Computer modeling and simulation help researchers
to better visualize pulmonary functions for faster, less
expensive clinical testing of innovative respiratory drugs.
By Jan De Backer, CEO, FluidDA nv, Kontich, BelgiumThierry Marchal, Healthcare Industry Director, ANSYS, Inc.
The cost of developing a new inhalation therapy drug for cut years from the development process and reduce costs respiratory diseases such as asthma, emphysema and by hundreds of millions of dollars.
cystic fibrosis is estimated at more than $1 billion — the
The current gold standard for testing airway diseases
highest in the pharmaceutical industry. This figure is is FEV1, the volume of air exhaled during the first second considerably more than for developing medications to of a forced expiratory maneuver started from the level of treat cancer or neurological disorders.
total lung capacity. Another approach in widespread use
The main cause of this extremely high cost is that for assessing patients with pulmonary disorders is the
current testing methods of evaluating respiratory drug Saint George Respiratory Questionnaire (SGRQ), a set of effectiveness are only coarse measures of patient long- questions aimed at comparative measurements of patient term outcome. Even so, such methods are extremely health.
time-consuming and expensive, as many patients must
These methods were developed primarily to measure
be tested over a long period of time. Researchers are long-term survival, but they lack the sensitivity to correlate addressing these issues with the emerging field of in silico with subtle differences in breathing that are more difficult modeling, which uses computer simulation to speed up to identify and quantify. Because of the uncertainty of medical studies and to provide greater detail than is these parameters and discrepancies between them, otherwise practical with extensive lab work and wide- researchers must spend considerable time and expense scale clinical trials. In particular, many in silico respiratory gathering data on drug effectiveness and averaging results studies are based on fluid dynamics
simulation to generate accurate images of pulmonary functions, such
as airway volume and resistance for
Animal Studies, Modeling .
individual patients. The technique
already has been used in studying the
Cost [million €]
respiratory structures of animals and 1200
— because the same functional
Patient-Specific Imaging and Simulation
parameters can be measured in
humans — enables researchers to
Existing Test Averaging Results
From Large Study Groups
proceed more efficiently from pre-
clinical to clinical trials. By accurately
quantifying these relatively small
changes in pulmonary functions, the
approach can demonstrate respiratory
Patent Expires at
drug effectiveness more quickly using
fewer patients. This has the potential to
Potential cost and time reduction in respiratory drug development through patient-specific functional imaging and computer simulation Based on 
ANSYS Advantage • 2010 Ansys, Inc.
across large groups of participants over extended periods of time.
The time frame for respiratory drug development is
staggering. Preclinical animal studies typically take two to four years, then additional time is needed to transition from animal studies to human clinical trials due to the lack of correlation and common denominators between the different species. Subsequent clinical trials last five to seven years and can involve thousands of patients. Regulatory agencies take up to three years to interpret and verify the clinical trial findings. The total time adds up to nine to 14 years before registration of the drug occurs and the medicine is available by prescription from healthcare professionals.
This leaves pharmaceutical companies with only a few
years to recoup development costs before the 15-year patent limit expires. Lengthy development drives up the retail price of respiratory drugs, severely delaying their availability to patients. The process often discourages pharmaceutical companies from risking considerable amounts of resources for an uncertain ROI (return on investment).
By quantifying a new class of functional parameters
linked more closely to pulmonary changes, computer modeling and simulation have the potential to significantly lower the time and cost of respiratory drug development. Resulting patient-specific functional-imaging data is an important component of this emerging field, called translational medicine. Researchers in this discipline continually search for parameters that can facilitate the transition of drugs from preclinical to clinical stages. Such Assessment of changes in airway volume and resistance through
methods already have been used to represent animal functional imaging using computational fluid dynamics
The Medical Value of in Silico Analyses
With the rapidly increasing computational power of
to the technology for future work. Likewise, the
standard PCs and the refinement of biomaterial
Grid-Enabled Medical Simulation System (GEMSS)
models, clinicians are showing a growing interest in
project aims to make biomedical vertical applications
the routine use of simulation. Clinicians do not have
available from the web with encouraging successes
the luxury of learning advanced user interfaces,
in applications such as stent interfaces.
however, so they need seamless interfaces between
Ongoing projects such as the Virtual Physiological
medical imaging and engineering simulation software.
