2003.

The new Expert Working Group called the second meeting with GSK - in the wake of the second BBC Panorama Seroxat program which aired May 11th 2003 - wanting to ensure all data relevant to Seroxat’s safety had been supplied and to discuss communications GSK may make with prescribing professionals. At this meeting GSK proffered briefing document relating to their intended application to extend indications for Seroxat to include use in children and drew the Agency’s attention to a safety issue which GSK had identified.

The significance of the GSK briefing document data provided robust evidence from controlled studies of a causal association between an SSRI and suicidal behaviour, previously refuted by some manufacturers. The safety concern GSK highlighted was indication of an increased rate of events relating to suicidal behaviour among paediatric patients with depressive illness treated with Seroxat, compared to placebo; GSK also stated the Agency might wish to bear this information in mind when considering the application for use in children.

In response to requests from the Agency GSK urgently submitted full clinical trial data in children on May 27th 2003, the increased risk of suicidal behaviour was drawn from pooled analysis of all the trials (a meta-analysis) and also failed to demonstrate that Seroxat was effective in the treatment of depressive illness in children and adolescents. The overall benefit-risk balance was not positive for treatment of depressive illness in under-18s, the CSM advised prompt communication and a letter issued June 10th 2003 to UK health professionals stating Seroxat should not be used for this indication.

The agency also advised GSK to submit a variation to UK marketing authorisations for Seroxat (Paroxetine Paxil) ‘contraindicating’ use for children and under-18’s.  Following this all other SSRIs were reviewed for safety and effectiveness in the treatment of depressive illness in children under 18 and adults, further advice statements were issued by the end of December 2003, first Fluvoxamine (Faverin Luvox) and then Citalopram (Cipramil Celexa), Escitalopram (Cipralex Lexapro) and Sertraline (Lustral Zoloft) were also ‘contraindicated’ for under-18s.

The Report of the CSM Expert Working Group published December 6th 2004 found all drugs in the SSRI class lacking efficacy and safety, simultaneously the National Institute for health and Clinical Excellence (NICE) published new Clinical Guidelines for the Treatment of Depression in adults, talking therapy, not drug therapy recommended for treatment of mild to moderate depression after a ‘watchful waiting’ period to facilitate possible self resolution.

The CSM Expert Working Group singled out Venlafaxine (Efexor Effexor) for its cardio toxicity, recommending cardiac monitoring for patients taking the drug and psychiatric practice prescription only - although this was discretely rescinded in 2006.

The CSM Expert Working Group also authorised Fluoxetine (Prozac Sarafem) -

a drug strongly indicated in many child and adult deaths by suicide and reported as causing similar side effects, adverse drug reactions and withdrawal symptoms as all other SSRI, SNRI drugs,
the drug Dr David Healy had corresponded with the MCA on November 4th 1999 with regard the suicide and paediatric increased prescription number issues -

for use in children and adolescents.

Until this point no antidepressant had been authorised or licensed for use in children, all prescribing of drugs of this type was off list and at the prescribing practitioners’ discretion.

Ironically - although it was widely reported that all drugs in the SSRI class bar Prozac were “banned” for children and under-18’s - in reality no SSRI is “banned” - to the contrary the investigation has resulted in one SSRI antidepressant drug being approved for paediatric use.

A drug has to be authorised and licensed for use before it can be “banned” - as no SSRI was approved, authorised or licensed for paediatric use in children and under-18’s, no SSRI has been “banned” - only ‘contraindicated' for use in treatment of depressive illness, and this is at the prescribing practitioners discretion as are most drugs – if they consider use of an SSRI drug would be beneficial to the patient, they can still prescribe any SSRI for the treatment of depression and any other indication - for any age group.

Clarified in the following quote from the MHRA website question and answers dated June 10th 2003,

ADVICE ON SEROXAT FROM THE COMMITTEE ON SAFETY OF MEDICINES

“ Q5. Is Seroxat licensed for the treatment of children and adolescents?

Seroxat has never been licensed for use in children and adolescents, however it is used in this age group outside its licence. Doctors may prescribe a medicine off licence if this is considered to be in the best interests of the patient.

Q6. My child is taking Seroxat for a condition other than depression – what should I do?

