Post on 14-Apr-2018
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Penetrating the Universal Emerging Market:
Answers to 10 Key Questions on Developing and Marketing Therapies for the
Aging Population
People try to put us down [Talkin' 'bout my generation]
Just because we get around [Talkin' 'bout my generation]
Things they do look awful c-c-cold [Talkin' 'bout my generation]
Hope I die before I get old[Talkin' 'bout my generation]
-Roger Daltrey, 1965
What the now 68 year old Roger Daltrey was likely
unaware of is that 55 years later, we would be
embarking upon the most pronounced growth of the
older population ever experienced. Similar to many in
his generation Mr. Daltrey would indeed be getting
old before he died(fortunately). In 1965, when this
iconic song was released, the global population of
those aged 60 and over was 200+ million
(approximately 6% of the worlds population); today it
is around 760 million (~11%). The United Nations
estimates that this number will grow to 1 billion in the
year 2020.1 By the year 2050, it is expected that
individuals 60 and older will comprise 21% of the
earths citizens numbering 2 billion. Likely considered
implausible in 1965, the fastest upsurge will be those
85 and older.
While this is all said, among the life sciences industry
geriatrics has often remained the proverbial elephant
in the room. For the most part, it is not considered anexciting population and clinical trials are more difficult
to design due to multiple comorbidities. Ironically,
the life sciences industry possesses the dual
responsibility for expanding the average lifespan as
well as ensuring the future health and optimal
function for those who reach older ages. A result of
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innovation such as drug and device-delivered
therapies to manage acute events and chronic
conditions such as accidents, coronary artery disease,
diabetes and even certain cancers and infectious
diseases are no longer a death sentence.
Nonetheless, the resulting longevity and
accompanying frailty predisposes individuals to a
whole host of other chronic ailments including
Alzheimers disease, heart failure, and other forms of
cancer and infections. Additionally, those with
chronic diseases such as diabetes and hypertension
are living longer with them. Taking therapy discovery
to the next level requires a 360 degree perspective on
what this population truly needs to ensure that older
individuals have access to therapies which have safety
and efficacy profiles specific to them and an
adequately informed health care delivery system.
It is well understood that addressing this demographic
shift comes with significant challenges. However, it
also affords an incredible opportunity for life science
companies who can take on this challenge by
specifically addressing this age group. Indeed there
exists a huge potential to differentiate a companys
products based on addressing this population with
specific drugs, devices, and therapies. This is attuneto the transformation of wheelchairs to scooters
and the growth of 55+ and assisted living
communities.
This white paper will address the critical questions for
the industry and suggest prospective approaches that
the industry can leverage as progressive companies
target the enormous global emerging market that is
older adults.
1. Why Are We Living Longer And What Are theConsequences?
The lengthened lifespan is the result of the coupling
of two critical factors, a decrease in mortality from
infectious diseases and breakthroughs in the
treatment of chronic diseases such as heart disease
which have lengthened the average lifespan.2 In the
early part of the 20th century, the introduction of
anti-infective agents including antibiotics and sulfa
drugs afforded life-saving therapy for individuals
afflicted with most infectious conditions. Vaccines
targeted to once epidemic diseases like smallpox,
measles, scarlet fever, diphtheria, and polio virtually
eliminated deaths from these conditions. In the case
of chronic conditions, using the example of heart
disease, improvements in risk factor management
such as cholesterol lowering and primary
percutaneous coronary intervention in the case of
acute myocardial infarction have allowed patients to
live significantly longer with heart disease than they
might have even 50 years ago.
Longevity opens up the risk for acquiring other
diseases not common in younger individuals such as
pneumonia, dementia and cancer.3 Aging also leads
to certain disabilities such frailty in a number of
individuals. In one Dutch study, approximately 10%
of community-dwelling adults 65 and older were
considered frail.4 Moreover the same chronic
conditions that were managed well enough to get
people to an old age still require careful control.
Physiologic changes in aging (discussed in thefollowing section) also may result in alteration in the
response to the drugs used to treat them.
