April 2015
In this issue:
1
Chairperson’s Report:
Cross Canada Primary Care
Updates
Targeted lung
denervation for
moderate to severe
COPD: a pilot
study.
4
6
Idiopathic
Pulmonary
Fibrosis
11
Anemia in COPD
patients
Chairperson’s Report
Spring is finally here, and as such time for a newsletter. I wanted to first thank those of you who have
recently joined our group. We sent out a generalized mailing to Family Physicians across the country
and got a wonderful response. It is clear that optimizing management of respiratory disease is important
to all of you!
This spring is particularly exciting due to an initiative that the FPAGC is doing in partnership with CME
Solutions and the team at Primary Care Updates. We have secured funding from a number of pharmaceutical companies to create two respiratory hours, one each for Asthma and COPD at the cross Canada
Primary Care Updates starting in May in Halifax. We will be presenting Saturday am at each of the venues listed before. Each speaker is an experienced FPAGC executive, with broad respiratory knowledge
and speaking experience. We can guarantee an interesting and informative session.
City
Speaker
Date
Location
PCU Halifax
May 22 & 23, 2015
World Trade Centre - Level 3
Alan Kaplan
PCU Edmonton
May 22 & 23, 2015
Shaw Conference Centre
Robert Hauptman
PCU Winnipeg
May 29 & 30, 2015
RBC Convention Centre
Robert Hauptman
PCU Niagara Falls
May 29 & 30, 2015
Four Points Sheraton
Anthony Ciavarella
PCU Ottawa
June 5 & 6, 2015
Ottawa Conf & Event Centre
Alan Kaplan
PCU Calgary
June 5 & 6, 2015
Robert Hauptman
PCU St. John's
June 12 & 13, 2015
PCU London
June 12 & 13, 2015
Ramada Plaza & Conf Centre airport
Comfort Inn - 106 Airport
Road.
London Convention Centre
PCU Toronto East
June 19 & 20, 2015
Sheraton Parkway North
Alan Kaplan
PCU Vancouver
June 19 & 20, 2015
VCEC - East Building
Anthony Ciavarella
Family Physician Airways Group of Canada
April 2015
Alan Kaplan
Josiah Lowry
1
But it gets even better! We are happy to report that we have received accreditation from the College of
Family Physicians (CFPC), we plan on this being a multiple touch-point program designed to teach, but
also reinforce the education, with the ultimate design to cause actual behavior change. While this
sounds straight-forward, it almost never happens in CME. How many times have you gone to a really
good talk, only to not actually make changes in your practice because of it??
Each of these steps will be accredited, along with the following projected time lines:
April 30, 2015
Target Date Continuum ready to go live
Marketing to PCU pre-reg delegates to start continuum / Pop Quiz #1
May 22 – June 20
PCU rolls out in 10 cities over 5 weeks (Live CME)
Videotaping Halifax for future online CME
Pop Quiz #1 to go to delegates before this as the first step!
June 22, 2015
Eligibility to non-PCU delegates to take online only continuum
Aug 22 – Sept 22
Pop Quiz #2 Opens for eligible PCU attendees (3 months post each city)
Sept 15, 2015
Continuum Closes to additional online only users as they need 7 months to complete the continuum
Nov 22 and beyond
Online Refresher Opens for eligible PCU attendees (3 months post Pop Quiz #2)
Dec 22 and beyond
Pop Quiz #3 Opens for eligible PCU attendees (1 month post Online Refresher)
April 17, 2016
Accredited Program Expires
Continuum Ends
Family Physician Airways Group of Canada
April 2015
2
This seems busy, and it is! But each step will be clearly given to all participants for this to be an easy
and hopefully entertaining process to go through. While there will be a little bit of homework, it is all
intended to be covered for Mainpro Credits through the CFPC. We have the support of the Respiratory
Medicine Communities of Practice Group of the College of Family Physicians as well.
Our goal is to educate, measure and review. We hope to potentially publish some of the outcomes of this
novel form of research, so thank you in advance for participating!
There is plenty else going on as you all know. New biologic therapies are being developed for asthma.
We have a number of new LABAs, LAMAs, and LABA/LAMAs released or being close to being released for COPD. Newer vaccinations for respiratory illnesses are becoming available for your patients.
This newsletter includes an article on idiopathic pulmonary fibrosis, an old disease revisited due to a
breakthrough of two new effective therapies.
