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A Peer-Reviewed Journal for Managed Care
and Formulary Management Decision-Makers

2017 Presages Dramatic Change VISIT US ONLINE AT WWW.PTCOMMUNITY.COM

For Federal Health Care Policies
Republicans Are Likely to Face Hiccups Along the Way
S. Barlas

A Comparison of Medication Histories

Obtained by a Pharmacy Technician Versus
Nurses in the Emergency Department
M. Markovic, PharmD; A. S. Mathis, PharmD; H. Lee Ghin,
PharmD, BCPS; M. Gardiner, PharmD, BCGP; and
G. Fahim, PharmD, BCPS

HEALTH CARE & LAW

Systemic Market and Organizational
Changes: Impact on P&T Committees
F. R. Vogenberg, RPh, PhD; R. Marcoux, RPh, MBA; and
M. M. Rumore, PharmD, JD, MS, LLM, FAPhA

PERSPECTIVE
Branko Fursts Radical Alternative
Is the Heart Moved by the Blood, Rather Than Vice Versa?
W. Alexander DRUG FORECAST
Zarxio (Filgrastim-sndz):
The First Biosimilar Approved by the FDA
M. Awad, PharmD Candidate; P. Singh, PharmD Candidate;
and O. Hilas, PharmD, MPH

MEETING HIGHLIGHTS
Society for Immunotherapy of Cancer
And
American Heart Association
W. Alexander
 Are you a formulary
decision maker?

Ask us
about LUCENTIS healthcare
economic information
Contact your Genentech Account Manager to learn more

2016 Genentech, Inc. South San Francisco, CA LUC/071216/0070b 11/16

 STATEMENT OF PURPOSE
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manage their formularies and establish medication-related
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es, quality/risk management personnel, administrators, Editor, PTCommunity.com: Chris Fellner
and others. (267) 685-3555
Feature articles address forthcoming drugs, biologic cfellner@medimedia.com
agents, and medical devices; guideline updates; drug utili-
zation evaluations; medication safety; and disease manage- News Writer: Janet Dyer
ment. Regular departments cover these topics as well as
drug legislation. ART
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Vol. 42 No. 1 January 2017 P&T

1

Cover: For centuries, the circulation of
the blood has been attributed to the
heart-as-pump model. But could the
disappointing findings for drug and
device remedies for the heart imply
the model may be flawed? We explore
an alternative autonomous circulation
theory on page 33. (Credit: Pixologic
Studio / Science Source)
DEPARTMENTS
Medication Errors
Survey reveals widespread
health workplace intimidation
Prescription: Washington
Plan to settle 340B disputes
is itself the focus of a dispute
Drug and Device News
Approvals, new indications,
regulatory activities, and more
Pharmaceutical
Approval Update
Olaratumab (Lartruvo) for
the treatment of soft tissue
sarcoma; bezlotoxumab
(Zinplava) for use with
an antibiotic to reduce
recurrence of C. difficile
infection; and doxylamine
succinate/pyridoxine hydro-
chloride (Bonjesta) for the
treatment of nausea and
vomiting during pregnancy
Drug Forecast
Zarxio (filgrastim-sndz), a
biosimilar for the treatment of
severe chronic neutropenia
Research Briefs
Back issues are available on
the PubMed Central archive.
Visit www.pubmedcentral.nih.gov
2 P&T January 2017 Vol. 42 No. 1
CONTENTS
January 2017
FEATURES
Letters to the Editor 22
2017 Presages Dramatic Change
For Federal Health Care Policies 24
But Republicans Are Likely to Face Some Hiccups Along the Way
President-elect Donald Trump campaigned on a promise to repeal Obamacare. We
review what effect the incoming administration may have on U.S. health care policy.
Stephen Barlas
4 HEALTH CARE & LAW
Systemic Market and Organizational Changes:
Impact on P&T Committees 28
The authors consider market stakeholder consolidation, market-driven efficiency
6 demands, consumerism, and legal enforcement of patient rights related to access to
appropriate drugs and posit how future P&T committees may approach these issues.
F. Randy Vogenberg, RPh, PhD; Rita Marcoux, RPh, MBA; and Martha M. Rumore,
PharmD, JD, MS, LLM, FAPhA
7
Branko Fursts Radical Alternative 33
Is the Heart Moved by the Blood, Rather Than Vice Versa?
We examine key evidence against the standard cardiac function model and describe
17 Branko Fursts alternative model with its implications for therapy and further exploration.
Walter Alexander
A Comparison of Medication Histories Obtained by a Pharmacy
Technician Versus Nurses in the Emergency Department 41
A study finds that medication histories obtained by the pharmacy technician in a busy
emergency department were much more accurate than those obtained by nurses.
Marija Markovic, PharmD; A. Scott Mathis, PharmD; Hoytin Lee Ghin, PharmD,
BCPS; Michelle Gardiner, PharmD, BCGP; and Germin Fahim, PharmD, BCPS
Challenges and Solutions in
Reducing Opioid Misuse and Abuse 47
We present some of the approaches to and challenges of the opioid crisis that
19
emerged from thought-leaders at an Academy of Managed Care Pharmacy symposium.
Peter Sonnenreich and Linda Geisler
MEETING HIGHLIGHTS
54 Society for Immunotherapy of Cancer 49
And
American Heart Association 50
We review key sessions from the Society for Immunotherapy of Cancer and the
American Heart Association annual meetings.
Walter Alexander
Editor-in-Chief
David B. Nash, MD, MBA
Dr. Raymond C. and
Doris N. Grandon Professor
The Jefferson College of Population Health
Philadelphia, Pennsylvania
Richard Afable, MD, MPH
President and Chief Executive Ofcer
Hoag Memorial Hospital Presbyterian
Newport Beach, California
Robert L. Barkin, MBA, PharmD
Professor, Faculty of Anesthesiology,
Family Medicine, and Pharmacology
Rush Medical College of Rush University
Chicago, Illinois
Clinical Pharmacologist
North Shore University Health System
Pain Centers
Skokie and Evanston, Illinois
Mark J. Baumel, MD, MS
President/Chief Executive Ofcer
Colon Health Centers of America, LLC
Mendenhall, Pennsylvania
Thomas Biancaniello, MD
Clinical Professor of Pediatrics
Columbia University
College of Physicians and Surgeons
Division of Pediatric Cardiology
New York, New York
Joseph E. Biskupiak, PhD, MBA
Research Associate Professor
Department of Pharmacy Practice
Director, Pharmacotherapy Outcomes
Research Center
College of Pharmacy, University of Utah
Salt Lake City, Utah
David A. Casey, MD
Vice Chairman, Department of Psychiatry
University of Louisville
Louisville, Kentucky
Alan Caspi, PhD, PharmD, MBA
President, Caspi & Associates
New York, New York
Burke A. Cunha, MD
Professor of Medicine
State University of New York at Stony Brook
Chief, Infectious Disease Division
Winthrop-University Hospital
Mineola, New York
Joseph C. English III, MD
Professor of Dermatology
Clinical Vice Chairman
for Quality and Innovation
Founding Director of Teledermatology
University of Pittsburgh
Department of Dermatology
Pittsburgh, Pennsylvania
EDITORIAL BOARD
Marvin M. Goldenberg, PhD, RPh, MS
President, Pharmaceutical and Scientic
Services
Marvin M. Goldenberg, LLC
Westeld, New Jersey
Nancy Greengold, MD, MBA
Chief Medical Ofcer
Sharp Grossmont Hospital/Sharp
HealthCare
La Mesa, California
Matthew Grissinger, RPh, FASCP
Director, Error Reporting Programs
Institute for Safe Medication Practices
Horsham, Pennsylvania
Rusty Hailey, PharmD, DPh, MBA, FAMCP
President, Pharmaceutical Operations
Senior Vice President, HealthSpring, Inc.
Nashville, Tennessee
Steven D. Hanks, MD, MMM, FACP
Executive Vice President
and Chief Medical Ofcer
The Hospital of Central Connecticut
New Britain, Connecticut
Michele B. Kaufman, PharmD, BCGP, RPh
Pharmacist, New YorkPresbyterian
Lower Manhattan Hospital, Pharmacy
Department
New York, New York
Grant D. Lawless, RPh, MD
Associate Professor of Clinical Pharmacy,
Pharmaceutical Economics and Policy
Director, Master of Science Program in
Healthcare Decision Analysis
School of Pharmacy
University of Southern California
Los Angeles, California
Burton Orland, BS, RPh
President
BioCaRe Consultants
Westport, Connecticut
Fred Joseph Pane, RPh, BS, FASHP, FABC
Senior Director, Customer Engagement
The Medicines Company
Parsippany, New Jersey
Lawrence Charles Parish, MD
Dermatologist, Editor-in-Chief
Clinics in Dermatology
Philadelphia, Pennsylvania
Associate Editor-in-Chief
Karl A. Matuszewski, MS, PharmD
Vice President
First Databank, Inc.
Clinical and Editorial
Knowledge Base Services
South San Francisco, California
Luke A. Probst, PharmD, BCPS
Director of Pharmacy Services
Upstate University Hospital/
Downtown Campus
Clinical Assistant Professor, Departments
of Pediatrics and Medicine
SUNY Upstate Medical University
Syracuse, New York
Sheldon M. Retchin, MD, MSPH
Executive Vice President of Health
Sciences, The Ohio State University
Chief Executive Ofcer, OSU Wexner
Medical Center
Columbus, Ohio
Vitalina Rozenfeld, PharmD, BCPS
Medical Affairs
AstraZeneca
Wilmington, Delaware
Fadia T. Shaya, PhD, MPH
Professor and Vice-Chair for Academic
Affairs
University of Maryland School of Pharmacy
Associate Director
Center on Drugs and Public Policy
Baltimore, Maryland
Arthur F. Shinn, PharmD, FASCP
President
Managed Pharmacy Consultants, LLC
Palm City, Florida
Brian Swift, PharmD, MBA
Vice President/Chief of Pharmacy
and Accreditation
Thomas Jefferson University Hospital
Associate Dean of Professional Affairs
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
F. Randy Vogenberg, RPh, PhD
Partner
Access Market Intelligence and National
Institute of Collaborative Healthcare
Greenville, South Carolina
Scott W. Yates, MD, MBA, MS
Center for Executive Medicine
Plano, Texas
Vol. 42 No. 1 January 2017 P&T
3
MEDICATION ERRORS
Unresolved Disrespectful
Behavior in Health Care
Practitioners Speak Up (Again)Part 1
Matthew Grissinger, RPh, FASCP
Mr. Grissinger, an editorial
board member of P&T, is
Director of Error Reporting
Programs at the Institute for
Safe Medication Practices
(ISMP) in Horsham, Penn-
sylvania (www.ismp.org).
The Institute for Safe Medication
Practices (ISMP) has discussed the topic
of bullying, incivility, intimidation, and
other forms of disrespectful behavior that
have run rampant in health care in past
P&T columns, while many remain silent
or make excuses in an attempt to minimize
the profound devastation that disrespectful
behavior has caused. Many years ago,
ISMP conducted a national survey regard-
ing intimidation in the workplace.1 Results
showed that disrespectful behaviors were
not isolated events, they were not limited to
just a few practitioners, they involved both
lateral (peer-to-peer) and interdisciplinary
staff (and not just physicians), and they
involved both genders equally. We
followed up in 2013 with a similar survey
to measure progress (or lack thereof).
Sadly, based on recent observations and
interactions with health care practitio-
ners along with the results of this survey,
disrespectful behaviors continue to erode
professional communication, which is
essential to patient safety.
In Part 1 of this report, we present what
respondents had to say about disrespectful
behaviors in the workplace and compare
the 2013 results to the 2003 survey.
Survey Respondents
Our 2013 survey included 4,884 respon-
dentsmore than double the respondents
in our 2003 survey. With the exception
of more physicians in the 2013 survey,
the respondent proles were quite similar.
Most respondents were nurses (68%)
or pharmacists (14%), but more than
200 physicians and almost 100 quality/
risk management staff also participated.
Most respondents (66%) were staff-
level practitioners, but leaders at the
4 P&T January 2017 Vol. 42 No. 1
manager/director/administrator level
were also represented (25%). Most
respondents had more than 10 years of
experience (70%) and were female (87%).
Practitioners Feel the Sting
Regardless of the source of disrespectful
behavior (physicians or others), respon-
dents in 2013 reported a wide variety of
behaviors encountered during the past
year. When ranked by frequency of
occurrence, the behaviors most often
encountered included:
Negative comments about
colleagues or leaders (encountered
by 73% at least once, by 20% often)
Reluctance or refusal to answer ques-
tions or return calls (77% at least
once, 13% often)
Condescending language or demean-
ing comments or insults (68% at least
once, 15% often)
Impatience with questions or hanging
up the phone (69% at least once, 10%
often)
Reluctance to follow safety practices
or work collaboratively (66% at least
once, 13% often)
The least frequent disrespectful behav-
iors encountered at least once during the
past year included:
Shaming, humiliation, or spreading
malicious rumors (46%)
Reporting staff to a manager (actual
or threat) (42%)
Insulting or slighting an individual
due to race, religion, or appearance
(24%)
Thrown objects (18%)
Physical abuse (7%)
Although these were the least frequent
behaviors encountered in aggregate
by respondents, it is truly a sad state
of affairs when nearly a quarter (24%)
of respondentsthats 1,148 practitio-
nersreported that at least one of these
behaviors were among the most frequent
they had encountered during the past
year. Furthermore, one of these behav-
iorsphysical abuseincreased from
4% to 7%, regardless of the source, and
from 5% to 8% when the source was a
physician. While respondents suggested
that some forms of disrespectful behavior
have lessened in the last decade, par-
ticularly impatience with questions or
the use of condescending language and
insults, many disrespectful behaviors con-
tinue to occur at an alarming frequency,
demonstrating little improvement.
Not Just Physicians
In both 2003 and 2013, respondents
reported that physicians and other pre-
scribers engaged in disrespectful behav-
ior more often than other health care pro-
fessionals. However, respondents in 2003
and 2013 also made it clear that its not just
physicians who behave in a disrespect-
ful mannerin many cases, encounters
have been nearly as frequent, or some-
times more frequent, with other health
care professionals. For example, in both
2003 and 2013, a little more than 40% of
respondents reported that both physicians
and other health care professionals had
reported (or threatened to report) them
to their manager during the past year. To
cite another example, between 63% and
69% of the 2013 respondents reported
resistance on the part of physicians, as
well as other health care professionals,
to following safety practices or working
collaboratively with others.
Furthermore, repeated occurrences of
disrespectful behavior did not arise from
a single menacing individual. Thirty-eight
percent of respondents in 2003 and 36% in
2013 reported that three to ve individuals
were involved in disrespectful behaviors,
while 19% and 21% respectively reported
that more than ve individuals were
involved in occurrences during the past
year. Respondents in 2013 also reported
that more nonphysicians than physicians
were involved in disrespectful behavior.