2. How is the Aging Population Different?Physiological changes occur with aging in all organ
systems.5 For example, the cardiovascular system is
affected by decreases in cardiac output, increase in
blood pressure and arterial stiffening via
arteriosclerosis. Individuals experience a decrease in
lung vital capacity and slower expiratory flow rates
coupled with impaired gas exchange. Progressive
elevation of blood glucose occurs with age on a
multifactorial basis Furthermore, aging impacts the
pharmacokinetics and pharmacodynamics of many
drugs by reducing hepatic metabolism (as low as 30-
50%) and renal function while increasing the volume
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of distribution of lipid soluble drugs since lead body
mass declines due to loss and atrophy of muscle
cells. Consequently this extends a drugs elimination
half-life.
3. Can Drugs Be Designed Specifically for OlderPeople?
Ideally, drugs destined for the geriatric population
should be developed so that they ideally fit the
needs of the aging body. They would produce
effects at a pace which maintains physiological
balance. This would be slow enough to reduce shock
to the system yet as quickly as possible to relieve
symptoms at minimal doses.
While such products do not yet appear to be
available, there is evidence of developments which if
applied effectively could eventually accomplish this
goal. For example, personalized medicine such as
intelligent dosing uses computer models to address
this challenge. The model takes into consideration a
multitude of factors to determine the ideal
medication dose for a given patient. In the area of
drug delivery, innovations such as a multi-unit
particulate system may allow drugs to be dosed in a
highly precise and individualized manner by allowing
a combination of different pellets within a capsule or
tablet to take effect at different times and at varying
strengths. More appropriate drug formulation is also
being examined; possibly greater availability of liquid
formulations, rapidly dissolving tablets, and even
drug-impregnated film that may be placed on the
tongue. Additionally, there has been interest among
some researchers to address deficits in visual and
tactile ability which result in difficulty of patients to
differentiate one pill from the other.
4. What About Including the Very Old in Trials?While the number of older patients enrolled in
clinical trials has somewhat increased over the first
decade of the new millennium, clinical trial data in
the very old and oldest old, i.e. patients over 75
and older and 85, respectively, is nevertheless
somewhat lacking. There is still not adequate data
available so that providers can be confident that the
medications they use in their geriatric patients are
safe and effective in this population. For example,
in a 2007 study sponsored by the Robert Wood
Johnson Foundation which reviewed 109 clinical
trials, it was revealed that a fifth of them excluded
patients above a specified age, and that almost half
of the remaining studies used criteria likely to
exclude the elderly disproportionatelyfrailty or
impaired cognition.6
In 1993, the FDA released guidelines focused on
increasing the amount of geriatric informationavailable in the label for drugs which will be
predominantly used in this population. 7 By 1997, a
Geriatric Use section was added to the label in
order to report any pharmacokinetic or
pharmacodynamic differences between the
geriatric and overall populations.8 Recently there
has been a greater push by regulatory agencies
both in the US and Europe with the release of ICH
guidelines titled, Guidance for Industry: E7 Studies
in Support of Special Populations: Geriatrics drivingtoward the goal of ensuring that real world
geriatric patients including oldest old, those with
comorbidities, and receiving concomitant therapies
are well-represented in clinical trials of new
therapies or formulations.9 At current time, these
remain only guidelines. The EU seems to be taking
a more aggressive role as the EMA as part of the
Agencys Road Map to 2015, has devised a
Geriatric Medicines Strategy and has even put
together a Geriatric Expert Group that is charged
with providing scientific advice to CHMP and the
EMA on issues related to the elderly.10
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5. I Have Heard of a Pediatric Indication. Isthere a Geriatric Indication?
True, most companies are familiar with filing for
pediatric indications. Since 1997, the opportunity to
obtain pediatric exclusivity has allowed companies tofurther differentiate their products as well as gain an
additional 6 months of protection against generic
competition in the United States. Pediatric dosing
makes excellent sense as drug metabolism in children
differs from that of adults thus increasing the risk of
adverse reactions and lack of efficacy. Such
differences are even observed across the span of the
pediatric age range. Without specific dosing in the
label, clinicians are playing guessing games with their
young patients.
When you take a careful look at the pediatric
situation with respect to the value of specific dosing,
it is easy to see how this parallels the geriatric field.
