|CODE OF PRACTICE AUTHORITY|
|12 Whitehall London SW1A 2DY Telephone 0171-930 9677 Facsimile 0171-930 4554|
PRIVATE AND CONFIDENTIAL
Our Ref: HJS/jr
14 September 2000
|Mr Charles Medawar|
|Director, Social Audit Ltd|
|PO Box 111|
|London NW1 8XE|
Dear Mr Medawar
Case AUTH/IFPMA/5/7/01 - Statements about Seroxat (IFPMA Reference C2001/01)
The International Federation of Pharmaceutical Manufacturers Associations (IFPMA) has referred to the Prescription Medicines Code of Practice Authority the complaint you made to it. IFPMA complaints which are referred to the Authority are those which relate to UK companies, usually involving their activities in other countries. The Authority deals with IFPMA complaints under its own Constitution and Procedure (as printed in the back of the enclosed copy of the ABPI Code of Practice for the Pharmaceutical Industry). Complaints made under the IFPMA Code are judged under the IFPMA Code. At the completion of proceedings the IFPMA is advised and can decide whether to accept the decision.
The Code of Practice Panel has completed its consideration of the complaint you made regarding statements about Paxil (paroxetine) said to have been made by Dr David Wheadon, at the time Vice President - Regulatory Affairs at SmithKline Beecham in the United States (now part of GlaxoSmithKline), during the ABC-TV "20/20" programme "A painful withdrawal" broadcast in the US on 25 August 2000.
Before complaining to I FPMA, you had written direct to Dr Wheadon about the matter on two occasions (8 September and 2 October 2000) but had received no reply.
complaint You stated that you had not seen the programme but you understood that Dr Wheadon's comments were: 'What we have seen in terms of the anecdotal reports [of withdrawal] is that it happens very rarely' and that it "occurs in only 2 out of every 1,000 patients who are discontinued appropriately and even then the symptoms are mild and short-lived".
Your understanding of the problem differed substantially from this assessment though it was, admittedly, very hard to put a figure on it. For the reasons set out below, you were inclined to think that withdrawal problems were very much more frequent and serious than SmithKline Beecham appeared to believe.
1 Under the UK "Yellow Card" (ADROIT) scheme, there had been far more spontaneous reports of withdrawl problems with paroxetine than for any other medicine of any kind (MCA/CSM, 1999). Indeed, you thought the number of reports relating to withdrawal problems with paroxetine exceeded the number of reports of withdrawal problems for all other medicines combined.
2. Withdrawal reactions were likely to be hugely under-reported, not least because [a] dominant symptoms of withdrawal included depression and other forms of psychic distress and were therefore liable to be confused with symptoms of the disorder for which the medicine was originally prescribed, [b] because many if not most prescribers appeared to be unaware that withdrawal reactions even existed (Young & Currie 1997) and [c] because most users liable to experience withdrawal reactions presumably never completed withdrawal, but continued to take the medicine (Hollister 1977).
Dr Leo Hollister's investigations into the dependence liability of the benzodiazepines, in the early 1960s, had convinced him there would be "a flood of reports of withdrawal reactions" for diazepam (Valium) and chlordiazepoxide (Librium), yet the flood never came. "The probable reason is that patients abort these reactions early on because they think their original symptoms are returning, and they get back on the drug. So we rarely see the full-blown picture" (Hollister 1977).
3 It seemed inherently improbable - especially in view of all the precedents (Medawar 1992) that there should be so much evidence of withdrawal distress if the incidence of withdrawal problems were anything like as low as SmithKline Beecham appeared to believe. Surely SmithKline Beecham was concerned that this was such a frequent topic of discussion on so many websites, some specifically dedicated to problems with paroxetine withdrawal? Visitors to Social Audit's website reported problems withdrawing from paroxetine more than any other SSRI. The number of visitors to the site was increasing steadily - now about 150,000 visitors per year. You could not conceive there would be such a high level of concern if the problem was, in fact, as rare as SmithKline Beecham had suggested.
4 Imperfect as it might be, the best evidence you knew of suggested that withdrawal symptoms were by no means uniformly "mild", as Dr Wheadon was reported to have said. Price et al (1996) reported on a follow-up survey of 192 spontaneous reports of withdrawal reactions to paroxetine, and classified 21% as 'mild', 58% as 'moderate' and 21% as 'severe'. Did SmithKline Beecham have better evidence than this, and on what basis had its own assessments been made?