I look forward to seeing you at Primary Care Today in Toronto in May, at any of the Primary Care Updates across the country this spring or at the Family Medicine Forum (the annual College of Family Physicians of Canada conference) in Toronto from November 11-14, 2015.
As always, please feel free to contact me with any respiratory question you have at [email protected]
Watch out for that spring mould, there are lots of old leaves left in your gardens because the snow hit
early this year...
Alan Kaplan MD CCFP(EM) FCFP
Chair, FPAGC
See page 4 for the FPAGC Continuum diagram
CLEARING THE AIR
The Asthma Society of Canada is holding its Second Annual Conference, May 4th and 5th, 2015 at the
Courtyard by Marriot Downtown in Toronto. By bringing together leaders from government, industry,
academia, and the not-for-profit sectors, we will examine asthma and respiratory allergies in a time of
climate change and issue a call-to-action for decision makers.
Clearing the Air is an opportunity to demonstrate that health and the environment are inextricably
linked. Asthma and allergies, including both the social and economic impacts of climate change on
respiratory health demand more attention from policy makers and the public.
We are pleased to announce our keynote address as Honourable Glen Murray, Ontario Minister of the
Environment and Climate Change.
Join us for this breakthrough World Asthma Day event. For more information, or to register and take
advantage of early bird tickets, ending March 27th, 2015, please visit: www.clearingtheair.ca.
Family Physician Airways Group of Canada
April 2015
3
Family Physician Airways Group of Canada
April 2015
4
Targeted lung denervation for moderate to severe COPD: a pilot
study.
Slebos et al. Thorax doi:10.1136/thoraxjnl-2014-206146
TLD is a bronchoscopic therapy based on ablation of parasympathetic pulmonary nerves that
release acetylcholine, which, in turn, leads to
smooth muscle constriction in the bronchi. It is
delivered through a dual-cooled radiofrequency
(RF) catheter which is designed to ablate targeted tissue at depth with minimal heating and
damage of the inner surface of the airway.
This ablation is intended to disrupt motor axons
within bronchial nerve branches running along
the outside of the main bronchi, thereby blocking parasympathetic signaling to the lungs and
decreasing neuronal release of acetylcholine;
i.e., acting like a muscarinic antagonist. This has
the potential to achieve a permanent sustained
effect, which cannot be done with medications.
The one-year trial involving 22 COPD patients,
12 who received ablation at 20 watts and 10 who
received ablation at 15 watts. The researchers
performed a series of pretreatment procedures,
including starting patients on tiotropium bromide in a minimum eight-day run-in period, and
conducting a pretreatment visual bronchoscopic
inspection of the airwaves. During rigid bronchoscopy under general anesthesia, researchers
placed and activated an electrode in up to eight
rotational positions per bronchus to complete a
circumference. The researchers used bronchoscopic and fluoroscopic visualization to guide
electrode positioning throughout treatment. They
staged two treatments per person, 30 days apart.
Patients required no post-procedure medications
and stopped taking tiotropium after treatment.
After one patient in the 20-watt group dropped
out, 11 of 11 patients in that group achieved the
primary endpoint of "freedom from documented
and sustained worsening of COPD directly attributable to TLD at one year," while nine of the
10 patients in the 15-watt group did so, resulting
in an overall 95% achievement.
Family Physician Airways Group of Canada
April 2015
While there was no mortality from this procedure, there were seven post-procedure serious
adverse events, including COPD exacerbation,
anaphylactic drug reaction, coronary artery bypass surgery, chest pain resulting in hospitalization, and gastroparesis. Four of those events happened to one person, however.
This study showed an improvement in exercise
endurance and quality of life compared with
medications. The procedures were technically
feasible 93% of the time. Primary safety endpoint was achieved in 95%. The clinical safety
profiles were similar between the two energy
doses. At 1 year, changes from baseline in the 20
W dose compared to the 15 W dose were: FEV1
(+11.6%±32.3 vs +0.02%±15.1, p=0.324), submaximal cycle endurance (+6.8 min±12.8 vs 2.6
min±8.7, p=0.277), and St George's Respiratory
Questionnaire (−11.1 points ±9.1 vs −0.9 points
±8.6, p=0.044).