Human Osteoporosis Project (VPHOP), RT3S and
Furthermore, a fully integrated workflow must be
ANGIOVISION multiply the opportunities to assist
developed for large-scale deployment of this
the medical world in lengthening life expectancy
technology in local hospitals.
and increasing quality of life through more effective
Several successful attempts to make numerical
orthopedic, stent and endovascular treatments,
modeling accessible and useful to the clinical
respectively. The upcoming decade will undoubtedly
world involve ANSYS tools. The @neuFuSE toolchain
see the development of computer-assisted surgery
(www.aneurIST.org) allows physicians to access more
(CAS) and the rapid penetration of in silico tech-
information about the risk of cerebral aneurysm
nology throughout the medical world, including in
rupture, for example. During one recent @neurIST
facilities close to home.
workshop, 90 percent of attending neurosurgeons
confirmed the clear added value brought by this
Healthcare Industry Director
solution and indicated high interest in gaining access
ANSYS Advantage • Volume IV, Issue 2, 2010
Segmentation of Sprague Dawley rat respiratory system illustrates modeling of the airway structures and corresponding lobar volumes derived from CT scans.
respiratory structures in studying inhalation profiles and inhaler selection and modeling has the potential to shorten deposition patterns for different respiratory devices. In the development time from patent filing to registration these studies, the common parameters of airway volume by years and to save hundreds of millions of dollars if and resistance determined through functional imaging the approach is used throughout the entire process of provide for a more efficient transition from preclinical to bringing a single drug to market.
The impact of such savings could be stunning. When
By changing the slope of the cost curve in a graph of costs for the development of new compounds are
development cost versus time, this translational approach reduced, the prices of these products could be lowered could alter the cost slope from preclinical to clinical trials without affecting profit margins, thus allowing for and significantly reduce expenses over the entire cycle. continuous research and development of innovative Furthermore, the approach could compress development new compounds in the pharmaceutical industry. time, moving registration forward much sooner and thus ultimately, the process could facilitate more sustainable increasing the time for the pharmaceutical company healthcare systems.
to market products under patent protection. Indeed,
Such savings are entirely possible in the foreseeable
patient-specific imaging and simulation coupled with future, given the tremendous strides made in previous
Animal Studies, Particle Deposition Modeling,
Safety & Efficacy
Computer-based functional imaging facilitates the translational approach in respiratory drug development through the use of common parameters in moving from preclinical studies to clinical trials.
ANSYS Advantage • 2010 Ansys, Inc.
studies and ongoing work in computer-based modeling and inhalation devices. Successes in this body of work and simulation. Promising work already is pushing the demonstrate the value of functional imaging in both envelope of functional imaging technology. Recent preclinical and clinical development stages as well as the developments in the field of computational fluid dynamics tremendous potential of the approach in revolutionizing and structural simulations have made it possible to the development of new inhalation compounds for simulate pulmonary airflow behavior in the pulmonary combating respiratory disease and improving the quality airways as well as to characterize surrounding tissue. The of life for patients worldwide. nresearch is based on geometries extracted directly from high-resolution computed tomography (HRCT) scans.
Based on this work, computer-based technologies  Adams, C.P.; Brantner, V.V. Estimating the Cost of New Drug
have the potential for researchers to perform modeling
Development: Is It Really 802 Million Dollars? Health Affairs, 2006
Mar–Apr, 25(2), pp. 420–428.
and simulations to derive functional parameters such as  De Backer, J.W.; Vos, W.G.; Devolder, A.; Verhulst, S.I.; Germonpré,
airway resistance as a biomarker on individual patients. A
P.; Wuyts, F.L.; Parizel, P.M.; De Backer, W. Computational Fluid
number of published trials — including FluidDA's studies
Dynamics Can Detect Changes in Airway Resistance in Asthmatics
— make use of these patient-specific HRCT-based
After Acute Bronchodilation. Journal of Biomechanics, 2008
models that were able to describe the distinct flow
patterns in the respiratory system. Certain of these  Burge, P.S.; Calverley, P.M.; Jones, P.W.; Spencer, S.; Anderson, J.A.;
Maslen, T.K. Randomised, Double-Blind, Placebo-Controlled Study
studies focused on the effect of inhalation medication and
of Fluticasone Propionate in Patients with Moderate to Severe
assessment of subsequent changes in airway volume
Chronic Obstructive Pulmonary Disease: the ISOLDE Trial. BMJ,
and resistance through functional imaging using ANSYS
(May 13), 320(7245), pp. 1297–1303.
FLuENT fluid dynamics software.
 De Backer, J.W.; Vos, W.G.; Burnell, P.; Verhulst, S.L.; Salmon, P.; De
Correlation studies indicate good agreement with
Clerck, N.; De Backer, W. Study of the Variability in Upper and Lower
Airway Morphology in Sprague-Dawley Rats Using Modern Micro-CT
clinical parameters. Similar methods can be used to
Scan-Based Segmentation Techniques. The Anatomical Record, 2009
assess animal respiratory structures in preclinical research
May, 292(5), pp. 720–727.
ANSYS Advantage • Volume IV, Issue 2, 2010
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Tilladelse til fremstilling og indførsel af lægemidler og mellemprodukter til human brug Manufacturer's / Importer's Authorisation regarding Human Medicinal Products Lægemiddelstyrelsen godkender hermed, at The Danish Medicines Agency hereby authorises 1. Autorisationsnummer Authorisation No. 22843 Virksomhed/fremstiller Name of manufacturer