Kelvin Lou & Sandy Mok · 2013. 10. 25. · market, after alarming statistics of addiction and...

This issue is dedicated to

Kelvin Lou & Sandy Mok

as a continuation of their vision and for their efforts

to pave the way

UBC PSSJ

2 UBC PSSJ Volume 1 | Issue 2 | September 23, 2013

Volume 1 | Issue 2 | September 23, 2013 UBC PSSJ 3

FOREWORD

Broadening Horizons

Michael Coughtrie, PhD1 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

The second issue of a newly established journal is in many ways more difficult to produce than the inaugural

one. However, the UBC PSSJ editorial team has certainly not found that challenge insurmountable, and new and

returning readers will be treated to another excellent and thought-provoking experience as they browse through

issue 2 of this unique journal.

With the main theme of Broadening Horizons this second issue covers a wide range of topics that

demonstrate the breadth and depth of the discipline of pharmacy, and that highlight very clearly the influence of

pharmacists in delivering healthcare on the frontline, in carrying out groundbreaking research and in teaching the

next generation of professionals. Particular high points of this issue include articles on inhalable nanoparticle

vectors, on the role of community-based clinical pharmacists, and on the particular challenges faced by

pharmacists working in developing countries. These are important and interesting topics that deserve to find a

wide audience and will no doubt generate debate and discussion among the readership.

This entirely student-led and –managed venture has been made possible by the dedication and talents of the

editorial and production teams (now comprising 25 students), and deserves to be highly successful; it has already

received national attention and commendation. I hope that readers will spread the word as widely as possible.

Roll on issue 3!

Michael Coughtrie, PhD

Professor and Dean

Faculty of Pharmaceutical Sciences

University of British Columbia


THE TEAM

Editorial Team

Editor in Chief Katie Milbers Case Reports Editors Sarah Cheng

Associate

Editors Alysa Pompeo, Elaine Xu

Review Article

Editors Julia Higgins, Nancy Zhou

Copyeditors

Scott Aldersey, Emma Attfield,

Alice Hou, Tina Lien, Kieran

Shah, Carly Webb

Financial Officer Jennifer Jun

Communications

Officer Gordon Ling

Layout Editors

Quaid Castle, Nicole Chaudhari,

Torey Lau, Shannon Lee, Cindy

Pan, Charissa So

Design Advisor Joan Ng

Original

Research Editors Yohan Choi, Gordon Ling

Public Relations

Team

Amy Le, Lily Liang, Torey

Lau, Tina Lien, Joan Ng

Editorial Editors Benton Attfield, Jaime Kwok Project Manager Nathaniel Ngo

Peer Reviewers

To preserve the blinding of our peer review process, peer reviewers will be listed in our next issue.

Alumni Advisors

Mr. Charles Au Ms. Amanda Chen Mr. Ernest Law

Mr. Nathaniel Ngo Ms. Victoria Su Ms. Lora Wang

Editorial Board

Dr. Brian Cairns Dr. Mary Ensom Dr. Urs Hafeli

Dr. Marc Levine Dr. Peter Loewen Dr. James McCormack

Ms. Penny Miller Ms. Tessa Nicholl Dr. Ingrid Price

Dr. Wayne Riggs Mr. Leon Wan

Faculty Supporters

Dr. Helen Burt Associate Dean, Research, University of British Columbia

Graduate Studies, UBC Faculty of Pharmaceutical Sciences

Dr. David Fielding Associate Dean, Academic, UBC Faculty of Pharmaceutical Sciences

Dr. Robert Sindelar Professor and Dean, UBC Faculty of Pharmaceutical Sciences

Dr. Kishor Wasan Associate Dean, Research and Graduate Studies, UBC Faculty of

Pharmaceutical Sciences

Faculty Sponsors

Ms. Tessa Nicholl Instructor, UBC Faculty of Pharmaceutical Sciences

Acknowledgements

The UBC PSSJ was made possible by the support of the UBC Faculty of Pharmaceutical Sciences and a grant from the UBC Teaching and Learning Enhancement Fund (TLEF).

Disclaimer and Copyright

Facts and opinions published in the UBC PSSJ are solely those of contributing authors and do not necessarily reflect the views of the editors,

UBC PSSJ, the UBC Faculty of Pharmaceutical Sciences, or the University of British Columbia.

UBC PSSJ provides immediate open access to its content upon the principle that making research freely available to the public supports a

greater global exchange of knowledge. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License.

Contact

Website: www.ubcpssj.org Email: [email protected] Facebook: www.facebook.com/ubcrxpssj

http://creativecommons.org/licenses/by-nc-sa/3.0/deed.en_US


TABLE OF CONTENTS

EDITORIAL

Small Molecules, Large Views 7

Katherine Milbers

REVIEWS

Research Advances in the Formulation of Inhalable 9

Chitosan-based RNA Interference Vectors

Alexander Kumar Mehta

OP-EDs

Pharmacists in the Developing World: Providing Impact 14

to the Poorest of the Poor

Jocelyn Conway, Kishor M Wasan

Pharmacy “On Deck” – the Bases Are Loaded 17

Mits Miyata

WORKSHOP

Critically Appraising Randomized Controlled Trials: 19

Is There Substance in Subgroups?

Ricky D Turgeon

PRACTICE ISSUES

Advancing Experiential Learning in Institutional 22

Pharmacy Practice: The University of British Columbia’s

AGILE Project

Mike Legal, Maggie Billingsley, France Carriere,

Peter Loewen, Peter Zed

WORKPLACE SPOTLIGHT

Evolving the Role of Community-based Clinical 26

Pharmacists

Larry Leung

POINT-COUNTERPOINT

Paper or Paperless? A Point-Counterpoint Student's 28

Perspective

Jason Tan, Mihailo Veljovic, Jessica Tom, Jordan Stewart


EDITORIAL

Small Molecules, Large Views

Katherine Milbers, B.Sc., B.Sc.(Pharm.) Candidate 20151 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

Katherine is the current Chief Editor of UBC PSSJ 2013-2014. The opinions expressed in this article are that of the author, and do not reflect the official position of UBC PSSJ.

The second issue of this journal is full of new

ways to look at pharmacy. From clinical practice in a

community setting to what a statistic might really be

saying, pharmacy practice and our ability to make

informed medication decisions is impacted. When

we think about expanding pharmacy practice and

broadening our horizons, often the cognitive areas of

practice – our clinical skills, counselling and

monitoring therapy – are thought of, but what is also

a dramatic improvement for pharmacy practice is the

development of novel drugs and drug delivery

technology. Here are but three examples of

medications which have the potential to improve

patient care and pose new challenges and

opportunities for the field of pharmacy. The

technologies they use help to mitigate side effects,

improve compliance and allow a whole new family

of compounds to treat ailments both right now and in

the future, since some of these new medications have

already arrived on the clinical stage.

Staying on Target: Amphotericin B Delivery

Amphotericin B is an older antifungal that is

used to treat severe systemic fungal infections. It is

also the first-line drug for visceral leishmaniasis, a

parasitic infection spread by the bite of sandflies

which settles in the tissues and causes fever,

swelling of the spleen and liver, and anemia (1). It is

always fatal without medical treatment and very

common in developing countries. Right now it is one

of the projects under the Neglected Global Diseases

Initiative, who also published an opinion piece in

this issue calling for pharmacists in global health.

Despite its high efficacy for this infection,

Amphotericin B is toxic to the kidneys, requiring

routine monitoring of renal function, and must be

administered intravenously since it is not orally

bioavailable (2). This is problematic in developing

countries, where time, cost, and loss of income by

the affected person make treatment less feasible.

However, there is ongoing research at UBC into the

development of an oral formulation that emulsifies

and forms small micelles in the gastrointestinal tract,

which helps its absorption and concentration in

affected tissues of the body (3). While this is only in

its beginning stages, the implications of such a drug

to pharmacy practice could be far-reaching. Oral

formulations would be more accessible to all

patients, without requiring hospitalization, and thus

pharmacists in the outpatient or community setting

could see this drug and be responsible for

monitoring its safety and efficacy. Oral amphotericin

B may also be effective for other types of systemic

fungal infections and thus, the fusion of micelle

technology with an older drug can lead to

revitalization and increase in its use worldwide.

Finding the “Off” Switch: siRNA

Amphotericin B repackaging is a good example

of an older drug that can be reused again with less

side effects, and to benefit a population in need.

However, novel dosage technologies are also being

used on an entirely new initiative, which can be used

to treat everything from cancer to herpesvirus: short-

interfering RNA (siRNA). This strategy for drug

treatment takes advantage of the body’s natural use

of siRNA, which is to selectively suppress the

expression of certain genes or gene products, and

uses it to turn “off” some the genetic changes that

occur in disease states. The difficulty with using this

as a treatment is that an siRNA, once in the body, is

rapidly degraded; therefore, packaging it in viral or

non-viral carriers that target it to the site of action is

being tried (4). This packaging has the ability to

target the drugs to the cell in question and greatly

reduce side effects, as with amphotericin B. Right

now, siRNA nasal sprays have been successfully

tested in volunteers as a treatment for the respiratory

syncytial virus – a respiratory infection which causes

significant mortality in children, elderly and

debilitated persons in the United States (5). As is

explored in the Review of this issue, inhalable

formulations are also being explored as a way to

effectively and noninvasively deliver a variety of

therapies which, for the first time, could treat a

variety of viruses and other genetically-oriented

diseases.

The potential consequences of this fusion

between drug (or biological molecule, in this

instance) and delivery system is potentially huge. It

would become possible to treat a wide variety of

diseases which are notoriously hard to treat, such as

viruses and cancer, by simply “turning off” the

gene(s) in question. It is a great example of


collaboration between disciplines for patient care.

The implications for pharmacy practice are also

huge. With genetic material being used to treat

diseases, pharmacists, as drug experts, will have to

become aware of a new battery of side effects and

interactions based around biological material, or how

a person’s genetic makeup will affect the action of

these new treatments. This makes a case for

awareness of the newly-emerging field of

pharmacogenomics, drug treating geared towards a

patient’s particular genetic makeup, and an untapped

market for pharmacists.

Repackaging and Renewal: OxyNEO®

We finish up with an example which is already

on the market: OxyNEO®. OxyNEO® was the

result of research in polymers and a fusion of drug

delivery with techniques borrowed from metallurgy,

to package oxycodone into a tamper-resistant

formulation. It uses a combination of mesoporous

hydrogel polymers that contain the drug compressed

into a tablet, then processed via heat-treatment

recrystallization, which resolves any impurities in

the tablet and recrystallizes it into a solid lattice

(6,7). This formulation enables sustained analgesia

over an 8 to 12 hour period while improving safety

by making tampering more difficult. This medication

was created in response to the removal of the regular

oxycodone controlled-release formulation from the

market, after alarming statistics of addiction and

fatalities came to light which stemmed from the ease

in which the old dual-polymer formulation could be

broken apart. The goal with this new therapy is to

allow an effective analgesic to remain on the market,

without allowing its formulation to be exploited and

patient safety put at risk.

Conclusion

As we can see, this is a field which is quickly

changing and which has already arrived to practice.