5 On the 20/20 programme, Dr Wheadon was also reported to have said that symptoms of withdrawal were short-lived and you said that you would be interested to know about the basis of this assertion. You asked this partly because a number of Social Audit's website visitors had been concerned about the long duration of withdrawal effects and partly because of the wide range (152 days) of withdrawal symptoms reported by Price et al. Did SmithKline Beecham know of any more reliable evidence than this (and from studies that overcame the confounding effect of people coping with withdrawal distress by re-starting paroxetine or switching to another SSRI)?
6 The estimate Dr Wheadon had given was subject to the qualification that users should have been "discontinued appropriately'. Did the company have any hard evidence to indicate approximately what percentage of withdrawals from paroxetine would be appropriately managed? And would SmithKline Beecham accept that the potential for significant withdrawal reactions (ie regardless of manner of withdrawal) for patients stabilised on normal doses for weeks (rather than months) was of the order reported by Rosenbaum et al (1999)? Their investigation suggested that perhaps half of all patients abruptly withdrawn from paroxetine experienced significant distress on withdrawal - reporting also high levels of symptoms on withdrawal (eg dizziness - 50%) unlikely to be connected with any relapse?
You had asked for citations to the evidence on which SmithKline Beecham relied and had enquired specifically whether the company had itself investigated, or commissioned, studies to elucidate the nature and extent of withdrawal problems.
A transcript of the 20/20 programme was provided by you.
In its letter forwarding the complaint, IFPMA drew attention to Sections 1.3 and I.7 of the IFPMA Code.
Response GlaxoSmithKline stated that it was its view that the I FPMA Code was not intended to cover the situation in which you found yourself. The Code was clearly intended to ensure good practice in the marketing or promotion of pharmaceutical products Indeed, the IFPMA Code was specifically known as the IFPMA Code of Pharmaceutical Marketing Practices. Dr Wheadon had agreed to be interviewed at the request of the broadcaster in order to respond to claims regarding adverse events and his participation clearly did not constitute marketing or promotional activity of any kind. He was merely responding to questions put to him. IFPMA's letter of 13 July 2001 referred to Sections I.3 and I.7 as the "relevant sections of the Code".
GlaxoSmithKline believed the suggested application of these sections in this way was not appropriate, as the sections were being taken out of context from the intended scope and purpose of the Code, which was to cover marketing and promotional activities and not invited participation in a television news magazine to respond to charges against a product.
In addition, you had complained about information presented on a television news magazine programme over which SmithKline Beecham had no editorial control. Although ABC-TV interviewed Dr Wheadon for the 20/20 programme, at its request, SmithKline Beecham did not collaborate or suggest to ABC-TV what subjects should be discussed with Dr Wheadon or how they should be discussed. Indeed, Dr Snyderman interviewed Dr Wheadon for more than one hour, yet ABC-TV chose to air less than three minutes of that interview, which was inserted at points within the programme. SmithKline Beecham had not been provided with a full transcript of the entire 75 minute interview and it had been unable to respond adequately to your challenge to statements that ABC-TV's programme attributed to Dr Wheadon. You challenged the following statements by Dr Wheadon and ABC-TV's Dr Snyderman, which from the context presumably referred to "discontinuation syndrome".
"Dr David Wheadon: What we have seen in terms of the anecdotal reports is that it happens very rarely.
Nancy Snyderman: (voice over) Dr David Wheadon is Vice President of Regulatory Affairs at SmithKline Beecham, the maker of Paxil. He says withdrawal, or as SmithKline Beecham prefers to call it, discontinuation syndrome, occurs in only 2 out of every 1000 patients who are discontinued appropriately. Even then he says the symptoms are mild and short-lived.
As discussed above, most of the statements at issue were attributed to Dr Wheadon by Dr Snyderman. He did not make these statements during the 20/20 programme, and SmithKline Beecham did not have any editorial control over the statements and the context in which they were used.
Regardless, the relevant statements in the programme were not inaccurate.
With respect to discontinuation syndrome or withdrawal syndrome, as Dr Snyderman herself acknowledged, the United States Product Information listed "withdrawal syndrome" as a rare event, observed and reported during the pre-marketing evaluation of paroxetine. As set forth in the Product Information, this was an accurate statement of the pre-marketing data as reported by investigators. Indeed the cumulative adverse experience data from the company clinical trial database for paroxetine, which contained information from studies across all current treatment indications, showed that investigators reported "withdrawal syndrome" in 7 of 8413 patients. SmithKline Beecham also received reports of individual symptoms in connection with discontinuation of treatment in clinical trials. However, the segment of Dr Wheadon's interview broadcast by ABC related to what the persons reporting the events described as a syndrome, and not as individual symptoms.