Impact on Safety
Almost half of the 2003 (49%) and 2013
(44%) respondents told us that their past
experiences with intimidation had altered
the way they handle order clarications
or questions about medication orders.
At least once during the year, 39% of
respondents in 2003 and 33% in 2013
had concerns about a medication order
but assumed it was correct rather than
interact with an intimidating prescriber.
Similar results were reported when the
prescribers stellar reputation led to
reluctance to question or clarify orders
despite concerns. More than one-third
of respondents in both 2003 (39%) and
2013 (38%) asked another professional
to talk to a particularly disrespectful pre-
scriber about the safety of an order. Small
improvements were seen between 2003
and 2013 in regard to asking a colleague
to help validate the safety of an order,
asking a colleague to talk to a disrespect-
ful prescriber on their behalf, or feeling
pressured to accept an order despite
safety concerns. However, there was no
reduction between 2003 and 2013 in the
percent of respondents who were aware
of a medication error during the year
in which disrespectful behavior played
a role.
Not Satised With
Organizational Efforts
It appears that the 2013 respondents
were less satised than the 2003 respon-
dents with organizational efforts to
address disrespectful behavior. Only 60%
of respondents in 2003 and 50% of respon-
dents in 2013 felt their organization had
clearly dened an effective process for
handling disagreements with the safety
of an order. Even less (33% in 2003, 14% in
2013) felt that the process allowed them
to bypass a particularly disrespectful
prescriber or their supervisor if neces-
sary. While 70% of respondents in 2003
reported that their organization/manager
would support them if they reported dis-
respectful behavior, just 52% of the 2013
respondents felt this way. In the end,
only 39% in 2003 and 25% in 2013 felt that
their organization dealt effectively with
disrespectful behavior.
Gender Makes Little Difference
Female respondents to the survey out-
numbered male respondents in both the
2003 and 2013 survey, but only minor
differences were reported in the fre-
quency with which each group encoun-
tered disrespectful behaviors. For
example, a higher percentage of male
respondents reported that they had,
during the past year, assumed that a
medication order was correct and safe
rather than interact with a particular
prescriber (2003: 48% male, 37% female;
2013: 40% male, 32% female). A higher
percentage of male respondents also felt
pressured to accept an order, dispense
a product, or administer a drug despite
concerns about its safety (2003: 53% male,
49% female; 2013: 43% male, 38% female).
In 2013, male respondents also reported
more frequently being reported to a
manager (49% male, 42% female) and
being physically abused by nonphysicians
(8% male, 5% female). On the other hand,
female respondents in 2013 reported that
more individuals were engaged in disre-
spectful behavior than reported by male
respondents.
Practitioner Type Differences
In the 2013 survey, nurses and phy-
sicians encountered about the same
frequency of disrespectful behavior by
physicians, although physicians reported
more nitpicking/fault-finding and
inappropriate joking, and less impatience
with questions than nurses. However, phy-
sicians reported signicantly less frequent
disrespectful behavior by other health
care professionals (nonphysicians) than
nurses and pharmacists. Nevertheless,
the frequency of disrespectful behaviors
toward physicians by nonphysicians was
unexpected. More than half of the physi-
cians reported encountering these behav-
iors by nonphysicians one or more times
during the prior year:
Negative comments about
colleagues (71%)
Refusal to answer questions or return
calls (68%)
Constant nitpicking/fault-finding
(56%)
Reluctance to follow safety practices
or work collaboratively (55%)
Impatience with questions (55%)
Condescending language, demeaning
comments, and insults (54%)
Overall, nurses and pharmacists also
encountered about the same frequency
of disrespectful behavior by physicians.
MEDICATION ERRORS
However, pharmacists reported more
frequent physician reluctance to follow
safety practices or work collaboratively
than nurses, and less nitpicking/fault-
nding, shaming, thrown objects, and
insults due to race, religion, gender, and
appearance than nurses. In contrast,
pharmacists experienced more frequent
disrespectful behavior by nonphysicians
than nurses, particularly a refusal to answer
questions or return calls, impatience with
questions, yelling and cursing, and being
reported to their manager.
Pharmacists also reported more fre-
quent effects from disrespectful behavior
than nurses in both the 2003 and 2013
surveys. For example, in 2013, 63% of
pharmacists and 30% of nurses reported
that, during the past year, they had
assumed a medication order was correct
and safe rather than interact with a par-
ticular prescriber. Pharmacists (57%)
asked another professional to talk to a
particular prescriber about an order more
frequently than nurses (36%). Pharmacists
(29%) also asked, suggested, or allowed
a physician to give a medication himself
despite concerns about the safety of an
order more often than nurses (17%). Very
similar ndings were reported in 2003.
While more nurses (54%) than pharma-
cists (41%) felt that their organizations had
dened an effective process for handling
disagreements with the safety of an order,
pharmacists (83%) reported greater dis-
satisfaction than nurses (74%) with their
organizations ability to deal effectively
with disrespectful behavior.
Summary
The results of our surveys expose
health cares continued tolerance and
indifference to disrespectful behavior.
These behaviors are clearly learned,
tolerated, and reinforced in the health
care culture, and little improvement
has been made in recent years. The
stressful health care environment,
particularly in the presence of produc-
tivity demands, cost containment, and
hierarchies that nurture a sense of status
and autonomy, have likely been the
most inuential factors. This creates an
environment in which victims may feel
they have no choice but to become
perpetrators and join in the practice.
Organizations have largely failed to
address disrespectful behavior for a variety
of reasons. First, some individuals who
continued on page 23
Vol. 42 No. 1 January 2017 P&T
5
PRESCRIPTION: WASHINGTON
Plan to Settle 340B Disputes Elicits Dispute
Roadblocks Remain to Quieting Drug Pricing Controversies
Stephen Barlas
Mr. Barlas is a freelance
writer in Washington,
D.C., who covers issues
inside the Beltway. Send
ideas for topics and your
comments to sbarlas@
verizon.net.
rug companies and hospitals are
D warring over a proposed adminis-
trative dispute resolution (ADR)
program1 meant to settle long-running
allegations over pricing and diversion
of drugs in the 340B program. In this
federally sponsored program, drug
manufacturers sell medications at a dis-
count to qualied hospitals and clinics,
allowing them to generate revenue to
expand services to generally low-income
populations.
Sylvia Yu, Assistant General Counsel
for Pharmaceutical Research and Man-
ufacturers of America, argues that it will
be impossible for drug companies to
access the ADR program because they are
unable to audit hospitals to see whether
discounted drugs have been diverted to
ineligible patients. The existing guidelines
for manufacturers to audit 340B entities,
issued in 1996, suffer from critical defects
that make manufacturer audits nearly
infeasible, Yu states. The result is a
blocked gateway to the ADR process for
manufacturers. And a one-sided ADR
system in which covered entities can insti-
tute ADR claims but manufacturers face
nearly insuperable barriers to instituting
ADR claims would weaken condence in
the integrity of the 340B program.
Congress created the 340B program
in 1992 for hospitals with high numbers
of uninsured patients, including certain
disproportionate-share hospitals, childrens
hospitals, freestanding cancer hospitals,
rural referral centers, sole community hos-
pitals, and critical access hospitals. Only
certain patients are eligible to receive the
discounted drugs, which can be dispensed
only in hospital outpatient pharmacies and
some local retail pharmacies.
6 P&T January 2017 Vol. 42 No. 1
Pharmaceutical makers dont like to
be forced to sell products at a discount,
but they must do so if they want to sell to
state Medicaid programs. The discounts
are problematic enough for them, but the
drug companies have argued for years that
covered entities, either consciously or due
to faulty billing systems, divert discounted
drugs to ineligible individuals. The hospitals
and clinics, for their part, complain they do
not have access to pricing data that would
assure them the discounted prices are what
they should be.
The purpose of the ADR process is to
resolve: 1) claims by covered entities that
manufacturers have overcharged them for
covered outpatient drugs; and 2) claims by
manufacturers that a covered entity has
violated the prohibition on diversion to
ineligible patients or duplicate discounts.
Historically, the Department of Health and
Human Services (HHS) has encouraged
manufacturers and covered entities to work
together to attempt to resolve disputes in
good faith. The ADR process is not meant to
replace those good-faith efforts, but would
be a last resort when those efforts fail.
The Ofce of Pharmacy Affairs (OPA),
part of the HHS Health Resources and
Services Administration (HRSA), which
administers the 340B program, has pro-
posed ideas about how the ADR process
might work,1 and various players have
voiced opinions. There would be a 340B
ADR panel with three voting members, who
would differ from case to case. They would
be drawn from the HHS or the Department
of Veterans Affairs. An OPA member would
serve as a nonvoting ex ofcio member.
No member of a given panel could have a
conict of interest.
A covered entity or manufacturer would
have to le a written claim within three years
of the date of the sale (or payment) at issue.
Covered entities could consolidate their
claims, or have them submitted by a trade
association, when those claims allege over-
charges by the same manufacturer for the
same drug.
How manufacturers might consolidate
their claims is trickier. First, the statutory
authority for implementing the 340B ADR
process does not permit consolidated claims
on behalf of manufacturers by associations
or organizations representing their inter-
ests. There is also some question whether
the consolidation of claims by manufactur-
ers generally is legal. Such consolidation
may be barred by what the HHS calls the
operational challenges presented by the
statutory requirement for a manufacturer
to rst audit the covered entity.
We believe that the 340B statute does
not bar association or organization claims
on behalf of manufacturers, states Wayne
Sichel, Head of U.S. Federal Policy for
Bristol-Myers Squibb.
One imagines that any ADR panel will
have its hands full, because key manu-
facturer pricing informationespecially
ceiling prices, which are closely linked
to the size of a rebateare not available
to covered entities. Hospitals argue that,
without such data, it will be hard for them
to claim they were overcharged for a drug.
The HRSAs proposed rule says the agency
will give the panel price ceiling data. That
wont help hospitals develop a strong case
that they were overcharged. We are very
concerned that our members do not have
access to ceiling prices, and will conse-
quently not be able to provide sufcient
documents to demonstrate claims for over-
charge, says Debbie Johnston, Senior Vice
President of Policy Development for the
Arizona Hospital and Healthcare Associa-
tion. The HHS is apparently developing a
system that would let hospitals access drug
prices, but no one seems to know when it
will be operational.
Given years of controversy over the 340B
program, an ironclad ADR program would
be welcome to both hospitals and drug
manufacturers. But legal roadblocks and
program shortcomings dont bode well for
the effectiveness of any ADR process.
REFERENCE
1. Health Resources and Services Admin-
istration. 340B drug pricing program;
administrative dispute resolution. Fed
Regist 2016;81(156):5338153388. Q
 NEW DRUG APPROVALS
Xultophy for Type-2 Diabetes
The FDA has approved Xultophy
100/3.6 (insulin degludec 100 units/mL
and liraglutide 3.6 mg/mL injection, Novo
Nordisk). The product, a once-daily combi-
nation of Tresiba (insulin degludec injec-
tion) and Victoza (liraglutide injection), is
indicated as an adjunct to diet and exercise
to improve glycemic control in adults with
type-2 diabetes that is inadequately con-
trolled on less than 50 units of basal insulin
daily or on less than or equal to 1.8 mg of
liraglutide daily. Xultophy 100/3.6 belongs
to a new class of diabetes treatments that
combine a basal insulin and a glucagon-
like peptide-1 receptor agonist in a single,
once-daily injection.
The approval of Xultophy 100/3.6 was
based on efcacy and safety data from
the DUAL clinical development program.
In three DUAL trials involving a total of
1,393 adults with type-2 diabetes, patients
who were inadequately controlled on
liraglutide or basal insulin therapy and
switched to Xultophy 100/3.6 achieved
reductions in hemoglobin A1c (HbA1c).
For adults uncontrolled on basal insulin,
Xultophy 100/3.6 demonstrated signi-
cant reductions in HbA1c from baseline
of 1.67% and 1.94%.
Source: Novo Nordisk, November 21,
2016
Intrarosa for Pain During Sex
For Postmenopausal Women
Intrarosa (Endoceutics, Inc.) has
received FDA approval for the treat-
ment of women experiencing moderate-
to-severe pain during sexual intercourse
(dyspareunia), a symptom of vulvar and
vaginal atrophy (VVA) due to meno-
pause. Intrarosa is the rst FDA-approved
product containing the active ingredi-
ent prasterone, which is also known as
dehydroepiandrosterone.
The efficacy of Intrarosa, a once-
daily vaginal insert, was established in
two 12-week, placebo-controlled trials
involving a total of 406 healthy post-
menopausal women, 40 to 80 years of
age, who identied moderate-to-severe