It is also but a snapshot of some of the ways which

new dosage forms will impact our practice. The

importance of primary literature and clinical studies

as an aid for pharmacists to make clinical decisions

for their patients is well-established; medications are

always subject to post-market testing for efficacy

and additional benefits, and pharmacy students are

taught that keeping up with this research is part of

good clinical practice. That said, it is also important

to look at the ways in which other areas of inquiry –

polymers, cell biology and genetics to name a few –

will impact our own. This promotes interdisciplinary

collaboration beyond other health professionals and

into the field of research, and also tells us something

about the interesting ideas that give life to the

therapies we dispense, counsel and monitor every

day.

References

1) Health Topics - Leishmaniasis [Internet]. World Health Organ.

[cited 2013 Sep 14]. Available from: http://www.who.int/topics/leishmaniasis/en/.

2) Lemke A, Kiderlen AF, Kayser O. Amphotericin B. Appl

Microbiol Biotechnol. 2005 Aug;68(2):151–62.

3) Ibrahim F, Gershkovich P, Sivak O, Wasan E, Wasan K.

Assessment of novel oral lipid-based formulations of

amphotericin B using an in vitro lipolysis model. Eur J Pharm Sci. 2012 Aug 15;46(5):323–8.

4) Peer D, Lieberman J. Special delivery: targeted therapy with

small RNAs. Gene Ther. 2011;18:1127–33.

5) DeVincenzo J, Lambkin-Williams R, Wilkinson T, Cehelsky J,

Nochur S, Walsh E, et al. A randomized, double-blind, placebo-

controlled study of an RNAi-based therapy directed against

respiratory syncytial virus. Proc Natl Acad Sci. 2010 May

11;107(19):8800–5.

6) Kopeliovitch D. Basic principles of heat treatment [Internet]. Subst Technol. [cited 2013 Sep 14]. Available from:

http://www.substech.com/dokuwiki/doku.php?id=basic_principles

_of_heat_treatment.

7) Biomaterial of the Month - Hydrogels [Internet]. Soc Biomater.

2007 [cited 2013 Sep 14]. Available from:

http://www.biomaterials.org/week/bio17.cfm.


REVIEW

Research Advances in the Formulation of Inhalable

Chitosan-based RNA Interference Vectors

Alexander Kumar Mehta, B.Sc., B.Sc.(Pharm.) Candidate 20161

1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

The advent of RNA interference techniques has opened up promising new avenues of research for the

development of new respiratory disease therapies. Harnessing small interfering RNA (siRNA)’s ability to

selectively and reversibly silence expression of mammalian genes tantalizes with its potential for use in

conditions ranging from lung cancer to viral infections. However, effective delivery of siRNA to its

intracellular target remains key to developing medical applications for this class of gene therapy agents. A

promising strategy for transfecting lung tissues lies in the inhalation of nanoparticles composed of siRNA

and chitosan – a cationic, biodegradable and biocompatible polymer. This review will focus on recent

research advances in the design of inhalable chitosan based nanoparticle vectors for the delivery of siRNA

to lung tissues. This fulfills a gap in the literature because while other review articles have focused broadly

on siRNA delivery to the lungs (1), none have focused extensively on chitosan.

Introduction

I. The RNAi Mechanism and Therapeutic

Potential

In recent years, small interfering RNA based

gene therapy has emerged as a promising avenue of

therapeutic research. Introducing double-stranded

short interfering RNA (siRNA) into human cells

has developed into a common strategy for

experimentally controlling gene expression; it

works through the activation of the RNA

interference (RNAi) mechanism, a highly

conserved cellular process which silences specific

genes by cleaving their cytoplasmic mRNA

products, dramatically lowering expression (2). The

typical pathway for RNAi activation begins when a

piece of double stranded RNA, either long or

organized in a short hairpin-like configuration, is

cleaved by an RNAse from an enzyme family

called Dicer into 21-26 base pair siRNAs (3). The

siRNA is then incorporated into a multi-protein

complex called RNA Induced Silencing Complex

(RISC) – becoming single stranded in the process –

and the complex then proceeds to bind selectively

to mRNA with sequences exactly homologous to

those of the siRNA (4). These are then cleaved by

an RNAse component of RISC called Argonaute

and following cleavage, the mRNA is rapidly

degraded (Figure 1) (4,9).

Although the longer RNA fragments mentioned

that require initial processing by Dicer have been

used as therapeutic agents in some experiments,

RNA fragments over 30bp in length are more likely

to induce an interferon mediated immunologic

response, so therapies involving the administration

of siRNA directly are more common. In fact, since

Figure 1. RNAi pathway.

Elbashir et al. (5) published evidence in 2001 that

synthetic siRNA could be used to activate RNAi in

mammals, interest in developing biomedical

applications has been intense. Some siRNA based

therapeutic agents have now demonstrated

promising results in clinical trials. One of the more

prominent recent examples is a subcutaneously

administered siRNA product targeting transthyretin

for the treatment of transthyretin-mediated

amyloidosis, a group of diseases caused

10 UBC PSSJ Volume 1 | Issue 1 | January 28, 2013

Figure 2. Chitin (left) and chitosan (right)

by transthyretin misfolding and aggregation into

insoluble amyloid fibrils. Its developer, Alnylam

Pharmaceuticals, has reported that phase II clinical

trials have shown statistically significant gene

silencing in 80% of treated patients and that it has

been generally well tolerated (6).

While siRNA has great promise for selectively

targeting and altering gene expression in cells, there

are many challenges with applying this technology.

Most prominently, because unprotected siRNA is

unstable and vulnerable to degradation by RNAses

(8), the difficulties posed by the instability of RNA

and in delivering sufficient quantities of the product

to its cytoplasmic target have vexed researchers in

this field. There have been over twenty potential

therapies that have gone to trial, but most have been

unsuccessful because of this (7). Furthermore, the

size and charge of siRNA means that it will not

diffuse through lipid membranes readily to reach its

intracellular target (9). As such, research has been

performed on a wide variety of delivery strategies,

from chemical modification of the siRNA, to

harnessing natural carriers like viruses and bacteria,

to the use of non-viral carriers (8). Non-viral carriers

such as chitosan have the advantage of being cheap

and easy to produce, as well as avoiding some of the

toxicity issues associated with using viral gene

therapy such as immune response and random

genetic defects caused by insertional mutagenesis,

which may result in cancer (9,10). Chitosan is the

most viable of the current polymers in development

right now for respiratory use, because of its low

toxicity (10). The toxicity of chitosan, while low,

still tends to increase with the charge density of

particles and with the molecular weight of the

polymers used (11). However, siRNA molecules

themselves also have a unique toxicity profile for

each cell type, arising from sequence-specific, off-

target effects (12). They also have less specific

toxicities arising from saturation of the protein

complexes with which they interact, and immune

stimulation (12).

II. Chitosan as a siRNA Carrier

Chitosan is a linear polysaccharide derived from

chitin, a common structural molecule found in the

cell walls of fungi and the exoskeletons of

arthropods and insects. Chitin is a linear chain of

β(1,4)-linked N-acetyl-D-glucosamine, and when

treated with sodium hydroxide monomers within the

polymer are randomly deacetylated and converted to

D-glucosamine. This forms chitosan, which is

defined as having a mix of acetylated and

deacetylated β(1,4) linked glucosamine monomers

(Figure 2). At slightly acidic pH, deacetylated

nitrogens in the chitosan become positively charged

and can interact with the negatively charged

phosphate groups of nucleic acids electrostatically to

form nanoparticles (8). This has been shown to

protect the siRNA from nucleases, and when the

particles have a net positive charge it also helps the

siRNA interact with negatively charged cell surfaces

(8, 14). Particles must lie within a size range of 50 to

300nm in order to efficiently transform cells, as this

size range is energetically favoured for endocytosis.

Transformation follows a path of particle entry into

the cell through endocytosis; release of the particle

through endosomolysis is due to a proton sponge

effect coupled with cationic swelling which occurs

as the endosome acidifies, and then disassembly of

the complex in the cytoplasm frees the siRNA to

interact with its target (8,14).

Chitosan has the advantage of being

biocompatible, biodegradable and cheap to produce,

but the susceptibility of unmodified complexes to

aggregation with blood serum proteins complicates

systemic administration (8,14). Intrapulmonary

administration, however, both takes advantage of

chitosan’s mucoadhesive and enhanced permeation

properties compared to siRNA alone and bypasses

these systemic challenges, representing a promising

avenue of research with the potential to create

accessible, non-invasive therapies. Howard et al. at

the Interdisciplinary Nanoscience Center at the

University of Aarhus developed a system for

pulmonary administration of chitosan/siRNA

nanoparticles through intranasal administration to

transgenic mice, demonstrating knockdown of

endogenously produced Green Florescent Protein

over the course of five days (15). This review will

focus on advances in the design of inhalable

chitosan-based siRNA vectors since this paper

published in 2006.

Methods


Pubmed, Embase, and Medline were searched for

the terms “inhalable” “chitosan” and “siRNA” which

yielded two results in total. It was also searched for

the terms “pulmonary”, “chitosan”, and “siRNA”

which yielded twenty one results in total. Primary

research articles pertaining to the topic of research

advances in the formulation of chitosan based RNAi

vectors of pulmonary administration were selected.

Six papers, comprising several experiments apiece,

matched the criteria of describing new techniques

meant to advance on the foundational method

described by the researchers from the University of

Aarhus (15).

Discussion

I. Chitosan Modifications

One strategy for improving the performance of

chitosan-based systems has been to modify the

chitosan itself. Luo et al (2012) performed an

experiment comparing the in vivo silencing of green

florescent protein in lung epithelial cells of

transgenic mice constitutively expressing GFP by

chitosan/GFP siRNA and guanidylated chitosan/GFP

siRNA, at weight ratios of 20 and 40 between the

polymers and the nucleic acid, delivered as an

aerosol by a nebulizer (16). The result was much

stronger silencing by guanidylated chitosan (GCS)

particles as measured by confocal microscopy and

Western Blot analysis (16). Many of the same

researchers demonstrated in 2011 that GCS forms

more stable complexation with DNA vs. unmodified

chitosan (CS) and that it had eight-fold higher peak

transfection efficiency (17). Moreover, MTT toxicity

analysis showed it to be less cytotoxic than chitosan

at the same concentrations (17). The authors

speculated that this was due to its greater solubility

at neutral pH, since chitosan required acetic acid to

solubilize, perhaps accounting for the difference in

cytotoxicity. Luo et al also demonstrated in vitro

with fluorescently labeled siRNA that a markedly

higher concentration of siRNA was present in the

cytosol of cells transfected with GCS particles vs.

CS particles, supporting that the in vivo silencing

observed in the mouse lung tissue was a product of

more efficient siRNA delivery and was not a side

effect of GCS administration (16). The mechanism

by which guanidylation improves transfection

efficiency is speculated to have to do with its ability

to hydrogen bond with the cell surface, and through

its association with the cell penetrating peptide

mechanism, a phenomenon by which the presence of

such groups facilitates the entry of cargo molecules

through the cell surface due to a poorly understood

and as yet unelaborated cellular process (17).