While many in the pediatric community warn that
children should not be treated as little adults, it could
be also cautioned that the elderly should not be
considered as vigorous adults. Most clinicians feel
that it is absurd to treat an 8 year old in exactly the
same manner as someone who is 35; why should itnot be just as illogical for a 75 year old to be treated
the same as a 35 year old? By its nature, aging
impacts the pharmacokinetics and
pharmacodynamics of many drugs. Reduced hepatic
metabolism (as low as 30-50%) secondary to changes
in hepatic blood flow, liver mass and hepatic
endothelium, reduction in renal function and
increased volume of distribution of lipid soluble drugs
all increase the elimination half-life of a drug. Altered
sensitivity, common to several drug classes of drugs,results in accentuated effects in the elderly.11 Put
together, this gives rise to an increase in adverse
events in this population. Accordingly, the medical
community is making due by practicing by the adage
of start low, go slow and in general, cutting the
dose of many common medications in the elderly.
Still, as these doses were not clinically studied, it is
not clear if as adverse events are attenuated the
drugs efficacy is being jeopardized.
Why havent we heard more about geriatric
exclusivity? Relative to the overall medication use in
the U.S, the elderly are a sizable population. Although
the 65 and older age group comprises only 13% of the
population, they account for approximately 34% of
prescription medication use. 12,13 Additionally, a recent
survey conducted by the CDCs National Center for
Health Statistics reported that almost 90% of
individuals 60 and older had used at least one
medication in the past month and 76% reported two
or more.14
It would make logical sense that drugs used
disproportionately by the elderly would already have
geriatric-specific dosing in their labeling. This is not
the case. Indeed, in a study performed by Steinmetz,
et al, looking at the 50 oral drugs most commonly
used by patients 65 and older in an in-patient setting,
only 8 contained some form of altered dosing
guidance in the label specific to geriatric patients.15
None included age-specific dosing.
In researching circumstances in which geriatric
exclusivity was granted, our search yielded only one.
In 2005, the FDA approved geriatric dosing for Savient
Pharmaceuticals Oxandrin (an anabolic steroid
indicated for weight gain) and granted the product 3-
year marketing exclusivity.16 This is quite notable
given the exclusivity for adding pediatric dosing is
limited to 6 months.
So goes the question of why companies are notpursuing geriatric dosing as a way to attenuate
competitive threat, both branded and generic.
Unmistakably, this pursuit does not make for a
clean trial as the elderly are more likely than their
younger counterparts to have more comorbidities and
thus be on other multiple medications. This is most
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likely why so few patients of 75 and older are
included in clinical trials in general, even for drugs
that are very appropriate to them. The opportunity
for industry is substantial. In addition to the potential
for an extra 3 years of exclusivity, providing specific
dosing guidance for geriatric patients will likely result
in providers using that particular drug over
competitors or even generics. They may feel
confident that they can circumvent adverse events
while maintaining the optimal level of efficacy. We
look forward to further discussion of geriatric
exclusivity and why it is not being utilized by life
science companies.
6. What Are Geriatric-Specific Endpoints?Most trials conventionally measure only endpoints
which tend to signify the efficacy of the therapy as
well as standard measures of safety and tolerability.
As noted earlier, age-related physiologic changes
may in fact alter an individuals response to a given
therapy. Some of these may include those which
impact cognition and function. Therefore, drugs
being evaluated for a geriatric population would
ideally include these endpoints which expand
beyond efficacy and safety for example, if the drugresults in delirium or incontinence.
Review of the literature, commentary, etc. has
revealed that there is still a call to action for such
endpoints. To confirm this, using the website
clinicaltrials.gov we performed a search of all
interventional trials involving patients >66 years of
age in which cognition was included as an outcome
measure. Out of 209 trials, only five did not
evaluating therapies for diseases involving the brainsuch as Alzheimers and Parkinsons disease.
Although there is significant interest in including
such endpoints for drugs used in older individuals,
the level of importance has not been recognized by
industry.