pain during sexual intercourse as their
most bothersome symptom of VVA.
The women were randomly assigned to
receive prasterone or a placebo vaginal
insert. Prasterone reduced the sever-
ity of pain experienced during sexual
intercourse compared with placebo.
Source: Endoceutics, November 17,
2016
Vemlidy for Hepatitis B
The FDA has approved tenofovir ala-
fenamide 25 mg (Vemlidy, Gilead Sci-
ences), a prodrug of tenofovir, as a once-
daily treatment for adults with chronic
hepatitis B virus (HBV) infection with
compensated liver disease. The approval
was based on positive 48-week data from
two international phase 3 studies involv-
ing 1,298 treatment-nave and treatment-
experienced adults.
A total of 425 HBeAg-negative patients
and 873 HBeAg-positive patients were
treated with either tenofovir alafenamide
or tenofovir disoproxil fumarate (TDF)
(Viread, Gilead Sciences) in studies
108 and 110, respectively. HBeAg, a
hepatitis B viral protein, indicates active
viral replication. Both studies met their
primary endpoint of noninferiority to
TDF, based on the percentage of patients
with plasma HBV DNA levels less than
29 IU/mL after 48 weeks of therapy.
Source: Gilead Sciences, November
10, 2016
Generic Approvals and Launches
Armodanil Tablets
Breckenridge Pharmaceutical, Inc.,
and its partner Natco Pharma Ltd. have
launched armodanil tablets (CIV) in
50-mg, 150-mg, and 250-mg strengths
after receiving final FDA approval.
Armodanil tablets are a generic version
of Nuvigil (Cephalon, Inc.), a prescription
medication indicated to improve wakeful-
ness in adults with excessive sleepiness
associated with obstructive sleep apnea,
narcolepsy, or shift work disorder.
Source: Breckenridge Pharmaceutical,
November 28, 2016
Metaxalone Tablets
The FDA has approved metaxalone
tablets USP, 800 mg (Lannett Company),
the therapeutic equivalent of Skelaxin
(King Pharmaceuticals/Pzer). Skelaxin
is indicated as an adjunct to rest, physical
therapy, and other measures for the relief
of discomforts associated with acute,
painful musculoskeletal conditions.
Source: Lannett Company, November
28, 2016
Memantine Hydrochloride Tablets
Lannett Company has secured FDA
approval to market memantine hydro-
chloride tablets USP, 5 mg and 10 mg
the therapeutic equivalent to Namenda
tablets 5 mg and 10 mg (Forest Labo-
ratories). The product is indicated for
the treatment of moderate-to-severe
dementia.
Source: Lannett Company, November
14, 2016
NEW INDICATIONS
Avastin for Ovarian Cancer
The FDA has given the nod to bevaci-
zumab (Avastin, Genentech), either in
combination with carboplatin and pacli-
taxel or in combination with carboplatin
and gemcitabine chemotherapy, followed
by bevacizumab alone, for the treat-
ment of patients with platinum-sensitive
recurrent epithelial ovarian, fallopian
tube, or primary peritoneal cancer.
Previously approved indications for
bevacizumab include rst- or second-
line treatment of patients with meta-
static colorectal cancer in combination
with intravenous 5uorouracil-based
Vol. 42 No. 1 January 2017 P&T
7
chemotherapy; second-line treatment of
patients with metastatic colorectal can-
cer who have progressed on a rst-line
bevacizumab-containing regimen, in
combination with uoropyrimidine/iri-
notecan- or fluoropyrimidine/oxaliplatin-
based chemotherapy; rst-line treatment
of patients with unresectable, locally
advanced, recurrent, or metastatic non-
squamous, nonsmall-cell lung cancer
in combination with carboplatin and
paclitaxel chemotherapy; and treatment
of metastatic renal cell carcinoma in
combination with interferon alfa.
Source: Genentech, December 6, 2016
Jardiance for Diabetes
Patients With CVD
The FDA has approved a new indica-
tion for empagliozin (Jardiance, Boeh-
ringer Ingelheim) to reduce the risk of
cardiovascular death in adults with type-2
diabetes (T2D) and cardiovascular dis-
ease (CVD). The FDAs decision was
based on a post-marketing study required
by the agency when it approved empa-
gliozin in 2014 as an adjunct to diet and
exercise to improve glycemic control
in adults with T2D. Empagliozin was
assessed in more than 7,000 patients with
T2D and CVD. In the study, empagliozin
was shown to reduce the risk of cardio-
vascular death compared with placebo
when added to standard-of-care therapies
for diabetes and atherosclerotic CVD.
Source: FDA, December 2, 2016
FluLaval Quadrivalent Vaccine
The FDAs Center for Biologics Evalua-
tion and Research has expanded the indi-
cation for FluLaval Quadrivalent inuenza
vaccine (GlaxoSmithKline) to include use
in children 6 months of age and older.
The vaccine was originally approved in
2013 for patients 3 years of age and older.
Source: GlaxoSmithKline, November
21, 2016
8 P&T January 2017 Vol. 42 No. 1
Opdivo for
Head-and-Neck Cancer
The FDA has approved nivolumab
(Opdivo, Bristol-Myers Squibb) for the
treatment of patients with recurrent or
metastatic squamous cell carcinoma of
the head and neck with disease progres-
sion on or after platinum-based therapy.
Nivolumab is the only immuno-oncology
treatment shown in a phase 3 study to
signicantly extend overall survival (OS)
for these patients.
In the CheckMate-141 trial, nivolumab
demonstrated signicantly superior OS
compared with the investigators choice
of therapy (i.e., methotrexate, docetaxel,
or cetuximab), with a 30% reduction in
the risk of death (hazard ratio, 0.70;
P = 0.0101) and a median OS of 7.5 months
compared with 5.1 months, respectively.
Nivolumab was previously approved
for use in patients with nonsmall-cell
lung cancer, metastatic melanoma, renal
cell carcinoma, or classic Hodgkins
lymphoma.
Source: Bristol-Myers Squibb,
November 10, 2016
Enbrel for Pediatric
Plaque Psoriasis
The FDA has approved a supple-
mental biologics license application
for the expanded use of etanercept
(Enbrel, Amgen), making it the rst
systemic therapy to treat pediatric
patients (417 years of age) with chronic
moderate-to-severe plaque psoriasis.
The approval was based on positive
efcacy results from a 48-week, phase 3
study in which signicantly more patients
who received etanercept than those who
received placebo achieved a Psoriasis
Area and Severity Index score of at
least 75the studys primary endpoint
at week 12 (57% versus 11%, respectively;
P < 0.001); a signicant difference was
observed as early as week 4.
Source: Amgen, November 4, 2016
FDA REVIEW ACTIVITIES
Priority Review Designations
Avelumab for Skin Cancer
The FDA has accepted for priority
review a biologics license application
for avelumab (EMD Serono/Pzer) as
a proposed treatment for patients with
metastatic Merkel cell carcinoma (MCC).
Avelumab is an investigational, fully
human anti-programmed death ligand-1
immunoglobulin G1 monoclonal antibody.
If approved, it would be the rst treatment
indicated for metastatic MCC in the U.S.
The submission was supported by data
from the JAVELIN Merkel 200 trial, a
phase 2 study involving 88 patients with
metastatic MCC whose disease had pro-
gressed after at least one chemotherapy
treatment. Avelumab was administered
at a dose of 10 mg/kg every two weeks.
The patients were followed for a median
of 10.4 months. An objective response (the
trials primary endpoint) was achieved in
28 patients (32%), including eight complete
responses and 20 partial responses.
Source: Merck, November 29, 2016
Keytruda for MSI-H Cancer
The FDA has accepted for review a
supplemental biologics license application
(sBLA) for pembrolizumab (Keytruda,
Merck Oncology), an anti-programmed
death-1 therapy, for the treatment of pre-
viously treated patients with advanced
microsatellite instability-high (MSI-H)
cancer. The FDA granted the application
a priority review with a target action date
of March 8, 2017.
The sBLA will be reviewed under the
FDAs accelerated approval program
based on the tumor response rate and
the durability of response. The FDA pre-
viously granted breakthrough therapy
designations to pembrolizumab for the
treatment of patients with unresectable
or metastatic MSI-H colorectal or non-
colorectal cancer.
Source: Merck, November 28, 2016
 Midostaurin for AML
The FDA has granted priority review
status to a new drug application for
midostaurin (Novartis), an oral, multi-
targeted kinase inhibitor, for the treat-
ment of newly diagnosed adults with acute
myeloid leukemia (AML) with an FMS-
like tyrosine kinase-3 (FLT3) mutation,
as well as for the treatment of patients
with advanced systemic mastocytosis. In
addition, a premarket approval application
for a midostaurin FLT3 companion diag-
nostic, developed by Novartis in collabora-
tion with Invivoscribe Technologies, was
accepted for review by the FDA.
The phase 3 RATIFY trial investigated
midostaurin plus standard chemotherapy
versus placebo plus standard chemo-
therapy in adults younger than 60 years
of age with FLT3-mutated AML. Those in
the midostaurin arm experienced a statis-
tically signicant improvement in overall
survival, with a 23% reduction in the risk
of death compared with the placebo arm
(hazard ratio, 0.77; P = 0.0074).
Source: Novartis, November 14, 2016
Fast-Track Designations
IFN Kinoid Vaccine for SLE
The FDA has granted fast-track sta-
tus to IFN Kinoid in Lupus (Neovacs),
an investigational vaccine for systemic
lupus erythematosus (SLE). Neovacs
research activities are focused on patholo-
gies associated with an overproduction of
endogenous cytokines. Specically, the
company is developing active immuno-
therapy involving the administration of
an immunogenic complex involving the
target cytokine (for example, interferon
alfa [IFN]) to a carrier protein. The
intramuscular injection of this kinoid
induces an immune response and
stimulates the production of polyclonal
antibodies against the target cytokines,
thereby blocking cytokine overproduction
and its biologic effects.
Source: Neovacs, December 7, 2016
Velusetrag for Gastroparesis
The FDA has given a fast-track
designation to velusetrag (Theravance
Biopharma) for the treatment of symp-
toms associated with idiopathic and
diabetic gastroparesis. Velusetrag is an
oral, once-daily investigational medication
for gastrointestinal motility disorders. It
is a highly selective agonist with high
intrinsic activity at the human 5-hydroxy-
tryptamine receptor 4.
An ongoing phase 2b, multicenter,
double-blind, randomized, placebo-
controlled, parallel-group trial is evaluat-
ing the efcacy and safety of velusetrag
in patients with diabetic (n = 100) or
idiopathic (n = 100) gastroparesis. Three
dosages of velusetrag (5 mg, 15 mg, and
30 mg once daily for 12 weeks) are being
evaluated. The primary endpoint is the
effect of velusetrag on symptoms in
patients with gastroparesis.
Source: Theravance Biopharma,
December 6, 2016
ASN100 for S. Aureus Pneumonia
The FDA has granted fast-track status
to ASN100 (Arsanis, Inc.) for the preven-
tion of Staphylococcus aureus pneumonia
in mechanically ventilated patients who
are at high risk for S. aureus pneumo-
nia. ASN100 is a combination of two fully
human monoclonal antibodies (ASN-1
and ASN-2) that collectively neutralize
six important S. aureus cytotoxins asso-
ciated with pneumonia pathogenesis.
ASN-1 neutralizes alpha-hemolysin, a
key S. aureus toxin responsible for lung
epithelial cell damage, in addition to four
S. aureus leukocidins responsible for lysis
of human phagocytic (immune) cells.
ASN-2 inactivates the remaining S. aureus
leukocidin, LukGH, which is a potent
human cytotoxin that is also responsible
for the lysis of human phagocytes.
Source: Arsanis, December 1, 2016
DS-8201 for Metastatic Breast Cancer
The FDA has granted a fast-track
designation to DS-8201 (Daiichi Sankyo
Company), an investigational human
epidermal growth factor receptor-2
(HER2)-targeting antibodydrug conju-
gate, for the treatment of HER2-positive
unresectable and/or metastatic breast
cancer in patients who have progressed
after treatment with HER2-targeted
therapies, including ado-trastuzumab
emtansine. DS-8201 consists of a human-
ized anti-HER2 antibody attached by a
peptide linker to a topoisomerase I inhibi-
tor. This linkerpayload combination
allows a higher drug-to-antibody ratio,
according to the products developer.
Source: Daiichi Sankyo, December 1,
2016
Tazemetostat for B-Cell Lymphoma
The FDA has granted fast-track
status to tazemetostat (Epizyme, Inc.)
for the treatment of patients with diffuse
large B-cell lymphoma (DLBCL) with
EZH2-activating mutations. Tazemetostat
inhibits EZH2, a histone methyltransfer-
ase that is increasingly understood to play
a role in the growth and proliferation of
a number of cancers, including DLBCL,
the most commonly diagnosed form of
non-Hodgkins lymphoma.
Tazemetostat is being evaluated as
monotherapy and in combination with
other agents in multiple cancer indica-
tions. Phase 2 studies of tazemetostat
as monotherapy are ongoing.
Source: Epizyme, November 28, 2016
Breakthrough Therapy Status
Brentuximab for Cutaneous Lymphoma
The FDA has granted a breakthrough
therapy designation to brentuximab
vedotin (Adcetris, Seattle Genetics, Inc.)
for the treatment of patients with CD30-
expressing mycosis fungoides (MF)
and primary cutaneous anaplastic large-
cell lymphoma (pcALCL) who require
Vol. 42 No. 1 January 2017 P&T
9
systemic therapy and have received one
prior systemic therapy. MF and pcALCL
are the most common subtypes of cutane-
ous T-cell lymphoma (CTCL), account-
ing for more than 75% of cases of the
disease. Brentuximab vedotin is an anti-
bodydrug conjugate directed to CD30,
which is expressed on skin lesions in
approximately 50% of patients with CTCL.
Source: Seattle Genetics, November
10, 2016
Orphan Drug Designations
VK0214 for Adrenoleukodystrophy
The FDA has granted orphan drug
status to VK0214 (Viking Therapeutics)
for the treatment of patients with x-linked
adrenoleukodystrophy (X-ALD). VK0214
is an investigational, orally available
thyroid receptor-beta agonist that selec-
tively modulates lipoprotein and tri-
glyceride levels in liver tissue. This mecha-
nism has been demonstrated to affect the
expression of the genes that are relevant
to the manifestation of X-ALD. In X-ALD,
mutations in the ABCD1 gene lead to the
accumulation of very long-chain fatty acids
(VLCFAs), which is believed to be a fun-