With regard to the frequency of anecdotal reports, as Dr Wheadon stated they had been very rare relative to the number of patient-treatments with paroxetine. SmithKline Beecham had reviewed its clinical safety database on several occasions since 1991, the year paroxetine was launched, for reports of withdrawal/discontinuation syndrome or symptoms. The reviews had consistently supported the statements made by or attributed to Dr Whea ' don on 20/20 regarding paroxetine. SmithKline Beecham's review, conducted in mid-2000 and prior to the airing of the ABC-TV programme, examined reports entered into the system between February 1991 and 14 September 1999; there were 1573 patient reports of withdrawal/discontinuation syndrome or symptoms and 1 1 61 reports of adverse experiences post-treatment. The number of reports was very small relative to the approximately 70 million patient-treatments estimated to have occurred from the launch of paroxetine to the time of analysis. The fact that symptoms had been reported did not establish a causal connection to a medicine.
Therefore the figures attributed to Dr Wheadon were very reasonable in the context of the reports available to SmithKline Beecham in its clinical trials database and its clinical safety database.
With respect to ABC-TV's Dr Snyderman's description of the symptoms as "mild and short-lived", the US Product Information for Paxil used the term "generally self-limiting".
The Committee for Proprietary Medicinal Products (CPMP) in Europe recently reviewed the issue of discontinuation symptoms in patients receiving SSRIs and it recommended that the summaries of product characteristics for these medicines contained the language: "majority of withdrawal reactions are mild and self-limiting".
Moreover, the data from the clinical trial programmes had shown that the adverse experiences reported following cessation of paroxetine were generally mild to moderate in severity. The majority of symptoms resolved themselves within two weeks and there was only a minimal requirement for corrective therapy to treat symptoms that might be associated with discontinuation of paroxetine treatment. Review of the post-marketing experience confirmed that the vast majority of reported events were mild to moderate in severity and were of a non-serious nature, as defined by regulatory authorities.
In summary, GlaxoSmithKline considered that the IFPMA Code was not intended to cover this situation. Regardless, it believed that Dr Wheadon's statements and those attributed to him were supported by the available data and were not in breach of Sections 1.3 and I.7 of the IFPMA Code.
Panel Ruling The Panel first considered whether the I FPMA Code applied at all to the circumstances at issue. GlaxoSmithKline contended that it did not. The only provisions of the Code likely to be relevant were those referred to by the IFPMA, Sections 1.3 and 1.7.
Section. I.3, under the heading "General Principles", stated:
Information in promotional material should be based on an up-to-date evaluation of evidence that is scientifically valid and should not give an incorrect or misleading impression. Prescribing information should be supported by this information and be in accordance with the local product authorisation or, where this is not applicable, should be in accordance with an authorisation issued by a regulatory authority in an industrialised country. Scientific data to support the claims and recommendations for use should be made available, on request, to healthcare providers."
The Panel considered that Section 1.3 could not apply because no promotional material was involved and no breach was ruled.
Section 1.7, also under the heading "General Principles", stated:
"Communications to the Public
Where it is permitted by law to communicate directly with patients regarding their prescription medicines, all such information should be accurate, fair and not misleading.
Where companies assist in the conduct of public/patient disease awareness programmes to meet growing demands of society for more information and enhance public understanding of disease prevention, signs and symptoms of medical conditions, illnesses, and available treatments, such activities should adhere to the highest standards of accuracy and support the role of the health care provider."
The Panel considered that whether this provision applied in the circumstances depended on the interpretation of the word "directly'. This might be taken to mean "directly" by means of letters, mailings and the telephone etc rather than "indirectly' through the medium of television, etc. This was the distinction which seemed to be made in the UK in the ABPI Code of Practice for the Pharmaceutical Industry in which the relevant provision referred to information made available to the public "either directly or indirectly'.
There was, however, an alternative interpretation of the IFPMA Code provision, which was that "directly' meant any communication to the public which did not go through the agency of a health professional. That would mean that "communicate directly" would cover not only letters etc sent to members of the public but also communication by use of press releases and participation in television programmes, etc. This seemed to fit in with the second paragraph of Section I.7 which dealt with assistance with disease awareness campaigns, etc. If the IFPMA Code did not cover comments made in the course of a television programme by a company spokesman it would be a surprising lacuna.
The Panel's view was that the matter came within the scope of the IFPMA Code. The Panel next considered the question of the evidence which was available to it. One of the statements at issue occurs in only 2 out of every 1,000 patients who are discontinued appropriately" was actually said by Dr Nancy Snyderman, an ABC News presenter, who attributed it to Dr Wheadon when stating "He says withdrawal, or as SmithKline Beecham prefers to call it, discontinuation syndrome, only occurs in 2 out of every 1,000 patients who are discontinued appropriately. Even then he says the symptoms are mild and short-lived".