Seroxat has never been approved for use in children under the age of 18, however your child may have been prescribed Seroxat outside of its licence if their doctor considers it is the best treatment for their condition. If your child has been prescribed Seroxat for a reason other than depressive illness – e.g. obsessive compulsive disorder or an anxiety disorder, and you are concerned about their treatment, you should contact your doctor and discuss your concerns.”

Following GSK’s May 21st and 27th 2003 voluntary document disclosures and their highlighting of safety concerns, on October 1st 2003 the Pharmacovigilance Group of the Agency referred the matter to the their Enforcement Group for a criminal investigation, reportedly because GSK had been accused of withholding information, the investigation according to Social Audits’ Charles Medawar took up to a reported “30 man years” of MHRA time to complete – resulting in the report dated March 6th 2008 and the finding - no case to answer.

Presumably as other drugs in the SSRI class were also subjected to the hypothetical under-18’s “banning” during the CSM Expert Working Group investigation and all also found in the end report to be lacking in efficacy and safety in treatment of mild to moderate depression in adults - similar documentation with safety and efficacy anomalies appertaining to those drugs must have been found lodged with the Agency or newly disclosed by their manufacturers and reviewed - yet no other manufacturer was indicated or investigated for withholding information or not raising concerns about safety issues - only GSK.

The Seroxat litigation lawyer Mark Harvey of Hugh James Solicitors, BBC Panorama's Shelley Jofre and SUG Groups have claimed credit for the investigation into GSK, the hypothetical SSRI “banning” for under-18’s and the investigation by the CSM Expert Working Group into the Safety of SSRIs (Seroxat) as victories of their campaign against GSK and Seroxat – although any victory could be considered ineffectual and hollow.

Unfortunately, to my knowledge, the GSK full trail documents not being submitted to the CSM EWG review until May 27th 2003 and the ‘hypothetical’ Seroxat “ban” for under-18’s announcement not being made by the MHRA until June 10th 2003 has been blamed for being “to late” to avert at least one adolescent’s suicide in late May 2003.  Could this death possibly have been avoided?

It would not be unreasonable to consider that had the planned March 2003 meeting not been intercepted and delayed by the Seroxat Litigation Lead Lawyer Mark Harvey and the SUG Groups - the May 2003 Expert Working Groups request for GSK's full paediatric trial results made on the same evidence initially presented in meetings between the CSM expert group , MHRA and GSK in November 2002 would have been made earlier – likewise the decision to contraindicate Seroxat for under-18’s and the June 2003 announcement could have been made in April 2003 and the late May 2003 suicide possibly averted.

Undoubtedly the first Panorama program brought focus to the SSRI issue and the November 21st 2002 CSM ad hoc meeting in its wake considered the class wide issue with the seriousness it deserved – however, the program effectively facilitated the hijacking of a drug class problem - which, according to UK National Prescription Cost Analysis statistics is ongoing and increasing - making it appear to be solely a problem with Seroxat.

This impression was reinforced by the second BBC Panorama Seroxat programs May11th 2003 airing, timed to precede the first meeting of the new CSM Expert Working Group and by Solicitors Hugh James’ Mark Harvey using the threat of a “judicial review” to attain compliance to their demands that the original expert group review panel be dissolved and GSK investigated.

This takeover and disregarding of the established ongoing 1998 investigation into the SSRI drug class - along with the efforts of the original expert group, Dr David Healy and others in raising awareness about the SSRI, SNRI drug class and their achievements in getting the withdrawal and suicide issues recognised and acknowledged by the UK MCA and CSM, and the EU PhVWP, all whom acted to implement amendments to both SPCs and PILs to include warning clarification with regard both issues by December 2001 – has, it appears, achieved little to address the drug class problems or stem the perpetually escalating numbers of SSRI, SNRI drug class prescriptions being issued.

Was the investigation into GSK instigated solely on complaints from the anti GSK, Seroxat litigation contingency and for what purpose - and could the MHRA’s “30 man years” have been better spent?