damental cause of the disease. Research
has shown that increasing the expression
of the ABCD2 gene can counteract this pro-
cess and lead to normalization of VLCFA
levels.
Source: Viking Therapeutics, December
6, 2016
Cellspan Esophageal Implants
The Cellspan esophageal implant
(Biostage, Inc.) has received an orphan
drug designation from the FDA as a means
for restoring the structure and function of
the esophagus after damage due to can-
cer, injury, or congenital abnormalities.
The patients own stem cells are taken
from a simple adipose/fat tissue biopsy,
expanded, and banked, and then seeded
onto a scaffold that mimics the natural
dimensions of the organ being regener-
10 P&T January 2017 Vol. 42 No. 1
ated. The biocompatible scaffold contain-
ing the stem cells is then implanted. The
proprietary technology was designed to
improve outcomes for patients by poten-
tially simplifying surgical techniques and
by prompting regeneration of the patients
own esophagus.
Source: Biostage, December 1, 2016
Risankizumab for
Pediatric Crohns Disease
The FDA has granted an orphan drug
designation to risankizumab (AbbVie) for
the investigational treatment of Crohns
disease in pediatric patients. Crohns
disease is an incurable chronic inam-
matory condition of the gastrointestinal
tract that can cause diarrhea, abdominal
pain, and weight loss.
Source: AbbVie, November 30, 2016
PRX-OTC for Ornithine
Transcarbamylase Deciency
PRX-OTC (PhaseRx, Inc.) has received
an orphan drug designation from the
FDA for the treatment of patients with
ornithine transcarbamylase deciency
(OTCD). OTCD is a rare liver disorder
caused by an inherited single-gene
deficiency that results in hyper-
ammonemia and can lead to irrevers-
ible neurological impairment, coma,
and death. PRX-OTC is an intracellular
enzyme replacement therapy designed
to replace the missing or defective
enzyme in patients with OTCD, thereby
correcting the disease.
Source: PhaseRx, November 28, 2016
APX001 for Fungal and Mold Infections
The FDAs Ofce of Orphan Products
Development has granted orphan drug
status to APX001 (Amplyx Pharma-
ceuticals) for the treatment of invasive
candidiasis, invasive aspergillosis, coc-
cidioidomycosis, and rare mold infec-
tions caused by Scedosporium spp.,
Fusarium spp., and Mucorales fungi
(including Mucor spp. and Rhizopus
spp.). APX001 is a rst-in-class small-
molecule drug candidate that targets
and inhibits the conserved fungal
enzyme Gwt1, thereby compromising
the growth of major fungal pathogens,
including Candida and Aspergillus.
Source: Amplyx Pharmaceuticals,
November 16, 2016
Napabucasin for Pancreatic Cancer
Napabucasin (Boston Biomedical) has
received an orphan drug designation from
the FDA for the treatment of patients with
pancreatic cancer. This is the second such
designation for napabucasin, an orally
administered agent designed to inhibit
cancer stemness pathways by targeting
STAT3; the rst designation was for gas-
tric cancer, including gastroesophageal
junction cancer.
Source: Boston Biomedical, November
14, 2016
ELX-02 for Mucopolysaccharidosis
The FDA has granted an orphan drug
designation to ELX-02 (Eloxx Pharma-
ceuticals) for the treatment of patients
with mucopolysaccharidosis type-1
(MPS-1). ELX-02 is a synthetic amino-
glycoside that has been developed as a
translational read-through drug for the
treatment of genetic diseases caused by
nonsense mutations.
MPS-1 is a chronic, progressive genetic
disorder caused by an enzymatic de-
ciency of alpha-L-iduronidase, which dis-
rupts the glycosaminoglycan catabolic
pathway, leading to an intralysosomal
accumulation of the substrates heparan
sulfate and dermatan sulfate. The accu-
mulation of these substrates disrupts the
movement of intracellular molecules,
resulting in the dysfunction of cells,
tissues, and organs.
Source: Eloxx Pharmaceuticals,
November 7, 2016
 Rare Pediatric
Disease Designation
VTS-270 for NiemannPick Disease
The FDA has granted a rare pediatric
disease designation to VTS-270 (Vtesse,
Inc.), an investigational drug for children
with NiemannPick type-C1 disease
(NPC). NPC is a progressive, irreversible,
chronically debilitating, and ultimately
lethal genetic disease.
In early 2016, the FDA granted break-
through therapy status for VTS-270,
which is currently in a pivotal phase 2b/3
clinical trial in NPC. The FDA also previ-
ously granted orphan drug status to the
medication.
VTS-270 is a mixture of hydroxy-
propyl betacyclodextrin (HPCD) with
a specic compositional ngerprint that
distinguishes it from other HPCD
mixtures.
Source: Vtesse, November 29, 2016
New Applications
Semaglutide for Type-2 Diabetes
Novo Nordisk has submitted a new
drug application to the FDA for sema-
glutide, a glucagon-like peptide-1 (GLP-1)
analogue administered once weekly for
the treatment of adults with type-2 dia-
betes (T2D).
The submission was based on results
from the SUSTAIN clinical trial program,
which included eight phase 3a studies
involving more than 8,000 adults with
T2D. In that program, once-weekly sema-
glutide was administered in combination
with oral antidiabetic agents and basal
insulin and demonstrated statistically
signicant and sustained blood glucose
control compared with that of sitagliptin,
extended-release exenatide, once-daily
insulin glargine U100, and placebo. In
addition, semaglutide was associated with
signicantly greater reductions in mean
body weight than the comparators.
Source: Novo Nordisk, December 5,
2016
Abilify Maintena for Bipolar I Disorder
The FDA has determined that the
supplemental new drug application for
expanded labeling of Abilify Maintena
(Otsuka/Lundbeck) for the mainte-
nance treatment of adults with bipolar I
disorder is sufficiently complete to
permit a substantive review. The
agency has set a target action date of
July 28, 2017.
Abilify Maintena, an atypical anti-
psychotic, is an intramuscular depot
formulation of aripiprazole. It is a
sterile lyophilized powder that, when
reconstituted with sterile water for
injection, forms an injectable suspen-
sion that can be administered monthly.
The product was approved in the U.S.
in 2013 for the treatment of adults with
schizophrenia.
Source: Otsuka, December 1, 2016
Abuse-Deterrent Oxaydo for Pain
Egalet Corporation has submitted
to the FDA a supplemental new drug
application for Oxaydo (oxycodone
hydrochloride, USP) tablets CII to
support an abuse-deterrent label claim
for the intravenous route of abuse.
The application includes in vitro data
demonstrating that Oxaydo resists the
extraction of oxycodone and, based
on its gelling properties, is more dif-
cult to draw into a syringe compared
with a nonabuse-deterrent immediate-
release (IR) oxycodone comparator.
Oxaydo is an IR oral formulation indi-
cated for the management of acute and
chronic moderate-to-severe pain for
which the use of an opioid analgesic
is appropriate.
Source: Egalet Corporation, December
1, 2016
Valbenazine for Tardive Dyskinesia
The FDAs Psychopharmacologic
Drugs Advisory Committee has agreed
to review data included in the new drug
application (NDA) for valbenazine
(Ingrezza, Neurocrine Biosciences) for
the treatment of patients with tardive
dyskinesia on February 16, 2017. The
FDA has granted priority review status
to the NDA, with a target action date of
April 11, 2017.
VMAT2 is a protein in the human
brain that is primarily responsible for
repackaging and transporting mono-
amines (dopamine, norepinephrine,
serotonin, and histamine) in presynaptic
neurons. Valbenazine is a highly selec-
tive VMAT2 inhibitor that modu-
lates dopamine release during nerve
communication.
Source: Neurocrine Biosciences,
November 29, 2016
OxyContin Bioequivalent
Intellipharmaceutics International,
Inc., has led a new drug application with
the FDA seeking authorization to mar-
ket Rexista abuse-deterrent oxycodone
hydrochloride extended-release tablets
in 10-mg, 15-mg, 20-mg, 30-mg, 40-mg,
60-mg, and 80-mg strengths.
Rexista is indicated for the manage-
ment of pain severe enough to require
daily, around-the-clock, long-term
opioid treatment and for which alterna-
tive treatment options are inadequate.
The submission was supported by data
from pivotal pharmacokinetic studies,
which demonstrated that Rexista is bio-
equivalent to OxyContin (oxycodone
hydrochloride extended release, Purdue
Pharma).
Source: Intellipharmaceutics Inter-
national, November 25, 2016
Guselkumab for Plaque Psoriasis
Janssen Biotech has submitted a bio-
logics license application to the FDA
seeking approval of guselkumab for the
treatment of adults with moderate-to-
severe plaque psoriasis. Guselkumab
is a human monoclonal antibody that
Vol. 42 No. 1 January 2017 P&T
11
targets interleukin-23, a protein that plays
a key role in the development of immune-
mediated inammatory diseases.
Source: Janssen Biotech, November
17, 2016
L-Glutamine for Sickle Cell Disease
The FDA has accepted for review a
new drug application for orally adminis-
tered pharmaceutical-grade L-glutamine
(Emmaus Life Sciences) for the treatment
of patients with sickle cell disease. Data
from a phase 3 study demonstrated a
reduction in the frequency of sickle cell
crises and hospitalizations, a reduction
in cumulative days hospitalized, and a
lower incidence of life-threatening acute
chest syndrome in 230 adult and pediatric
patients. If approved, the product would
be the rst potential new treatment for
adults with sickle cell disease in nearly
20 years.
Source: Emmaus Life Sciences,
November 8, 2016
Biosimilar Herceptin
Mylan and Biocon Ltd. have sub-
mitted a biologics license application
for MYL-14010, a proposed biosimilar
trastuzumab, to the FDA. The product
is a proposed biosimilar to Herceptin
(Genentech), which is indicated to treat
certain human epidermal growth factor
receptor-2-positive breast and gastric
cancers. Mylan and Biocon believe it to
be the rst submission of a proposed
biosimilar trastuzumab in the U.S.
Source: Mylan, November 8, 2016
Stivarga for Liver Cancer
Bayer has submitted a supplemen-
tal new drug application to the FDA to
have its cancer medication regorafenib
(Stivarga) approved for the second-line
treatment of patients with unresectable
hepatocellular carcinoma (uHCC). Rego-
rafenib, an oral multikinase inhibitor,
is currently indicated for patients with
12 P&T January 2017 Vol. 42 No. 1
metastatic colorectal cancer or locally
advanced, unresectable, or metastatic
gastrointestinal stromal tumors.
The submission was based on positive
data from the phase 3, placebo-controlled
RESORCE trial, which investigated rego-
rafenib in 573 patients with uHCC whose
disease had progressed during treat-
ment with sorafenib (Nexavar, Bayer).
The patients were randomly assigned to
receive regorafenib or placebo plus best
supportive care.
The study met its primary endpoint of
a statistically signicant improvement in
overall survival (OS) with regorafenib.
Median OS was 10.6 months for rego-
rafenib compared with 7.8 months for
placebo.
Source: Bayer, November 7, 2016
Complete Response Letter
Heplisav-B Vaccine
Dynavax Technologies Corporation
has received a complete response letter
(CRL) from the FDA regarding its bio-
logics license application for Heplisav-B
(hepatitis B vaccine, recombinant [adju-
vanted]) for the immunization of adults
18 years of age and older against hepatitis
B infection. The CRL seeks information
on several topics, including clarica-
tion of specic adverse events of special
interest; a numerical imbalance in the
number of cardiac events in one study;
new analyses of the integrated safety
database across different time periods;
and post-marketing commitments.
The vaccine was previously the subject
of a CRL in 2012.
Heplisav-B is an investigational
hepatitis B vaccine for adults that
combines hepatitis B surface antigen
with a Toll-like receptor 9 agonist to
enhance the immune response. The vac-
cine is administered in two doses over
one month.
Source: Dynavax Technologies,
November 14, 2016
CLINICAL TRIAL NEWS
Tagrisso for Lung Cancer
Promising results have been reported
from a phase 3 study of osimertinib
(Tagrisso, AstraZeneca) in the second-
line treatment of patients with epider-
mal growth factor receptor T790M
mutation-positive locally advanced or
metastatic nonsmall-cell lung cancer.
Osimertinib improved progression-free
survival (PFS) by 5.7 months compared
with standard platinum-based doublet
chemotherapy (10.1 months versus
4.4 months, respectively; hazard ratio
[HR], 0.30; P < 0.001). Moreover, in the
34% of patients with central nervous
system metastases at baseline, PFS
was signicantly greater with osimer-
tinib than with platinum-based doublet
chemotherapy (8.5 months versus
4.2 months, respectively; HR, 0.32).
Source: AstraZeneca, December 6,
2016
Bosulif for CML
Positive results have been reported
from a phase 3 comparison of bosutinib
(Bosulif, Pzer/Avillion) and imatinib
as rst-line treatments in patients with
chronic-phase Philadelphia chromosome-
positive (Ph+) chronic myeloid leuke-
mia (CML). The study met its primary
endpoint of a superior major molecular
response at 12 months with bosutinib
compared with imatinib. Bosutinib is cur-
rently indicated in the U.S. for the treat-
ment of adults with Ph+ CML who were
resistant to or intolerant of prior therapy.
Bosutinib is an oral, once-daily tyrosine
kinase inhibitor that inhibits the Bcr-Abl
kinase, which promotes CML; it is also an
inhibitor of Src-family kinases. Bosutinib
was approved by the FDA in September
2012 for the treatment of adults with Ph+
CML who were resistant to or intolerant
of prior therapy.
Source: Pzer, December 5, 2016
 Jaka for Myelobrosis
A pooled analysis of ve-year follow-
up data from the phase 3 COMFORT-I
and COMFORT-II trials has suggested
that earlier treatment with ruxolitinib
(Jaka, Incyte Corporation), a rst-in-
class Janus kinase-1 (JAK1) and JAK2
inhibitor, may result in an improved
survival advantage for patients with
intermediate- or high-risk myelobrosis
compared with best available therapy
or placebo. The ndings showed pro-
longed survival in patients treated
with ruxolitinib, with the risk of death
reduced by 30% compared with the con-
trol groups. Ruxolitinib also showed an
overall survival advantage in various
