Monday, 18 October 2010

Is the Seroxat Group Action Litigation Order no: 68 Compromised by its Own Defining Issue?

The UK Seroxat Group Action Litigation, Order No:68, is being brought under the Consumer Protection Act 1987 (CPA)
“A product is defective if, at the time of circulation, it is not as "safe as persons generally are entitled to expect," taking account of a number of factors including any instructions or warnings provided with the product and the manner in which it has been marketed.”
In proving a case of a “defective product” the only need is to show the product – in this case GlaxoSmithKline’s (GSK) drug Seroxat (Seroxat UK, Paxil USA) - was not up to consumers’ expectations.

However, lead Lawyer Mark Harvey of Hugh James Solicitors, Cardiff has chosen to include a Defining Issue stipulation that any adverse effects and discontinuation, withdrawal difficulties suffered by the Seroxat “user” has to be
“to a greater extent than all other Selective Serotonin Re-uptake Inhibitors (SSRIs)”
HM Courts Service: Seroxat Group Litigation Order no: 68.
The report of the Committee on Safety of Medicines (CSM), Expert Working Group (EWG) on SSRI Antidepressants, published December 2004, found all drugs in the class lacking in safety, efficacy and causing discontinuation problems in up to 80% of consumers.

It’s unclear why the “stipulation” has been included, as The CSM Expert Working Group report on all SSRI Antidepressants effectively proved the Group Action litigants case against GSK by finding their product Seroxat not being as "safe as persons generally are entitled to expect,".

December 2004, Seroxat Group Action Litigation case proved and won -

baring lead lawyer Mark Harvey’s inclusion of the apparently unnecessary and possibly untenable Defining Issue “stipulation”.

To prove the Seroxat Group Action by justifying the included “stipulation” raises the need to examine criteria that differentiate the drugs in the SSRI, SNRI class within the restricted Defining Issue of discontinuation, withdrawal and drug classification.

This depends on the two theories of what causes discontinuation and withdrawal and the issues of selectivity nature, affinity and potency; dose related drug action classification; definition by acronym classification; and external evidence.

All interrelate, and other than the issue of selectivity nature, affinity and potency, focus on two drugs in the class the SSRI paroxetine (Seroxat) and SNRI venlafaxine (Wyeth, Efexor UK, Effexor USA).

The CSM EWG into SSRI Antidepressants used pharmacological characteristics and the 1999 Tatsumi et al study to compare Half-life and the Potency and Affinity of the drugs on the central nervous system neurotransmitters. Finding all drugs have binding affinities to different monoamine transporters, primary effects on different receptors and cause secondary changes in receptor numbers and receptor function at the synapse.

1 - The issue of selectivity nature, affinity and potency is the most complicated – defining whether Seroxat is worse than any other drug in the class by comparing drugs with different intrinsic values that despite their acronym name classification titles i.e. SSRI, SNRI etc - are not “pharmacologically “clean”” or defined in action of selectivity “to the Serotonin system”, all also affecting to varying degrees noradrenalin and dopamine.  This aspect is covered in more detail here.
The Tatsumi et al study results are valued using Kd or dissociated constant – as explained on the table the lower the Kd the higher the affinity to the transporter.

Affinity Kd ratings show –
Paroxetine (Seroxat) has the highest affinity to Serotonin at 0.1 - just point 0.2 higher that Sertraline (Pfizer, Lustral UK, Zoloft USA) the second highest at 0.3.

Potency findings published by CSM, EWG are not clear because they have not stated whether they are rating Potency on the Affinity to Serotonin alone or Serotonin (5HT), Noradrenalin (NA) and dopamine (DA).

Potency rating show –
Paroxetine (Seroxat) is the “most potent” with the “lowest selectivity” and Sertraline (Lustral) the “second most potent”.

However, when comparing the Affinity and Potency with other drugs in the class - that all to varying degrees effect 5HT, NA and DA and as Paroxetine (Seroxat) is the least selective and only has a negligible 0.2 higher Affinity to Serotonin than Sertraline (Lustral), total Affinity and Potency Kd values to 5HT, NA and DA could be used to assess this point.

Combined Kd Affinity and Potency values to Serotonin (5HT), Noradrenalin (NA) and Dopamine (DA) show –
Sertraline (Lustral) has the highest combined Affinity and Potency with a Kd 445.3 and the least selective Paroxetine (Seroxat) is second highest with a combined Kd of 530.1.

2 - The two theories of what causes discontinuation and withdrawal is explained by Dr David Healy in the “HALTING SSRIs” document, one theory is the shorter half-life of paroxetine (Seroxat) and venlafaxine (Efexor) makes these drugs more problematic, the second theory is regarding the potency of paroxetine and venlafaxine. This aspect is covered in more detail here.