The authors are now testing the significance of
the TLD therapy in a randomized controlled
manner, with the enrollment in a larger randomized Phase II trial that is called AIRFLOW-1
(NCT #02058459). The first patient in this latest
trial last entered in October2014 with plans to be
treating patients in 15 European sites before the
end of the year. Holaira Inc., of Minneapolis,
Minnesota, funded this study
Editors Note:
Just as we have seen the advent of bronchial
thermoplasty in asthma, a physical/electric treatment to the lungs may be of benefit in COPD.
The trick will be, once proven successful, to decide the correct patient for an interventional procedure.
5
Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis (IPF) is a chronic
and debilitating disease, characterized by progressive scarring of the lung.1,2 (fig 1) It is the most
common form of idiopathic interstitial pneumonias
affecting the lung parenchyma. The progressive
scarring of the lung tissue and interstitial space
over time is irreversible and significantly impairs
proper gas exchange, thus often leading to respiratory failure. While a number of environmental and
patient-related risk factors have been proposed, the
precise cause of the disease remains unknown.
COPD exacerbations. Oftentimes a correct diagnosis may take several months or years.7,8 In addition
to exertional dyspnea and dry cough, other common signs of IPF are inspiratory bibasilar crackles
(initially evident in the basal areas of the lung) ,
fatigue, cyanosis, and finger clubbing 5,9. These
symptoms, especially dyspnea and cough, cause
significant impairment to the quality of life for patients.
IPF should be considered in any patient over 40
with unexplained shortness of breath and dry
IPF is a fairly rare disease; however, there exists
cough. Testing by HRCT is crucial for diagnosis
no reliable, large scale data sets on its incidence
through determining the presence of a specific raand prevalence. In Canada, using definitions emdiological pattern (usual interstitial pneumonia,
ployed by a large retrospective health claims study UIP). In the case an HRCT cannot provide concluin the U.S., the incidence has been estimated to be sive results, the diagnosis can be confirmed by surbetween 2,300 -5,600 cases, whereas the prevagical lung biopsy, after weighing the risk/benefits
lence ranges between 5,000-15,000 patients3.
of this procedure for an individual patient. Specialized Interstitial Lung Disease clinics in some
The overall prognosis of IPF is quite poor; median Canadian cities provide venues to confirm fresurvival has been reported as 2-3 years postquently complex diagnoses, provide comprehendiagnosis, rates lower than the majority of the most sive treatment, as well as aid in registering into
common cancers4. Most patients face a gradual
clinical trials or lung transplant for select patients.
deterioration; however due to the heterogeneity of
the disease, some may progress rapidly or experiIPF is believed to be the result of an aberrant
ence episodes of rapid deterioration, known as
wound healing process following repetitive injury
5,6
acute exacerbations . Given the short median
10
survival, timely diagnoses are thus critical for pa- to the lung epithelium . Initially it was hypothesized inflammation was the major underlying comtient management. The most common symptoms
of IPF are gradual in onset, initially presenting as ponent driving fibrosis in IPF, however, this outlook has changed due to the lack of efficacy of
dyspnea (shortness of breath) upon exertion and
high dose corticosteroids alone or in combination
5
dry cough. These early, non-specific symptoms
with other agents11. As recently as 2011, published
are commonly mistaken for ageing, cardiac distreatment guidelines recommended best supportive
ease, asthma or COPD.7,8 . Such misdiagnosis, or
ignoring early symptoms, may explain why IPF is therapy for IPF patient management (supplemental
oxygen, pulmonary rehab, and lung transplant in
rarely diagnosed immediately. This is extremely
important as we are unable to predict how individ- appropriate individuals) and weak or no support for
ual patients with IPF will progress due to the afore- the use of a majority of investigational agents.
mentioned heterogeneity of the disease (However, However, 3 published studies in 2014 in the New
England Journal of Medicine will almost certainly
there is a growing body of literature supporting
genetic factors as determinants of disease survival). alter current treatment practices.