patient subgroup analyses, including
age, gender, disease type, risk status,
JAK2V617F mutation status, baseline
spleen length, anemia, white blood cell
count, and platelet count.
Source: Incyte Corporation,
December 4, 2016
Vonvendi for Blood
Loss in Surgery
Positive results have been reported
from a phase 3 trial of Vonvendi (von
Willebrand factor [recombinant], Shire)
to treat bleeds in elective surgical
settings for adults with severe von
Willebrand disease (VWD), the most
common inherited bleeding disorder.
Vonvendi is an on-demand recombi-
nant treatment for adults with VWD
and replaces von Willebrand factor,
one of several types of proteins in the
blood that are needed to facilitate proper
blood clotting missing in patients with
VWD. The study met its primary end-
point, indicating that Vonvendi effec-
tively controlled bleeding and blood loss
during an operation in adults under-
going major, minor, and oral elec-
tive surgical procedures. The results
from this study will form the basis of a
supplemental new drug application
to the FDA, in which Shire will request
an expanded indication for Vonvendi.
Source: Shire, December 2, 2016
Lyrica for Pediatric Epilepsy
Pzer has announced positive results
from a phase 3 study that evaluated the
use of pregabalin (Lyrica) capsules
CV and oral solution CV as adjunctive
therapy for pediatric epilepsy patients
4 to 16 years of age with partial-onset
seizures. Adjunctive treatment with
pregabalin 10 mg/kg per day resulted
in a statistically signicant reduction in
seizure frequency compared with pla-
cebo (the primary efcacy endpoint).
The 12-week, double-blind, placebo-
controlled, randomized, parallel-group
study involved 295 pediatric patients in
18 countries.
In the United States, pregabalin is indi-
cated for the treatment of bromyalgia,
diabetic nerve pain, spinal cord injury
nerve pain, and pain after shingles in
adults. The medication is also indicated
for the treatment of partial-onset seizures
in adults with epilepsy who take one or
more drugs for seizures. Pregabalin is
not approved as adjunctive therapy for
pediatric epilepsy patients with partial-
onset seizures.
Source: Pzer, December 1, 2016
Psilocybin for Anxiety and
Depression in Cancer Patients
When combined with psychological
counseling, a single dose of a mind-
altering compound contained in psyche-
delic mushrooms signicantly lessened
mental anguish in distressed cancer
patients for months at a time, according
to the results of a clinical study led by
researchers at the New York University
Langone Medical Center.
Published online in December in the
Journal of Psychopharmacology, the study
showed that one-time treatment with
the hallucinogenic drug psilocybin
the use of which requires federal waiv-
ers because it is a banned substance
brought relief from distress that lasted
for more than six months in 80% of the
29 study patients monitored, based on
clinical evaluation scores for anxiety and
depression.
Source: NYU Langone Medical
Center, December 1, 2016
Pulmaquin for Lung Infection
Pulmaquin (Aradigm Corporation), a
once-daily inhaled formulation of cipro-
oxacin, has failed to meet the primary
endpoint in a late-stage study involving
patients with non-cystic brosis bronchi-
ectasis (non-CF BE) who had chronic
lung infections with Pseudomonas
aeruginosa. In another study, however,
Pulmaquin was deemed to have had a
statistically significant benefit over
placebo.
The primary endpoint in both trials
was an increase in the median time to the
rst mild, moderate, or severe pulmo-
nary exacerbation (PE). The key second-
ary efcacy endpoint in both studies was
the frequency of PEs during the 48-week,
double-blind treatment period.
In the ORBIT-3 trial, the median time
to the rst PE was 221 days in the Pul-
maquin group compared with 136 days
in the placebo group (P = 0.8488).
Pulmaquin-treated patients showed a 13%
reduction in the frequency of PEs during
the 48-week treatment period compared
with those given placebo (P = 0.3125).
In the ORBIT-4 trial, the median time
to the rst PE was 230 days in the Pul-
maquin group compared with 163 days in
the placebo group (P = 0.0462). In addi-
tion, there was a 37% reduction in the
frequency of PEs during the 48-week
treatment period in the Pulmaquin
group compared with the placebo group
(P = 0.0007).
Source: Aradigm Corporation,
December 1, 2016
Vol. 42 No. 1 January 2017 P&T
13
 Herceptin Biosimilar
For Breast Cancer
Pzer has announced that its pivotal
REFLECTIONS B3271002 trial, a com-
parative safety and efcacy study of
PF-05280014 versus Herceptin (trastu-
zumab, Genentech), met its primary end-
point. PF-05280014 is a monoclonal anti-
body that is in development as a potential
biosimilar for all approved indications of
Herceptin. Currently, Herceptin is indi-
cated for the treatment of human epider-
mal growth factor receptor-2 (HER2)-
positive breast cancer and gastric cancer.
The randomized, double-blind trial
demonstrated equivalence in the primary
endpoint of the objective response rates
for PF-05280014 and Herceptin admin-
istered in combination with paclitaxel
in rst-line patients with HER2-positive
metastatic breast cancer after 25 weeks
of treatment.
Source: Pzer, November 29, 2016
Cosentyx for Psoriatic Arthritis
New data have shown that secukinu-
mab (Cosentyx, Novartis), a fully human
interleukin-17A inhibitor, delivered
sustained improvements in the signs
and symptoms of psoriatic arthritis
(PsA)including patient-reported
painduring three years of treat-
ment. In the rst year of a three-year
open-label extension study, 77% of PsA
patients achieved at least 20% improve-
ment in American College of Rheuma-
tology response criteria. The new data
also showed that response rates were
consistent from year 1 (69%) to year 3
(77%).
Source: Novartis, November 14, 2016
Baricitinib for RA
New data analyses of two phase 3
studies have shown that treatment with
baricitinib (Eli Lilly/Incite Corporation)
resulted in improvements in rheumatoid
arthritis (RA) symptoms regardless of the
14 P&T January 2017 Vol. 42 No. 1
patients age, body mass index, or previ-
ous treatment with conventional synthetic
disease-modifying antirheumatic drugs.
At week 12, in the baricitinib 4-mg group,
67% of patients less than than 65 years of
age and 68% of patients 65 years of age
or older showed at least a 20% improve-
ment according to American College
of Rheumatology criteria (ACR20). In
the group that received placebo, 40% of
patients less than 65 years of age and
43% of patients 65 years or age or older
achieved an ACR20 response.
Baricitinib is a once-daily oral selective
Janus kinase-1 (JAK1) and JAK2 inhibi-
tor currently in late-stage clinical studies
for the treatment of inammatory and
autoimmune diseases.
Source: Eli Lilly, November 14, 2016
Simponi Aria for
Ankylosing Spondylitis
A pivotal phase 3 study has demon-
strated the efcacy of the intravenous
anti-tumor necrosis factor (TNF)-alpha
therapy golimumab (Simponi Aria,
Janssen) in patients with active anky-
losing spondylitis (AS). Data from the
GO-ALIVE trial showed that 73% of
patients with active AS receiving goli-
mumab 2 mg/kg achieved the primary
endpoint of at least a 20% improve-
ment in the Assessment in Ankylosing
Spondylitis criteria at week 16, compared
with 26% of patients receiving placebo
(P 0.001). In July 2013, golimumab
received FDA approval as a 30-minute
infusion for the treatment of adult patients
with moderately to severely active
rheumatoid arthritis in combination with
methotrexate.
Source: Janssen, November 14, 2016
Long-Acting Buprenorphine
For Opioid Addiction
Positive results have been reported
from a pivotal phase 3, randomized,
double-blind, double-dummy, active-
controlled trial of weekly and monthly
subcutaneous injections of buprenor-
phine (Braeburn Pharmaceuticals/
Camurus) for the treatment of patients
with moderate-to-severe opioid use
disorder. Long-acting buprenorphine
achieved the studys primary endpoint
of statistical noninferiority compared
with daily sublingual buprenorphine/
naloxone (the current standard of care)
in terms of the response to treatment.
Buprenorphine maintenance therapy
is currently considered the gold stan-
dard for the treatment of opioid use
disorder, with more than one million
patients receiving buprenorphine in the
U.S. and Europe. Currently, most patients
receiving buprenorphine take daily doses.
Source: Braeburn Pharmaceuticals,
November 14, 2016
Romosozumab for Decreased
Bone Mineral Density in Men
Results from the phase 3 BRIDGE
trial have shown that, in men with osteo-
porosis, treatment with the investiga-
tional agent romosozumab (Amgen/
UCB) resulted in a signicant 12.1% gain
in bone mineral density (BMD) at the
lumbar spine compared with placebo
at 12 months (the studys primary end-
point) (P < 0.01). Both secondary end-
points were also met, with romosozumab
showing a statistically signicant increase
in BMD at the total hip (2.5%) and the
femoral neck (2.2%) at 12 months (both
P < 0.01 compared with placebo). Romo-
sozumab is a bone-forming monoclonal
agent that inhibits the activity of the
protein sclerostin.
Source: Amgen, November 14, 2016
Ibalizumab for HIV
A 24-week phase 3 study has conrmed
the safety and efcacy results with ibali-
zumab (Theratechnologies, Inc./TaiMed
Biologics) observed in a previously com-
pleted phase 2b trial, despite the fact that
the patient population in the phase 3
investigation had higher levels of multi-
drug-resistant human immunodeciency
virus-1 ( HIV-1) and more advanced dis-
ease at the time of enrollment. Ibalizumab
is a humanized monoclonal antibody.
The results indicated that 33 of the
40 patients (83%) met the primary end-
point of a reduction of at least 0.5 log10
in the viral load after seven days of treat-
ment with ibalizumab. After 24 weeks of
treatment, the mean reduction in the viral
load was 1.6 log10, and 48% of the patients
showed a viral load reduction of more
than 2.0 log10.
Source: Theratechnologies, November
10, 2016
Binimetinib/Encorafenib
For Melanoma
A pivotal phase 3 trial of binimetinib
plus encorafenib (Array BioPharma/
Pierre Fabre) in patients with BRAF-
mutant melanoma has met its primary
endpoint, with the combination sig-
nicantly improving progression-free
survival (PFS) compared with vemu-
rafenib, a BRAF inhibitor, alone. The
median PFS for patients treated with bin-
imetinib/encorafenib was 14.9 months
compared with 7.3 months for patients
treated with vemurafenib (hazard ratio,
0.54; P < 0.001). Binimetinib is a late-
stage small-molecule MEK inhibitor,
and encorafenib is a late-stage small-
molecule BRAF inhibitor, both of which
target key enzymes in this pathway.
Source: Array BioPharma, November
9, 2016
Spinraza for Spinal
Muscular Atrophy
Spinraza (nusinersen, Biogen/Ionis
Pharma) provided a signicant improve-
ment in motor function compared with
placebo (the primary endpoint) in a
phase 3 study of patients with later-onset
spinal muscular atrophy (SMA). SMA is
characterized by the loss of motor neu-
rons in the spinal cord and lower brain
stem. This results in severe, progres-
sive muscular atrophy and weakness.
Over time, patients with the most severe
form of SMA can become paralyzed and
have difculty in breathing and swallow-
ing. Patients with SMA do not produce
enough survival motor neuron (SMN)
protein, which is caused by a defect in
the SMN1 gene. Spinraza is an antisense
oligonucleotide that alters the splicing of
SMN2, a gene almost identical to SMN1,
which results in the increased production
of fully functional SMN protein.
Source: Biogen, November 7, 2016
Orkambi in Children With CF
Positive results have been reported
from a phase 3 study of Orkambi (luma-
caftor/ivacaftor, Vertex Pharmaceuticals)
in children 6 through 11 years of age with
cystic brosis (CF) who have two copies
of the F508del mutation. The study met its
primary endpoint of an absolute change
in the lung clearance index (LCI2.5) after
24 weeks of treatment, demonstrating a
statistically signicant improvement in
LCI2.5 among patients treated with Ork-
ambi compared with those given placebo.
At baseline, the mean LCI2.5 was 10.28.
Children treated with Orkambi experi-
enced an improvement in lung function
of 1.09 compared with placebo after
24 weeks (P < 0.0001).
Source: Vertex Pharmaceuticals,
November 7, 2016
Minocycline Foam for Acne
Foamix Pharmaceuticals has com-
pleted patient enrollment in two phase 3
trials designed to evaluate the efcacy
and safety of FMX101, a topical 4% mino-
cycline foam, in the treatment of patients
with moderate-to-severe acne. The two
pivotal studies are being conducted simul-
taneously, and results are expected in the
rst half of 2017.
A total of 961 patients were enrolled
in the two trials. Patients who complete
the 12- week double-blind portion of the
studies will have the option to continue in
a long-term open-label safety extension,
which will evaluate the safety of intermit-
tent use of FMX101 for up to an additional
nine months.
Source: Foamix Pharmaceuticals,
November 28, 2016
Daprodustat for Anemia
Associated With Renal Disease
GlaxoSmithKline has begun a phase 3
development program investigating
daprodustat, an oral hypoxia-inducible
factor prolyl hydroxylase inhibitor, as
a treatment for anemia associated with
chronic kidney disease (CKD). The
program includes two clinical trials.
The rst trial, ASCEND-D, will enroll
approximately 3,000 dialysis-dependent
patients with CKD-associated anemia
who are switching from an erythropoietin-
stimulating agent (ESA). The second trial,
ASCEND-ND, will enroll approximately
4,500 nondialysis-dependent patients
with CKD-associated anemia and will
include patients who are either switching
from or nave to an ESA. For both stud-
ies, the coprimary endpoints are the time
to the rst occurrence of major adverse
cardiovascular events and the mean
change in hemoglobin levels between
baseline and the efcacy period (i.e.,
the mean during weeks 28 to 52). The
studies will assess whether daprodus-
tat is noninferior to recombinant human
erythropoietin on these endpoints.
Source: GlaxoSmithKline, November
25, 2016
DEVICE APPROVALS
TroClose1200 Trocar
The FDA has cleared the TroClose1200
(Gordian Surgical), a new trocar with an
