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

Thank you for your letter of 22 July, advising us of the outcome of the Panel’s consideration of our complaint. This letter gives notice that we have decided to appeal and outlines the basis on which we shall do so. We rely on all evidence previously offered as well as one or two new pieces, together with the following observations and clarifications.

This will be our second appearance before the Appeal Board in less than a year; we should therefore explain why we are pursuing this complaint. It is not because of the wording of one clause or another, nor to do with the niggling detail of who said what and how. The point is, there is a problem with paroxetine and similar drugs and that both the cause and remedy have everything to do with honest communication of precisely the kind the Code of Practice says it requires.

It is now clear that SSRI and related antidepressants, and paroxetine in particular, induce withdrawal symptoms of sufficient severity and frequency to cause unprecedented levels of adverse reports from doctors and patients. We offer as new evidence (See Appendix) data from the Medicines Control Agency, showing the number of Yellow Cards sent in (to July 2002) for the top 20 drugs suspected of causing withdrawal reactions. The absolute numbers are almost meaningless, but the ranking order clearly indicates a problem: Paroxetine is top of the list, in a league of its own, and five of the top six drugs are SSRI/SRNIs.

We contend that reports from users, collectively, are of real value in helping to understanding the aetiology and nature of this problem, also in pointing towards solutions. The people who wrote to us, and many like them, will not be happy to learn that the company proposes to bury their problems in some database, loftily declining to offer any comment on their overall meaning, murmuring about bias, invalidity, lack of reliability and the impossibilities of verification. Here we are in this brave new world of transparency, "concordance" and "The Expert Patient" (ABPI, 2000), teetering on the brink of trusting companies enough not to fear Direct-To-Consumer Advertising - and there is the biggest pharmaceutical company in Europe, simply saying it doesn’t want to know. We ask the Appeal Board to rule that users’ comments may be counted as admissible evidence under the Code, and to request GSK to give a proper account of its assessment of their meaning.

We believe these comments point to a deep and dangerous misunderstanding that now exists and think it reasonable to request the Company takes steps to remedy the persisting failures of communication that will only make it worse. The nub of the problem is that the company is relying on a definition of "dependence" that is profoundly confusing to users and probably many doctors as well.

That is not surprising because the word "dependence" was recently radically redefined. Until the 1990s, health professionals understood that withdrawal symptoms on their own signalled "dependence" – just as users knew that not being able to stop a drug, especially after repeated and determined attempts, signalled that the drug was habit forming and that the user might feel addicted or hooked. Then the definition was radically changed: suddenly "dependence" meant there had to be other features of drug abuse, as explained in our original complaint. It is clear that there is great scope for confusion and we contend that the company’s response is seriously deficient in not addressing such an obvious and important point. GSK surely realises that the definition they rely on is widely misunderstood, but they do not acknowledge the possibility at all.

The company has simply not responded to the WHO statement (1998) cited in our complaint, that the SSRIs may indeed be drugs of dependence even within the formal definitions that now apply. Does GSK accept this; if not why not?

"There is obviously some confusion about the concept of dependence ... The simplest definition of drug dependence given by WHO is 'a need for repeated doses of the drug to feel good or to avoid feeling bad' (WHO, Lexicon of alcohol and drug terms, 1994). When the patient needs to take repeated doses of the drug to avoid bad feelings caused by withdrawal reactions, the person is dependent on the drug. Those who have difficulty coming off the drug even with the help of tapered discontinuation should be regarded as dependent, unless a relapse into depression is the reason for their inability to stop the antidepressant medication.

… In general, all unpleasant withdrawal reactions have a certain potential to induce dependence and this risk may vary from person to person. Dependence will not occur if the withdrawal symptoms are so mild that all patients can easily tolerate them. With increasing severity, the likelihood of withdrawal reactions leading to dependence also increases …" (WHO Drug Information, 1998)

We invite members of the Appeal Board to take account of what members of the public might infer, when assured that a drug is not habit forming, addictive or liable to cause dependence. We also offer as evidence of the existence of some sort of "dependence" problem with paroxetine – and confusion over meanings - the definition relied on by DAWN. This is the nationwide Drug Abuse Warning Network operated by the Substance Abuse and Mental Health Services Administration of the US Department of Health & Human Services:

"Dependence: A physiological or psychological condition characterized by a compulsion to take the drug on a continuous or periodic basis in order to experience its effects or to avoid the discomfort of its absence (e.g., had to take, had to have, needed a fix)"

If GSK completely rejects this interpretation – which seems to us to pretty much reflect public understanding - it should explain why. Why does the company see no need to need to clarify its meaning, and to reduce the high likelihood of misunderstandings, given the relevant requirements of the Code? Why does it rely instead on a narrow interpretation by the two authors of a BMJ article (especially when they failed to disclose that they were echoing the views of a seven strong "Consensus Panel" convened by Eli Lilly & Co, the manufacturers of Prozac)?

It seems unacceptable that resolution of this issue through self-regulation should stand or fall on the question of exactly what Mr. Chandler said. On the balance of probabilities, he clearly conveyed to the journalist in question that what some paroxetine users felt to be a problem was barely a problem at all. Assuming he followed the brief in the GSK "Reactive Key Messages and Issues Document" (19 December 2001), that is certainly what he would have wanted to convey.