The first trial, PANTHER-IPF, investigated the
This is further complicated with the negative imtriple combination of N-acetylcysteine (NAC, an
pact of unpredictable acute exacerbations –
following an exacerbation, median overall survival antioxidant thought to repair the oxidative damage
is ~ 2 months for an IPF patient12; a much greater leading to fibrosis in IPF) with the immunosuppressive agents azathioprine/prednisone compared
impact than typically observed in patients with
Family Physician Airways Group of Canada
April 2015
6
to NAC alone andplacebo. While some benefit was
observed with the triple therapy combination in
previous studies, the triple therapy arm in PANTHER (NAC/azathioprine/prednisone) was terminated early due to an increased risk of death and
hospitalizations. The trial continued with NAC
monotherapy vs. placebo; the primary endpoint was
not met as NAC did not preserve lung function, nor
slowed disease progression relative to placebo.
were adjudicated by an external blinded committee,
nintedanib significantly reduced the risk of exacerbations in the pooled study group by almost 70%.
(fig 6) The trial was not powered to detect differences in mortality, however a numerical trend in
reducing all-cause mortality was observed.
The rate of lung loss in patients with IPF varies
from a rapid aggressive form to a slower progressive form. Either one can have acceleration of disThe ASCEND trial is the latest of 4 phase 3 studies ease due to an IPF exacerbation. (fig 2) These are
comparing perfenidone with placebo in IPF. Cur- defined in trials as unexplained worsening or develrently it is unknown how the drug exerts its antifi- opment of dyspnea within 30 days or new diffuse
brotic activities. After mixed results in the primary pulmonary infiltrates on chest X-ray and/or HRCT,
endpoints of some of the earlier phase 3 studies
or parenchymal abnormalities with no pneumothowhich led to approval in some countries (e.g. Cana- rax or pleural effusion (new ground-glass opacida) but not others (e.g. U.S.), ASCEND was deties) . These are separate from acute worsening
signed to confirm its efficacy. In the study percaused by other issues such as infection, left heart
fenidone met its primary outcome by significantly failure, pulmonary embolism or other cause of
reducing FVC decline relative to placebo over a
acute lung injury.
one year period (reported as a categorical change in
FVC – i.e. proportion of patients who had an absoIn primary care, we are an important cog in the
lute decline >10% of FVC percent predicted over
management of this disease. Understanding how to
the study period).(fig 3) Other secondary endpoints were also met, including 6-minute walk test, identify the symptoms of IPF, or at least interstitial
but there was no effect on dyspnea, all-cause mor- lung diseases, is especially relevant as new antifibrotic agents become available which may slow
tality, or death due to IPF in the single study. A
disease progression. Making the correct diagnosis
pre-specified mortality analysis of pooled data
allows institution of the proper therapy as bronchofrom the ASCEND and 2 earlier of pirfenidone
dilators often given for presumed COPD are of no
mentioned above did provide evidence that perfenidone may reduce mortality in patients with IPF value. Spirometry will not show obstruction, and
()fig 4) although this was not incorporated into its will likely show restriction. Full PFTs will show
decreased gas exchange and the Diffusion capacity
label here or in the U.S.
will be reduced.
Finally, the INPULSIS trials were two identical
phase 3 studies investigating the effect of
nintedanib compared to placebo in IPF. Nintedanib
is a tyrosine kinase inhibitor that specifically targets three receptors and downstream signaling
pathways implicated in IPF pathogenesis (plateletderived growth factor receptor, fibroblast growth
factor receptor, and vascular endothelial growth
factor receptor). Both INPULSIS trials met their
primary endpoints: nintedanib significantly reduced
the rate of decline in FVC over one year compared
to placebo.(fig 5) One of the trials also showed
that nintedanib significantly reduced investigator
reported acute exacerbations; when exacerbations
Family Physician Airways Group of Canada
April 2015
Once pulmonary fibrosis is entertained, there is
a significant differential diagnosis that
must be entertained including infection,
drug reaction and connective tissue disorders. HRCT is often diagnostic, but surgical biopsy may be necessary. Fortunately,
there are Interstitial Lung disease clinics
across the country to assist our community
respiratory specialists if necessary. Your
patient may also be considered for lung
transplantation, which has been shown to
reduce the risk of death by 75% after adjustment on potential confounding variables13.
7
We will need to support our patients through the
new therapies as mentioned, and GI side effects are
common. In addition, prevention of infectious exacerbations can be considered with appropriate vaccinations. Acute exacerbations of IPF are often a
disease altering event and these also may be reduced by anti-fibrotic therapies. The ATS suggests
treating GERD in these patients also, as it may assist in disease progression.
2.
3.
4.
5.
6.
