Social Audit Ltd
P.O. Box 111 London NW1 8XG
Telephone/Fax: 0207 586 7771
mail@socialaudit.org.uk and http://www.socialaudit.org.uk
http://www.socialaudit.org.uk/4632-XSA.htm#Dear
Heather Simmonds, Director
Prescription Medicines Code of Practice Authority
12 Whitehall
London SW1A 2DY
20 May 2002
Dear Mrs Simmonds,
We wish to make a formal complaint under the Code of Practice for the Pharmaceutical Industry about statements relating to the safety of Seroxat (paroxetine, GlaxoSmithKline) made on behalf of the company by Mr. Alan Chandler, Director of Corporate Media UK. In considering this case, we ask the Code of Practice Authority to take into account the circumstances and outcome of our previous complaint about this company Case AUTH/IFPMA/5/7/01 Statements about Paxil (IFPMA Reference C2001101) which related to comparably misleading statements made about the same drug.
1. In an article by Anastasia Stephens in The Independent of 1st October 2001, Mr Chandler was reported as saying (of paroxetine and other SSRIs) "Theres no reliable scientific evidence to show they cause withdrawal symptoms or dependency." I telephoned him on 3rd October to ask if he had been accurately quoted. He confirmed he had: "Absolutely, Anastasia reported exactly what I said". I then wrote to Mr Chandler, asking him to substantiate his statement, "by reference to any authoritative body of opinion in agreement with you or failing that, by any medically qualified person within GlaxoSmithKline PLC"
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 we did not pursue the issue, as Social Audit was then engaged in the aforementioned complaint against GSKs Dr David Wheadon, who had claimed that withdrawal reactions from paroxetine were very rare. We did produce Mr Chandlers statement and response at the Appeal Board hearing, but no adjudication was involved.
2. We would have left it at that, had we not seen reported comments of the same general kind, attributed to Mr Chandler, reported by Catherine Jackson (Editor) in an article in the April 2002 issue of Mental Health Today: "You have a product thats 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 [doctor and patient information leaflets] 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"
I wrote to Mr Chandler again, on 7 April 2002, asking him to confirm he had been accurately quoted. Three weeks later, I wrote again with the same request, as I had received no response. Mr Chandler replied on 3rd May. He declined either to confirm or deny the remarks attributed to him. It was open to him to deny he would ever have said anything like, "there have been one or two reports of discontinuation symptoms with abrupt cessation", but he did not. That statement is misleading and unacceptable for reasons explained and amply documented in our earlier complaint. As Mr Chandler knew, or ought to have known, withdrawal reactions indicative of dependence have been reported with paroxetine (e.g. to the WHO Centre at Uppsala and to the Medicines Control Agency) more than any other drug.
3. The statements complained of clearly violate Article 7 of the WHO Ethical Criteria ". 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 ." These statements also fall short of the requirements of the IFPMA Code: "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) "
We have previously supplied both the Authority and the Company with evidence of our concerns relating to the nature, extent and severity of withdrawal symptoms and dependence with paroxetine in particular, the monograph (Medawar, 1997) published in the International Journal of Risk and Safety of Medicine and the further evidence reported (1997-2001) on our website, The Antidepressant Web. However, we outline below the facts that persuade us that the Company is in breach of several provisions of the ABPI Code of Practice, under which this complaint is made.
3.2 "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"
The statement, "There have been one or two reports of discontinuation symptoms with abrupt cessation" especially in the context of a reference to tens of millions of satisfied users is tantamount to claiming that withdrawal reactions are very rare (traditionally, <1:10,000). Though the Summary of Product Characteristics does not put a figure on the incidence, all available evidence indicates this is a grotesquely misleading under-estimate. The EMEA/CPMP position paper published in April 2000, acknowledged that withdrawal reactions were "well-recognised." They also stated that the term 'withdrawal reactions' should be used, not 'discontinuation reactions' as has been proposed by some marketing authorisation holders". The incidence of withdrawal reactions reported in the US label since modification by the FDA in late 2001 is greater than 1:100 and should therefore be described as "common". The implication that withdrawal symptoms occur only with "abrupt cessation" is unwarranted.
7.2 "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."
Mr. Chandlers statement that, "there is no scientific evidence that Seroxat leads to addiction and dependency" is not inconsistent with the SPC. But we contend it is unfair, ambiguous and misleading, all the more so as a statement directed to a lay readership. The assertion that paroxetine is not a drug of dependence relies on [a] the lack of evidence to which EMEA/CPMP referred; and [b] a studiedly narrow and inappropriate interpretation of the definition in the 10th edition of the International Classification of Diseases. See Appendix One.