Efforts are being made by regulators to encourage
the inclusion of such geriatric-specific endpoints. In
the U.S. and in Europe, regulatory bodies have stated
the goal of ensuring that drugs used primarily in the
older population have been in clinical trials which
adequately represent these patients. The E7
(referred to earlier) specifies that certain specific
adverse events and age-related efficacy endpoints
should be actively sought in the geriatric population,
e.g., effects on cognitive function, balance and falls,
urinary incontinence or retention, weight loss, and
sarcopenia.9
7. How Will Such Innovations Be Paid For?It is impossible to have a discussion about health
care for the aging population without mentioning
cost-containment policies. As we discuss the role of
innovation in ensuring that quality and fulfillment of
life are achieved while extending it, a key question
is how this will all be paid. Moreover, are cost-
containment policies with respect to newer more
expensive therapies counterintuitive as they may
result in higher costs down the road? In certain
situations failure to use a certain medication may
result in severe consequences for which thetreatment may outweigh the cost of the actual
medication. This involves a careful cost-benefit
analysis to show that not using a certain medication
will in fact raise the cost of treatment.
In 2006, enacted as part of the Medicare
Modernization Act of 2003, older individuals were
now eligible for formal Medicare prescription plans
(Medicare Part D) either through Medicare
Prescription Drug Plans (PDP) or Advantage plans.
At the same time these plans offer the geriatric
population greater access to medications overall,
they are still somewhat restrictive. Given the latest
news regarding the elevated stroke risk in older
women with atrial fibrillation (AF) regardless of
anticoagulation status, we looked at the availability
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within these plans, of newer agents approved for
stroke prevention in AF, specifically Pradaxa and
Xarelto. In clinical trials in which the median age
was 71, Pradaxa demonstrated an advantage over
warfarin while Xarelto was comparable. Both
agents obviate the frequent monitoring and dietary
restrictions required for warfarin therapy. We
evaluated formularies for Medicare prescription
drug benefits offered by two of the top health
insurers in the U.S (one was a PDP and the other an
Advantage plan) to determine coverage of these
agents. The Advantage program did not cover
either drug. Although the PDP offers both drugs,
they are Tier 3 with an associated co-pay of $35-$45
and necessitate prior authorization. In comparison,
warfarin is Tier 2 with the co-pay ranging from $8 to
$12 co-pay with no prior authorization required.
The issue of prior authorization for Medicare plans
has been increasing. Based on results of the
Avalere Health Analysis in 2011, the percent of
drugs requiring prior authorization has increased
from 12.4% in 2008 to 16.7% in 2011.17
8. Are There Other Means to DifferentiateCurrent and Future Therapies for theGeriatric Market?
Snowfish feels that highlighting the safety and
necessity in this particular patient population can
build meaningful differentiation. This involves a
review of the drugs being used in older patients and
how they are used. Based upon this assessment, if
a particular product is not demonstrating benefit in
this patient population or places them at an
increased risk for an adverse drug reaction, a
suitable alternative should be identified and
developed.
An example of this is the Beers Criteria. Dr. Mark
Beers in collaboration with other experts released
the Beers Criteria for Potentially Inappropriate
Medication Use in Older Adults, informally known
as Beer's Criteria. The criteria is a reference for
healthcare professionals as it outlines drugs for
which the risks outweigh the benefits in those 65
years and older. 18 With a handful of revisions since
its inception, the Beers Criteria remains the
foremost guide to drugs which either pose high risks
of adverse effects or seem to have limited
effectiveness in the geriatric population. Currently
it categorizes drugs in the following ways: (1)
potentially inappropriate for older people because
they either pose high risks of adverse effects or
appear to have limited effectiveness in older
patients (2) potentially inappropriate for older
people who have certain diseases or disorders
because these drugs may exacerbate the specified
health problems (3) used with caution in older
adults.
In the meantime, other tools have been developed
including the Screening Tool of Older Persons
(STOPP) criteria.19 Furthermore various
mechanisms to reduce the prescribing of potentially
inappropriate drugs (PIMs) in the elderly have been
put in place at the regional and local levels.