 “On the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants” published December 2004

“2.2 Suicidal behaviour in association with SSRIs

In the UK, this issue was first reviewed by the CSM following publication of a case series by Teicher et al (1990)[7] which stimulated scientific debate and intense media interest. In 1992, following further review, an article was published in the 'Current Problems in Pharmacovigilance' which stated "there is little to support the suggestion that fluoxetine induces suicidal or aggressive behaviour"[8].

Following close monitoring of spontaneous suspected adverse drug reaction reports, there was a UK exercise in 1998-2000 to develop harmonised safety information for all SSRIs. During this process, the CSM advised that the summary of product characteristics (SPC) should reflect the general clinical experience that suicidal behaviour may increase in the early stages of treatment with any antidepressant.

Dr (now Professor) David Healy raised the issue of suicidal behaviour with SSRIs in his publication ‘A Failure to Warn’ in 1999[9]. Concerns were also raised that SSRIs may be associated with the development of psychomotor restlessness/akathisia-like restlessness, which in turn may precipitate agitation and suicidal behaviour[10].

The CSM considered the available data in June 2000 and concluded that it was impossible to answer the question of whether SSRIs caused suicidal behaviour in a small subpopulation of patients. It was decided that the issue should be kept under review and formally reviewed every two to three years.

The CSM advised that patient information leaflets for the SSRIs, as with any antidepressants, should be updated to include a warning that suicidal thoughts may occur or increase in the early stages of treatment and that urgent medical advice should be sought in the event of such symptoms.

The UK presented the assessment on suicidal behaviour with SSRIs to the Pharmacovigilance Working Party (PhVWP) in 2000. All EU member states agreed with the scientific conclusions of the UK assessment.

The CSM considered data relating to suicidal behaviour, aggression and akathisia in December 2001 and concluded that:
• the evidence was not sufficient to confirm a causal association between SSRIs and suicidal behaviour, although an effect in a small high-risk population could not be ruled out;
• the risk of akathisia occurring in association with treatment should be added to the SPCs of all SSRIs.
This assessment report was then discussed at the PhVWP which agreed with the conclusions of the UK assessment report but considered that further discussion was required about the definition of the term akathisia.

On 21 November 2002, a group of CSM and external experts was called together to hear Dr (now Professor) David Healy present his research in relation to suicidal behaviour, including a reanalysis of human volunteer studies on fluoxetine.

The conclusions of this meeting were that:
• the evidence presented did not justify a change to the regulatory position;
• changes to the UK Seroxat PIL were required to clarify warnings on withdrawal reactions.
The meeting recommended the following further work to investigate suicidal behaviour:
• a study using the GPRD;
• reanalysis of clinical trial data on fluoxetine.

A further meeting of this expert group had been planned for March 2003. However, the Seroxat User Group, a group of 4,000 patients and former patients, called into question the independence of the members of the group in view of declarations of interest in the pharmaceutical industry by two members. Following legal advice, the meeting in March was cancelled and the group dissolved. It was important that this work was continued, and in May 2003 the CSM established its Expert Working Group on the Safety of SSRIs.”

CMS EWG Quote References
1 - Lejoyeux M et al (1996) ‘Antidepressant withdrawal syndromes’ CNS Drugs 5: 278-292.
2 - Stoukides J A & Stoukides C A (1991) ‘Extrapyramidal symptoms upon discontinuation of fluoxetine (letter).’ Am J Psychiatry 148(9): 1263.
3 - MCA/CSM (1993) Current Problems in Pharmacovigilance 19.
4 - Medawar C (1997) ‘The Antidepressant Web.’ Int J Risk Safety Med 10: 75-126.
5 - http://www.emea.eu.int/pdfs/human/press/pp/277599en.pdf
6 - MCA/CSM (2000) Current Problems in Pharmacovigilance 26
7 - Teicher MH et al (1990) ‘Emergence of intense suicidal preoccupation during fluoxetine treatment.’ Am J Psychiatry 147:207-210
8 - MCA/CSM (1992) Current Problems in Pharmacovigilance 18.
9 - Healy D (1999): ‘A Failure to Warn [editorial].’ Int J Risk Safety Med 12: 151-6
10 - Lane RM (1998). ‘SSRI-induced extrapyramidal side effects and akathisia: implications for treatment.’ J
Psychopharmacology. 12: 192-214.