integrated closure system for suturing
abdominal-wall incisions during laparo-
Vol. 42 No. 1 January 2017 P&T
15
scopic surgical procedures. The device
acts as both a trocar, through which surgi-
cal instruments enter the abdomen, and
a device to close internal incisions made
during surgery. The sutures are inserted
into the tissue at the beginning of the
procedure and anchored to remain in
place throughout the operation, allowing
the incisions to be closed quickly upon
removal of the device.
Source: Gordian, December 7, 2016
Insulia Diabetes-
Management Software
Paris-based company Voluntis has
received FDA 510(k) clearance for the
Insulia Diabetes Management Compan-
ion, a global digital device for patients
with type-2 diabetes who are being
treated with insulin. The prescription-
only medical device works with Sanos
Lantus (insulin glargine injection) and
Novo Nordisks Levemir (insulin detemir
[rDNA origin] injection). A patient may
use the application via a Web portal, on
a smartphone, or on a tablet. The device
will be available in the rst half of 2017.
The Insulia device provides patients
with insulin dose recommendations
and educational coaching messages in
response to blood glucose values and
other diabetes-related data. The device
also supports a variety of treatment plans
and evidence-based insulin adjustment
rules used in routine clinical practice.
Source: Voluntis, December 6, 2016
Xonrid Gel for Dermatitis
Induced by Radiotherapy
Xonrid gel (Helsinn Integrative Care),
a topical gel for radiotherapy-induced
dermatitisclassied as a medical device
in the European Unionhas received
510(k) FDA clearance. This allows the
product to be marketed in the U.S. for
the management of the burning and
itching associated with radiation
dermatitis.
16 P&T January 2017 Vol. 42 No. 1
The nonsterile water-based gel forms
a protective barrier on skin to increase
moisture and to reduce water loss. Its
contents include emollients, preserva-
tives, skin-conditioning agents, viscosity-
increasing agents, emulsifying agents,
and binders. The gel is applied three
times per day or as needed.
Source: Helsinn Integrative Care,
December 1, 2016
PolyPlex Wound Dressing
The FDA has approved PolyPlex wound
dressing (Global Health Solutions), a
rst-of-its-kind, petrolatum-based topical
gel indicated for the management of acute
and chronic wounds. The gel provides
protection against bacteria, fungi, and
yeasts without irritating fragile, healing
tissue, according to the manufacturer. It
will be available in January 2017 through
McKesson Medical-Surgical.
Source: Global Health Solutions,
November 28, 2016
XEN Glaucoma
Treatment System
The FDA has cleared the XEN glau-
coma treatment system (Allergan),
consisting of the XEN45 gel stent and
the XEN injector, for use in the United
States. The system reduces intraocular
pressure (IOP) and is indicated for the
management of refractory glaucoma for
which previous surgical treatment has
failed or in patients with primary open-
angle glaucoma, and pseudoexfoliative or
pigmentary glaucoma with open angles
that are unresponsive to maximum toler-
ated medical therapy. XEN is implanted
through an ab-interno approach and
reduces IOP by creating a new drainage
channel with a permanent implant that
becomes exible.
Source: Allergan, November 22, 2016
Ormev IV Bag
The FDA has given the OK to a prior
approval supplement (PAS) for Ormev
(acetaminophen, Mallinckrodt Pharma-
ceuticals) injection available in an
intravenous (IV) bag, which will provide
health care providers with an additional
delivery option. The PAS to the approved
new drug application for Ofirmev
included the addition of a new container
closure and manufacturer. The poly-
propylene bags will be manufactured by
Fresenius Kabi. Mallinckrodt anticipates
product availability in the second quarter
of 2017.
Ormev injection is the only IV formu-
lation of acetaminophen to be approved
and marketed in the United States. The
FDA approved the drug in November
2010. Ormev is indicated for the man-
agement of mild-to-moderate pain; the
management of moderate-to-severe pain
with adjunctive opioid analgesics; and the
reduction of fever.
Source: Mallinckrodt, November 8,
2016
Propeller Platform
For Ellipta Inhaler
The FDA has cleared the Propeller
platform (Propeller Health) for use
with the Ellipta inhaler (GlaxoSmith-
Kline). The digitally guided platform
is designed to help patients and their
physicians better understand asthma
and chronic obstructive pulmonary
disease and to help improve the symp-
toms and outcomes of these chronic
respiratory diseases. With proprietary
sensor technology, software, and ser-
vices, the platform integrates informa-
tion from multiple sources, including
connected medications, and then uses
machine intelligence to help individuals
manage their condition.
Source: Propeller Health, November
7, 2016 Q
 Pharmaceutical Approval Update
Mary Choy, PharmD, BCGP, FASHP
Olaratumab (Lartruvo)
Manufacturer: Eli Lilly and Company, Indianapolis, Indiana
Date of Approval: October 19, 2016
Indication: Olaratumab, a platelet-derived growth factor
receptor-alpha (PDGFR-)-blocking antibody, is indicated in
combination with doxorubicin for the treatment
of adult patients with soft tissue sarcoma (STS)
that is not amenable to curative treatment with
radiotherapy or surgery and that has a histologi-
cal subtype for which an anthracycline-containing
regimen is appropriate.
Drug Class: PDGFR- antagonist
Uniqueness of Drug: Olaratumab was approved
by the Food and Drug Administration (FDA) under
its accelerated program in combination with doxo-
Mary Choy, PharmD,
rubicin as a rst-line therapy for patients with STS. BCGP, FASHP
Continued approval for this indication will be con-
tingent upon verication and description of clinical benet in
the conrmatory phase 3 study, ANNOUNCE.
Warnings and Precautions:
Infusion-related reactions. Infusion-related reactions
(IRRs) occurred in 70 of 485 patients (14%) who received at
least one dose of olaratumab across clinical trials. For 68 of
those 70 patients (97%), the rst occurrence of an IRR was in
the rst or second cycle. Grade 3 or higher IRRs occurred in
11 of 485 patients (2.3%), with one fatality (0.2%).
IRRs caused permanent discontinuation of olaratumab in
2.3% of patients, and interruption of infusion occurred in 10% of
patients. All 59 patients with grade 1 or 2 IRRs resumed olara-
tumab; 12 of these patients (20%) had a grade 1 or 2 IRR with
rechallenge. The incidence of IRRs in the overall safety database
(N = 485) was similar (18% versus 12%) between those who
did (56%) and those who did not (44%) receive premedication.
The symptoms of IRR included ushing, shortness of breath,
bronchospasm, or fever/chills. In severe IRR cases, symptoms
manifested as hypotension, anaphylactic shock, or cardiac arrest.
Monitor patients during and following the infusion for signs
and symptoms of IRRs in a setting with available resuscitation
equipment. Discontinue olaratumab for grade 3 or 4 IRRs.
Embryo-fetal toxicity. Based on animal data and its mecha-
nism of action, olaratumab can cause fetal harm when adminis-
tered to a pregnant woman. Advise women of the potential risk
to the fetus and to use effective contraception during treatment
with olaratumab and for three months after the last dose.
Dosage and Administration: The recommended dose of
olaratumab is 15 mg/kg administered as an intravenous (IV)
infusion over 60 minutes on days 1 and 8 of each 21-day cycle
until disease progression or unacceptable toxicity. Premedicate
with diphenhydramine (2550 mg IV) and dexamethasone
(1020 mg IV) prior to olaratumab on day 1 of cycle 1. For the
rst eight cycles, olaratumab is administered with doxorubicin.
Dr. Choy is an Associate Professor at Touro College of Pharmacy
and a Clinical Pharmacist at Metropolitan Hospital in New York,
New York.
In patients who experience grade 1 or 2 IRRs, interrupt the
olaratumuab infusion. After resolution, resume the infusion
at 50% of the initial rate. In patients with neutropenic fever/
infection or grade 4 neutropenia lasting longer than one week,
discontinue administration of olaratumab until the absolute
neutrophil count recovers to 1,000/mcL or greater
and then permanently reduce the dose to 12 mg/kg.
Commentary: The FDA approval of olaratumab
is based on the results of a phase 2 study that
showed a signicant improvement in patient survival
with a combination of doxorubicin plus olaratumab
compared with doxorubicin alone (a median gain of
11.8 months). The most common adverse reactions
of olaratumab plus doxorubicin in 20% or more of
patients are nausea, fatigue, musculoskeletal pain,
mucositis, alopecia, vomiting, diarrhea, decreased
appetite, abdominal pain, neuropathy, and head-
ache. The most common laboratory abnormalities occurring
in 20% or more of patients were lymphopenia, neutropenia,
thrombocytopenia, hyperglycemia, elevated activated partial
thromboplastin time, hypokalemia, and hypophosphatemia.
Sources: Eli Lilly and Company, Lartruvo prescribing
information
Bezlotoxumab (Zinplava)
Manufacturer: Merck and Co., Inc., Whitehouse Station,
New Jersey
Date of Approval: October 18, 2016
Indication: Bezlotoxumab, a human monoclonal antibody
that binds to Clostridium difcile toxin B, is indicated to reduce
recurrence of C. difcile infection (CDI) in patients 18 years
of age or older who are receiving antibacterial drug treatment
for CDI and are at a high risk for CDI recurrence. It is not
indicated for the treatment of CDI and should only be used in
conjunction with antibacterial drug treatment of CDI.
Drug Class: Monoclonal antibody
Uniqueness of Drug: The Centers for Disease Control
and Prevention estimated that CDI caused almost 500,000
illnesses and 29,000 deaths within one month of initial diagnosis
in 2011. CDI recurs in roughly 20% of people who have had the
infection. Bezlotoxumab is specically indicated for adults who
are taking an antibiotic for CDI and are at risk of becoming
infected again. Not an antibiotic itself, bezlotoxumab binds
to and neutralizes toxin B, one of several toxins produced by
C. difcile and the one considered central to the life-threatening
virulence of the bacteria.
Warnings and Precautions:
Heart failure. Heart failure was reported more commonly
in the two phase 3 clinical trials in bezlotoxumab-treated
patients compared with placebo-treated patients. These adverse
reactions occurred primarily in patients with underlying con-
gestive heart failure (CHF). In patients with a history of CHF,
15 of 118 bezlotoxumab-treated patients (12.7%) and ve of
104 placebo-treated patients (4.8%) had the serious adverse reac-
tion of heart failure during the 12-week study period. In addi-
Vol. 42 No. 1 January 2017 P&T
17
 Pharmaceutical Approval Update
tion, there were more deaths in bezlotoxumab-treated patients
(23 of 118; 19.5%) than in placebo-treated patients (13 of 104;
12.5%) during the 12-week study period. The causes of death
varied and included cardiac failure, infections, and respiratory
failure. In patients with a history of CHF, bezlotoxumab should
be reserved for use when the benet outweighs the risk.
Dosage and Administration: Administer bezlotoxumab
during antibacterial drug treatment for CDI. A single dose
of 10 mg/kg administered as an intravenous infusion over
60 minutes is recommended. Bezlotoxumab must be diluted
prior to infusion.
Commentary: The Food and Drug Administration approval
of bezlotoxumab was based on two phase 3 trials, MODIFY I
and II. MODIFY I enrolled 1,452 patients (median age,
65 years) in 19 countries, and the MODIFY II study enrolled
1,203 patients (median age, 67 years) in 17 countries. The
studies were conducted in both hospital and outpatient settings,
and the primary outcome measure in each trial was the number
of participants who had CDI recurrence in the 12 weeks follow-
ing bezlotoxumab administration. CDI recurrence was dened
as the development of a new episode of diarrhea (three or more
loose stools in 24 or fewer hours) and a positive lab stool test
for toxigenic C. difcile after clinical cure of the initial episode.
Nausea, fatigue, fever, and headache were among the most
common adverse events experienced on the day of infusion
or within four weeks of infusion. Heart failure emerged as a
serious adverse reaction 12 weeks after therapy.
Sources: Merck and Co., Inc., Zinplava prescribing
information
Doxylamine Succinate/Pyridoxine Hydrochloride
(Bonjesta)
Manufacturer: Duchesnay USA, Inc., Bryn Mawr,
Pennsylvania
Date of Approval: November 14, 2016
Indication: Bonjesta is a xed-dose combination of
doxylamine succinate and pyridoxine hydrochloride indicated
for the treatment of nausea and vomiting during pregnancy
in women who do not respond to conservative management.
Each extended-release tablet contains 20 mg of doxyl-
amine succinate, an antihistamine, and 20 mg of pyridoxine
hydrochloride, a vitamin B6 analogue.
Drug Class: Antiemetic agent
Uniqueness of Drug: The combination of doxylamine
succinate and pyridoxine hydrochloride has been the subject
of many epidemiologic studies designed to detect possible
teratogenicity. No increased risk for congenital malformations
has been reported based on these studies.
Warnings and Precautions:
Somnolence. This medication may cause somnolence due
to the anticholinergic properties of doxylamine succinate, an
antihistamine. Women should avoid engaging in activities
requiring complete mental alertness, such as driving or operat-
ing heavy machinery, while using this medication until cleared
to do so by their health care provider. Doxylamine succinate
and pyridoxine hydrochloride use is not recommended if a
woman is concurrently using central nervous system depres-
sants, including alcohol. The combination may result in severe
drowsiness leading to falls or accidents.
18 P&T January 2017 Vol. 42 No. 1
Concomitant medical conditions. This medication has
anticholinergic properties and therefore should be used with
caution in women with asthma, increased intraocular pressure,
narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal
obstruction, or urinary bladder-neck obstruction.
Dosage and Administration: The initial recommended