Jiang et al (2009) studied aerosol-delivered

particles composed of siRNA and chitosan modified

with polyethylenimine (PEI). PEI has been well-

studied as an RNAi vector due to the very high

transfection efficiencies it has shown in experiments,

attributable to the dense, highly charged particles it

produces in association with siRNA (9, 18). Its use,

however, has been limited because of significant

toxicity issues (9, 18). Jiang et al showed that

chitosan conjugated with PEI had higher transfection

efficiencies than a PEI control particle alone in small

cell lung cancer in vitro (18). They also

demonstrated considerably lower toxicity in CS-PEI

vs PEI alone. Unfortunately, the study did not

compare transfection efficiency of CS-PEI vs. CS

particle control, nor did it compare the toxicity of the

two, and this could be an avenue of future research.

The study did, however, confirm the CS-PEI as an

efficient polymer for aerosol administration to lung

tissue (18).

N,N,N-trimethylated chitosan (TMC) has

emerged in non-lung studies as an interesting

chitosan modification because it displays greater

solubility and particle stability at neutral pH

compared to chitosan, and can reversibly open tight

junctions (19). However, it hasn’t always shown

significantly greater transfection efficiencies

compared to unmodified chitosan at neutral pH,

despite the higher stability, and transfection

efficiencies are sometimes shown to be similar (20).

Varkouhi et al. 2010 showed that thiolation of TMC

particles resulted in much higher silencing compared

to unthiolated TMC particles in in vitro experiments

on a human lung cancer line, achieving 60-80%

silencing activity vs. 40% for unmodified TMC (21).

Moreover, they also showed that thiolated TMC

maintained its silencing efficiency in the presence of

hyaluronic acid while TMC did not, indicating that

thiolation could be an important advance in helping

this technology better stabilize in the presence of

competing macromolecules (21). The authors

propose that the particles are more stable

extracellularly because of the disulfide bonds that

arise between the thiolated molecules, but that this

doesn't especially reduce intracellular release

because the bonds are broken in the cytosol by the

relatively high number of reducing agents present

there (21).

II. Targeting Ligands

Both Luo et al. and Jiang et al. also experimented

with the addition of targeting ligands to their

particles. Luo et al chemically coupled salbutamol, a

chemical that bind β2 adrenergic receptors, to GCS

and found higher silencing and transfection

efficiencies for salbutamol GCS (SGCS) compared

to GCS in vitro and in vivo (16).They also compared

in vitro the transfection efficiencies of GCS vs.

SGCS on cell lines expressing β2 adrenergic

receptors and those that do not express them, finding

higher silencing efficiency of SGCS vs. GCS for cell

lines expressing β2 adrenergic receptors and no

significant increase in efficiency in cell lines that do

not express them (16). This demonstrates that

addition of this targeting ligand can direct vectors to


a specific cell line and make transfection of it more

efficient. The authors speculated that in addition to

concentrating more particles at the cell surface for

uptake by non-specific endocytosis, binding of the

salbutamol receptor could also have initiated

receptor mediated endocytosis, as this receptor is a

G-protein coupled receptor known to have a

relationship to this endocytic pathway (16).

Jiang et al., in looking to target their particles to

cancer cells, conjugated their CS-PEI copolymer

with folate, as the cells they were targeting were rich

in folate receptors (18). Addition of the molecule

was associated with strong increases in silencing in

vitro and in vivo, and strong increases in transfection

efficiencies in vitro (18). This further supports the

addition of targeting ligands for inhalable vectors.

III. Lyophilisation

Many experiments performed to date have

created their siRNA-chitosan particles in aqueous

solutions using the electrostatic attraction between

chitosan and the siRNA. Unfortunately, these

particles have a short shelf life, losing activity

quickly through aggregation (22). Researchers from

the laboratory at the University of Aarhus have

recently attempted to address this problem by

researching lyophilisation of the particles so as to

increase the amount of time they remain stable (22).

Particles were freeze dried into wells to which cells

were later added for transfection (22). They used

sucrose as a lyoprotectant at concentrations from 0 –

10% and found that even at 10% concentrations,

particle size remained constant, although at sucrose

concentrations that were too low the particles formed

large aggregates upon reconstitution, likely due to

the lack of sufficient sucrose to inhibit the mobility

of the particles and thus their interactions with each

other (22).

Silencing experiments using a human lung

cancer cell line demonstrated that freeze dried

particles retained their ability to silence genes in an

siRNA concentration dependant manner (22). Over a

period of two weeks, particles lyophilised in 10%

sucrose solution decreased in transfection efficiency

of cancer cells from 67% to 38%, and over 2 months

to 32% (22). In cytotoxicity studies, no changes

were found in particles protected by low sucrose

concentrations, but in particles preserved with 10%

sucrose, viability was reduced to 90%. A

macrophage cell line, however, was shown to be

more sensitive to toxicity secondary to transfection

with all agents tested, with viability ranging from

only 33% to 38% (22), perhaps indicating

macrophages as an important lung cell type to study

for toxicity in the future. While the results do not

seem to indicate that lyophilisation is an ideal

treatment for inhalable siRNA particles for clinical

use at this time, it does show that lyophilised

particles retain significant silencing two months after

treatment and fairly low toxicities in one lung cell

type, establishing lyophilisation as a possible area

for future innovation that would allow these products

to be more widely used clinically then would

otherwise be possible with short shelf lives.

IV. Pulmonary Delivery of siRNA

Building on the research on rats conducted by

Howard et al.(15), a recent paper by Sharma et al.

examined the stability, physicochemical properties

and cytotoxicity of chitosan-packaged siRNA

nanoparticles following nebulisation, using a jet

nebuliser (23). They concluded that free siRNA did

not survive nebulisation, but that it was preserved

intact when encapsulated within nanoparticles (23).

They also studied the cytotoxicity over 24H of

nanoparticles on cultured human lung cancer cells

and found no cytotoxicity at 2.6micrograms/ml and

cell viability of 85% at the highest concentration

which was 83micrograms/ml, concluding that these

concentrations did not significantly affect cell

viability and were appropriate for in vivo

applications (23). Importantly, they also confirmed

the stability of these chitosan particles at pH6.5, the

likely pH they would encounter in the lung (23).

These results confirm that nebulisers can be used as

a viable and efficient delivery system for eventual

clinical applications.

A paper describing the invention of

chitosan/siRNA inhalable dry powder was also

published this year by Tomoyuki Okuda et al (24).

They produced a dry powder using the supercritical

carbon dioxide technique, producing long needles

that were not suitable to inhalation, but which could

be made so through manual grinding to fragments

10-20micrometres in length (24). Their findings

were that the process had little effect on the

physicochemical properties of the particles; that

encapsulated siRNA remained stable in lung

homogenate; that naked siRNA did not survive the

process; and that the powder silenced gene

expression in vivo in rats with genetically

engineered lung tumors of colonic origin (24).

Moreover, the study revealed the biodistribution of

inhaled siRNA, showing that inhaled naked siRNA,

while not particularly stable systemically, travels to

the liver within 0.5h following inhalation and then to

the small intestine within 6h (24). Retention of

siRNA in the lung, however, is greatly increased

when the siRNA is complexed with chitosan,

whether that be in dry powder form or in aqueous

solution and what's more, dry powder seemed to

deliver a higher dose of particles to the lung surface

in less time compared to solution (24). Finally, the

dry powder was able to affect gene silencing in the

tumor in vivo, whereas chitosan/siRNA in solution

had little effect (24).

Conclusion

Small interfering RNA are a class of nucleic

acids that can induce RNA interference, a natural


mechanism that can be used to selectively silence the

expression of individual genes. Delivering these

nucleic acids to cells involved in disease states has

potential as a strategy for treating a broad spectrum

of diseases which could be ameliorated by down-

regulation of specific genes. Chitosan is a siRNA

delivery vector which holds much promise because

of its biodegradability and biocompatibility, but

because it interacts with blood proteins much of its

promise lies in respiratory administration to lung

tissues. This makes it a vector that may someday be

used to treat diseases like lung cancer, respiratory

syncytial virus, and asthma. Chitosan is the most

viable of the current polymers in development right

now for respiratory use, because of its low toxicity.

Research has occurred on several strategies to

improve the efficacy chitosan/siRNA for this

purpose. Researchers have chemically modified

chitosan in an attempt to create more stable particles

or to increase transfection efficiencies. Transfection

efficiencies have also been increased through the

addition of targeting ligands, which also serve to

increase specificity. Finally, there has also been

physical chemistry research done on these particles

in an attempt to develop convenient and cheap

delivery mechanisms for the clinic. All of these

research advances represent positive movement

towards addressing the challenges this technology

faces on the road towards clinical application.

References

1) Ramsey JM, Hibbitts A, Barlow J, Kelly C, Sivadas N, Cryan

SA. 'Smart' non-viral delivery systems for targeted delivery of

RNAi to the lungs. Ther Deliv. 2013:59-76

2) Macrae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ,

Adams PD, Doudna JA. Structural Basis for Double-Stranded

RNA Processing by Dicer. Science. 2006;311(5758):195-8.

3) Vázquez-Ortiz G, Piña-Sánchez P, Salcedo M. Great potential

of small RNAs: RNA interference and microRNA. Rev Invest Clin. 2006;58(4):335-49.

4) Watson, James D. Molecular Biology of the Gene. San

Francisco, CA: Cold Spring Harbor Laboratory Press; 2008. pp.

641–648.

5) Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA

interference in cultured mammalian cells. Nature.

2001;411(6836):494-8.

6) Clayton C. Alnylam Reports Positive Top-Line Results for

ALN-TTRsc, a Subcutaneously Administered RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR-

Mediated Amyloidosis [Internet]. Business Wire. July 11th 2013

[cited July 18th 2013]; Available from: http://www.businesswire.com/news/home/20130711005039/en/Al

nylam-Reports-Positive-Top-Line-Results-ALN-TTRsc-

Subcutaneously

7) Kubowicz P, Żelaszczyk D, Pękala E. RNAi in clinical studies. Curr Med Chem. 2013;20(14):1801-1816.

8) Alameh M, Dejesus D, Jean M, Darras V, Thibault M, Lavertu M, Buschmann MD, Merzouki A.

Low molecular weight chitosan nanoparticulate system at low N:P ratio for nontoxic polynucleotide delivery. Int J Nanomedicine.

2012;7:1399-414

9) Lee JM, Yoon TJ, Cho YS. Recent Developments in

Nanoparticle-Based siRNA Delivery for Cancer Therapy. BioMed Res Int. 2013:782041

10) Durcan N, Murphy C, Cryan SA. Inhalable siRNA: potential as a therapeutic agent in the lungs. Mol Pharm. 2008;5(4):559-66.

11) Kean T, Thanou M. Biodegradation, biodistribution, and

toxicity of chitosan. Adv Drug Delivery Rev. 2010; 62(1):3-11.

12) Jackson AL & Linsley PS. Recognizing and Avoiding siRNA

Off-Target Effects for Target Identification and Theapeutic Application. Nat Rev Drug Discov. 2010;9:57-67.

13) Jreyssaty C, Shi Q, Wang H, Qiu X, Winnik FM, Zhang X et al. Efficient Nonviral Gene Therapy Using Folate-Targeted

Chitosan-DNA Nanoparticles In Vitro. ISRN Pharm. 2012:36927.

14) Howard KA, Kjems J. Polycation-based nanoparticle delivery

for improved RNA interference therapeutics. Expert Opin Biol

Ther. 2007 Dec;7(12):1811-22.