Since publication of the ICD-10guidelines, the World Health Organisation (1998) has published a statement on "Selective serotonin reuptake inhibitors and withdrawal reactions," which makes 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 can and do cause dependence; and [c] that in the last analysis, the patients experience with the drug is the test of whether or not a drug causes 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)
Referring specifically to Mr. Chandlers comment that, "there have been one or two reports of discontinuation symptoms with abrupt cessation", we refer to the published evidence cited in our previous complaint. We accept 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 have consistently reported an incidence of withdrawal problems far greater than the incidence proposed by GlaxoSmithKline. Typical figures are 3/6 cases (50%) reported by Barr et al (1994); 5/13 - 38.5% (Keuthen et al, 1994); 10/50 - 20% (Coupland et al 1996); and 5/12 - 41.6% (Bhaumik & Wildgust, 1996). One recent review concluded as follows:
"In summary, with several newer antidepressants, including, sertraline, paroxetine and venlafaxine, abrupt discontinuation after a moderate length of treatment leads to at least 1 out of 3 patients spontaneously reporting one or more discontinuation symptoms. Higher rates are reported when information on symptoms is solicited and in one study (Rosenbaum et al, 1998) approximately 2 out 3 paroxetine and sertraline recipients fulfilled criteria for a discontinuation syndrome. " (Haddad, 2001)
In addition to the aforementioned study by Rosenbaum at el (1998), we refer to the study reported by Oehrberg and associates (1995); the correspondent in the published paper is 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 is especially significant because GlaxoSmithKline indicated in response to our 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 SKB 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 and associates is over twice the number on the whole SKB clinical trials database. Not only was this trial excluded from the Company database, but it also signals an incidence of withdrawal reactions far in excess of the low levels the company implicitly claims.
Nor can the assertion that withdrawal symptoms are very rare (<1:10,000) be reconciled with evidence from spontaneous reporting. However troublesome the interpretation of these data may be, the major confounding factor is under-reporting. Yet by September 2001, the Committee on Safety of Medicines had received 1,242 reports of withdrawal reactions to paroxetine a far higher number than for any other drug on the ADROIT database. The prominence of paroxetine in the ADROIT tabulation is underlined by the analysis by Price and colleagues in the Medicines Control Agency/Committee on Safety of Medicines: "withdrawal reactions with paroxetine constitute a greater proportion of reports (5.1%) than with the other SSRIs (0.06-0.9%). (Price et al, 1996)
The same picture emerges from the data generated by the Uppsala Monitoring Centre (27 January 2001), which has operational responsibility for the WHO's Programme for International Drug Monitoring. The table below identifies drugs on the Centre's database that have attracted most reports of withdrawal problems indicative of dependence. By a wide margin, paroxetine tops this list.
DRUG NAME |
REPORTS |
| Paroxetine |
2003 |
| Venlafaxine |
1058 |
| Alprazolam |
842 |
| Sertraline |
585 |
| Hyoscine |
519 |
| Fenfluramine |
450 |
| Fluoxetine |
402 |
| Tramadol |
389 |
| Phentermine |
371 |
| Methadone |
316 |
| Lorazepam |
282 |
| Dexfenfluramine |
277 |
| Diazepam |
192 |
| Triazolam |
188 |
| Clonazepam |
112 |
We further object to the statement that, "there have been one or two reports of discontinuation symptoms with abrupt cessation", on the grounds that SmithKline Beecham has known for many years that the frequency of withdrawal symptoms was likely to be substantial, following studies on healthy volunteers, carried out in the 1980s: "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 Medicines Control Agency, 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 complained of is that withdrawal symptoms exist only when there is abrupt cessation of treatment. In our previous complaint, we requested the company to produce such relevant evidence as it had to support this assertion, but it did not respond. We have no problem accepting that gradual reduction of dosage may attenuate withdrawal problems, but clearly it does not abolish them. Gradual tapering of dosages had been employed in the three cases reported by Barr et al; in four of the five cases reported by Keuthen et al; and "the majority of cases occurred despite slowly tapered withdrawal" in the series reported by Coupland et al. See also CADRMP, 1998; DTB, 1999, below). Referring to the practice of dose tapering on cessation of treatment, on 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).
7.9 "Information and claims about side effects must reflect available evidence or be capable of substantiation by clinical experience "
We rely on the arguments and evidence set out above. We also invite the company to inspect the 1000-odd spontaneous reports from SSRI users on the Social Audit website, the large majority of which relate to (a) withdrawal and dependence problems with paroxetine (Paxil, Seroxat, Aropax) rather than other SSRIs; and (b) reactions that are unexpectedly severe, disabling and often intensely disturbing. Our website is only one of several where users so complain. We submit that such a volume of reports, describing severe problems of a kind that manufacturers routinely deny and of which many prescribers appear unaware, can and should be considered "available evidence" within the meaning of the Code. We submit in support of this complaint a selection of comments posted on our website relating to users experience of dependence of paroxetine; see Appendix Two.
20.2 "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"
We rely 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.
2. "Activities or materials associated with promotion must never be such as to bring discredit upon, or reduce confidence in, the pharmaceutical industry.
We recognise that the Authority regards a ruling of a breach under Clause 2 as a sign of particular censure, to be used sparingly. We nevertheless request that a breach under this provision be ruled, taking into account:
- The outcome of our previous complaint, and the companys acceptance of that decision and "assurance that they will take all possible steps to avoid similar breaches of the IFPMA Code occurring in the future". (The remarks attributed to Mr. Chandler do not suggest that steps have been taken, but we keep an open mind on this. If the company has taken any steps, we invite them to explain what has been done.)