dose is one extended-release tablet orally at bedtime (day 1).
If this dose adequately controls symptoms, the patient should
continue taking one tablet daily at bedtime on the next day.
However, if symptoms persist on day 2, the daily dose may
be increased to one tablet in the morning and one tablet at
bedtime. The maximum recommended dose is two tablets per
day, one in the morning and one at bedtime. The medication
should be taken on an empty stomach with a glass of water,
and should be swallowed whole. The tablets should not be
crushed, chewed, or split.
Commentary: There have been no efcacy and safety
trials conducted with Bonjesta. A double-blind, randomized,
multicenter, placebo-controlled study was conducted to support
the safety and efcacy of 10-mg doxylamine succinate and
10-mg pyridoxine hydrochloride tablets (a different formulation
and dosage strength) in the treatment of nausea and vomit-
ing during pregnancy. Women 18 years of age or older at
seven to 14 weeks gestation (median, nine weeks) with nausea
and vomiting were randomized to 14 days of 10-mg doxyl-
amine succinate and 10-mg pyridoxine hydrochloride tablets
or placebo. The primary efcacy endpoint was the change from
baseline at day 15 in the Pregnancy Unique-Quantication
of Emesis (PUQE) score. The PUQE score incorporates the
number of daily vomiting episodes, number of daily heaves, and
length of daily nausea in hours for an overall score of symptoms
rated from 3 (no symptoms) to 15 (most severe). At base-
line, the mean PUQE score was 9.0 in the 10-mg doxylamine
succinate and 10-mg pyridoxine hydrochloride tablets arm and
8.8 in the placebo arm. There was a 0.7-point mean decrease in
nausea and vomiting symptoms from baseline in PUQE score
at day 15 with 10-mg doxylamine succinate and 10-mg pyridox-
ine hydrochloride tablets (95% condence interval, 0.21.2;
P = 0.006) compared with placebo.
Sources: Duchesnay USA, Inc., Bonjesta prescribing
information Q
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DRUG FORECAST
Zarxio (Filgrastim-sndz):
The First Biosimilar Approved by the FDA
Mina Awad, PharmD Candidate; Pavit Singh, PharmD Candidate; and Olga Hilas, PharmD, MPH
INTRODUCTION
Leukocytes are the bodys main defense
against infection. The most abundant
leukocytes are neutrophils, also called
granulocytes, which are important in
ghting various microorganisms. There-
fore, a decline in neutrophilsa condition
called neutropeniamay predispose an
individual to a host of illnesses.1
Absolute neutrophil count (ANC) is
generally used to grade the severity
of neutropenia, although there is no
standard classication system.2 Neutro-
penia is dened as an ANC of less than
1.5 x 109/L, and its presentation may
be mild (11.5 x 10 9/L), moderate
(0.50.99 x 109/L), or severe (less than
0.5 x 109/L).2 In addition, neutropenia
can be acute (occurring over hours to
a few days) or chronic (lasting months
to years).1
The most common causes of neutro-
penia in adults are infections, followed
by drug-induced neutropenia.2 Acquired
bone marrow diseases (e.g., leukemia,
lymphoma, aplastic anemia) are relatively
common causes of neutropenia in adults,
as are certain nutritional deciencies.2
Approximately half of cancer patients
receiving chemotherapy experience some
type of neutropenia and are at increased
risk for infection.3 Other risk factors
for neutropenia include bone marrow
transplantation (BMT) and autologous
peripheral blood progenitor cell (PBPC)
collection and therapy. The latter is usu-
ally performed in patients undergoing
chemotherapy.3
Mina Awad and Pavit Singh are PharmD
Candidates (2017) at St. Johns University in
Queens, New York. Dr. Hilas is an Associate
Professor at St. Johns University. Drug
Forecast is a regular column coordinated by
Alan Caspi, PhD, PharmD, MBA, President of
Caspi and Associates in New York, New York.
Disclosure: The authors report no nancial or
commercial relationships in regard to this article.
EVOLUTION OF G-CSF
Myeloid growth factor therapy has
now become the standard of care in the
treatment of severe chronic neutropenia
(SCN).2,4 The myeloid-specic cytokine
granulocyte-colony simulating factor
(G-CSF) is the primary growth factor
used to increase neutrophil produc-
tion. The gene for human G-CSF was
transduced and incorporated through
recombinant DNA technology into
Escherichia coli and developed into the
drug filgrastim (Neupogen, Amgen,
Inc.), which was approved by the Food
and Drug Administration (FDA) in
1991.5 Pegylated G-CSF, developed as
peglgrastim (Neulasta, Amgen, Inc.),
is another alternative used in patients
with SCN since its initial FDA approval
in 2002.6 In 2012, the FDA approved
another G-CSF, tbo-lgrastim (Granix,
Teva, Inc.).7
The Patient Protection and Affordable
Care Act (PPACA), signed into law by
President Obama in 2010, paved the way
for the expedited development of less
costly alternatives to FDA-approved bio-
logics. The biosimilars provision in the
PPACA creates an abbreviated licensure
pathway for biologics that are demon-
strated to be biosimilar to or inter-
changeable with an already-approved
biologic in terms of efcacy, safety, purity,
and potency. (Minor differences in clini-
cally inactive components are permitted.)
The biosimilar is bound to the same regu-
lations as the reference entity and must
also adhere to FDA standards.8
The FDA approved lgrastim-sndz
(Zarxio, Sandoz, Inc.), the rst biosimilar
product available in the United States, in
March 2015. Zarxio has the same mecha-
nism of action, route of administration,
strength, and dosage form as Amgens
Neupogen.9
MECHANISM OF ACTION
Endogenous G-CSF is a lineage-
specic colony-stimulating factor pro-
duced by monocytes broblasts, and
endothelial cells. It regulates the pro-
duction of neutrophils within the bone
marrow and affects neutrophil progenitor
proliferation differentiation, and selected
end-cell functions (including enhanced
phagocytic ability priming of the cellular
metabolism associated with respiratory
burst antibody-dependent killing, and the
increased expression of some cell surface
antigens). G-CSF is not species-specic
and has been shown to have minimal
direct in vivo or in vitro effects on the pro-
duction or activity of hematopoietic cell
types other than the neutrophil lineage.10
INDICATIONS
Zarxio is approved for several indica-
tions, the rst of which is to decrease
the incidence of infection in patients
with nonmyeloid malignancies receiv-
ing myelosuppressive chemotherapy
associated with a signicant incidence
of febrile neutropenia. It is approved
to reduce the time to neutrophil recov-
ery and the duration of fever following
induction or consolidation chemotherapy
treatment of patients with acute myeloid
leukemia (AML); and to reduce the
duration of neutropenia and neutropenia-
related clinical sequelae (e.g. febrile
neutropenia) in patients with nonmyeloid
malignancies undergoing myeloablative
chemotherapy followed by BMT. In
addition, Zarxio is indicated to mobilize
autologous hematopoietic progenitor
cells into the peripheral blood for collec-
tion by leukapheresis; and for chronic
administration to reduce the incidence
and duration of sequelae of neutropenia
(e.g. fever infections oropharyngeal
ulcers) in symptomatic patients with
congenital cyclic or idiopathic
neutropenia.10
DOSAGE AND ADMINISTRATION
Zarxio may be administered as a sub-
cutaneous injection, a short intravenous
(IV) infusion over 1530 minutes, or a
continuous IV infusion, dependent on the
indication.10
Vol. 42 No. 1 January 2017 P&T
19
DRUG FORECAST
For patients with cancer receiving
myelosuppressive chemotherapy and/or
consolidation chemotherapy for AML,
the recommended dose is 5 mcg/kg per
day by any of the three approved routes
of administration. A complete blood
count (CBC) and platelet count should
be performed before the patient begins
treatment. During treatment, monitor the
patient twice weekly for changes in ANC
and platelet count. Zarxio is not recom-
mended in patients with an ANC greater
than 10,000/mm3.10
Zarxio should not be administered
within the 24-hour period before chemo-
therapy and should be administered at
least 24 hours after cytotoxic chemo-
therapy. ANC levels will increase tran-
siently one to two days after the rst treat-
ment. To ensure a sustained response,
administer Zarxio daily for up to
two weeks or until the ANC has reached
10000/mm3 following the expected
chemotherapy-induced neutrophil nadir.10
For patients with cancer who have
undergone BMT, the recommended dos-
age is 10 mcg/kg daily, which should
be administered as an IV infusion for no
longer than 24 hours. Administer the rst
dose of Zarxio at least 24 hours after cyto-
toxic chemotherapy and at least 24 hours
after bone marrow infusion.10
For patients with cancer undergoing
autologous PBPC collection and therapy,
the recommended dosage is 10 mcg/kg
per day given by subcutaneous injection.
Administer Zarxio for at least four days
before the rst leukapheresis procedure
and continue until the last leukapher-
esis procedure. Although the optimal
duration of Zarxio administration and
leukapheresis schedule have not been
established administration of lgrastim
for six to seven days with leukapheresis
on days 5 6 and 7 was found to be safe
and effective.10
For patients with suspected SCN, con-
rm the diagnosis by evaluating serial
CBCs with differential and platelet counts,
and by evaluating bone marrow morphol-
ogy and karyotype. If Zarxio is used before
conrming the correct diagnosis, diagnos-
tic efforts may be impaired, thus impairing
or delaying the evaluation and treatment
of an underlying condition (other than
SCN) causing the neutropenia.10
The starting dose for patients with
congenital neutropenia is 6 mcg/kg as a
twice-daily subcutaneous injection. The
20 P&T January 2017 Vol. 42 No. 1
recommended starting dosage in patients
with idiopathic or cyclic neutropenia is
5 mcg/kg as a single daily subcutaneous
injection.10
PIVOTAL PHASE 3 STUDY
A rigorous program of clinical trials
that demonstrates no clinically meaning-
ful differences between the biosimilar
product and the reference product must
be completed for a biosimilar to receive
FDA approval.8 The totality of evidence
presented to the FDA for Zarxio com-
pared with Neupogen showed no clinically
meaningful differences between them.11
The phase 3 PIONEER trial, a ran-
domized, double-blind, parallel-group,
multicenter study, was conducted to
demonstrate the noninferiority of Zarxio
to Neupogen in the prevention of neutro-
penic complications in 218 breast cancer
patients treated with myelosuppressive
chemotherapy.12 The study also pro-
vided safety and efcacy outcomes for
Zarxio compared with Neupogen. Key
inclusion criteria encompassed patients
with histologically proven breast cancer
approved for neoadjuvant or adjuvant
chemotherapy; women 18 years of age
and older; estimated life expectancy of
more than six months; an Eastern Coop-
erative Oncology Group performance
score of 2 or less; adequate bone marrow
function prior to chemotherapy admin-
istration; and an ANC of 1.5 x 109/L or
greater, a platelet count of 100 x 109/L
or greater, and a hemoglobin level of
10 g/dL or greater.12
Patients were initially randomized to
either Zarxio or Neupogen. Half of the
patients remained on the therapy started
in the rst treatment cycle for the dura-
tion of the trial, while the other half of the
patients received alternating treatment
with either Zarxio or Neupogen starting
with the second cycle of chemotherapy.
This design was used to assess whether
switching the therapies during the treat-
ment period had any impact on safety,
efcacy, and immunogenicity.12
Patients in the study received
5 mcg/kg of Zarxio or Neupogen daily
starting on day 2 of each chemotherapy
cycle and continued until ANC levels
recovered to 10 x 109/L or for a maxi-
mum of 14 days of treatment, whichever
occurred rst. The primary endpoint was
duration of chemotherapy-induced severe
neutropenia, which was dened as the
number of consecutive days with grade 4
neutropenia (ANC less than 0.5 x 109/L).
Secondary efcacy endpoints included
incidence of febrile neutropenia by cycle
and across all cycles; the number of days
of fever for each cycle; depth of ANC
nadir; time to ANC recovery; frequency of
infections by cycle and across all cycles;
and incidence and duration of hospital-
ization due to febrile neutropenia. Safety
endpoints included incidence, occur-
rence, and severity of serious adverse
events, local tolerability at the injection
site, and systemic tolerability.12
The mean duration of grade 4 neutro-
penia in cycle 1 was approximately
1.2 days (range, zero to four days) in both
groups. The mean difference in duration
of neutropenia was 0.04 days. The inci-
dence of febrile neutropenia was low in
both groups, with no clinically relevant
differences for cycle 1. The mean time to
ANC recovery in cycle 1 was also similar
for Zarxio compared with Neupogen. In
all, there were no substantial differences
between the treatment arms.12
The data assessed from cycle 2, which
represented switching the therapies about
halfway through the trial, also showed
similar results for all treatment arms. The
incidence of febrile neutropenia in the
group that received the same treatment
throughout the study was 2.3%, while
the incidence in the group that switched
therapies was 6.7%, which did not exceed
the noninferiority margin of 15%.12
The safety analysis included a total
of 214 patients, approximately 96.3% of
whom experienced one adverse event.
Most adverse events were related to
chemotherapy, and the safety proles
of Zarxio and Neupogen were similar.
No statistically signicant difference in
safety was reported.12
The most frequent treatment-emergent
adverse events for the two therapies were
alopecia, nausea, asthenia, fatigue, and
bone pain. The most notable adverse drug
reactions were bone pain (Zarxio, 23%, ver-
sus Neupogen, 33%) and musculoskeletal
pain (Zarxio, 7%, versus Neupogen, 2%).12
ADVERSE DRUG REACTIONS
Adverse drug reactions vary according
to the indication for which Zarxio is used.
The most common adverse reactions in
patients with nonmyeloid malignancies
receiving myelosuppressive anticancer
drugs are pyrexia, pain, rash, cough, and