15) Howard KA, Rahbek UL, Liu X, Damgaard CK, Glud SZ, Andersen MØ et al. RNA interference in vitro and

in vivo using a novel chitosan/siRNA nanoparticle system.

Molecular Therapy. 2006;14:476-484.

16) Luo Y, Zhai X, Ma C, Sun P, Fu Z, Liu W, Xu J. An

inhalable β -adrenoceptor ligand-directed guanidinylated chitosan

carrier for targeted delivery of siRNA to lung. J Control Release.

2012 Aug 20;162(1):28-36.

17) Zhai XY, Sun P, Luo YF, Ma CN, Xu J, Liu WG. Guanidinylation: a simple way to fabricate cell penetrating

peptide analogue-modified chitosan vector for enhanced gene

delivery. J. Appl. Polym. Sci. 2011;121:3569–3578.

18) Jiang HL, Xu CX, Kim YK, Arote R, Jere D, Lim HT, Cho MH, Cho CS. The suppression of lung tumorigenesis by aerosol-

delivered folate-chitosan-graft-polyethylenimine/Akt1 shRNA

complexes through the Akt signaling pathway. Biomaterials. 2009;30(29):5844-52.

19) Sahni JK, Chopra S, Ahmad FJ, Khar RK. Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a

polymeric absorption enhancer: Synthesis, characterization and

applications. J Pharm. Pharmacol. 2008;60(9):1111-9.

20) Dehousse V, Garbacki N, Jaspart S, Castagne D, Piel G, Colige A, Evrard B. Comparison of chitosan/siRNA and

trimethylchitosan/siRNA complexes behaviour in vitro. Int J Biol

Macromol. 2010;46(3):342-9.

21) Varkouhi AK, Verheul RJ, Schiffelers RM, Lammers T,

Storm G, Hennink WE. Gene silencing activity of siRNA polyplexes based on thiolated N,N,N-trimethylated chitosan.

2010;21(12):2339-46.

22) Andersen MØ, Howard KA, Paludan SR, Besenbacher F,

Kjems J. Delivery of siRNA from lyophilized polymeric surfaces. Biomaterials. 2008;29(4):506-12.

23) Sharma K, Somavarapu S, Colombani A, Govind N, Taylor

KMG. Nebulised siRNA encapsulated crosslinked chitosan

nanoparticles for pulmonary delivery. Int J Pharm. 2013;455(1-2):241-7.

24) Okuda T, Kito D, Oiwa A, Fukushima M, Hira D, Okamoto H. Gene Silencing in a Mouse Lung Metastasis Model by an

Inhalable Dry Small Interfering RNA Powder Prepared Using the

Supercritical Carbon Dioxide Technique. Biol Pharm Bull. 2013;36(7):1183-91.


OP-ED

Pharmacists in the Developing World: Providing

Impact to the Poorest of the Poor

Jocelyn Conway, B.Sc.1

Kishor M Wasan, RPh, PhD, FAAPS, FCAHS1,2 1Neglected Global Diseases Initiative, University of British Columbia, Vancouver, British Columbia, Canada 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Can you imagine waking up with a splitting

headache and not having access to a simple pain

relief medication like ASA (Aspirin ®)? What if you

were diagnosed with cancer, or an infectious disease

like malaria, and did not have access to the

medicines that would save your life? What if

accessing the necessary medicine was possible, but

you could not be sure of its quality, or how to

properly administer it? These situations exist in far

too many countries and their effects on the health of

the world’s poorest populations are a travesty.

Access to medicines is a global problem consisting

of several component parts and is a fascinating study

that, if it interests you, could change the trajectory of

your career.

The Neglected Global Diseases Initiative (NGDI)

at UBC is an umbrella organization working for

investigators who are researching diseases that

disproportionately affect the poor. One of our

contributions to this research is the development of

our Model of Collaboration1 (MoC) (See Figure 1).

Our mission is to develop interventions for neglected

global diseases and ensure their delivery to those in

need. The usefulness of our model is that it describes

the traditional drug discovery and development

pipeline, and goes beyond it to further encompass

the supply chain, research on the ground, and policy

work at global and national levels.

How can pharmacists and pharmaceutical

scientists interact with and contribute to this model

in order to provide increased access to medicines

and improved health outcomes?

Research and Development of Medicines

The drug pipeline for neglected global diseases is

still relatively small but it is growing rapidly. As of

2012, there were 173 drugs and 203 vaccines in

development through this pipeline, of which almost

60% were targeted for HIV/AIDs, Malaria, and

1The Model is an amalgamation of the traditional drug

R&D pipeline; recently defined health systems research by

Remme, et. al. in 2012 (1), and the Harvard model of

Access as defined by Frost & Reich in 2008 (2).

Figure 1. NGDI Model of Collaboration

Tuberculosis (3). That leaves just 67 remaining drug

candidates for 17 different neglected tropical

diseases which altogether affect almost one billion

people. New discoveries are needed and potential

drug candidates need to be developed in order to

increase the likelihood of successful clinical trials

and regulatory approval. Taking the MoC into

account during pharmaceutical drug research and

development stimulates attention to down-the-line

factors such as end-user costs versus benefits,

tropical stability, and whether a medication could be

expected to be adopted by the country, health unit,

health professional, and patient.

Quality of Medicines and Delivery System

Challenges

The World Health Organization (WHO) has

developed a “Model List of Essential Medicines” for

both the adult and pediatric populations (4). These

lists contain over 277 medicines for a full range of

diseases and conditions. When we see the word

‘essential’ we may naturally think that this means

accessible. Unfortunately, and particularly in low-

resource countries, this is not necessarily the case. In

2009, a study of the availability of 17 common

pediatric drugs in the capital cities of 14 African

countries revealed that at primary care health clinics,

less than 50% of these medicines were available.

This number improved to only 60% when

surrounding retail pharmacies were included (5).


Needless to say, these numbers would probably have

been much lower in rural areas.

There is also the issue of quality control. Just

because you have the medicine you need does not

guarantee that it will work. In diseases with a high

mortality rate like malaria medicine, quality is

especially important, particularly in children under

five years old. The quality of antimalarial

medications is quite variable, and they are a frequent

target for counterfeiting (6). In fact, a six country

study that tested several types of antimalarials for

content and dissolution properties recorded failure

rates between 20% and 50% (7).

The NGDI recently collaborated with UCLA San

Francisco and the WHO to study the quality of

pediatric medicines in developing countries. Despite

the inclusion of 70 papers, we concluded that there is

a paucity of quality testing in developing countries

reported in the literature. Another important finding

was that substandard medicines were reported as

such due to poor manufacturing standards or

degradation through poor storage conditions within

tropical environments almost as often as they were

being reported as counterfeit products. More quality

testing studies need to report testing results by level

of distribution in the supply chain so that further

investigations of poor storage can take place (8).

Health Systems Research and Operational

Research

Another problem contributing to inadequate

access to medicines is the need to increase the

number of staff in the pharmaceutical health sector

at both the professional and technical levels. The

International Pharmaceutical Federation reports that

they are working closely with the WHO to map and

contribute to workforce planning and educational

opportunities and have described this process as

challenging, particularly in several African

countries. They report that there is a stark contrast

between the density of pharmacists per 10,000

people in low-income (< 1) and high-income (~ 10)

countries, and that the greater density of pharmacies

versus pharmacists to staff them in low-income

countries also suggests access challenges (9).

Another important factor in medicine quality is

proper drug storage. In the NGDI review, only 7.7 %

(4/52) of studies took notice of actual pharmacy

conditions, prescription filling practices, or the

credentials of counter persons where the samples

were collected. More attention to this area through

operational research is needed.

Policy Work

Essential medicines, intellectual property, and

regulatory changes are all examples where policy

work is needed. Researchers here at UBC have also

been involved in research and development policy

and have been working to provide standards for

pediatric clinical trials in order to provide safe

pediatric dosages and formulations for medicines

(10,11).

Career Considerations

This overview of the pharmaceutical sciences in

developing countries is intended to highlight areas

where research could provide a positive impact.

Pharmacy students can contribute by choosing a

career in global health. There are many paths to

consider: 1) work in research and development to

develop medicines for diseases of the poor, 2)

provide quality testing of essential medicines in

developing countries, 3) highlight and work towards

changing the storage conditions and pharmacy

practices in low-resource settings, or 4) work with

policy makers to contribute to new safer

formulations for pediatric medicines. Any of these

areas might take your career on a path you least

expect.

References

1) Remme JHF, Adam T, Becerra-Posada F, D’Arcangues C,

Devlin M, Gardner C, et al. Defining research to improve health systems. PLoS Med. 2010 [cited 2011 Sep 10];7(11):e1001000

2) Frost LJ, Reich MR. ACCESS: How do good health

technologies get to poor people in poor countries? Cambridge: Harvard Series on Population and International Health; 2009.

3) Developing new drugs and vaccines for neglected diseases of

the poor: The product developer landscape [Online]. Bio Ventures for Global Health; 2012 [cited 2013 May 18]. Available from:

URL:http://www.bvgh.org/LinkClick.aspx?fileticket=h6a0cJK9dr

g%3d&tabid=91.

4) Third WHO model of essential medicines for children.

[Online]. World Health Organ; 2011 [cited 2012 Jan 05].

Available from: URL:http://www.who.int/medicines/publications/essentialmedicin

es/en/index.html.

5) Robertson J, Forte G, Trapsida J-M, Hill S. What essential medicines for children are on the shelf? [Internet]. Bulletin of the

World Health Organ. 2009 [cited 2012 Jan 05];87(3):231–7.

Available from: URL:http://www.scielosp.org/scielo.php?script=sci_arttext&pid=

S0042-96862009000300018&lng=en&nrm=iso&tlng=en.

6) Kelesidis T, Kelesidis I, Rafailidis P, Falagas M. Counterfeit or substandard antimicrobial drugs: a review of the scientific

evidence. [Online]. J Antimicrob Chemother. 2007 [cited 2012

Jan 05];60(2):214–36. Available from: URL:http://www.ncbi.nlm.nih.gov/pubmed/17550892

7) Bate R, Coticelli P, Tren R, Attaran A. Antimalarial drug

quality in the most severely malarious parts of Africa - a six country study. [Online]. PloS One. 2008 [cited 2012 Jan

05];3(5):e2132. Available from:

URL:http://www.ncbi.nlm.nih.gov/pubmed/18461128.

8) Conway J, Bero L, Ondari C, Wasan K. Review of the quality

of pediatric medications in developing countries. [Internet]. J

Pharm Sci. 2013 [cited 2013 Apr 10];102(5):1419–33. Available from: URL:http://www.ncbi.nlm.nih.gov/pubmed/23450511.

9) Gal G. 2102 FIP Global pharmacy: workforce report. [Online].