Regardless of available to tools and initiatives,
considerable use of PIMs persists. A study from agroup at Weill Cornell Medical College identified
38% of U.S-based older adult patients receiving
home care were prescribed at least one PIM.20 A
similar prevalence was found in Australia in which
40% of a sample of community-dwelling older
adults was found to use at least one PIM.21 Lack of
awareness among the general community of
healthcare professionals may be one major reason
for this relatively high rate of PIM use. A survey of
eighty-nine physicians revealed that despite the fact
that an estimated 25% of their practice consisted of
patients > 65, many exhibited a poor knowledge of
PIMs and were unaware of prescribing guidelines
such as the Beers criteria.
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9. Is There an Adequate Supply Geriatric Experts toDrive Innovation?
A 1990 Institute of Medicine report titled Drug
Development for the Geriatric Population
commented that in the late 1980s there werefew geriatric trained faculty in medical schools.22
They blamed those circumstances on the lack of
drive to develop a geriatric research
environment.
As of 2012, there were 137 Liaison Committee on
Medical Education (LCME)-accredited medical
schools in the US. The encouraging news is that
the vast majority of schools offer in some form,
geriatric education or training. Still, the majority
of the faculty who lead these programs do not
have formal geriatric training; as of 2005, only
44% of directors of geriatric academic programs
underwent either geriatric fellowship or earned a
Certificate of Added Qualifications in geriatric
medicine. Furthermore, of schools awarding a
degree of doctor of medicine (MD), only seven
reported having a full-fledged department.
Instead, they tend to be divisions or sections of
other departments such as internal medicine. Asexpressed in a 2009 article by Bernard, et al, a
department provides for a seat at the table with
respect to budgeting, strategic planning and
allocation of resources within an academic
institution.23 Such status may indeed enhance
research program development. It should also be
noted that as of this posting, unlike pediatrics,
geriatrics is still considered a subspecialty. In
contrast, in 16 countries within the EU, geriatrics
is indeed a specialty.
10.Who Are the Current Life Science Players inthe Aging Market?
A handful of pharmaceutical companies have been
beginning to take an interest in therapies for
diseases of aging and those for frailty itself. Inparticular, Sanofi has instituted the Aging
Therapeutic Strategic Unit. This department is
charged with rethinking how treatments to the
aging population should be developed and
delivered. According to an article discussing the
Unit, there is concentration in detecting,
preventing and reversal of age-related
dysfunctions, disorders, and diseases including
Alzheimers, chronic pain, osteoarthritis, hearing
disorders, sarcopenia/frailty.
Pfizer put out a report titled Preventive Care and
Healthy Aging which was commissioned through
the Economist Business Intelligence Unit.3 This
report highlighted the significance of healthy aging
and the value of preventative care with respect to
reducing the cost of care and profiled eight
countries: Brazil, China, India, Japan, Russia, South
Africa, the U.K. and the U.S. It not only
summarized the significant challenges that must beovercome to implement this approach, but also
underscored the benefits that governments (and
citizens) can reap by implementing certain
changes. In general, this report reinforced the
notion that globally, we tend to take a very
reactive approach to healthcare delivery which is
counterintuitive to the care of older individuals.
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Conclusion
Well beyond what Roger Daltrey envisioned in the
1960s, his generation is spearheading the shift in
the global population to where eventually, one-fifth
will be aged 60 or older. It is medical innovation thathas both allowed for this phenomenon and that will
be necessary to maintain the health and well-being
along with longevity.
The issues described in this paper emphasize the need
for creativity within the life science industry in order
to take advantage of the various opportunities related
to the aging population. For example, recognizing that
patients will require continuation of therapy for
chronic conditions for many years after the initial
diagnosis, the industry can ensure that these
treatments are as effective and safe for a patient at
70 as it was at 50 and leverage this as a competitive
advantage.
1. World Population Ageing 2009. Available at:http://www.un.org/esa/population/publications/WPA2009/WPA2009_W
orkingPaper.pdf. Accessed 1/3/12
2. Global Health and Population Aging.http://www.prb.org/pdf07/TodaysResearchAging4.pdf. Accessed 1/3/12.
3. Preventive Care and Health Aging A Global Perspective. EconomistBusiness Unit. Available at:
http://digitalresearch.eiu.com/healthyageing/report. Accessed 1/3/12.
