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Drugs on test

Tom Feilden | 10:53 UK time, Friday, 17 October 2008

Herceptin  Well, at least one thing is clear: when the National Institute for Health and Clinical Excellence (NICE) approves a new drug for use in the Health Service we can be sure it's been through a rigorous and extensive appraisal involving a series of randomised controlled trials...or at least we could.  

In an astonishing turn of events the chairman of NICE, Sir Michael Rawlins has turned this established wisdom on its head. Arguing that RCT's have been elevated to an "undeserved pedestal" and holding out the prospect that, in future, some drugs could be approved without meeting this exacting gold standard.

Talking at the Royal College of Physicians Sir Michael said the current methods for testing the effectiveness of new drugs were flawed, and the NHS needs a new, more flexible, system for assessing clinical evidence that takes more account of observational studies.

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Randomised trials are certainly expensive: according to one manufacturer the average cost per patient rose from £6,300 in 2005 to £9,900 in 2007. Where the benefits of a drug are obvious or dramatic RCT's are often unnecessary, and where the treatment is designed to target a rare condition the results can be inconclusive.

NICE has come under sustained attack in recent years over the length of time it takes to assess new drugs. In August the National Kidney Foundation branded the regulator's decision not to licence four new kidney cancer drugs as "barbaric, damaging and unacceptable". At the time Sir Michael responded by launching his own withering attack on the pharmaceutical industry and the overpricing of medicines to boost profits. "We are told we are being mean but what nobody mentions is why the drugs are so expensive".

It may be that in appealing for more flexibility Sir Michael is hoping to develop a little more wiggle-room to approve drugs that, although safe and effective, don't perform well in randomised trails.


  • Comment number 1.


    I find the NICE guidelines in the area of respiratory disease are totally inadequate, even scientifically wrong and have made representations to this effect to the Brirish Lung Foundation. I have submitted evidence supporting my assertions, but have been denied any access to their technical committees. My proposals are summarised below:


    In April 2002 I gave up the use of bronchodilators for good. I have lived with Chronic Obstructive Pulmonary Disease (COPD) for 40 years and, in the course of about 20, taken all the treatments that conventional medicine had to offer its respiratory patients. Over the last six years, since giving them up, I have spent my time trying to understand why bronchodilators do not work.

    I have always taken responsibility for managing my own condition and this meant that I took up yoga. I even trained, at the age of 65, as a yoga teacher and continue with a class aimed at helping people with breathing problems. I also spent much of my free time hill walking until unable to do so because of the progress of the disease. With both these activities, one quickly finds that the exercise of breath control is essential. An integral part of yoga is controlling one's breath.

    Professor Buteyko observed, many years ago, that patients suffering from asthma spent much of their time breathing too much. This was most evident when they were at rest or engaged in simple activity, such as watching television, reading, listening to the radio, or even just digesting a meal. This chronic over breathing has the detrimental effect that the level of carbon dioxide retained in the lungs, is less than optimal. It is a well established fact that concentration of carbon dioxide (Pa[CO2]) in the arterial bloodstream needs to be held at a constant level (denoted by a partial pressure of 5.3 kPa.) in order to ensure a stable acid/alkali state (denoted by ph of 7.35). This sets the optimal value for the partial pressure of carbon dioxide in the alveoli (air sacs) in the lungs; ie. PA[CO2] =5.3 kPa

    If the concentration of carbon dioxide in the alveoli is lower than that in the bloodstream passing through the capillary blood vessels of the gas exchange system, then the body has a problem. It cannot retain enough carbon dioxide in the arterial blood for its essential needs, because of diffusion via the alveoli. It has to find another mechanism to provide it. I call this mechanism an "induced asthmatic reaction". The body actually shunts carbon dioxide rich, but oxygen poor, blood directly from the venous system into the arterial system. This is the basis for "pure asthma" and all its unpleasant symptoms, such as inflammation, excess mucus production and even bronchial spasm. This is why asthmatics breathe more than they need when resting. In other words, dysfunctional breathing is the cause of asthma rather than vice versa. The body does not live happily with this condition because it has some difficulty in eliminating excess carbon dioxide.