The Hague: International Pharmaceutical Federation; 2012 [cited 2013 May 10]. Available from:

URL:http://www.fip.org/static/fipeducation/2012/FIP-Workforce-Report-2012/?page=hr2012.

http://www.scielosp.org/scielo.php?script=sci_arttext&pid=S0042-96862009000300018&lng=en&nrm=iso&tlng=en

http://www.scielosp.org/scielo.php?script=sci_arttext&pid=S0042-96862009000300018&lng=en&nrm=iso&tlng=en

http://www.ncbi.nlm.nih.gov/pubmed/18461128

http://www.ncbi.nlm.nih.gov/pubmed/23450511

http://www.fip.org/static/fipeducation/2012/FIP-Workforce-Report-2012/?page=hr2012

http://www.fip.org/static/fipeducation/2012/FIP-Workforce-Report-2012/?page=hr2012


10) Neglected Global Disease Initiative annual report 2012 [Online]. Neglected Global Disease Initiative 2012 [cited 2013

May 10]. Available from:

URL:http://www.ngdi.sites.olt.ubc.ca/files/2013/01/NGDI-UBC-

Annual-Report-2012.pdf

11) WHO and StaR Child health. Use of standards in paediatric clinical trials in developing countries meeting. [Online].

Amsterdam: 2009 Oct 28 [cited 2012 Jan 05]. Available from:

URL:http://www.who.int/childmedicines/progress/Amsterdam_M

eeting.pdf

http://www.ngdi.sites.olt.ubc.ca/files/2013/01/NGDI-UBC-Annual-Report-2012.pdf

http://www.ngdi.sites.olt.ubc.ca/files/2013/01/NGDI-UBC-Annual-Report-2012.pdf

http://www.who.int/childmedicines/progress/Amsterdam_Meeting.pdf

http://www.who.int/childmedicines/progress/Amsterdam_Meeting.pdf


OP-ED

Pharmacy “On Deck” – the Bases Are Loaded

Mits Miyata, B.Sc.(Pharm.), ACPR1,2

1Lower Mainland Pharmacy Services, Vancouver, BC, Canada 2British Columbia Ministry of Health Services, Victoria, BC, Canada

I’ve always admired the popular quotes of Yogi

Berra, a former Major League Baseball catcher,

outfielder and manager who played most of his 19-

year professional career with the New York

Yankees. His sayings have an unintentional wisdom

that transcends the world of baseball and, in my

opinion, have direct relevance to issues currently

facing the pharmacy profession.

“The Future Ain’t What it Used to Be”

When students ask me what I think the future of

hospital pharmacy will look like, I have only one

certain answer; it will be different than what it is

now. The practice of hospital pharmacy has evolved

significantly from the early days of being strictly

relegated to managing the drug product inventory

out of a hospital basement, and it will continue to

evolve along with the health care system. Exactly

what this future will look like depends on our

collective will and vision; the changing needs and

expectations of patients, the public, and government;

the future health system model; legislative

alignment; and successful advocacy by our

pharmacy leaders.

“If the World Were Perfect, it Wouldn’t Be”

Change happens because of a belief that there

must be a better way to do things. Having said that,

the path to change is never an easy one, nor has it

ever been. In British Columbia, many bold and

forward-thinking pharmacy leaders of the past faced

and overcame significant obstacles in order to

introduce and establish the direct patient care role

that has become familiar to most pharmacists. These

visionary leaders believed that new roles would

promote safer, more effective, and more efficient

health care for patients. Supportive advocacy was

provided by the Canadian Society of Hospital

Pharmacists (CSHP), a voluntary organization of

pharmacists across Canada, committed to moving

the profession forward through education, advocacy,

and collaboration. Several outstanding individual

clinical pharmacists, undeterred by others

questioning their new patient-focused role,

established strong inter-professional relationships

and provided excellent patient care that eventually

created acceptance and a demand for this new role.

Figure 1. New York Yankee catchers Lawrence

“Yogi” Berra and Elston Howard (1).

“If You Don’t Know Where You Are Going,

You Might Not Get There”

So, what will the future practice of hospital

pharmacy look like? This will largely depend on

what each of you wants the future of pharmacy to

look like. A clear vision, a collective will, and a

personal commitment towards achieving that vision

are key elements that will close the gap between “the

dream” and “the practice”. There are numerous

guiding documents available that help to envision

future practice (2-4). In 2007, the CSHP adopted

CSHP 2015, a program which articulates a practice

vision through goals and objectives that are to be

achieved in hospital pharmacy practice by 2015. In

2008, the Canadian Pharmacists Association (CPhA)

developed a “Vision for Pharmacy” in its Blueprint

for Pharmacy initiative. In 2010, the Association of

Faculties of Pharmacy of Canada (AFPC) released a

report on Education Outcomes for First Professional

Degree Programs in Pharmacy in Canada, in

recognition of the future educational needs for

pharmacists. Provincial legislation in many

provinces has been modified to enable expanded

scopes of practice for both pharmacists and

pharmacy technicians.

All of these initiatives point toward a different

future for hospital pharmacy practice. Opportunities

include:


Utilizing pharmacists’ expanded scope of

practice such as collaborative prescribing,

ordering tests, and monitoring patient-

specific parameters to

o Ensure that intended efficacy and

safety of drug therapy is achieved

o Enable efficient, independent

practice to achieve drug therapy

outcomes, and

o Better integrate into, and

contribute to, the interdisciplinary

setting

Utilizing pharmacy technicians’ expanded

scope of practice to release pharmacists

from distributional activities, and

Increasing the role of pharmacists in

primary care settings (symptom

management, immunizations, and drug

therapy education) and chronic disease

management settings (protocol

management, monitoring, and referral).

Advances in technology will affect the way

pharmacists and pharmacy technicians practice, with

expanded use of:

Automation technology (automated

cabinets, robotics) for safer drug

distribution systems

Portable technology (smart phones, wireless

devices) for more timely access to clinical

information, and provide for enhanced

patient safety, and

Intelligent software to enable timely and

appropriate clinical decision-making based

on integration of evidence-based literature,

patient-specific data, and documentation

into the electronic health record.

“It's Pretty Far, but it Doesn't Seem Like it”

Although some of the changes appear to be a

long way off, others are already in practice at some

institutions. Some pharmacists are practicing in

collaborative prescribing arrangements with specific

physicians. Many hospital pharmacists are ordering

lab tests to support drug monitoring and dosage

adjustment (e.g. anticoagulation programs). Many

community pharmacists are administering

vaccinations. Pharmacy technicians are running most

distribution functions. Many sites have implemented

automated dispensing systems (Pyxis or Omnicell),

and at least one health authority is utilizing iPhones

to conduct clinical work. Much of the future is

already here.

“It's Deja-Vu, All Over Again”

Like the pharmacy pioneers of the past, current

pharmacy leaders are advocating for legislative

changes to enable more effective and efficient care.

The CSHP is focusing its advocacy campaigns on

scopes of practice, expanded residency positions,

and improved medication-related seamless care

processes. Clinical pharmacists continue to provide

excellent care and feed demand for these services.

Educational pharmacy institutions continue to

prepare students for an expanded role in patient care.

Despite significant progress, there is still a long

way to go. Hospital pharmacists must continue to

believe in the benefits and viability of this future role

and take steps to ensure it happens. Pharmacists will

need to push boundaries, and assist the CSHP in

achieving its advocacy objectives by maintaining

ongoing membership, recruiting those who do not.

Pharmacy leaders need to keep pushing for the

future. This work will be ongoing for years to come.

As Yogi Berra most eloquently stated, “It ain’t

over ‘til it's over”. In the meantime, the bases are

loaded and Pharmacy is well positioned for a home

run.

References

1) Lawrence Berra and Elston Howard Picture [image on the internet]. 2010 [cited 2013 Sep 9]. Available from:

http://www.flickr.com/photos/boston_public_library/6383747451.

2) Canadian Society of Hospital Pharmacists: CSHP 2015 – Goals

and Objectives [Internet]. 2007 [cited 2013 May 25]. Available

from: http://www.cshp.ca/dms/dmsView/2_CSHP-2015-Goals-and-Objectives-Feb-25%2707-w-Appdx-rev-May%2708.pdf.

3) Background paper for the development at the Blueprint for

Action for the Pharmacy Profession in Canada. Canadian Pharmacists Association 2005 Nov.

4) Education outcomes for first professional degree programs in

Pharmacy (entry-to-practice programs) in Canada. Association of Faculties of Pharmacy of Canada [Internet]. 2010 Jun 3 [cited

2013 May 25]. Available from:

http://www.afpc.info/downloads/1/AFPC_Education_Outcomes_

AGM_June_2010.pdf.


WORKSHOP

Critically Appraising Randomized Controlled

Trials: Is there Substance in Subgroups?

Ricky D Turgeon, B.Sc.(Pharm.), Pharmacy Resident1 1Lower Mainland Pharmacy Services, Vancouver, BC, Canada

“Half of what you'll learn in medical school will

be shown to be either dead wrong or out of date

within five years of your graduation; the trouble is

that nobody can tell you which half—so the most

important thing to learn is how to learn on your

own.” – David Sackett, father of evidence-based

medicine

The evidence-based medicine (EBM) movement,

particularly the popularization of randomized

controlled trials (RCTs), has facilitated large

therapeutic advances. In addition to ascertaining the

efficacy and safety of new treatments, RCTs have

also led to the discovery of harmful effects of

interventions long accepted as beneficial. A recent

example of this is the ACCORD trial (1,2). This trial

showed that, contrary to conventional beliefs,

aggressive control of blood glucose and blood

pressure in type 2 diabetics produced increases in

mortality and serious adverse events, respectively.

Despite the strengths of RCTs, they are rarely

without their own limitations that must be carefully

considered during their interpretation.

In this PSSJ Workshop, we will discuss one of

the aspects of RCTs that often misleads healthcare

professionals: Subgroups.

Large clinical trials often include patient

populations with a range of characteristics including

age, gender, race, comorbidities, severity of illness,

etc. Subgroup analysis is a statistical technique that

divides trial participants into two or more cohorts

based on a certain characteristic, such as pre-existing

cardiovascular disease or stage of cancer. The effect

of the intervention on each of these subpopulations

separately is then assessed. The goal of this approach

is to individualize care based on patient factors.

However, subgroup analyses are frequently overused

to mine for positive results, often leading to spurious

conclusions (3). Subgroup analysis also contributes

to a problem in clinical trials known as multiplicity.

That is, if we test a sufficient number of hypotheses,

we are bound to eventually find a positive result

purely by chance, also known as a false positive. On

the other hand, loss of power from dividing the trial

population into increasingly smaller populations can

also contribute to falsely concluding that an

intervention has no effect in a subgroup, known as a

false negative.

The authors of the ISIS-2 trial illustrate how

subgroups can mislead us (4,5). In this trial,

investigators assessed the efficacy and safety of

aspirin and streptokinase, separately or combined,

versus placebo in patients with suspected myocardial

infarction. Aspirin reduced mortality in the overall

population, but among 40 subgroups evaluated it

was no better than placebo in those born under the

Gemini or Libra astrological signs, those with a prior

myocardial infarction, and in diabetics. Many

readers would dismiss the first subgroup and

contemplate the latter two based on biological

plausibility, though it is highly likely that all of these

are chance findings due to the sheer number of

subgroups observed. Thus, without criteria with

which to assess the validity of these subgroups,

readers may be compelled to withhold lifesaving

aspirin in individuals having a heart attack.

In an attempt to improve the rational

interpretation of subgroups, Sun and colleagues

proposed 11 criteria to evaluate the credibility of

subgroup analyses (Table 1) (6). In this article, we

will interpret the results of the female gender

subgroup of the Heart Protection Study (HPS) using

the Sun et al criteria (7).

