Article Text


CFC transition
  1. Department of Respiratory Medicine
  2. North West Lung Centre
  3. Wythenshawe Hospital
  4. Manchester M23 9LT, UK
    1. A H MORICE
    1. Academic Department of Medicine
    2. The University of Hull
    3. Castle Hill Hospital
    4. Cottingham
    5. East Yorkshire HU16 5JQ, UK
    6. a.h.morice{at}
      1. M L EVERARD
      1. Paediatric Respiratory Unit
      2. Sheffield Children's Hospital
      3. Sheffield S10 2TH, UK
      4. m.l.everard{at}

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        Dr Everard wrote such a wide ranging polemic against inhaled therapy that it is difficult to know where to start. While the article contains a good deal of sense, it also contains a number of inaccuracies and misperceptions. I think the record needs to be put straight.

        Firstly, Dr Everard says that inhaled insulin will be in use in 2001. However, as far as I am aware, no application for delivery of insulin as an aerosol has yet been submitted to the FDA. New devices for the delivery of insulin are under trial, but the earliest they are likely to get to the market is 2002. They are likely to be relatively complex devices costing perhaps 100 times more than the current price for a salbutamol metered dose inhaler (MDI).

        Secondly, Dr Everard berates the pharmaceutical industry for its efforts in moving away from chlorofluorocarbon (CFC) MDIs. In 1996, when the Montreal protocol came into force, there was a real risk that MDIs for use in asthma/COPD would no longer be available. The industry started 10 years ago to try to reformulate MDIs but the technical challenge has been enormous and complicated by intellectual property issues. Only now, more than a decade later, are a sufficient number of CFC free MDIs coming to the market so that the transition can be completed over the next 2–4 years. This has cost a huge amount of money. But where is the evidence that they prevented new chemical entities for asthma coming to the market? If such clinically efficacious compounds were available, then I am certain that they would have been commercially exploited.

        Thirdly, Dr Everard is correct in stating that the MDI in some ways is a less than ideal inhalation device. The new hydrofluorocarbon (HFC) beclomethasone product (Qvar, 3M Pharmaceuticals) has a much smaller particle size, not by design but by necessity. This results in something like 5–6 times more drug being deposited peripherally in the lung but only twice the therapeutic effect compared with the MDI it replaces. This product has given a big “wake up call” to the industry and we should all be asking which particle size really is ideal, particularly for inhaled steroids. Is it different, for example, for beclomethasone versus budesonide versus fluticasone? I am also unaware of any data that monodispersed aerosols are more efficacious or safer than aerosols with a more broad range of particle size.

        Fourthly, Dr Everard mixes in with the discussion of technology a rather paternalistic view of patient compliance. If only patients would do as they are told and take their medication all would be well. Does anyone ever complete a course of antibiotics? We badly need more information about why patients do not adhere to medication regimes and what information they need about their disease and the treatments used. But isn't this true for all therapies? Dose counters to improve compliance might be valuable for MDIs—but where is the evidence that they are cost effective, or even that doctors or patients want them?

        I am firmly convinced that the MDI, along with the dry powder inhaler (DPI), is here to stay. They are remarkably cheap, instantly effective as bronchodilators, and have an excellent therapeutic ratio for inhaled steroids for most asthmatics. Many patients can use up to 2000 doses per year without their inhaler letting them down, and perhaps it is not surprising that they become reliant on them. Certainly they can be improved upon. Novel devices using aqueous and hydrocarbon propellants are on their way. But if Dr Everard sees any viable and cost effective alternatives, then let us hear about them.


        Mark Everard's superb leading article1-1 railing against the numerous inadequacies of inhaled therapy delivered by pMDIs is to be applauded, but ultimately is an unsatisfying tract since it does not point to any solutions applicable in the here and now. The single most important advance in the treatment of asthma at the beginning of the 21st century would be to wean ourselves—and by that I mean the UK since the process is already well advanced in continental Europe—from the use of these archaic impediments to treatment. Everard is right that the regulatory authorities bear a heavy burden of guilt by requiring devices which result in greater lung deposition to undergo much more extensive, and therefore costly, investigation than “me too” devices mimicking the appalling performance of pMDIs. I have witnessed the “detuning” of novel inhalers that he refers to in order to limbo under this bureaucratic hurdle. Removing the equivalence straight jacket for inhaler devices would, at a stroke, allow currently available devices to be used to their maximum and not minimum potential.

        Why are the British so hooked on the inadequate and obsolete pMDI? It is simply that the currently available alternative—dry powder inhalers—are perceived to be more costly. This view has been led by the Department of Health who have calculated that swapping device for device would cost them a great deal of money. This, however, is the accountancy of the madhouse. Because dry powder inhalers are more efficient at drug delivery, the Fairy Liquid argument holds and the cost of treatment rather than the cost of the device should be used in their calculations. Of course, such back of the cigarette packet arithmetic should be banished by the new god of evidence based medicine. So what is the evidence on cost? Howarthet al have performed an audit of patients who have been transferred to dry powder inhalers because they were unable to use pMDIs.1-2 The cost of treatment with inhaled steroids was actually lower with dry powder inhalers. The only randomised controlled trial using the overpriced Turbohaler came to a similar conclusion.1-3 Thus, what little evidence that is available suggests that prescribing even premium priced dry powder inhalers for the delivery of inhaled steroids may be cheaper than using pMDIs. There can be no argument that there is a cost impediment with the more recent introduction of generic dry powder inhalers which are competitive even on a device for device basis.