4.
Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence offrailty in community-dwelling older persons: a systematic review. J Am
Geriatr Soc. 2012;60(8):1487-92.
5. Boss GR. Age-Related Physiological Changes and Their ClinicalSignificance. West J Med .1981;135(6).
6. Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA.Examining the evidence: a systematic review of the inclusion and analysis
of older adults in randomized controlled trials. J Gen Intern Med. 2011
Jul;26(7):783-90.
7. US Food and Drug Administration Guideline for industry. Studies insupport of special populations: geriatrics. 1994. Available at:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM
129519.pdf. Accessed 1/3/13.
8. Federal Register (62 Federal Register 45313-45326). August 27, 1997.9. Guidance for Industry E7 Studies in Support of Special Populations:
Geriatrics. Available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM189544.pdf. Accessed 1/3/13.
10. EMA Geriatric Medicines Strategy. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/
02/WC500102291.pdf. Accessed 1/3/13.
11. Crooks J, Stevenson IH. Drug response in the elderlysensitivity andpharmacokinetic considerations Age Ageing.1981;10(2):73-80.
12. Ferrini A, Ferrini R. 2000. Health in the Later Years. 3rd edition. Boston,MA, McGraw Hill.
13. Centers for Disease Control and Prevention and The Merck CompanyFoundation. The State of Health and Aging in America 2004.
14. Gu Q, Dillon CF, Burt VL. Prescription Drug Use Continues to Increase: U.S.Prescription Drug Data for 2007-2008. Available at:
http://www.cdc.gov/nchs/data/databriefs/db42.htm. Accessed 1/4/13.
15. Steinmetz KL, Coley KC, Pollock BG. Assessment of geriatric information on thedrug label for commonly prescribed drugs in older people. J Am Geriatr Soc.
2005;53(5):891-4.
16.
Savient Pharmaceuticals Files Citizens' Petition with the FDA for Oxandrin.Available at: http://investor.savient.com/releasedetail.cfm?releaseid=189758.
Accessed 1/4/13.
17. Initial Trend Analysis of 2011 Medicare Prescription Drug Plan Formularies.Available at:
http://www.avalerehealth.net/news/archive/Avalere_Health_Analysis_of_2011_
Part_D_Formularies.pdf. Accessed 1/4/13.
18. American Geriatrics Society 2012 Beers Criteria Update Expert Panel.American Geriatrics Society updated Beers Criteria for potentially inappropriate
medication use in older adults. J Am Geriatr Soc. 2012;60(4):616-31
19. Gallagher P, OMahony D. STOPP (Screening Tool ofOlder Persons potentiallyinappropriate Prescriptions): application to acutely ill elderly patients and
comparison with Beers criteria. Age Ageing. 2008; 37(6): 673-679.
20. Bao Y, Shao H, Bishop TF, Schackman BR, Bruce ML. Inappropriate medication ina national sample of US elderly patients receiving home health care. J Gen Intern
Med. 2012 Mar;27(3):304-10.
21. Beer C, Hyde Z, Almeida OP, Norman P, Hankey GJ, Yeap BB, Flicker L.. Qualityuse of medicines and health outcomes among a cohort of community dwelling
older men: an observational study.Br J Clin Pharmacol. 2011 ;71(4):592-9.
22. Report of a workshop - Drug Development for the Geriatric Population. 1990.Available at:
http://books.google.com/books?id=HUErAAAAYAAJ&printsec=frontcover&sourc
e=gbs_ge_summary_r&cad=0#v=onepage&q&f=false. Accessed 1/5/13.
23. Bernard MA, Blanchette PL, Brummel-Smith K. Strength and influence ofgeriatrics departments in academic health centers. Acad Med. 2009;84:627-632.
Melissa Hammond is Managing Director at Snowfish and an industry leader regarding the implications and opportunities of the g row
geriatric population to the life sciences industry. Snowfish provides actionable insights for the life sciences industry and has worked w
leading companies for nearly a decade. To learn more about Snowfish, please go to www.snowfish.net or call +1 -703-759-6100.
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