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Asthma may cause anything from trivial symptoms to intractable breathlessness and treatment needs to be tailored accordingly. To provide a rational and easily applicable approach to prescribing for asthma, most clinical guidelines on asthma management rank the drugs available in hierarchical order, simplified in a series of steps.1 ,2 For the British guidelines these range from a β agonist as required (step 1) to the need for oral corticosteroids (step 5).1 Patients can be started at any step and, indeed, if their asthma is poorly controlled may well be advised to start on oral corticosteroids and reduce treatment when control is achieved. The guidelines do not mean that all patients with asthma of a given severity should be treated in an identical fashion, since patients clearly vary in their response to drugs. What the stepped approach is attempting to do is to suggest a hierarchy in which treatment is most likely to provide the best value for a patient with asthma of a given severity.
Fortunately most patients lie towards the mild end of the asthma spectrum and can be managed with an occasional β agonist or regular prophylactic treatment with low dose inhaled corticosteroid or a cromone. In a recent community survey in Nottinghamshire only 16% of patients were on step 3 or above,3 a relatively small proportion of the asthmatic population but still some three quarters of a million people in the UK. Furthermore, these are the patients with most morbidity and hospital admissions and who consume the most medical time and resources,4 ,5 and the figure quoted may well be an underestimate of the number of patients who should have been on step 3 or above. Determining which options should be available at step 3 has implications for a large number of patients, for the health service, and for the pharmaceutical industry.
In the first British guidelines on asthma management published in 1990, high dose inhaled corticosteroid was the only option at step 3.6 Long acting β agonists were added as an alternative in the most recent review of these guidelines1 and long term studies support this approach.7-10 With the introduction of leukotriene modifying drugs there is a further potential contender and some would push the case for theophyllines to be considered. The merits of the different drugs will be debated by the various guidelines committees and it is not our brief to pre-empt the outcome of these discussions. It seems sensible, however, to start to debate the criteria that should be used to decide whether a drug should be introduced at step 3 rather than at step 4.
We would start by suggesting that, in principle, the only criteria for including a drug at step 3 should relate to its efficacy and safety and the balance between the two. To many this will seem self-evident, but the frequent attempts to justify the use of a drug on the grounds of its mechanism of action suggests that this is not universally accepted. Purists would argue that it should be the effectiveness of a drug that should be considered rather than its efficacy, but effectiveness is more difficult to study and rarely measured in practice.
Simplifying the criteria to efficacy and safety is conceptually simple but the practical assessment is less straightforward. Randomised controlled clinical trials can provide much of the information required to assess the short term effects of a drug, on efficacy in particular, but they are less able to provide information on the effects of long term use over many years and this is often required to assess safety fully. Furthermore, not all controlled trials are relevant to guidelines. We discuss some of the pitfalls in using controlled trials and the difficulties that have to be faced when evidence from controlled trials is not available.
Assessing data from randomised controlled clinical trials
PRIMARY OUTCOME MEASURES SHOULD BE RELEVANT TO EFFICACY AND SAFETY
If efficacy and safety are the criteria that should be used to position a drug, it follows that the only end points from clinical trials that should be considered are those directly relevant to the patient such as symptoms, relief inhaler use, lung function, quality of life, asthma exacerbations, adverse effects, and mortality. Even lung function is a proxy measure though its practical value is widely recognised. Knowing the effect of a drug on a particular cell or mediator is relevant to our understanding of the way that a drug works but not to its value in clinical practice. It is worth remembering that inhaled corticosteroids were recommended for use in patients with asthma in the early 1970s because they improved asthma symptoms and lung function and had few adverse effects11; it was another 20 years before their effects on airway inflammation were confirmed in patients with asthma.12
SOME STUDIES ARE MORE RELEVANT TO GUIDELINES THAN OTHERS
New drugs for asthma are often studied in highly selected patients and this may be entirely appropriate for certain purposes. Such studies are not relevant to positioning a drug, however, as the size of response in a selected group of patients may bear little relation to the effect of the drug in the “run of the mill” patient with asthma. Patients in one study of montelukast were clearly atypical, for example, since their increase in forced expiratory volume in one second (FEV1) in response to salbutamol was more than 40%.13 We cannot assume that the response to montelukast would be the same in a more representative asthmatic population where the response to a β agonist is probably closer to 10%. The studies used to inform guidelines should involve patients who are broadly representative of asthmatic patients treated at step 3.
