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Pharmaceutical Manufacturing and Packing Sourcer

The Best is the Enemy of the Good

Current drug delivery devices offer substantially less than the drug manufacturer and patient require, and the industry needs to consider where positive steps should be taken

Good drug delivery devices are no longer enough;we need the best.The market for mechanical and electromechanical drug delivery devices continues to be an important and growing segment of the pharmaceutical and healthcare industries.With evidence of strong progress in the inhalation market, there are exciting challenges ahead for drug delivery device developers and manufacturers.

Growth in the drug delivery devices market is being driven by a number of significant factors, including slowing NCE pipelines and drug patent expirations, new biological drugs, ageing patient populations, and greater influence and choice from patients.This latter point is precipitating greater degrees of ‘medical device consumerism’, as existing, poorly designed device technologies are being challenged by an increasingly enlightened and demanding patient population.

On a global scale, healthcare systems are facing the issue of burgeoning and unsustainable healthcare economics. This is giving rise to a shift in emphasis away from purely treating patients towards focusing on better clinical outcomes for patients, as well as early disease diagnosis and, better still, more proactive disease avoidance and preventative medicine.

These factors are compounding and creating a compelling case for further drug delivery device technology innovation as a cost-effective means of introducing new patient benefits, increased product differentiation, extended product lifecycles and improved patient outcomes.

Focusing on inhalation – and more specifically asthma – the market for drug products is valued at around $26 billion ($17 billion for portable inhalers) and has grown at around 10 per cent CAGR for the past five years. This highly device-dependant therapeutic area is driven by the need for portable inhaler devices that can safely and effectively deliver drugs to the lung. Slowing drug pipelines are forecast to reduce market growth rates to around five per cent, despite the growing incidence of chronic conditions such as asthma and COPD. This is leading to increased emphasis on device technologies to bring greater patient benefits and help extend drug product lifecycles through differentiation.

Cost of Disease Management

Prescribing and medication costs are the tip of the iceberg for asthma care, with the majority of the cost burden relating to the consequences of poor or uncontrolled disease management.These costs include direct costs, such as emergency hospitalisations, as well as indirect costs through lost productivity, such as time off work, early retirement and premature death. In the US alone, 23 million people suffer from asthma (6.8 million of which are children), and over 50 per cent are believed to have poorly controlled asthma.This leads to 500,000 hospitalisations and 3,884 deaths in 2005 (up 18 per cent from 1994), at a direct cost of $19 billion to the US healthcare system (1).The situation is exacerbated by continued increases in prevalence of asthma associated with lifestyle changes and improved diagnosis.

Paradoxically, asthma is a highly controllable disease through the use of prophylactic therapies, such as corticosteroids, and good patient compliance.The real issue is one of poor compliance through factors such as incorrect device use or failure to use at all.

Inhaler Technologies

Within the portable inhaler segment, the metered dose inhaler (MDI) has long been the mainstay technology of the industry, with a history of over 50 years.The inherent valve technology incorporated into these devices has not changed significantly over this period, and the technology provides a cost effective drug delivery solution to pharmaceutical companies.However, the MDI is not considered to be a highly differentiated device technology and is becoming less favoured by pharmaceutical companies introducing NCEs and patented molecules. As a result, the MDI is rapidly becoming the delivery system of choice for generic drug products and emerging markets where cost is a greater factor. Consequently, the number of NCEs going through the clinic in MDI devices is dropping.

By contrast, over recent years the dry powder inhaler (DPI) market has been an area of far greater device development, and one with a large market potential still to be addressed. A quick review of the literature reveals around 40 to 50 DPIs in various stages of development.The story for marketed products is, however, somewhat different with only a handful of devices achieving regulatory and market approval and more than 90 per cent of DPI drug sales confined to two or three devices. It is also interesting to note that a great deal of new device development is seeking to replicate, rather than improve on, the delivered dose performance of the incumbent technologies which, on the face of it, appears to be an opportunity missed. Alternative portable inhalers based on liquid droplet technologies are gaining interest and can achieve high lung deposition performance. At present, these products remain fairly niche – presumably due to their relatively high cost of goods and industry attitudes towards reimbursement.

Inhaler Performance The delivered drug dose performance of the MDI is intrinsically low, with estimates of around 15 to 20 per cent lung deposition when used under optimal conditions and, more typically, 10 to 12 per cent.This situation is significantly impaired by considerable patient-to-patient variability due to issues of poor device usage, with estimates of less than five per cent lung deposition in poor use cases. Poor use of devices and increased evidence of failure modes are particularly common in paediatric and geriatric patient populations.

There are many failure modes associated with poor MDI usage; these range from failing to shake the device before use or holding the device incorrectly, to poor breath coordination and inappropriate inspiratory airflow when triggering the device. A study in paediatric patients revealed 45 per cent were improperly used through more than one of seven identified failure modes (2).

An additional concern with the MDI relates to its environmental impact.The 1987 Montreal Protocol ruling for the phase-out of CFCs has transitioned the MDI market away from CFC to HFA propellants, and in doing so has overcome concerns over ozone depletion. However, HFA propellant systems, while better than CFCs, still contribute very significantly to the greenhouse effect.To illustrate the point, HFA propellant 134a, commonly used in MDI devices, has a global warming potential (GWP) that is 1,300 times greater than that of carbon dioxide.

Despite the drawbacks of a relatively poor delivered dose performance and negative environmental impact, the MDI has proved to be a very reliable and extremely cost effective technology. Its place in the market is likely to remain for many years to come due to the technology’s acceptable efficacy and relatively high cost-to-benefit ratio.