Do Women Benefit from Statins? Answers

from a Heart Protection Study Subgroup

Analysis

Cardiovascular disease is the second leading

cause of death in Canadian women (8). Despite this,

women who have had a cardiovascular event receive

fewer evidence-based interventions than men (9).

This may stem from a reluctance to apply findings

from RCTs in cardiology to women due to the

disproportionate inclusion of males in these studies.

The Heart Protection Study was a 5-year double-

blind, placebo-controlled randomized trial designed

to assess the safety and efficacy of statin therapy in

over 20,000 men and women at high-risk of death

from cardiovascular disease (7).

During study design, investigators selected seven

baseline characteristics (10), including gender, for


Design HPS (7) female subgroup

1. 1) Is the subgroup variable a characteristic measured at baseline (optimal)

or after randomization? At baseline

2. 2) Is the effect suggested by comparisons within (optimal) rather than

between studies? Within

3. 3) Was the hypothesis specified a priori? Yes (10)

4. 4) Was the direction of the subgroup specified a priori? No

5. 5) Was the subgroup effect one of a small number of hypothesized effects

6. tested?

Seven subgroup pre-specified

(10)

Analysis

7. 6) Does the interaction test suggest a low likelihood that chance explains

8. the apparent subgroup effect? No

9. 7) Is the significant subgroup effect independent? Does not apply

Context

10. 8) Is the size of the subgroup effect large? Does not apply

11. 9) Is the interaction consistent across studies?

Meta-analysis finds no

significant test for interaction

(11)

12. 10) Is the interaction consistent across closely related outcomes within

13. the study?

First major vascular event was

the only outcome tested for

subgroup effect

14. 11) Is there indirect evidence that supports the hypothesized interaction

15. (e.g. biological rationale)? None presented

Is there credible evidence for a subgroup effect?

It is unlikely that there is a

difference in the relative effect of

statins on major vascular events

between men and women based

on this trial Table 1. Criteria to assess the credibility of subgroup analyses from Sun et al (6).

Received: March 8, 2013

Revised: August 3, 2013

which they would conduct subgroup analyses to see

if the effect of treatment varied based on these

features (positive criteria 1, 2, 3 and 5 in Table 1).

They did not, however, specify how they

hypothesized the subgroup would influence the

treatment’s effect (i.e. whether females would derive

more or less benefit from statins than males;

negative criterion 4).

Before proceeding to interpreting the separate

efficacy estimate for the female subgroup, it is first

important to evaluate the test for interaction. This

statistical test assesses the likelihood that a

difference between groups is due to chance. In this

case, the p-value for the test for interaction between

males and females was 0.76 (far above the

traditional 0.10 threshold for statistical significance

used for this test), suggesting that any apparent

subgroup difference is due to chance (negative

criterion 6; obviates criteria 7 and 8). A look beyond

this study confirms a lack of a gender difference in a

subsequent meta-analysis of trials (criterion 9) (11).

Authors did not present subgroup analyses for the

different components of the “major vascular event”

outcome, such as death, though it is unlikely that

there are differences given the uniformity of the

overall outcome (criterion 10). Finally, there is no

strong biological rationale for a gender difference in

statin efficacy (criterion 11). Given all of the above,

we can be reasonably certain that statins provide the

same relative benefit in women as they do in men.

The validity of a subgroup analysis is not

determined simply by achieving a high score on a

checklist. Sun et al propose that credibility of a

subgroup effect lies on a continuum (6). Due to the

high risk of chance findings, I am usually cautious in

interpreting subgroups, requiring criteria 1 through 5

to be satisfied, as well as replication in one

additional study, or at the very least a statistically

significant test for interaction, before I incorporate

these findings into my therapeutic decisions. In a

case where the subgroup effect is not sufficiently

credible, such as in the above Heart Protection Study

illustration, I will instead use the overall trial relative

effects to estimate the benefits for my patients in a

specific subgroup. Thus, the Heart Protection

Study’s overall relative risk reduction of 24% with

statin treatment can be applied to the 17.7% absolute

risk of a major vascular event over 5 years in women

receiving placebo to derive an absolute risk

reduction of 4.2% with statin therapy, which can

also be reported as a number needed to treat of 24.


References

1) The Action to Control Cardiovascular Risk in Diabetes Study

Group. Effects of intensive glucose lowering in type 2 diabetes. N

Engl J Med. 2008;358:2545–59.

2) ACCORD Study Group. Effects of intensive blood-pressure

control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.

3) Rothwell PM. Treating individuals 2: subgroup analysis in

randomised controlled trials: Importance, indications, and interpretation. Lancet. 2005;365:176–86.

4) ISIS-2 Collaborative Group. Randomised trial of intravenous

streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet.

1988;2:349–60.

5) Horton R. From star signs to trial guidelines. Lancet. 2000;355:1033–4.

6) Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect

believable? Updating criteria to evaluate the credibility of

subgroup analyses. BMJ. 2010;340:c117.

7) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised

placebo-controlled trial. Lancet. 2002;360:7–22.

8) Leading causes of death, by sex [Internet]. Ottawa (ON): Statistics Canada; 2012 [cited 2013 Mar 8]. Available from:

http://www.statcan.gc.ca/tables-tableaux/sum-

som/l01/cst01/hlth36c-eng.htm

9) Lahoud R, Howe M, Krishnan SM, Zacharias S, Jackson EA.

Effect of use of combination evidence-based medical therapy after

acute coronary syndromes on long-term outcomes. Am J Cardiol. 2012;109:159–64.

10) MRC/BHF Heart Protection Study Collaborative Group.

MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide

range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J. 1999;20:725–

41.

11) Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: A sex-based

meta-analysis. Arch Intern Med. 2012;172:909–19.


PRACTICE ISSUES

Advancing Experiential Learning in Institutional

Pharmacy Practice:

The University of British Columbia's AGILE Project

Michael Legal, B.Sc.(Pharm.), ACPR, PharmD1,2

Maggie Billingsley, B.Sc.(Pharm.) Candidate 20142

France Carriere, B.Sc.(Pharm.) Candidate 20142

Peter Loewen, B.Sc.(Pharm.), ACPR, PharmD, FCSHP2,3

Peter Zed, B.Sc., B.Sc.(Pharm.), ACPR, PharmD2

1Providence Health Care, St. Paul’s Hospital, Vancouver, BC, Canada 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada 3Vancouver Coastal Health, Vancouver, BC, Canada

Introduction

Experiential education describes an approach

where educators purposefully engage with learners

in direct experience and focused reflection in order

to increase knowledge, develop skills, and clarify

values (1). In health care, direct exposure typically

involves bringing learners into the clinical practice

environment. This exposure is critical in cementing

the practical and critical thinking skills learners need

in order to develop into independent practitioners

(2,3). While the benefits of experiential education in

health care are well described, organizing and

delivering placements may be associated with

significant challenges for academic institutions and

for practice sites (4). A shortage of preceptors and

experiential sites is a common issue identified by

academic programs, while practice sites and

preceptors often describe challenges in managing

teaching workload alongside existing workplace

demands (4,5).

In pharmacy, experiential placements are

typically offered in community practice settings and

in hospital (or institutional) settings. The Canadian

Council for Accreditation of Pharmacy Programs

(CCAPP) requires a minimum of 16 weeks of

experiential for degree programs leading to a

Bachelor of Science in Pharmacy (6). Mostly, these

placements are secured via a relatively informal

request/offer system between faculty experiential

coordinators and preceptors or sites. As above,

availability of placements is at times an issue

particularly for institutional placements. It is

expected that the challenge associated with locating

adequate numbers of placements will only intensify

in the coming decade. A major reason for this is a

shift in pharmacy degree programs in Canada. In

2011 all of the faculties of pharmacy in Canada

agreed to pursue an entry to practice Doctor of

Pharmacy as the standard first-degree program in

pharmacy in Canada. CCAP requires a minimum of

40 weeks of experiential placements in entry to

practice doctor of pharmacy programs. This will

amount to a doubling of the required amount of

experiential time from existing Bachelor of Science

in Pharmacy programs.

In British Columbia, the Faculty of

Pharmaceutical Sciences will transition to its entry to

practice doctor of pharmacy program beginning in

2015 or 2016. The current Bachelor of Science in

Pharmacy program includes 20 weeks of experiential

placements (4 weeks of which are institutional) (7).

The new entry to practice program (currently in the

planning stages) is expected to require over 40

weeks of experiential placements. Also, the Faculty

recently increased enrolment in the Bachelor of

Science in Pharmacy program from 165 students to

224 students starting in 2011. Both of these changes

will place stress on placement capacity in BC.

Anecdotally there appears to be an adequate number

of community experiential placements to

accommodate these changes. However, in the

institutional setting it is clear that capacity will be an

issue. An additional challenge in BC relates to the

placement needs of the other pharmacy experiential

programs.

The UBC Doctor of Pharmacy program admits 8

students annually who each require 12 one-month

long placements (mostly in the institutional setting).

In addition BC has a well-developed hospital

pharmacy practice residency program administered

by the health authorities. Over 30 pharmacy practice

residents complete 8 to 9 one-month long

institutional placements annually. The experiential

needs of these learners can create competition for the

limited institutional placement capacity in BC. At

the same time there is great potential for mutual

benefit and collaboration between the three


programs to enhance the experience of learners and

leverage peer assisted learning. It is also clear that a

comprehensive system of supports will be needed for

both preceptors and learners. The faculty recognizes

these challenges and opportunities and embarked on

the AGILE project to further explore the

possibilities.

Discussion

I. The AGILE Project

AGILE stands for Advancing Experiential

LearninG In InstitutionaL Pharmacy PracticE and

was initiated by the Faculty of Pharmaceutical

Sciences at UBC. The project falls within the

Faculty's Practice Innovation portfolio. The goal of

the AGILE project is to develop recommendations

that will inform new approaches to institutional

experiential pharmacy education in British Columbia

and to address capacity concerns and associated

challenges. The recommendations will pertain to

several key areas as follows:

Preceptor-learner models that can be

tailored to the needs of specific sites

Support structures for preceptors and

learners during experiential placements

Knowledge resources/faculty resources

Preceptor training, credentialing, and

incentives

Role and job description of health

authority/faculty educational support

positions

Roles and responsibilities of senior learners

while supervising junior learners

The project began in November 2012 and will

run for one year. A project lead was identified who

was responsible for designing and executing the

project methodology. One of the major aims of

AGILE is to foster broad engagement of the many

stakeholders involved in the pharmacy experiential

education that occurs in BC’s six health authorities.

Key stakeholders across the province include health

authority pharmacist-preceptors, coordinators, and

directors as well as faculty and pharmacy learners.

The feedback from these stakeholders will form the

basis of AGILE's recommendations.

A one-year multi-phase approach for the project

was outlined (Figure 1). Background research and

planning, stakeholder engagement, analysis and

reporting of recommendations were among the key

steps identified in executing the mandate of the

project. At the time of writing the project has just

completed the stakeholder engagement phase

(project phase 2).