If according to the first theory - which includes a switch to fluoxetine (Ely Lilly Prozac UK and USA) Half-life 1 to 4 days - the cause of discontinuation and withdrawal is dependant on the shortness of Half-life - venlafaxine (Efexor) has the shortest Half-life of 5 hours - paroxetine (Seroxat) is considerably longer at 20 hours.

The second theory - which includes a switch to citalopram (Lundbeck, Cipramil, Celexa) Kd 1.2 - with regard paroxetine (Seroxat) and venlafaxine (Efexor) being “relatively more potent serotonin reuptake inhibitors” is possibly itself called into question by the findings of the CSM, EWG and Tatsumi et al study as venlafaxine has a Kd value of 152 making it, other than mirtazapine, the least “potent serotonin reuptake inhibitor” of the drugs studied.

This possibly places the whole onus of discontinuation and withdrawal problems inherent with all drugs in the SSRI, SNRI class back on a drugs Half-life as citalopram’s Half-life at 36 hours, is longer than both paroxetine (Seroxat) and venlafaxine (Efexor) – and would possibly benefit some as with the fluoxetine switch.

3 - The dose related drug action classification issue, Wyeth are the only manufacturer of those drugs studied to have specified that their drug works on more than one neurotransmitter, however it is the opinion of Dr David Healy in the “HALTING SSRIs” document and the MHRA that although Venlafaxine is named by the acronym SNRI it’s mode of action is that of an SSRI up to doses of 150 mg, over this it has an additional mode of action to become a serotonin and noradrenalin reuptake inhibitor. This aspect is covered in more detail here

4 - The drug definition by acronym classification title by definition the difference between an SSRI and an SNRI should be dependant on selectivity and potency of action i.e. to serotonin or noradrenalin. In the case of the SSRI, SNRI drug class no drug is “selective” to one monoamine transporter, all drugs effect serotonin and noradrenalin, paroxetine (Seroxat) with Kd of 40 to the noradrenalin transporter has a considerably higher affinity than venlafaxine at a NA of Kd 9400. This aspect is covered in more detail here.

5 - The issue of external evidence, as covered briefly here is dependant on the MHRA, Yellow Card Scheme adverse drug reports and media coverage that has influenced those reports. The MHRA has received considerably more adverse event reports for paroxetine (Seroxat) than any other drug in the class, however, the December 2004 CSM). EWG Report drew attention to the influence of the media coverage and a number of obviously duplicated reports made with regard paroxetine (Seroxat) and it has been noted that BBC Panorama published and issued it’s own Yellow Cards that were accepted by the MHRA.

I will return to the influence of media coverage, the BBC, Panorama, UK Government officials and departments, the Seroxat User and Hugh James Solicitors in more depth in future posts - but the media coverage has had a profound influence on this aspect, as the Richard M Martin, Margaret May, and David Gunnell, Department of Social Medicine, University of Bristol study “Did intense adverse media publicity impact on prescribing of paroxetine and the notification of suspected adverse drug reactions? Analysis of routine databases, 2001–2004” shows.

Is the UK Seroxat Group Action Litigation, Order No:68 compromised by Lead Lawyer of Hugh James, Cardiff, Mark Harvey’s included Defining Issue “stipulation”?

1 - Does an Affinity and Potency to serotonin of Kd 0.2 higher than Sertraline (Lustral) make Paroxetine (Seroxat) the worst drug in the class …. or does the highest combined Affinity and Potency Kd to serotonin, noradrenalin and dopamine make Sertraline (Lustral) a worse drug than the least selective Paroxetine (Seroxat)?

2 - If the theory is that discontinuation and withdrawal is caused by the drugs short Half-life …. does SNRI venlafaxine’s (Efexor) half-life of 5 hours make it more difficult to withdraw from than the SSRI Paroxetine’s (Seroxat)?
3 - Is Wyeth’s honest mode of action classification of venlafaxine (Efexor) being an Serotonin Noradrenalin Reuptake Inhibitor (SNRI), although acting as an Selective Serotonin Reuptake Inhibitor (SSRI) in doses up to 150 mg, likely to be disregarded as the SSRI Paroxetine’s (Seroxat) has the highest Affinity and Potency Kd to noradrenalin of any SSRI, SNRI studied?

4 - Can a drugs classification be defined by a catchy marketing tool or will the acronym SNRI be overruled by the scientific facts?

5 – Has the unprecedented media coverage and in particular the BBC’s Panorama issued Yellow Cards damaged the integrity of the MHRA, the system and the case dependant adverse events report evidence?

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