RAPID RESPONSES FROM BMJ.COM: Anti-inflammatory end points

principle simple and straightforward. They would have been able to do an even more thorough job had they been provided with the data on individual patients from the studies, but their conclusion is convincing and important. With any new drug that has therapeutic activity, an appropriate dosage regimen must be worked out from a clear understanding of the pharmacokinetics and the dose-response relation. When these are known, sensible decisions can be made on the starting dosage, the minimum time to allow before increasing the dose, dose increments, and the maximum useful dose. Why did it take until now, from the first marketing of fluticasone in 1993, to discover that the maximum useful dosage for most cases is only about half of that hitherto recommended by guidelines and the manufacturer? How did the data emerge, and why were they not used earlier? My guess is that the scientists at GlaxoWellcome (sponsor of the trials in the meta-analysis) and at the Medicines Control Agency and the clinicians and academics working on asthma had not appreciated the need for and value of systematic reviews and appropriate meta-analysis. Also, few systematic reviews have yet examined dose-response relations. Another contributory factor is that clinicians rarely think critically about the dose-response relations of the drugs they use. Many drugs have been introduced at doses that later were found to be too high; and usually years have passed, with unnecessary toxicity, before action was taken. This is not acceptable. As Holt and colleagues hint, it is time to reexamine the dose-response data for beclomethasone propionate and budesonide, drugs whose maximum dosages also seem to be about twice what they should be. It is likely that the dose-response relations of other drugs should be revisited. We need to identify the most important of them and begin. A major obstacle is access to the data. In the case of fluticasone “data on individual patients could not be made available” by GlaxoWellcome. Although Sir Richard Sykes commendably committed the company to openness, there are different degrees of openness. It would of course have taken time and money to extract the data, and a reanalysis carries the risk of embarrassing findings—but the Medicines Control Agency always has access to the data. Whether it uses them is another question. Because the Medicines Control Agency is wedded to secrecy, we are unlikely to learn the answer. Making sure that the dosages that are used best serve the patients should be near the top of the agenda for regulators and the prescribing community. Right now this item seems to be nowhere on the agenda—but that needs a separate article. ✦