Figure 1. AGILE project - timeline and phases. The AGILE project was divided into 4 discrete phases in order to allow the

project to complete all aspects of its mandate within the November 2012- November 2013 project term. Phase 2, Health

Authority Pharmacy and Stakeholder Engagement, was the longest and most critical phase of the project. Phase 3 and 4 focus

on developing the project recommendations (informed by the feedback obtained in Phase 2).


The AGILE project was fortunate to receive a

significant funding grant from the UBC Teaching

and Learning Enhancement Fund. This support

allowed the project to employ 4 part time student

assistants and a qualitative research associate. The

students have been actively engaged in organizing

site visits, focus groups and surveys. The qualitative

research associate has already begun analyzing the

stakeholder feedback.

II. Project Methodology

A comprehensive literature search, review of

approaches used in other health care experiential

programs in North America and the writing of a

project protocol were the first steps. In order to

capture and analyze feedback in a rigorous manner

the project was designed to employ principles of

qualitative research (8-11). A structured, scientific

approach was chosen so that the project's findings

could later be shared through scholarly publication

and presentation. This is important because faculties

and their institutional partners in other parts of

Canada will face similar issues in the coming years.

Sharing AGILE's findings will hopefully aid them as

they implement their own program changes.

The stakeholder engagement phase of the project

employed focus groups, in-depth interviews,

electronic surveys and website discussion. The

feedback obtained through these processes was

captured as either audio recordings (which were

transcribed into verbatim written transcripts), written

field notes, or electronic data.

Analysis of stakeholder feedback is set to occur

in the summer of 2013 and will identify key themes.

Reflections on the Process to Date

The literature search and review of approaches to

experiential education elsewhere revealed a number

of strategies worthy of consideration.

A important strategy for the sustainability of

future experiential education relates to forming

formal partnerships between universities and

institutional sites (4,12,13). A partnership allows the

university to have assurances of rotation supply and

availability while the institutional sites benefit from

logistic and direct support for learners on rotation

and for preceptor development. Some perceived

ingredients to successful partnerships were the

presence of college faculty at practice sites,

integration of students and residents into the site, and

alignment of student roles with pharmacy

department initiatives (14). In addition it is

important to ensure that competing responsibilities

and clinical workload of preceptors is considered in

this equation.

A major strategy to increase capacity is the use

of novel rotation models such as “multi-placements”

and tiers. In pharmacy education the dominant

model is the 1:1 (preceptor to learner) model also

known as the apprenticeship model. Several groups

advocate adopting 1:2 or greater preceptor to learner

models (multi-placements) or a tiered model

(sometimes referred to as the medical model) where

a senior learner supervisors one or more junior

learner (15,16). There is little high quality evidence

to guide the optimal choice of rotation model. A

systematic review of the allied health literature

which included mainly occupational therapy and

physiotherapy studies concluded that there is no one

model that is superior to another (17). However 1:2

and greater models seem to be viewed positively by

learners and facilitate peer-assisted learning (17-19).

The literature also suggests that learners need be

given real patient care responsibilities and should

have some autonomy to learn (2-4). There is

evidence that pharmacy learners can have a tangible

impact on patient care by providing comprehensive

care or by providing specific targeted services

(20,21). Indeed there is a great potential for learners

to contribute to meeting the profession’s goals and

improving patient care.

III. Stakeholder Engagement (Phase 2)

During the stakeholder engagement phase visits

were organized to sites in all 6 BC Health

Authorities. In addition, focus groups were

conducted with 3rd and 4th year undergraduate

pharmacy students, pharmacy practice residents, and

doctor of pharmacy students. At the time of writing

nearly 70 discrete meetings or site visits had been

completed. Hours of recorded focus group

discussion and field note documentation has been

collected and analysis is planned through the

summer months.

There was excellent participation by the health

authority coordinators, preceptors, and pharmacy

learners at all levels. It is clear that preceptors are

committed to ensuring the success of pharmacy

learners but more assistance in this endeavor is

needed. Competing responsibilities, lack of physical

space to host multiple learners at institutional sites,

and the need to extensively orient undergraduate

students were some major challenges identified by

preceptors. Learners described a desire to feel better

prepared for their institutional placements so that

they can maximize the success of these placements.

It is evident that small and large scale changes will

be necessary to address the challenges facing

pharmacy experiential programs in BC.

More detailed analysis of the stakeholder

feedback will be required to identify a

comprehensive list of challenges and workable

solutions. This information will form the basis of the

final project recommendations.


Conclusions

Experiential education is a critical component of

pharmacy degree programs. In BC a proactive

approach has been taken to respond to the challenges

arising from program enrolment and curriculum

changes. There is great potential to develop strong

and mutually beneficial partnerships between health

authorities and the faculty. These relationships

should recognize the importance of experiential

education and maximize the role of the learner as a

practitioner while providing "on the ground" support

for preceptors. It is clear that, while BC has some

unique challenges, many issues will be common

across the country. In fact a National Stakeholder

meeting occurred in Winnipeg in November 2012

which identified a number of priority action items

relating to pharmacy experiential education (22). It

will be valuable to share the results of AGILE with

other jurisdictions in Canada and work together to

develop common strategies for the future.

References

1) Association for Experiential Education [Internet]. 2013 [cited

2013 Jun 24]. Available from: http://www.aee.org/about/whatIsEE

2) Rathbun RC, Hester EK, Arnold LM, Chung AM, Dunn SP,

Harinstein LM, et al. Importance of direct patient care in advanced pharmacy practice experiences. Pharmacotherapy. 2012

Apr;32(4):88-97.

3) Hall K, Musing E, Miller DA, Tisdale JE. Experiential training for pharmacy students: time for a new approach. CJHP. 2012

Jul;65(4):285-93.

4) Rosenwax L, Gribble N, Margaria H. GRACE: an innovative program of clinical education in allied health. J Allied Health.

2010;39(1):11-16.

5) Cox CE, Lindblad AJ. A collaborative approach to improving and expanding an experiential education program. Am J Pharm

Educ. 2012 Apr;76(3):1-5.

6) The Canadian Council for Accreditation of Pharmacy Programs. Accreditation standards and guidelines for the first

professional degree in pharmacy programs [Internet]. 2013 [cited

2013 Jun 21]. Available from: http://www.ccapp accredit.ca/site/pdfs/university/CCAPP_accred_standards_degree

_2012.pdf

7) UBC Faculty of Pharmaceutical Sciences - clerkship descriptions [Internet]. 2013 [cited 2013 Jun 24]. Available from:

http://cpd.pharmacy.ubc.ca/content/clerkship-descriptions

8) Pope C, Mays N. Reaching the parts other methods cannot reach: an introduction to qualitative methods in health and health

services research. BMJ. 1995 Jul;311(6996):42.

9) Mays N, Pope C. Qualitative research: rigour and qualitative research. BMJ. 1995 Jul;311:109.

10) Kitzinger J. Qualitative research: introducing focus groups.

BMJ. 1995 Jul;311(7000):299.

11) Britten N. Qualitative research: qualitative interviews in

medical research. BMJ. 1995 Jul;311:251.

12) Smith KM, Phelps PK, Mazur JE, May JR. Relationships between colleges of pharmacy and academic medical centers. Am

J Health-Syst Pharm. 2008 Sep;65(18):1750-4.

13) Murray TA, Crain C, Meyer GA, McDonough ME, Schweiss DM. Building bridges: an innovative academic-service

partnership. Nurs Outlook. 2010 Sep;58(5):252-60.

14) Scheckelhoff DJ, Bush CG, Flynn AA, Myers CE, Kahaleh

AA, Knapp KK, et al. Capacity of hospitals to partner with

academia to meet experiential education requirements for pharmacy students. Am J Pharm Educ. 2008 Oct;72:1-20.

15) Johnson TJ, Teeters JL. Pharmacy residency and the medical

training model: is pharmacy at a tipping point? Am J Health-Syst Pharm. 2011 Aug;68(16):1542-9.

16) Zellmer WA. Expanding the number of positions for

pharmacy residents: highlights from the Pharmacy Residency Capacity Stakeholders’ Conference. Am J Health-Syst Pharm.

2011 Oct;68(19):1843-9.

17) Lekkas P, Larsen T, Kumar S, Grimmer K, Nyland L, Chipchase L, et al. No model of clinical education for

physiotherapy students is superior to another: a systematic review.

Aust J Physiother. 2007;53(1):19-28.

18) Budgen C, Gamroth L. An overview of practice education

models. Nurse Education Today. 2008 Apr;28(3):273-83.

19) Martin M, Morris J, Moore AP, Sadlo G, Crouch V. Evaluating practice education models in occupational therapy:

comparing 1:1, 2:1 and 3:1 placements. BJOT. 2004

May;67(5):192-200.

20) Chase P. Rethinking experiential education (or does anyone

want a pharmacy student?). Am J Pharm Educ. 2007

Apr;71(2):27.

21) Mersfelder TL, Bouthillier MJ. Value of the student

pharmacist to experiential practice sites: a review of the literature.

Ann Pharmacother. 2012 Apr;46(4):541-8.

22) The future of experiential education in Canada: a stakeholder

workshop. Association of Faculties of Pharmacy of Canada

[Internet]. 2012 Nov 16 [cited 2013 Jun 24]. Available from: http://afpc.info/downloads/1/Report-experiential-education-

workshop.pdf

http://cpd.pharmacy.ubc.ca/content/clerkship-descriptions


WORKPLACE SPOTLIGHT

Evolving the Role of Community-based Clinical

Pharmacists

Larry Leung, B.Sc.(Pharm.)1 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

Introduction

What does it mean to be a clinical pharmacist in

the community? What kinds of activities would you

consider to be clinical? We were challenged with

these questions during our time in the Community

Pharmacy Residency program at the University of

British Columbia. During that time, we saw an

obvious need for expanded clinical support among

all areas of healthcare practice in the community.

Unfortunately, there were a lack of training

opportunities, employers, and workplace sites to

support what we feel are a growing number of

pharmacists that want to address those needs. This

inspired us to create our organization Clinicare

Pharmacists Inc.

Clinicare Pharmacists Inc. has been providing

non-dispensing, innovative pharmacy services in the

primary care setting across British Columbia since

2010. We are a group of pharmacists dedicated to

improving the quality and efficiency of care being

provided by working collaboratively as part of the

community healthcare team. While there are other

organizations offering clinical-type services, the

definition of “clinical work” is inconsistent and

limited. The purpose of this article is to share one

idea of what it means to be a clinical pharmacist in

the community and to showcase what services we

provide.

Discussion

In BC, the definition of a clinical service is

guided by the BC Pharmacy Association and

includes the administration of injections and

medication reviews (1). While these are indeed

clinical services, we believe the scope of practice

and the role of the clinical pharmacist in the

community goes beyond these services. We know

there are pharmacists that are practicing beyond

traditional boundaries of clinical services and

providing enhanced care to patients. There are many

examples of publicly and privately funded programs

across Canada including the Family Health Teams in

Ontario, pain management and rehabilitation clinics

in Alberta, Home and Community Care programs,

and diabetes and hemoglobin A1c clinics. Some of

these programs offer a more collaborative

opportunity to work with other clinicians, while

others are more readily scalable to multiple retail

centers. We see the evolving role of clinical

pharmacists in the community to include integrating

all of the available information in conducting a

thorough patient history, ordering pertinent lab

work, performing basic physical assessments,

performing medication reconciliation and review,

using appropriate documentation, formulating

evidence-based and patient-specific

recommendations, and prescribing with or without a

delegation of authority.