COMPARATIVE DATA ARE REQUIRED IN THE SAME PATIENTS
We can assume that any drug, and certainly new drugs on the market, will have demonstrated efficacy and a reasonable safety profile to satisfy the requirements of the regulatory authorities. The question when positioning a drug therefore is not whether it works but how effective it is in relation to the other drugs available. This can only be determined by a direct comparison of the two drugs in the same patients. Comparing the response of two drugs in different populations is dangerous. The FEV1 response to a long acting β agonist has ranged from 4%14 to 13%9 in different studies and a similar range can be found for all drugs, depending crucially on the inclusion criteria used for the study. Studies can be designed to ensure that a given drug is more likely to be effective—for example, by only including in studies of long acting β agonists patients who demonstrate good reversibility.
LARGE STUDIES ARE REQUIRED BUT WHO FUNDS THEM?
The need for large studies to provide clear cut answers about the effects of treatment in patients with asthma has been appreciated relatively recently. Such studies are expensive and hence tend to be carried out by large pharmaceutical companies. Although this has resulted in several high quality studies addressing important clinical questions, such dependence on industry limits the scope of the studies that are undertaken and it would undoubtedly be healthier if more independent funding were available. The reasons why almost no published studies instigated by the pharmaceutical industry reflect adversely on their product are multifactorial but selection of the study design and patients who are most likely to benefit from their drug is clearly one factor. If more independent support for large studies was available there would still be the potential problem that many prospective studies require placebo inhalers and their availability is currently dependent on the goodwill of the pharmaceutical industry. Once a drug is on the market it would surely be reasonable for companies to be required to provide placebo inhalers at a reasonable price.
Use of information from sources other than randomised clinical trials
Data from controlled clinical trials should be used to inform guidelines whenever possible, but such trials do not, and sometimes cannot, provide all the information required to make a balanced judgement of the efficacy and safety of competing drugs. This is particularly true for assessing the adverse effects of a drug which may increase with duration of treatment, as with oral corticosteroids. A rare but serious adverse effect such as aplastic anaemia with chloramphenicol also needs to be considered when producing guidelines. But how does a very rare risk of an arrhythmia or Churg-Strauss syndrome compare with a more widespread increase in the risk of osteoporosis 20 or 30 years later? Assessment of the importance of such effects is difficult, as instanced by the range of views on the importance of systemic effects from long term use of inhaled corticosteroids. This does not mean that the questions are unimportant nor that the effects are necessarily trivial. Responsible prescribing attempts to take such long term effects into account, something we do every day when advising or prescribing to patients. Guidelines need to do the same, presumably by a sensible assessment of the evidence that is available, albeit evidence that is less robust than that obtained from randomised trials. This is much more difficult than summarising the findings of controlled trials and the challenge perhaps is to be able to summarise the way we make these decisions and judgements more explicitly.
Conclusion
Step 3 is likely to remain the most contentious area of the asthma guidelines. Some of the difficulties in determining the positioning of drugs in the guidelines are due to problems that will always be difficult to answer, such as assessing a rare risk and balancing risks and benefit. Others, however, are due to a paucity of appropriate large comparative studies in relevant patients. Well designed studies comparing the different drugs available in appropriate patients will help to determine their efficacy and safety relative to each other. Other approaches such as post-marketing surveillance may be required to determine the longer term effects of the drugs. Treatment for asthma is often taken for decades, if not throughout life, so the long term effects—beneficial and adverse—are important considerations when positioning a drug in the guidelines.