    During the course of my work on identifying the mechanics of optimal breathing, it became clear that the pump that is incorporated in the action of the lungs has distinct performance characteristics that need to be followed in order to satisfy the need to hold a concentration of CO2 at 5.5%. It transpires that one needs to breathe a tidal volume that is 3.5 times the dead space in the lungs. For a resting normal adult male, the dead space will be about 0.15 litres, with a tidal volume of 0.5 litres. When one has asthma, one does not satisfy this relationship. This ratio will tend to rise from 3.5 up to 4.5, say. If one now takes a bronchodilator, then this has the effect of increasing the dead space and, hence, the ratio will revert to around the value 3.5. This relieves the sense of breathlessness, but one has, by this mechanism, reinforced the over breathing, originally observed by Professor Buteyko.

    It is a fact that once the patient is controlling his/her asthma with the aid of bronchodilation, they will inevitably need to increase the dosage over time, just to maintain the stable state of chronic over breathing. This is normally accommodated by eventually moving to a regime of continuous bronchodilation, using say, Salmeterol. The problem then arises that the patient is increasingly inured to the "beneficial" effects of this class of drug and when they need to break a bronchial spasm, they no longer are able to get the required effect from a dose of, say, Salbutamol: which can even lead to a fatal outcome.

    The Buteyko method of breath control aims to eliminate chronic over breathing by teaching one to breathe through the nose, while using the diaphragm. By limiting the duration of the in breath, one reduces the tidal volume and thereby restores the optimal relationship between dead space (VD) and tidal volume (VT). This will eliminate the drive to over breathe and reduce the load on the heart and respiratory system, relieving the symptoms associated with the asthma reaction. By mastering the Buteyko system of breathing, one can "cure" asthma and eliminate the use of bronchodilators, which have known side effects such as immune system suppression and increased stress.

    In the case of COPD, we still need to maintain the optimal ratio (VT/VD = 3.5) in order to avoid chronic over breathing and, hence, an asthmatic reaction. To do this, we now have to manipulate the exhaled breath. With COPD one invariably has difficulty in breathing out fully. Emphysema, one of the conditions associated with COPD, causes the bronchial tubes to lose their natural elasticity and, as a consequence, they collapse during exhalation because of a reduction in pressure. This means that the ratio, VT/VD, is less than optimal. To counteract this, one has to adopt a resting breath which is increased in duration from that which comes naturally. This involves using a yoga based breathing practice, which uses the muscles in the throat to maintain a back pressure in the lungs, during the course of the whole of the out breath. Such a technique means that one has to slow down the breathing rate. The aim is to make the patient's reflex breath conform to the optimal ratio (VT/VD = 3.5). Consequently, if the dead space has increased from 0.15l to 0.20l, say, then one's tidal volume should now have increased to 0.70l. Thus, for COPD, the way to combat breathlessness is to breathe slower and longer.

    The current fashionable treatment for COPD is that of "continuous bronchodilation”. Drugs such as Salmeterol and/or Tiotropium (designed to maintain their "reliever" action over 24 hours, using single or twice daily dosages) are prescribed. It is in the nature of the process that the dead space will be increased. This forces one to breathe even slower and longer (which does not come naturally) to maintain the optimal ratio. Such a medication regime can, and will in my experience, induce quite a severe asthmatic response. In the terminal stages of the disease, the tidal volume needed will ultimately exceed the vital capacity of the patient. Use of continuous bronchodilation will greatly hasten the onset of this process and lead to an earlier death than would otherwise be the case.

    Modern instrumentation, which greatly facilitates the teaching of a relevant breathing technique, appropriate to each diagnosed condition, has become available quite recently. This Capnometer monitors the breath by sampling, via nasal cannulae, the air passing in and out through the nose. It has the advantage, that it is virtually non intrusive, and yields continuous data on carbon dioxide levels. It is well established that the end tidal value for carbon dioxide concentration is equal to the steady level in the lungs. We thus have a direct reading for PA[CO2] which can be compared to the optimal value of 5.3 kPa. This allows a trainee to see how (by manipulating their out breath) they can raise the end tidal value to the desired level. With such an instrument in their hands nurses or other competent persons, can readily teach patients to manipulate their breathing under a range of conditions. The response and capabilities of individual patients will vary greatly but all will be able to derive benefit from such training.

    I have, for some time now, been making the case for an approach that differs fundamentally from that specified in the relevant NICE guideline . The intention will be to set up a pilot study here in Scotland that will aim to establish the protocols that will govern a broader based study aimed at demonstrating the value of a management scheme based on the principles outlined above.

    Alan Moore
    Revised, February 2008

    As a long term supporter of the BLF I find their position "censoring any such discussion within their organisation quite intolerable, given their self proclaimed role of being the main body representing respiratory patients' interests. One has to believe that the pharmaceutical industry is exerting an unhealthy influence upon their supposed independence.


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