SSRIs, EMEA and the CPMP
1. BackgroundTo what extent are the risks of antidepressants (notably SSRIs) appreciated by the EU medicines control authorities - the European Medicines Evaluation Agency (EMEA) and its advisory body, the Committee on Proprietary Medicinal Products (CPMP)? This question was specifically prompted by EMEA's letter to Social Audit of 23 June and by a brief discussion of the issues with EMEA, a few days later.
The EMEA letter elaborates on the detail of process, for possible reasons discussed below. It explains that antidepressants are regulated not under the European system, but by national drug control agencies, like the MCA/CSM. However, in this case, an exception was made: by chance, the European authorities were able to look at SSRIs (because of some disagreement between national drug control agencies about the biological equivalence of a new generic version of fluoxetine, in relation to Prozac, the original brand).
In the event, EMEA/CPMP decided it would not be appropriate to include any statement in the drug labelling (data sheet/SPC) about dependence. However, they did recommend that a warning be included about the possibility of withdrawal reactions, and the European Commission has been asked to ratify the following wording: "Withdrawal reactions have been reported in association with Selective Serotonin Reuptake Inhibitors (SSRIs). Symptoms usually include nausea and dizziness. Avoid abrupt discontinuation of treatment."
2. What is this warning saying to whom? The average doctor or patient would understand from this that antidepressant withdrawal reactions were of minor significance - neither serious nor affecting more than a few - and that any risk of dependence with SSRIs would be negligible.
Equally important, these words tell the manufacturers that "dependence" is a not an issue with the authorities. The warning says that, if it came to a showdown, there would be support for something of a 'development risk' defence - roughly speaking, the argument that noone is to blame if everyone was unaware of some risk. This would tend to reduce both provider liabilities, and the user's scope for redress.
The warning reflects the views of a strong consensus, and expresses the opinion of what are legally recognised in the EU as the "Competent Authorities". The weight of their opinion is great. Warnings published in the Summary of Product Characteristics (SPC) are intended to give definitive advice to prescribers (also users) on drug properties and effects - and express the views of experts, not just from around Vauxhall, but from all over Europe.
3. How did this warning come to pass? The CPMP is responsible for formulating EMEA's opinion on drug safety questions and the CPMP, in turn, relies on advice from one of its five working parties. The relevant advice came from the Pharmacovigilance Working Party, which is responsible for examining "any questions relating to drug hazards". The Chair of the working party is Dr S.M. Wood (MCA/CSM), joint head of the school of rare and mild (Price et al., 1996)
It was the MCA that defined the scope of the enquiries that led eventually to the new warning proposed by the EMEA/CPMP. The Agency's terms are spelt out in the Alert/Alerte circulated to its European partners in December 1997. This asked: how many cases of SSRI withdrawal and dependence have been reported in your country, and what warnings are there in your product literature? The object of the exercise seems to have been to standardise warnings rather than establish the true risks.
The whole thing is complicated because all European medicines control agencies rely on the same sort of "pharmacovigilance" systems - though the MCA's is generally regarded as one of the best. Thus, national agencies would have wanted to show solidarity with the MCA, if only to affirm their confidence in themselves - notwithstanding the fact that the methodologies and interpretations they rely on could be expected to produce estimates of risk perhaps 1000-times lower than those from dedicated studies.
There are question marks about process; in particular, what does one make of EMEA's elaborate explanation about addressing this as a side issue? Was it a simple snub, a display of openness? Could it be a coded message ('we know the warning is awful, but we're not really responsible')? Or is it to emphasise the unanimity of the different national agencies? Whatever else, the message seems to be: 'we did not address your questions, but we have the answers for you. By due process (but no formal analysis of risk) we have unanimously decided that there is no risk of dependence, no basis for concern.'
4. What is this warning not saying? The context endows these words of warning with powerful authority, but they take little account of much evidence. The warning is clearly based, not on the evidence of risk, but on lack of evidence of harm - and the main source is prescribers. This is worrying first, because user experience matters; secondly, because the providers have been blind. Although antidepressant withdrawal symptoms are a commonplace, most prescribers have been unaware of their existence, throughout the past four decades. Prescribers have also repeatedly been told that these drugs don't cause "dependence", and are therefore less likely to report it. All this misunderstanding has been compounded by reliance on a new definition of that term, remote from public understanding. Accordingly, the EMEA/CPMP neither informs nor warns of the following:
[a] that manifestations of withdrawal may differ greatly with different SSRIs;
[b] that the reported incidence of withdrawal problems is much higher with some SSRIs than others;
[c] that virtually all antidepressants, not only SSRIs, have a characteristic withdrawal syndrome;
[d] that significant withdrawal symptoms are experienced by perhaps 30% of users, of which only a tiny fraction are ever recognised and/or reported;
[e] that symptoms of withdrawal may easily be mistaken as evidence of relapse, and therefore of the need for continued drug treatment;
[f] that withdrawal symptoms may be severe, even after gradual withdrawal, and that close medical supervision may be needed;
[g] that the apparent severity and visibility of withdrawal reactions might depend on dosage, duration of treatment and type of antidepressant drug - as well as on the individual users;
[h] that the reasons why some experience withdrawal symptoms are unclear, and that it is not possible to predict accurately who will and won't;
[i] that reported withdrawal symptoms are many and varied, and that neither nausea nor dizziness may predominate; and
[j] that users should be warned of the possibility of withdrawal symptoms, and advised that they do not signal a depressive relapse;
The clinical evidence justified this warning at least five years ago, since when consumption has doubled and millions of users have been exposed. In the meantime, the benefit:risk ratio is shifting, as it becomes clearer that antidepressants lack specificity of effect on depression, and that their effects are closely linked to placebo factors.
5. Conclusions? These words seem useless as a "warning", if not negligent in their disregard for risk and of the opportunities for reducing it. The evidence suggests that, on this occasion, the European medicines control system has simply facilitated the recycling of MCA data. The warning that has emerged from this process seems remarkable, not only for the risks it presents for users, but for what it conveys about the triumph of process over content, and the limitations of European harmonisation. The possibility of an appeal against the EMEA/CPMP decision should be examined.
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|14 July 1998|