        Everard rightly points out that the issues of compliance, competence, and contrivance are closely interlinked. What is rarely taken into account in the equation is the patient preference. We have recently analysed the results of three separate studies comparing the market leading pMDI with the Clickhaler in terms of patient preference in 118 paediatric and 221 adult patients.1-4 Significantly more (63%) preferred the dry powder inhaler to the pMDI (28%) (p<0.01). The dry powder inhaler was also significantly better on other criteria such as ease of use and ease of preparation. Similar results have been obtained in a meta-analysis of comparative studies of 802 patients using the dry powder device Easyhaler.1-5 If patient preference is a surrogate for compliance, then two of Everard's three Cs can be dealt with today by transferring patients not optimally managed on pMDIs to dry powder devices.

        The third C—contrivance—will be tackled shortly with the advent of new chip technologies already available in nebulised devices such as the Halolite Adaptive Aerosol Delivery (AAD) system. In Hull, Kastelik and Aziz have recorded patient compliance in 23 subjects using the AAD system and have unsurprisingly found that 20% of patients were poor compliers (<70% of doses). We have been unable to detect this lack of compliance during a formal structured interview or on diary record cards. In future the identification of such problems with smaller devices attached to inhalers will not only be of great medical benefit but also, I suspect, will be led by cost. Vast sums of money are wasted in health care by poor adherence to treatment. The use of such technology may become a financial imperative in the future.


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        author's reply I would like to thank Professors Woodcock and Morice for their thoughts on this subject. The divergence in their views is of interest. Unfortunately, Professor Woodcock appears to have misunderstood the purpose of the article when he characterises it as “polemic against inhaled therapy”. The article was written precisely because I do recognise the importance of inhaled therapy and, in particular, the importance of inhaled corticosteroids for the treatment of asthma. Since aerosol therapy is so important, it should be clear that patients deserve to be provided with devices that deliver the drugs reliably and safely to the lungs.

        More than a decade ago pharmaceutical companies understandably decided to develop CFC replacement pMDIs. This was not because this was the best solution for patients but because at the time it appeared to be the quickest and cheapest solution. Much to their dismay, they found that this has proved to be a very expensive and long winded exercise. It is, however, important to recognise that the major error in judgement at that time was not that they underestimated the difficulties involved, but the failure to recognise the limitations of the pMDI as a delivery system for drugs other than short acting β agonists. The pMDI was a brilliant solution for a particular problem but does not effectively meet the needs of drugs such as inhaled corticosteroids. The challenges for device developers are, firstly, that they must develop a device that can deliver drug effectively to the lungs and, secondly, to produce devices that all patients can and will use effectively. The pMDI and many other technologies can generate aerosols that will deliver drug to the lungs but there has been little effort to meet the second objective. pMDIs are simple to use but very difficult to use effectively. It is inevitable that novel devices will come to the market in coming years, not least because of expiry of drug patents. However, to ensure that all patients derive maximum benefit from this form of therapy in the future it is important to understand the limitation of current delivery systems and to place patient issues squarely at the forefront of future developments. There is now a vast range of novel and impressive technologies available, but unfortunately aerosol scientists appear all too often to be caught up in this exciting technology, forgetting that devices are only there to serve the consumer. The technology is not an end in itself but a means to an end.

        The article deliberately avoided proposing specific solutions as the pharmaceutical companies do face many challenges. A major problem is that we do not have a simple method of assessing the “therapeutic index” of a given device so it is very difficult to determine whether a novel device and/or drug is “as safe” as others on the market; the principle of using the “lowest effective dose” therefore remains the best guide. Consideration of the issues of compliance, competence and contrivance are, however, essential if future devices are to meet the needs of patients. The studies Professor Morice cites are certainly a move in the right direction since they attempt to address the relative benefits of drug/device combinations in the real world.

        Professor Woodcock was indeed correct to note that it will be at least a year before inhaled insulin is used in clinical practice. This error was noted soon after the article went to press and a correction to this effect appeared on the Thorax website before the article appeared in print and on page 978 of the November 2000 issue of Thorax.2-1 He is, however, incorrect in both his estimation of the complexity of the device and of its likely price; any increase in cost will not be attributable to the production of the device but the premium charged for a novel form of treatment. The issue was raised to illustrate the point that simple to use, effective devices can be developed to serve specific functions.

        My views on compliance are far from paternalistic. As noted in the article, non-compliance is common in all diseases and the factors contributing to it are complex. There are no easy solutions for an issue that is responsible for excess morbidity, mortality, and healthcare costs. However, modern technology can certainly impinge on this area since, as Professor Morice notes, it is possible not only to monitor whether a device is used but also to monitor whether the device is used correctly. Monitoring compliance is likely to be introduced in North America if managed care organisations find that they can reduce costs. I do not know if patients or doctors want such facilities in their delivery systems, but since it is now possible to monitor compliance in this way, a grown up, informed debate should be initiated. Certainly, objective compliance data can significantly improve the quality of a consultation by allowing the patient and professional to concentrate on the factors adversely affecting compliance in an open and honest dialogue.

        It is to be hoped that in the future novel devices will use appropriate technology to meet the needs of the patient rather than developing devices that force patients to adapt to the technology.


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