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Pharmaceutical Manufacturing and Packing Sourcer
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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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