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Russell, in his editorial “Very high‐dose corticosteroids: panacea or poison?1”, speculates about the reasons why “the practice of using increasingly high doses of inhaled corticosteroid therapy, particularly of fluticasone, became commonplace in the UK.” He blames doctors: “it appears that better disciplined clinicians elsewhere in the world were less willing to stray beyond licensed dosages” and also the raising of the licensed dose of fluticasone propriate in children, from 200 to 400 μg/day, although this happened in 2001, at least 5 years after this prescribing practice became commonplace.2
The question as to how this situation arose is important, and was discussed by a judge at a fatal accident inquiry3 in 2005 into the death of a 5‐year‐old girl in 2001 from adrenal crisis due to high‐dose inhaled fluticasone propriate. It was this death that prompted the recent investigation of adrenal function in children with asthma, prescribed fluticasone propriate >500 μg/day.4
At the inquiry, evidence was heard from the treating clinicians and others including a pharmacist, paediatricians, a chest physician, representatives of the Medicines and Healthcare Products Regulatory Agency (formerly the Medicines Control Agency) and GlaxoSmithKline (GSK), the manufacturers of fluticasone propriate. Evidence was heard that at the time of the launch of fluticasone propriate, the product monograph claimed “mean plasma cortisol concentrations remained within the normal range for adults and children, demonstrating that even at high doses (2000 micrograms), fluticasone is well tolerated with regard to systemic effects”, and “in a substantial majority of patients, even at daily doses of fluticasone of 2000 micrograms, no adverse effect on adrenal function or reserve has been shown”.5 In addition GSK promotional literature highlighting safety claims—for example, “negligible oral bioavailability”—was presented. The judge found “that failure by Glaxo to qualify the claims regarding negligible oral bioavailability by referring to the fact that there continued to be absorption of significant amounts of the drug from the lungs, is likely to have made a considerable contribution to a positive view being taken by many members of the medical profession when making decisions about the use of this drug, particularly in high doses”.
The Director of Primary Care at GSK had described the dosages used by the prescribing doctors in the case as “exceptional”. However, as can be seen in the paper by Paton et al, this was clearly not the case, and the judge opined: “it seems to me that, in order to monitor the safety and use of a drug, a drugs company must ensure that it is fully informed as to the way in which the drug is currently being used in clinical practice. Accordingly, consideration of the actual use in practice of fluticasone should have been an essential part of the monitoring of its safety in use.” She continued: “the drugs company ought to have taken steps to review a marketing strategy which is based upon safety claims and to remind practitioners of the potential risks of prescribing high doses, even of this drug”.
It had also been claimed that the responsibility of “off‐licence” prescribing rested with the prescriber; however, the judge commented “it seems to me that a drug manufacturer does not carry out its promotional and marketing functions conscientiously and responsibly if it fails to take this reality (ie, the widespread nature of “off‐licence” prescribing in paediatrics) into account. It also seems to me that in the light of this fact, a drugs company must be particularly assiduous in ensuring that extreme caution is exercised when claims are made about the safety of a drug.”, and continued: “I am satisfied that the advertising and promotion of fluticasone was aimed at, and contributed towards, establishing a feeling of confidence in the enhanced safety of this particular drug within a medical profession which had already become complacent about the safety of inhaled corticosteroids generally”. She concluded: “the emphasis placed upon the safety of fluticasone in its promotion and marketing, including the advertising of the drug and the fact that no steps were taken by the company, through its representatives or otherwise, to bring to the attention of clinicians at least the changes to the SPC [Summary of Product Characteristics], which were based upon all the evidence available at that time, contributed to the complacency by many within the medical profession about its safety, which in turn contributed to high doses of this drug being prescribed and, accordingly, is a fact that is relevant to the circumstances of this death”.
Although the Medicines Control Agency had published a bulletin in 19986 reviewing the safety of inhaled steroids, the judge commented, “the terms of the bulletin were not sufficiently robust and did not sufficiently reflect concern about the practice of prescribing high doses of inhaled corticosteroids, proportionate to the potential risks in so doing”.
She also criticised the British Guidelines on Asthma Management 1995 Review and Position Statement,7 which “lacked clarity in relation to the maximum recommended dosage of fluticasone for children under 5 years” and that this had contributed to the decision to prescribe high doses of fluticasone in the case.
Finally, she recommended “that the appropriate authorities should consider conducting a review of the practice of general practitioners and hospital specialists when prescribing inhaled corticosteroids, with a view to assessing whether it is appropriate to issue comprehensive guidelines in relation to issues concerning prescribing, specialist referral, informing patients about possible side‐effects and monitoring to detect side‐effects and in relation to ancillary matters such as the issue of steroid cards”. No such review appears imminent and one can only hope that the findings of Paton et al provides further evidence for the urgency in carrying out this task.
Paediatricians, GSK and the Medicines and Healthcare products Regulatory Agency (MHRA) were first alerted to the practice of prescribing high‐dose fluticasone propriate, and its potential consequences, in 1996.8 Unfortunately it has taken the lives of at least 2 children, near deaths of several dozen and a judgement from the fatal accident inquiry to provoke any significant action.
Several questions remain unanswered. Were sufficiently sensitive methods of measuring adrenal suppression used in safety studies? By 1998, GSK had already published data showing that there was no dose response relationship for inhaled fluticasone propriate and 08.00 h cortisol and 24 h urinary cortisol,9 so why have many studies continued to use these tests as the main methods for measuring side‐effects?10 Was the MHRA aware of the limitations of these two tests when they increased the licence for fluticasone propriate in children from 200 μg/day to 400 μg/day, and do they still consider them appropriate for assessing the safety of inhaled corticosteroids?
I agree with Russell that the situation with regard to the prescription of high‐dose inhaled corticosteroids, which was allowed to develop despite warnings as far back as 1996, was “sphincter‐threateningly scary”. The prevention of a similar situation arising again will depend on the better control and scrutiny of the pharmaceutical industry's claim for its products, the MHRA better fulfilling its role to protect patients and, most of all, a medical profession independent of drug company influence and more sceptical about their claims.
Competing interests: None.