For those patients with more severe illness, access 7.
to pulmonary rehabilitation is important and end of
8.
life care will become an issue further along. You
may be the person to initiate Oxygen therapy as the 9
disease progresses.
We can now do something substantial for this disease; make the diagnosis, and make it earlier!
1.
Raghu G et al. Am J Respir Crit Care Med
2011;183:788-824.
10.
11.
12.
13.
ATS and ERS. Am J Respir Crit Care Med
2002;165:277-304.
Raghu et al. Am J Respir Crit Care Med 2006;
174: 810-816.
Vancheri C et al. Eur Respir J 2010; 35P:
496-504.
Ley B et al. Am J Respir Crit Care Med 2011;
183:431-40.
Kim et al. Proc Am Thorac Soc 2006;3:
285-292
Collard HR et al. Respir Med 2007:101:
1350-1354.
Meltzer EB and Noble PW. Orphanet J Rare Dis
2008; 3: 8 doi:10.1186/1750-1172-3-8.
Borchers et al. Clin Rev Allergy Immunol
2011;40:117-134.
Gunther et al., Eur Respir Rev 2012, 21:152160.
Ryu et al., Mayo Clin Proc 2014
Sing et al, Eur Resp J 2011 37: 356-363
Thabut G et al. J Thorac Cardiovasc Surg.
2003;126(2):469–475
Pathology (Fig 1)
Family Physician Airways Group of Canada
April 2015
8
Progression of illness: (fig 2)
IPF: variable natural history
Lung microinjuries
Onset
of symptoms
Survival 9%)
Acute
exacerbations
Asymptomatic period
(months to years)
Slow progressive
course
Rapid
progressive
course
0
1
2
3
4
5
6
Time (years)
7
8
9
10
• Most patients experience a slow but steady worsening of
their disease:
– About 10% experience unpredictable acute exacerbations that may initiate
the terminal phase of their disease
• A minority of patients have a short duration of illness with a rapidly
progressive clinical course
King TE et al. Lancet 2011;378(9807):1949–1961.
Pirfenidone and lung function (fig 3)
Pirfenidone slows the decline in mean FVC
Change in FVC
0
Pirfenidone (N=278)
Mean Change (ml)
–100
–200
–300
–400
Placebo (N=277)
–500
0
13
26
39
52
Week
•
The mean decline from baseline in FVC was −235 mL vs. −428 mL (pirfenidone
vs. placebo; absolute difference, −193 mL; relative difference, 45.1%; P<0.001)
FVC, forced vital capacity
King TE et al. N Engl J Med. 2014;370(22):2083−2092.
Family Physician Airways Group of Canada
April 2015
9
Pirfenidone and mortality(fig 4) :
Pirfenidone reduces relative risk of
death or disease progression by 43%
Progression-free Survival
Patients (%)
100
90
80
70
No. at Risk
Pirfenidone
Placebo
Pirfenidone (N=278)
60
50
40
Placebo (N=277)
Hazard ratio, 0.57 (95% CI, 0.43–0.77)
P<0.001
30
20
10
0
0
13
26
Week
39
52
276
273
269
262
243
225
219
192
144
113
King TE et al. N Engl J Med. 2014;370(22):2083−2092.
Nintedanib and lung function(fig 5)
0
-50
-100
-150
-113.6
-200
-250
-300
-223.5
109.9 mL/year
(95% CI: 75.9, 144.0)
p<0.001
Nintedanib 150 mg bid (n=638)
Placebo (n=423)
Mean (SE) observed change from baseline in FVC (mL)
Adjusted annual rate (SE) of decline in FVC (mL/year)
Primary efficacy endpoint in pooled data
Nintedanib 150 mg bid
Placebo
0 2 4 6
12
24
Week
36
52
No. of patients
Nintedanib
626
616 613
604
587
569
519
Placebo
417
408 407
403
395
383
345
*Adjusted mean difference vs placebo at week 52 based on MMRM 110.6 mL (95%CI: 83.2, 137.9) p<0.001)
Nintedanib is an investigational compound and is not yet approved for sale; its safety and efficacy have not yet been fully established
Family Physician Airways Group of Canada
April 2015
Richeldi L., et al. N Engl J Med 2014;370:2071-82.