According to GlaxoSmithKline, the interview with Dr Wheadon had taken over one hour but only about three minutes of it had been used in the broadcast. The Panel considered that the crucial element was what Dr Wheadon had said in the interview not what had been selectively chosen for inclusion in the broadcast programme. The Panel did not have a transcript of the original interview. Even a balanced and fair interview could be made to appear imbalanced, unfair and misleading by selective quotation. A parallel could be drawn with the consideration of press reports in the UK under the ABPI Code of Practice. What was considered in relation to the Code was not what had been published in the media, but what had actually been said by the company concerned in the press release or press pack which had given rise to the published report.
In relation to the broadcast at issue, the only contentious statement actually made by Dr Wheadon was 'What we have seen in terms of the anecdotal reports is that it happens very rarely'. GlaxoSmithKline had submitted that the statement made by Dr Wheadon, and those attributed to him, were supported by the available data and were not in breach of the IFPMA Code.
The Panel noted that the US Product Information listed "withdrawal syndrome" as a rare event. GlaxoSmithKline had submitted that investigators had reported it in 7 out of 8143 patients. In Europe, the CPMP had recently reviewed discontinuation symptoms in patients on SSRIs and had recommended that the summaries of product characteristics for these medicines should say that 'the majority of withdrawal reactions are mild and self-limiting". The Panel noted that the CPMP position paper referred to Mr Medawar.
One of the recommendations in the CPMP SSRI paper referred to the fact that for the majority of compounds evidence from well designed preclinical studies with respect to dependency and withdrawal was incomplete. Further clinical studies might be necessary to better define the frequency and severity of withdrawal reactions in particular with regard to best conditions of treatment discontinuation. The CPMP paper stated that any statements relating to the frequency of withdrawal reactions should be based on the results of clinical trials where these were available.
The Panel noted that the spontaneous reporting rates of withdrawal/discontinuation syndrome did not necessarily equate with the incidence of the effect. The number of reports of withdrawal/discontinuation syndrome and the number of reports of adverse experience posttreatment received by SmithKline Beecham were submitted to be at 1573 and 1161 respectively, small in relation to the extensive usage of paroxetine.
The Panel considered that the issue of the level and seriousness of withdrawal/discontinuation problems with paroxetine was a difficult one but, on the evidence before it, the Panel considered that the broadcast statement made by Dr Wheadon, and the broadcast statements attributed to him, were not unreasonable.
The Panel ruled that there had been no breach of Section I.7 the IFPMA Code.
In accordance with the Constitution and Procedure for the Authority, you can appeal the Panel's decisions if there are reasons for so doing. If you appeal both yourself and GlaxoSmithKline will be entitled to appear or be represented before the Code of Practice Appeal Board. The Appeal Board includes independent members and a membership list is enclosed.
Notice of appeal must be received within ten working days of receipt of notification and must be accompanied by reasons for the appeal. Your notice of appeal would therefore be due by Monday, 1 October. If work or holiday commitments make this date difficult please contact us to arrange an extension.
In accordance with Paragraph 7.2 of the Constitution and Procedure i am enclosing a copy of GlaxoSmithKline's response to the complaint.
Heather Simmonds (Mrs)
|Director||Heather Simmonds||0171-747 1438|
|Secretary||Etta Logan||0171-747 1405|
|Deputy Secretary||Jane Landles||0171-747 1415|
CODE OF PRACTICE APPEAL BOARD MEMBERSHIP LIST
Mr Nicholas Browne QC
Dr D J D Farrow (General Practitioner)
Dr M A Wiison (General Practitioner)
Dr J B Edelman (Hospital Consultant)
Mrs L J Stone (Community Pharmacist)
Mr D E Hands (Practice/Formulary Pharmacist)
Mrs M G Baker MBE (Representing patients interests)
Dr S Bews (Medical Director, Yamanouchi Pharma Ltd)
Dr R J Donneily (Medical Director, Janssen-Cilag Ltd)
Mr K Hemming (President, Fujisawa Limited)
Dr D M Humphreys (Corporate Medical Adviser, International Medical Affairs,
Boehringer lngelheim Limited)
Dr C G O'Bryan-Tear (Medical Director, Bristol-Myers Squibb Pharmaceuticals Limited)
Ms S Pezzack (UK Legal Counsel, Eli Lilly & Co Limited)
Mr A Sheppard (Vice President, Western Europe, Pliva London Limited)
Mr T N Williams (Director of Business Planning, Merck Sharp & Dohme Limited)
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