Efforts have been made to improve MDI user performance, primarily in the areas of spacers, breath coordination and dose counting mechanisms for improved ease of use and patient compliance.These innovations have been slow to come however, and significant further opportunities to improve on this core device technology do exist.

DPI products are growing in popularity and represent the main alternative to MDIs. According to Datamonitor, approximately 67 per cent ($11.5 billion) of drug sales from portable inhalers come from DPI devices, yet they only account for 13 per cent of device volumes shipped. The remaining 33 per cent of sales are attributed to MDI based products, yet this accounts for 86 per cent of the volume. The success of this DPI value proposition has been greatly assisted by drugs such as Advair/Seretide and Spiriva, which are primarily offered in DPI presentations. The market opportunity for DPI development is therefore compelling for pharmaceutical companies.

By following sales data and market dynamics, it could be inferred that DPIs are better devices than MDIs – but is this really the case? What do we mean by ‘better’? Looking at the product areas more closely, the data on the leading marketed DPI compared to its MDI counterpart suggests that the delivered dose to the lungs is better but only marginally so, with research indicating a figure of around 15 per cent for the DPI compared to 10 per cent for the MDI (3). Even at 15 per cent, this is still an extremely low level of the drug reaching the lung, and by itself does not account for the very clear market success in uptake.

The success of recent DPI products more likely finds its roots in the pharmaceutical company’s ability to differentiate its product in the market. Furthermore, the high cost and technical barriers associated with formulating and developing inhalation drug and device combination products, together with strong intellectual property positions, make it difficult for generic competitors to adopt fast follower entry strategies into the market.

Clearly, this is not the full picture and there are pros and cons for both MDI and DPI device technologies; they are prescribed to patients for different reasons and according to specific patient factors. Ultimately, the patient must be able to use the device easily and derive clinical benefit from the drug delivery technology.

Despite the arguments for the current technologies, poor lung deposition remains an issue. The consequence of poor lung deposition often manifests itself as high levels of oropharyngeal deposition – an undesirable side effect associated with portable inhalers and a particular concern with the increased use of corticosteroids in the treatment of asthma. Long-term use to treat chronic asthma can cause oral thrush (fungal infections that develop inside the mouth). In children and teenagers, they can stop or slow growth and affect the function of the adrenal glands, and in older people, corticosteroids may increase the risk of high blood pressure and bone disease such as osteoporosis.

What Can We Do Differently?

We have to address the issue of poor compliance. Compliance issues result from either failing to take medication or failing to take the medication correctly. Training and education play an important role, and a great deal can be done from the time of first diagnosis and prescribing, up to the time when patients become established in a well adhered-to regimen. Unfortunately in many cases the latter stage is never achieved. Establishing a reliable and effective regimen will only occur if both the patient and clinician have access to good quality information that raises awareness and helps address issues of poor compliance early. Once bad habits form, they are hard to break.

The current emphasis of healthcare systems is very much on therapy cost. This is driving device costs down and discouraging enhanced features and improvement in device performance. The answer lies in a more holistic approach to patient treatment, therapy costs and reimbursement mechanisms. Greater emphasis on total cost and better patient outcomes is needed, and here technology will play a key role, especially through increased device functionality.

If we accept that prophylactic therapy is the right way forward, then it makes sense to focus future development efforts here.We need to substantially raise the bar and achieve much higher levels of lung deposition to overcome the side effects of oropharyngeal deposition.This will give increased confidence to prescribe corticosteroids to paediatric and geriatric patient groups that are more vulnerable to the risks of side effects with this class of medication, and in general will be beneficial to the broader patient population.Designing high performance devices is readily achievable, but the industry appears to be opting for the less ambitious goal of replicating existing product performance, perhaps in pursuit of a less complex regulatory approval path.

As a minimum requirement, inhalers must be capable of efficiently, safely and reliably delivering medication. They should also be capable of far greater end user interaction, informing patients of incorrect use and encouraging proper use. This can be achieved through a variety of means including intuitive, easy to use inhaler designs, devices that provide real-time feedback to allow patients to refine their technique, simple patient reminders for when to take medication, and data storage for device use history retention.

Patients and their clinicians should have access to well laid out, easy to interpret inhaler use data, and indeed data from complimentary diagnostic devices such as peak flow meters and spirometers. This will enable patients to be more proactive and take far greater control of their treatment through early visibility of compliance issues. It will also facilitate a more informed discussion between patients and clinicians and enable better anticipation and preventative action to be taken in order to avoid serious relapses or hospitalisations.

Conclusion

Greater emphasis needs to be placed on device design and correct device use to ensure that devices not only function better, but that they fit better with patient lifestyles, are more intuitive to use, and provide greater feedback to patients and clinicians. This will require increased investment to create better devices and healthcare information management systems; but over the long-term it will pay dividends through reduced healthcare costs and better patient prognosis.The bottom line is this: inhalers should work better.The technology is available today, so we do not need to wait another 50 years.

References

1. American Lung Association 2008
2. Scarfone RJ, Caparro GA, Zorc JJ and Zhao H, Demonstrated use of metered-dose inhalers and peak flow meters by children and adults with acute asthma exacerbation, Arch Pediatr Adolesc Med 156: pp378-383, 2002
3. Dolovich M, New propellant-free technologies under investigation, J Aerosol Med 12: S9-S17, 1999




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Phil Lever is Commercial Director for Cambridge Consultants’ drug delivery devices business arm and is responsible for new device development programmes. Educated at the University of Birmingham where he studied Chemistry, he has extensive experience within the medical and drug delivery devices industry, particularly in inhalation and injection technologies. Previous roles include Director of Strategic Planning and Marketing at Consort Medical, Commercial Director at Bespak, and Director of Odem Ltd, an inhalation technology company.
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