Coleg Meddygaeth Prifysgol Cymru

University of Wales College of Medicine

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Adran Meddygaeth Seicolegol / Department of Psychological Medicine
Adran Cymru y Gogledd / North Wales Department
Pennaeth Adran / Head of Department
Yr Athro /Professor Michael J. Owen
Bangor
Dr. D. Healy (Cyfarwyddwr)

 

Dr Keith Jones, Director 4 November 1999
Medicines Control Agency
Market Towers, 1 Nine Elms Lane
LONDON SW8 5NQ

Dear Dr Jones,

As you may have seen or have been told, there was a lengthy piece in the Guardian Weekend Supplement on Prozac on Saturday October the 30th. I enclose a photocopy and a set of background materials. One is a research brief on the piece. A second is a liability time-line, which refers to internal documents from Eli Lilly that are now in the public domain as a result of the Forsyth case.

In brief I believe the Prozac story represents one of the most significant bioethical issues of our time. There are however two very specific aspects of it that I wish to focus on in this letter which I believe may be of concern to the MCA.

The first point, mentioned in both the Guardian article and the background briefing, is the question of legal jeopardy in which we currently place patients we recruit to clinical trials as these are at present conducted.

The problem is that the Prozac story indicates very clearly that Lilly has used side-effects data collected by spontaneous report methods to argue that neither akathisia nor emotional blunting of any sort occur on Prozac and therefore neither of these effects could possibly contribute to suicides or homicides on this drug. Now even if you disregard the RCT evidence, the epidemiological studies, the test re-test studies as well as Lilly's own internal memoranda indicating that Prozac causes people to commit suicide, the fact that Lilly have behaved in this way on this issue suggests that patients are in considerable legal jeopardy if either Lilly or other pharmaceutical companies treat the side-effects data that emerges from clinical trials in this way.

You will not need this point spelt out in detail but for example the side-effect data on sexual dysfunction with the SSRIs collected by spontaneous reporting methods appeared to indicate a problem occurring at a 5% level of frequency where systematic checklist approaches later indicated an incidence around 50%. Unless complemented by systematic checklists, the side-effect data from spontaneous reporting methods on this issue of sexual dysfunction would indicate that the problem barely exists and patient data could conceivably have been used to argue just this point in court. This would, I'm sure you would agree, be entirely inappropriate. It constitutes a state of affairs amounting to legal jeopardy.

I raise the problem in part because there is a very simple answer to it. Some national group, such as the United Kingdom, could very readily remedy things and not only for psychiatry but for all of medicine world-wide. As you will know all major clinical trials these days are multi-national and multi-site. Should UK ethical committees insist, if side-effects data are collected by spontaneous reporting methods, that the consent form should indicate clearly that these data will only be used for marketing purposes and that they have no validity for legal purposes, the current poor situation as regards collection of clinical trial data could effectively continue without putting patients in a state of legal jeopardy.

An alternative would be for ethical committees to state that they would prefer systematic checklists. A great number of companies I have talked to have indicated that they too would prefer this.

Were the United Kingdom to stand firm on an issue like this the rest of the world would have to change as the same protocols apply cross-nationally.

The second issue has to do with the clinical liability that prescribers of Prozac in this country presently run. There was an ambiguous outcome to the Forsyth case, further details of which I would be happy to relay to you. In brief the critical issue for us as prescribers are that lawyers viewing this case will henceforth, unlike the lawyers in the Forsyth case, target both the company and the prescriber whereas in the Forsyth case only the company was targeted. This means that prescribers who may be essentially blameless will find themselves in court, the strategy being to enquire of them Whether they have ever been informed in lectures, symposia or other forums that there were hazards of this type associated with Prozac, that these hazards could be forestalled by appropriate warning and minimised by appropriate antidotes.

My informal research on this point suggests strongly that very many general practitioners as well as A&E Dept doctors and others have recognised a phenomenon of patients becoming suicidal on SSRIs (Prozac in particular) within two or three weeks of starting treatment.. Far from advocating a switch of treatment at that point they frequently advise the patient to continue treatment. This is disastrous. The advice is offered in the apparent belief that this indicates that the drug is working to increase drive and in due course will lift the person's mood. It is not. The evidence is compelling that just this kind of patient is at the very greatest risk of further serious adverse events and that a risk of suicide of possibly 1/1000 Prozac takers is converted into a 1/10 risk by doing just this.

Both of these points, it seems to me, must be of concern to you. The issues are quite different to any problems that were ever raised in relation to benzodiazepine or SSRI dependence, where there is considerable ambiguity involved in deciding what constitutes dependence. In this case there are very clear internal company documents and a pattern of behaviour, possibly stemming from legal advice, that is inconsistent with prescription only arrangements.

Based on RCT evidence from a number of companies, epidemiological studies and other sources, at a conservative estimate I believe one person per week has killed themselves in the UK for every week that Prozac has been available over and above the number that would have done so if the same patients had been left untreated and one person per day has attempted suicide with unknown consequences for their future risk of suicide. I would be happy to go through this evidence with you, if this would help and indeed I would be happy to have the error of my ways pointed out if anyone can see a problem with my figures or logic.

Against the background outlined above, I feet particularly impelled to act as I am doing now in writing to you having been the convenor and author of a report on childhood psychopharmacology for the British Association for Psychopharmacology, which supported the prescription of psychotropic drugs to children and teenagers in appropriate circumstances and with appropriate monitoring. This document has not led directly to increased rates -of prescribing of SSRIs to adolescents in this country but it has done nothing to put a brake on what has been a dramatic increase in' recent years. Unfortunately, I now find my in-tray filling with files on teenagers committing suicide within a week or two of commencing Prozac. It is this that makes the problem difficult to walk away from.

David Healy MD FRCPsych
Director, North Wales Department of Psychological Medicine

 

Uned Hergest, Ysbyty Gwynedd, Bangor, Gwynedd LL27 2PW
Ffn: (01248) 384452 Ffacs: (01248) 371397
Hergest Unit, Gwynedd Hospital, Bangor, Gwynedd LL27 2PW
Tel: (01248) 384452 Fax: (01248) 311397

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