10
Nintedanib and acute exacerbations (fig 6)
Anemia in COPD patients
Boutou AK1, Hopkinson NS1, Polkey MI1.Anaemia in chronic obstructive
pulmonary disease: an insight into its prevalence and pathophysiology. Clin
Sci (Lond). 2015 Mar;128(5):283-95. doi: 10.1042/CS20140344
There is a growing literature regarding the extra-pulmonary manifestations or co-morbidities of COPD,
which can have a significant impact on symptom burden and disease progression. The prevalence of
anaemia in COPD has a prevalence that varies between 4.9% and 38% depending on patient characteristics and the diagnostic criteria used. Systemic inflammation seems to be an important factor for its
establishment and repeated bursts of inflammatory mediators during COPD exacerbations could further
inhibit erythropoiesis. Other factors such as renal impairment, malnutrition, low testosterone levels,
growth hormone level abnormalities, oxygen supplementation, theophylline treatment, inhibition of angiotensin-converting enzyme and aging itself are additional factors that could be associated with the
development of anaemia. This review evaluates the published literature on the prevalence and significance of anaemia in COPD and explains the reasons for the high variability reported and investigates
the complex pathophysiology underlying the development of anaemia in these patients.
Editors Note:
The patient with COPD is multimorbid, with CV disease, osteoporosis, mental health and visual comorbidities. Add anemia to the list.
Family Physician Airways Group of Canada
April 2015
11
The Board of Directors
CHAIR
Alan Kaplan
17 Bedford Park Avenue
Richmond Hill, ON L4C
2N9
Bus:905-883-1100
Fax: 905-884-1195
[email protected]
VICE CHAIR
Anthony Ciavarella
27107 Fraser Highway
Aldergrove, BC V4W 3R2
Bus:604-856-3321
Fax: 604-857-2231
[email protected]
SECRETARY/
TREASURER
Robert Hauptman
Salvus Family Medical Clinic
62 -143 Liberton Drive
St. Albert, AB T8N 6A7
Bus:780-460-4562
Fax: 780-460-4550
[email protected]
DIRECTORS
REASEARCH CHAIR
Jacques Bouchard
Clinique de medecine familiale de la Malbaie
515 rue St-Erienne
La Malbaie, PQ G5A 1W7
Bus:418-683-8393
Fax: 418-687-9024
jacques.bouchard@videotr
on.ca
John Rea
104-348 Muskoka Rd 3 N
Huntsville, ON P1H 1H8
Bus:705 789 2355
Fax: 705-789-1051
[email protected]
John Li
1789 Mountain Road, Suite
207
Moncton, NB E1G 1A7
Bus:506-859-8696
Fax: 506-383-8224
Douglas Tweel
199 Grafton St
Charlottetown, PEI C1A
1L2
Bus:902-629-8843
Fax: 902-628-6024
[email protected]
[email protected]
Josiah Lowry
Suite 200,
100 Colborne St. W
Orillia, ON L3V 2Y9
Bus:705-327-3330
Fax: 705-327-7675
[email protected]
ADMINISTRATION
Glyn Smith
132 Warwick Road
Edmonton AB T5X 4P8
Bus: 866-406-4345
Fax: 780-475-7968
[email protected]
www.fpagc.com
Robert Woodland
Major’s Path Family Practice
#301, 35 Major’s Path
St. John's, NL A1A 4Z9
Bus:709-579-2324
Fax: 709-579-3419
[email protected]
Ken Bayly
701 Ave P North
Saskatoon, SK S7L 2W1
Bus: 306-382-5854
Fax: 306-382-7477
[email protected]
Andrew Cave
1A1 8440 112 Street
Edmonton AV
Bus: 780-433-4211
[email protected]
John Kirkpatrick
8 Peppett Street
North Sydney
Nova Scotia, B2A 2M7
Bus: 902-794-2868
Fax: 902-794-4448
[email protected]
Gordon Dyck
Clearspring Medical Clinic
1 – 390 Main Street
Steinbach, MB R5G 1Z3
Bus:(204) 326-6111
Fax: 204-326-6952
[email protected]
The FPAGC wishes to thank the following companies for their continued support of our
programs:
AstrraZeneca
Bayer
Boehringer Ingelheim
CV Technologies
Family Physician Airways Group of Canada
GlaxoSmithKline
Merck Frost
Novartis
Pfizer
April 2015
Takeda
Talecris
Trudell Medical International
12