- The evidence provided indicates an established pattern of unacceptable behaviour
- That misleading statements were made to a lay rather than professional audience
- Mr. Chandlers seniority in the company.
- The damaging consequences of such statements for patients and prescribers alike.
In relation to this last point, we emphasise that the users comments attached in Appendix II are representative of recurrent themes: many prescribers are not aware of the significance of withdrawal and dependence problems (Young & Currie, 1997); users are not often warned about the possibility of withdrawal effects and dependence; prescribers are 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 medication are obliged to resume drug taking, much against their free will; withdrawal effects may be extremely distressing and disabling; and withdrawal and post-withdrawal effects are reported to be worse than the condition for which the drug was prescribed.
For the record, and in support of this complaint, we are again enclosing a copy of our monograph (Medawar, 1997). Please let me know if you require any further information. We look forward to hearing from you.
Yours sincerely,
Charles Medawar
References
ADROIT: Medicines Control Agency drug analysis print for paroxetine dated 12/09/01.
L.C. Barr, W.K. Goodman, L.H. Price, Physical symptoms associated with paroxetine discontinuation (letter). Am J Psychiatry 1994 Feb, 151 (2), 289.
S. Boseley: Murder, suicide. A bitter aftertaste for the wonder depression drug, The Guardian, 11 June, 2001. See:http://www.guardian.co.uk/Archive/Article/0,4273,4201752,00.html
S. Bhaumik, H.J. Wildgust, Treatment outcomes including withdrawal phenomena with fluoxetine and paroxetine in patients with learning disabilities suffering from affective disorders (Letter), Human Psychopharmacology, 1996, 11, 337-338.
N.J. Coupland, C.J. Bell, Serotonin Reuptake Inhibitor Withdrawal, J. Clin. Psychopharmacol., 1996, 16, 3, 356-362
S. C. Dilsaver, Antidepressant withdrawal syndromes: phenomenology and pathophysiology, Acta Psychiatr. Scand., 1989, 79, 113-117.
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).
FDA: labelling changes for Paxil, approved 28 September 2000, posted 16 November 2000 athttp://www.fda.gov/medwatch/safety/2000/sep00.htm#paxil
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); .
N.J. Keuthen, P. Cyr, J.A. Ricciardi, et al,. Medication withdrawal symptoms in obsessive-compulsive disorder patients treated with paroxetine. J Clin Psychopharmacol, 1994 June, 14 No 3, 206-207
C. Medawar, The Antidepressant Web, Int J Risk & Safety in Medicine 1997 October, 10, 2, 75-126. See numerous additions, 1998-2001, athttp://www.socialaudit.org.uk/5100what
S. Oehrberg, P.E. Christiansen, K. Behnke, A.L. Borup, B. Severin, J. Soegaard, H. Calberg, R. Judge, J.S. Price, P.C.Waller, S.M. Wood (Medicines Control Agency), A.V.P. Mackay (Committee on Safety of Medicines): A comparison of the post-marketing safety of four selective serotonin reuptake inhibitors including the investigation of symptoms occurring on withdrawal, Br. J. Clin. Pharmacol., 1996, 42, 757-763.
J F Rosenbaum, M Fava, S L Hoog, R C Ascroft, W B Krebs: Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Randomised Clinical Trial, Biol Psychiatry, 1998, 44, 77-87.
Uppsala Monitoring Centre: printout dated 27 January 2001 of Most reported dependence drugs 68 to date"
World Health Organisation: Ethical Criteria for medicinal drug promotion (Geneva, WHO, 1988)
World Health Organisation: WHO Drug Information, 1998, 12, 3, 136-138.
World Health Organisation: International Classification of Diseases, 10th Edition. (Geneva, WHO, 1992)
AH Young, A Currie, Physicians knowledge of antidepressant withdrawal effects: a survey, J. Clin Psychiatry, 1997, 58 (suppl 7), 28-30.
Appendix One
"A definite diagnosis of dependence should usually be made only if three or more of the following have been experienced or exhibited at some time during the previous year:
(a) a strong desire or sense of compulsion to take the substance;
(b) difficulties in controlling substance-taking behaviour in terms of its onset, termination or levels of use;
(c) a physiological withdrawal state ... when substance use has ceased or been reduced, as evidenced by the characteristic withdrawal syndrome for the substance; or use of the same (or a closely related substance) with the intention of relieving or avoided withdrawal symptoms
(d) evidence of tolerance, such that increased doses of the psychoactive substance are required in order to achieve effects originally produced by lower doses (clear examples of this are found in alcohol and opiate dependent individuals who may take daily dose sufficient to incapacitate or kill non-tolerant users);
(e) progressive neglect of alternative pleasures or interests because of psychoactive substance use, increased amount of time necessary to obtain or take the substance or to recover from its effects;
- persisting with substance use despite clear evidence of overtly harmful consequences, such as harm to the liver through excessive drinking, depressive mood states consequent to periods of heavy substance use, or drug related impairment of cognitive functions; efforts should be made to determine that the user was actually, or could be expected to be, aware of the nature and extent of the harm ..."