In our original complaint (relating to Clause 7.2), we conceded that Mr Chandler’s statement that, "there is no scientific evidence that Seroxat leads to addiction and dependency" was not inconsistent with the SPC – though we thought it unfair, ambiguous and misleading, especially when directed to a lay readership. We still do, contending that Clause 3.2 of the ABPI does not override the above requirements – i.e. that concordance with the Summary of Product Characteristics is necessary, but not in itself sufficient for compliance with the ABPI Code. ("The promotion of a medicine must be in accordance with the terms of its marketing authorization and must not be inconsistent with the particulars listed in its summary of product characteristics"). This distinction appears to have been lost on the company: "the information in our briefing document is consistent with our Seroxat SmPC and published data, being a factual and balanced document, which underwent the required internal approval process." We invite the Appeal Board to rule that this clause is intended to mean that product information must comply with statutory requirements, not that compliance with this provision satisfies the requirements of the Code provisions cited above.

Interpreting the Code in this spirit, we contend that the brief on which Mr. Chandler would have relied ("Reactive Key Messages and Issues Document" - 19 December 2001) is itself in breach of Code requirements, in several respects: 

• "Discontinuation symptoms are completely different to addiction or dependence …"

Comment: This is highly misleading for reasons stated; it also demonstrates the blurring of meaning achieved with the word, "discontinuation". Withdrawal symptoms are a prime indicator of dependence (WHO, 1998) and, in the formal definition used until 1990, were in themselves sufficient for a formal diagnosis of ‘dependence’.

The company increases the risk of misleading drug users and prescribers by persisting in use of the term "discontinuation". This is not consistent with the SPC (Clause 3.2). The EMEA (2000) evaluation on which GSK otherwise relies states: "The term ‘withdrawal reactions’ should be used, not ‘discontinuation reactions’, as has been proposed by some marketing authorisation holders." Similarly, the CSM/MCA (1998) concluded, "that it would be inappropriate to change medical terminology in this way." In effect, the Company is claiming: "Withdrawal symptoms are completely different to addiction or dependence". This is clearly not true.

• "The European Regulatory Body the CPMP (Committee for Proprietary Medicinal Products) 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 MCA (Medicine Control Agency) and CPMP have concluded that SSRIs do not cause dependency/addiction."

Comment: again this statement is misleading, in the absence of any qualification. For lack of evidence, both the CSM and the EMEA were a great deal more tentative in their conclusions than the company. GSK has wrongly concluded that lack of clear evidence of dependence is equivalent to clear evidence of lack of dependence.

Comment: GSK again relies on lack of evidence to make exaggerated assertions. It is also inaccurate. There is, for example, reliable evidence of abuse from the afore-mentioned Drug Abuse Warning Network. DAWN has recently published tabulations of reports received from a sample of hospitals operating 24-hour Emergency Departments, in 21 US metropolitan areas, of episodes involving deliberate use of prescribed/diverted pharmaceutical products. (Excluded are accidental overdose or adverse reactions, unless these occurred in combination with an illicit drug). Benzodiazepines accounted for 8% of mentions; antidepressants for 6% of mentions:

-Sertraline (6,670 mentions in 2000), which was unchanged from the previous 2 years."

• "As recommended by the British National Formulary (BNF) and the European Medicines Evaluation Agency (EMEA), the likelihood of discontinuation symptoms is minimised by gradually tapering the daily dose."

Comment: Neither the BNF nor the EMEA statement uses the word ‘minimise’. It is inappropriate because it adds to the impression that withdrawal reactions may readily be controlled although, "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). The BNF proposes a six months taper in patients ending long-term treatment: that makes it quite clear that it can be very hard to stop, even if many people manage well.

In short, we are suggesting that whatever Mr Chandler said, it would have reflected some of the lack of balance, misleading information and partial interpretation in the company’s briefing document, "Reactive Key Messages and Issues Document" (19 December 2001).

Finally, we contend that the finding in favour of the company, on the grounds that the Panel was unable to determine precisely what had been said, is unjustified for the following reasons:

Returning to the point we made at the outset, we emphasise that we would readily drop this appeal if GlaxoSmithKline accepted the need to properly address the problems that now exist and agreed to take prompt and effective steps to deal with them. Failing this, we would wish to pursue our complaint, notably under Clause 2 of the Code, relating to promotional activities that "bring discredit upon, or reduce confidence in, the pharmaceutical industry." Now having seen the promotional materials ("Reactive Key Messages and Issues Document" of 19 December 2001), which guided Mr. Chandler, and on which the Company generally relies, we are more than ever convinced of an established pattern of unacceptable behaviour.

I appreciate that the appeal process follows a strict time schedule, but please note that I shall be out of circulation until 2^nd September.

Yours sincerely,
Charles Medawar

ADROIT: Medicines Control Agency drug analysis print July 3^rd 2002.

EMEA/CPMP: Position Paper on Selective Serotonin Uptake Inhibitors (SSRIs) and Dependency/Withdrawal Reactions, EMEA/CPMP/2775/99, (London: European Medicines Evaluation Agency, Committee on Proprietary Medicinal Products, 12 April, 2000).

P. Haddad, Antidepressant discontinuation syndromes, Drug Safety, 2001, 24(3), 183-197.

International Federation of Pharmaceutical Manufacturers Associations, Self-Regulation of Marketing Practices (Geneva: IFPMA, 1997), Code of Pharmaceutical Marketing Practices (1982-2001); .

World Health Organisation: Ethical Criteria for medicinal drug promotion (Geneva, WHO, 1988)

World Health Organisation: WHO Drug Information, 1998, 12, 3, 136-138.