The main focus of our practice has been in

addressing what we think is one of the greatest areas

of need – the need for a clinical pharmacist in family

physician offices. Our work is exactly how you

might imagine it, with the typical workflow not

unlike that of physicians. We have our own exam

room at each site with full access to the patient

charts or electronic medical records (EMR). Patients

are booked in to our schedule either by referral from

another team member or by patient self-referral for

any medication-related issues. Appointment times

vary between 30-60 minutes. Once a patient arrives

for an appointment, we conduct the encounter,

document our findings in the chart, and then if

needed, the physician joins at the end to review our

recommendations and approve any changes. Each

patient is given goals and monitoring end points with

any change in therapy and if necessary, a follow-up

visit is booked. Once a care plan has been created for

the patient, we will often call their pharmacy and

review any important notes with them in addition to

communicating any medication changes. Ideally the

combination of a chart review, a PharmaNet review,

and a quick chat with the physician is the most

efficient. Patients are referred to us for a variety of

different issues and drug therapy problems (DTPs).

On average, every patient we see has at least 3

DTPs. While every practice site is unique with their

challenges, the most common DTPs we see relate to

compliance issues, the need for additional drug

therapy, and drug interactions. Physicians will most

commonly identify patients for referral to us when

there are suspected adverse drug events, questions

regarding complicated medication profiles,


recommendations on what third or fourth line agent

could be tried, or when the tapering or titration of

different medications is required.

In this system, we have worked with over 40

different family physicians, specialists, and nurse

practitioners in medical offices providing regular,

ongoing clinical pharmacy support. There are several

advantages in working side-by-side with the

physician when doing an assessment and

formulating recommendations: you have access to

the patient’s past medical history including

diagnoses, relevant blood work, and previous consult

notes from specialists, and you can communicate

your recommendations directly to the prescriber.

Discussing different recommendations with the

physicians has led to a better understanding of why

certain changes were made. In some instances these

discussions required the physician to educate us on

the rationale of therapy, usually when the patients

had complicated comorbid conditions. It also has led

to instances where we provided education to the

physicians about the best evidence for different

medications. The responses we have received from

the healthcare professionals and patients we have

worked with have been tremendous. As medication

specialists, pharmacists are incredibly important on

any healthcare team and most patients and

physicians wonder why these services are not more

readily available.

Conclusion

With the recent changes in pharmacy practice

and the introduction of publicly funded

reimbursement for non-dispensing activities, there

have been many variations in what community-

based clinical pharmacy services are offered and

how they are implemented. These changes have been

instrumental in the natural evolution of our

profession, but they have not been without

challenges. What does it mean to be a clinical

pharmacist in the community? What kind of

activities would you consider to be clinical? There is

no doubt that all pharmacists utilize their clinical

judgment on a daily basis, including in the

dispensing of medications. However, if pharmacists

do not have a good understanding of what we can do

within our scope of practice, then we cannot expect

other healthcare professionals or government

organizations to understand, let alone seek our

expertise and reimburse us for it. We understand that

our collaborative model of practice is only one of

many innovative ways to practice pharmacy. It is our

goal that this model of practice become more readily

available to those pharmacists that wish to pursue it.

References

1) British Columbia Pharmacy Association. Clinical pharmacy

services [Internet]. 2011 [updated 2013 Mar; cited 2013 Jun 14].

Available from: http://www.bcpharmacy.ca/clinical-pharm-services


EDITORIAL

Paper or Paperless? A Point-Counterpoint Student’s

Perspective

Jason Tan, B.Sc.(Pharm.) Candidate 20141

Mihailo Veljovic, B.Sc.(Pharm.) Candidate 20141

Jessica Tom, B.Sc.(Pharm.) Candidate 20141

Jordan Stewart, B.Sc.(Pharm.) Candidate 20141 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

September 2012 marked the beginnings of implementing a paperless curriculum in all years of

pharmacy. This was done primarily with the goal of reducing the environmental impact of the Faculty.

Handouts and class notes, which were previously printed en masse for the students then distributed in

class, became available exclusively online for the incoming first-year Class of 2016 and in upper years

note-printing by the professor was reduced significantly. The result of this policy is that the students

either A) bring an electronic device to class (laptop, tablet etc.) to annotate their notes on electronically, or

B) print their notes individually prior to each lecture, and continue to use paper copies of notes. Students

pay a yearly printing fee and have access to a printer and computers in the building’s computer lab.

Additionally, as a pilot project one 3-hour final exam for the Class of 2014 was written as an in-class

electronic exam, wherein the students had to bring in an electronic device of their own to access the test as

hosted by the online learning management system. The purpose of this article was to gather feedback

from the affected students regarding the transition from paper to “paperless”; it was conducted via a

survey delivered over the Facebook social media survey platform on March 10th 2013. Students were

informed that the survey was being conducted for the purposes of constructing a point-counterpoint

argument and encouraged to give feedback either by commenting directly on the original post with their

thoughts, or if preferring to remain anonymous, were able to privately message the authors with their

thoughts. Proponents of both sides of the argument were encouraged to contribute, by having a raffle for

a $25 gift card to be randomly drawn from the list of contributors. The comments were collected, and the

following article was synthesized from both the collective results and each author’s opinions.

Paperless

Leaving your comfort zone must be, by

definition, a slightly uncomfortable process. For a

generation of students who spent their entire

educational careers working with paper-based

material, UBC Pharmacy’s paperless policy

represented exactly that. However, just because

something may be foreign at first does not mean it is

a negative change.

The first reason for supporting the paperless

policy is apparent, yet so important that it must be

mentioned: paperless learning is better for the

environment. Printing paper copies of all class notes

requires hundreds of pieces of paper, per student, per

year. Anything that slows down deforestation and

therefore global warming should be a priority.

The technical advantages electronic notes have

over traditional paper-based ones are so numerous

they cannot all be listed. Electronic notes are

portable, easy to organize, can be accessed from

multiple devices and are easy to backup in case you

lose the original copy. Furthermore, notes can be

quickly shared via various methods (e.g. internet,

portable USB drives), and make the practice of

manually copying or photocopying a thing of the

past. Information can be quickly and effortlessly

located by employing a simple search for key words.

Additionally, most people are able to type more

quickly and neatly than they can handwrite, making

electronic notes more legible and more efficient.

Looking at paper-based note taking, it is easy to

spot many downfalls. Paper notes are difficult to

edit, and transferring information between different

paper-based documents by hand is very tedious.

Moreover, printed notes have a limited and fixed

amount of space available for note taking, while

large diagrams, missing slides, and extra space are

easily added to electronic notes. With electronic

notes, you can supplement class material with

images and text off the Internet, which provides a

great way to enrich class notes. Some students with

iPads even used the device’s built-in camera to

photograph diagrams drawn in class, and inserted

these photos directly into their notes. The extensive

capacity for editing that comes standard with

electronic note taking gives it a huge advantage over

paper-based notes.


A problem that exists in many classes, especially

those with guest lecturers, is that the note package

for a given day’s lecture may not be available until

the morning of, or may be an edited version of what

was originally posted. While students who take

electronic notes can simply download the most

current note package at the beginning of lecture,

those who rely on bringing printed notes to lecture

may have outdated lecture packages or no package at

all.

A paperless system better reflects the direction of

healthcare in BC. With BC’s new eHealth program

and the move towards electronic health records,

keeping lecture notes electronic allows for greater

integration and improved accessibility of

information. Hospital pharmacy residents, for

example, could use a single tablet computer to

simultaneously browse a patient’s charts, current

online guidelines and pharmacy lecture notes that

detail the pathophysiology of those medical

conditions. Pharmacists in the community will also

benefit by having electronic notes on hand, as these

notes are more readily available. The speed and

precision, with which desired pieces of electronic

information can be found, combined with the

portability of this information, allows for

improvement in patient care.

It is clear that paperless systems of education are

superior to their paper-based precursors. It is time to

embrace the future and all the advantages that come

with it, advantages for both students receiving an

education and the people these students will one day

help.

Paper

A paper-based education should not be removed

as an option in pharmacy education. One of the main

arguments supporting going paperless is to protect

our environment, which is imperative and reflects a

greater social conscience. However, many current

students request or print out their own notes anyway

if the notes are not provided in class, bringing the

actual environmental benefit of a school mandated

“paperless” policy into question. Furthermore, many

lecturers only provide a minimum amount of paper

notes based on class interest and actual usage,

suggesting that a natural shift towards paperless

learning would occur if the use of paperless methods

becomes more common with each new intake of

students, and current students who are more

comfortable with paper-based learning would not be

disrupted. Nonetheless, many students are in

opposition to electronic-based learning. Slightly

more than half the responses received (35/67) are

against the paperless system. There are several

common reasons why students prefer paper

handouts.

Learning styles are individual, and some students

require paper notes to study as they retain

information better when it is printed or handwritten.

Most current students have used paper-based

learning their entire student careers, and are most

comfortable with it. Furthermore, paper notes are

more conducive to drawing diagrams, chemical

structures, graphs and equations. Some students state

that staring at computer screens for long periods is

draining, causing dry eyes, strain and headaches.

For many students, instituting that electronic

devices be mandatory poses a burden on students

facing financial hardship. Also, laptops can be heavy

and cumbersome, and are not always reliable. The

Connect software is often incompatible with tablets,

which is particularly problematic for students who

use iPads as their primary device. Finally, the

Internet can be distracting (e.g., social media,

videos, etc.) to students and those sitting in their

vicinity.

With regards to writing electronic exams,

students are more vehemently against this process as

current technology does not allow students to cross

out answers or make notes, and it takes a

considerable amount of time to scroll through to read

questions or go back to previous questions. Some

feel these constraints negatively impact their

performance.

Furthermore, several students also voiced

concerns that lecture notes are not posted early

enough on Connect for students to have sufficient

time to print notes before class, however, switching

completely over to paperless education as a result of

this minor difficulty does not seem like a reasonable

solution to the problem. A suggestion was made that

slides be posted 1-slide-per-page, as it provides more

space for taking notes on the computer, and those

printing can format to print as many slides per page

as they wish.

To date, a wealth of strong evidence looking at

the direct association between electronic-based

learning and assessment, and short and long-term

outcomes, such as grades and application of

knowledge to real world settings or future success is

lacking. It is difficult to justify a major change from

paper to paperless education without strong evidence

showing significant benefit to both students and

educators when a significant portion of the student

body would still prefer paper-based education. Most

importantly, students want their opinions and voices

to be heard, and their freedom of choice to be

respected. Thus, given the demand, the option of

paper handouts should still be available for students

review.


Thank you to our peer reviewers from Volume 1, Issue 1, entitled

“Pharmaceutical Innovation: The Paths Less Traveled”

Dorothy Cram

Sandi Hutty

Ernest Law

Dr. Jennifer Teng

Junine Toy

Tony Seet

Dr. Jennifer Shiu

Kelvin Lou & Sandy Mok · 2013. 10. 25. · market, after alarming statistics of addiction and...

Documents

Transcript of Kelvin Lou & Sandy Mok · 2013. 10. 25. · market, after alarming statistics of addiction and...