Dear Mrs Simmonds,

Thank you for your letter of 12 February. We have decided to pursue our complaint against GlaxoSmithKline, notably in relation to the "Reactive Key Messages and Issues Document" dated 19 December 2001. Our reasons are essentially as stated in our letter to you of 1 August 2002. It was disappointing you decided not to consider them as an integral part of our earlier complaint, all the more so when you say it is now up to us to take the initiative to have these statements reviewed. It’s down to the PMCOPA, not us, to see the Code upheld.

1. Our starting point is that GSK knew, or ought to have known, [a] that significant numbers of Seroxat users find it both difficult and distressing to stop taking this drug when they decide to do so – even when they gradually reduce the dosage over long periods of time; [b] that significant numbers of users are not advised by their doctors that this may be so; [c] that the dangers of mistaking withdrawal symptoms for relapse are real; and above all [d] that deep misunderstandings surrounding the meaning of "dependence". We have supplied ample evidence of these problems and the reasons for them, both in citations from learned journals and in testimony from patients. Unless GSK disputes any of the above, we will not overload you.

2. The World Health Organisation continues to express concern about the situation. The WHO Uppsala Monitoring Centre’s database of ADRs identifies paroxetine above all other drugs as causing withdrawal symptoms indicative of "dependence" – and WHO is also concerned about the confusion that surrounds this word "dependence" 

"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)

At its meeting on 27 September 2002, (which I attended by invitation), the WHO Expert Committee on Drug Dependence again drew attention to this problem, and will shortly publish a report specifically on this problem.

The above WHO statement generally accords with public understanding. People generally consider and describe themselves "addicted" to or "dependent" on a drug when they try hard to stop taking it and find they can’t. Many users say they have experienced this with paroxetine and other SSRIs.

3. GlaxoSmithKline have gone out of their way to emphasise that Seroxat is "non habit-forming," not "addictive" and not a drug of "dependence." They did so in the GSK "Reactive Key Messages and Issues document." This is an important document that should have been prepared with "particular care" – a direct link between the company and the consumers of its products, and the public at large. We complain specifically about the following statements and claims:

4. "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."
Complaint: The categorical statement, "Seroxat is not addictive", in the absence of any qualification, is highly misleading. The assertion, "Seroxat is clearly shown as being neither addictive nor causing dependence" is also highly misleading and inconsistent with the SPC. No such thing has been "clearly shown": the lack of available evidence clearly precludes any such statement (EMEA, 2000). This is tantamount to claiming a drug is "Safe", without qualification. This categorical denial of risk is inappropriate: it should at least be as circumspect as the message relayed to health professionals, in the SPC. The EMEA/CPMP (2000) found: "The available clinical evidence does not suggest that the SSRIs cause dependence. However the lack of evidence does not prove the absence of a problem…"; "For the majority of compounds, evidence from well-designed preclinical studies with respect to dependency and withdrawal was incomplete …"; "The available preclinical and clinical evidence does not suggest that SSRIs cause dependence."

5. "Discontinuation symptoms are completely different to addiction or dependence …"
Complaints: Use of the term "discontinuation symptoms" is inappropriate and highly misleading – in suggesting that the symptoms experienced on stopping medication are different from "withdrawal symptoms," which they are not. Persistent use of the term "discontinuation" 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 (26 March 1998) concluded, "that it would be inappropriate to change medical terminology in this way." In effect, the Company is claiming that the symptoms experienced when trying to stop taking the drug are not withdrawal symptoms at all. This is clearly not true. The whole point of the regulatory decisions by EMEA and the CSM is that withdrawal symptoms and discontinuation symptoms should not be differentiated – which GSK has persisted in doing.

6. "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."
Complaint: 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.

7. "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." Complaint: GSK again relies on lack of evidence to make exaggerated and misleading assertions. Nor are they accurate. In fact, dependence syndrome has been reported for all SSRIs through the Uppsala Monitoring Centre (UMC), and paroxetine (with fluoxetine and sertraline) are among the top 30 drugs for which drug dependence has ever been reported to the UMC (To June 2002). See Table.

Drug name	Withdrawal syndrome reports (ws)	Drug dependence reports (dd)	Ratio (%) dd/ws
Fluoxetine	419	109	26.0
Sertraline	631	69	10.9
Mirtazapine	17	1	5.9
Fluvoxamine	69	4	5.8
Nefazodone	83	4	4.8
Paroxetine	2,380	91	3.8
Citalopram	107	3	2.8
Venlafaxine	1,185	13	1.1

There is also some evidence of abuse from the US 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: In 2000, the most frequently mentioned SSRIs (Table 2.4.0) were: Citalopram (3,458 mentions), which more than doubled from 1999 to 2000; Sertraline (6,670 mentions in 2000), which was unchanged from the previous 2 years; Fluoxetine (7,939 mentions), which decreased 19 percent from 1998 to 2000; and Paroxetine (8,020 mentions), which rose 105 percent from 1994 to 2000.

8. "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."
Complaint: 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.

9. The messages in the GSK "Reactive Key Messages and Issues document" demonstrate pedantic and unyielding reliance on technical definitions and interpretations that almost defy public understanding. These messages fail to recognise and address the widespread and evident controversy and confusion over definitions and meanings, as explained above. They fall far short of Code requirements to provide clear, reliable and balanced information, as specified below. Specifically, we contend that this company brief falls short of Code requirements in Relevant code provisions include the following:

"…. All promotion-making claims concerning medicinal drugs should be reliable, accurate, truthful, informative, balanced, up-to-date, capable of substantiation and in good taste. They should not contain misleading or unverifiable statements or omissions likely to induce medically unjustifiable drug use or to give rise to undue risks …." (Article 7: World Health Organisation, Ethical criteria for medicinal drug promotion, 1998).

"Information must be provided with objectivity, truthfulness and in good taste accurate, fair and objective and presented in such a way as to conform … to high ethical standards" (I.2) … based on an up-to-date evaluation of evidence that is scientifically valid and should not give an incorrect or misleading impression (I.3) …"… in "Communications to the Public" … all information "should be accurate, fair and not misleading", and companies "should adhere to the highest standards of accuracy". (I.7). IFPMA Code

"Information about medicinal products must be accurate, balanced, fair, objective and sufficiently complete to enable the recipient to form his or her own opinion of the therapeutic value of the medicinal product concerned. It should be based on an up-to-date evaluation of scientific evidence and reflect that evidence clearly. It must not mislead by distortion, undue emphasis, omission or in any other way." (EFPIA Code, Article 3)

"Information, claims and comparisons must be accurate, balanced, fair, objective and unambiguous and must be based on an up-to-date evaluation of all evidence and reflect that evidence clearly. They must not mislead either directly or by implication." (ABPI Code, clause 7.2)

"Information about medicines made available to the public .. must be … presented in a balanced way … and must not … be misleading with respect to the safety of the product" (ABPI Code, clause 20.2)

As stated above, use of the term "discontinuation symptoms" instead of withdrawal symptoms" is inconsistent with the SPC. The Company would not be allowed to use the term "discontinuation symptoms" in statements directed to prescribers. It is a flagrant breach of both the spirit and letter of the Code to do so in communication (via the press and media)with consumers. (ABPI Code, clause 3.2)

10. In our previous complaint, we offered to drop our Appeal if GlaxoSmithKline accepted the need to properly address the problems we have described. These have become progressively more serious and widespread over the years. The Company has failed to rise to the occasion, and the promotional materials about which we complain give evidence of an established pattern of unacceptable behaviour. On these grounds, we wish to complain, under Clause 2 of the Code, that GSK has been and is involved in promotional activities that "bring discredit upon, or reduce confidence in, the pharmaceutical industry."

References and further data on which we rely was provided in our letter to you of 1 August 2002.

Yours sincerely,
Charles Medawar                             cc: Dr David Healy, Dr Andrew Herxheimer, Anne Winyard

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