dyspnea (5% or greater difference in inci-
dence compared to placebo). In patients
with AML, adverse reactions include pain,
epistaxis, and rash (2% or greater differ-
ence in incidence compared to placebo).
Patients with nonmyeloid malignancies
undergoing myeloablative chemotherapy
followed by BMT most often experience
rash (5% or greater difference in inci-
dence compared to placebo). In patients
undergoing PBPC mobilization and col-
lection, the most common adverse effects
are bone pain, pyrexia, and headache
(5% or greater difference in incidence
compared to placebo). Pain, anemia,
epistaxis, diarrhea, hypoesthesia, and
alopecia may occur (5% or greater differ-
ence in incidence compared to placebo)
in patients with SCN.10
WARNINGS AND PRECAUTIONS
Splenic ruptures and sickle cell
crises, including fatal cases, have
been reported after treatment with
lgrastim products. In addition, treat-
ment may cause acute respiratory
distress syndrome; serious allergic
reactions, including anaphylaxis; glo-
merulonephritis; alveolar hemorrhage
and hemoptysis; thrombocytopenia;
leukocytosis; and cutaneous vasculi-
tis. Symptomatic patients should be
monitored for capillary leak syndrome.10
Cytogenetic abnormalities and trans-
formation to myelodysplastic syndromes
(MDS) and AML have been reported in
patients with SCN treated with lgrastim
products.10
Because the G-CSF receptor through
which Zarxio acts has also been found
on tumor cell lines, the possibility that
the treatment acts as a growth factor for
any tumor type cannot not be excluded.10
Simultaneous use of Zarxio with chemo-
therapy or radiation therapy has not been
evaluated and is not recommended.10
Growth factor therapy has been
associated with transient positive bone-
imaging changes, which should be taken
into account when interpreting nuclear
imaging results.10
DRUG INTERACTIONS
Zarxio administration is not recom-
mended within 24 hours of cytotoxic
chemotherapy because of the increased
risk of sensitivity of rapidly dividing
myeloid progenitor cells in response to
chemotherapy.10
CONTRAINDICATIONS
Zarxio is contraindicated in patients
with a history of serious allergic reactions
to human G-CSF, such as lgrastim or
peglgrastim.10
SPECIAL POPULATIONS
Pregnancy and Lactation
There are no adequate and well-
controlled studies of lgrastim products
in pregnant women; studies in rats and
rabbits revealed no fetal malformations,
although rabbits administered two to
10 times the human dose experienced
maternal toxicity, reduced embryo-
fetal survival, and increased abortions.
Because the risk to humans is unknown,
lgrastim products should be used during
pregnancy only if the potential benet
justies the potential risk to the fetus.10
It is unknown if lgrastim products
are excreted in human milk; therefore,
caution should be exercised if they
are administered to women who are
breastfeeding.10
Pediatric Use
Because the Zarxio prelled syringe
may not accurately measure volumes less
than 0.3 mL, the direct administration of
a volume less than 0.3 mL is not recom-
mended due to the potential for dosing
errors.10
Several studies have established the
pharmacokinetics, safety, and effective-
ness of lgrastim in pediatric patients.
Additional information is available from a
post-marketing surveillance study, which
includes long-term follow-up of patients in
the clinical studies and information from
additional patients who entered directly
into the post-marketing study. Of the
731 patients in the surveillance study,
429 were pediatric patients less than
18 years of age (range, 0.917 years). Long-
term follow-up data suggest that height
and weight are not adversely affected in
patients who received up to ve years of
lgrastim treatment. Limited data from
patients who were followed for 1.5 years
did not suggest alterations in sexual matu-
ration or endocrine function.10
Pediatric patients with congenital types
of neutropenia (Kostmanns syndrome,
congenital agranulocytosis, or Schwach-
manDiamond syndrome) have devel-
oped cytogenetic abnormalities and have
undergone transformation to MDS and
AML while receiving chronic lgrastim
DRUG FORECAST
treatment. The relationship of these events
to lgrastim administration is unknown.10
Geriatric Use
In three randomized, placebo-
controlled trials of a total of 855 lgrastim-
treated patients receiving myelo-
suppressive chemotherapy, 232 patients
were age 65 years or older and 22 were
age 75 years or older. No overall differ-
ences in safety or effectiveness were
observed between these patients and
the younger population. Clinical studies
of lgrastim in other approved indica-
tions (i.e., BMT recipients, PBPC mobi-
lization, and SCN) did not include suf-
cient numbers of patients 65 years of age
and older to determine whether elderly
people respond differently than those
who are younger.10
COST
Zarxio is provided in prelled syringes
in dosage strengths of 300 mcg/0.5 mL
and 480 mcg/0.8 mL. The average
wholesale prices (AWPs) of Zarxio are
$331 and $527 for 300 mcg/0.5 mL and
480 mcg/0.8 mL, respectively.13 In
contrast, the AWPs of Neupogen in
the same dosages, also provided in
prelled syringes, are $389 and $620,
respectively.13
P&T COMMITTEE
CONSIDERATIONS
A biosimilar product is identical in
function to its reference biologic drug,
but offers a lower-cost alternative. Zarxio,
the rst biosimilar approved by the FDA,
offers lower costs, potentially greater
accessibility to treatment, and increased
exibility in prescribing, which makes it
a landmark agent for future biosimilars.
P&T committees can consider adding
Zarxio to their formularies alongside or
in place of Neupogen to treat neutropenia.
CONCLUSION
Neutropenia is a condition that, if left
untreated, can result in signicant health
consequences. With its FDA approval,
Zarxio is the rst biosimilar to provide an
alternative to Neupogen that is similar in
safety and efcacy. This allows providers
and the market more than one option in
treating the various forms of neutropenia
at a lower cost.
continued on page 23
Vol. 42 No. 1 January 2017 P&T
21
 LETTERS TO THE EDITOR
Transition From Paper to Computerized
Pharmacist Clinical Decision Support
To the Editor:
The progress of electronic pharmacy clinical decision
support has been limited because of problems of interoperability
between and within electronic medical records (EMRs). EMRs
in use in hospitals are predominantly rst-generation EMRs
with 1970-style hierarchical databases that predate the advent
of relational database systems (RDBSs). These non-RDBSs
require the creation of computer applications, application
program interfaces, for an external application to access the
data stored in these non-RDBSs.
This is the root cause of the data silos and data islands
problem, where data are isolated to a single organization or
abandoned to a single unit within an organization. Hospital
pharmacy faces this issue as data are trapped in the EMR.
First-generation EMR providers adopted the enterprise busi-
ness model, where the customer relies on that single EMR for
all its information. Thus the very design of the rst-generation
EMRs supports the lack of interoperability; there was never
any intention to share the data with any outside entity. This
is a shrewd business model to maintain a local monopoly on
the data.
Most computer applications providing pharmacist clinical
decision support (RxCDS) require the user to type in the data
because the EMR will not share them. Fortunately, EMRs are
good at generating printed reports. Where there are printed
paper reports, there was once a text le, e.g., MyReport.txt.
Most hospital pharmacies periodically have a pharmacist
patient prole report generated to be used in the event of EMR
downtime. Likewise, most hospital nursing departments have
something to use for patient data as a backup to EMR failure.
We electronically mined EMR pharmacy downtime reports
intended as printed paper reports to collect patient-specic
data for use in an RxCDS application. The data automatically
populate into the RxCDS.
First, we found a pharmacist patient prole le and a prior
12-hour patient lab le on our local area network. Next, we
had our Information Technology Department increase the
frequency of the reports to generate them every two hours,
so we are never more than two hours behind in the data.
This eliminates the largest obstacle to the progress of an
RxCDS application: A data source is now available. Why
create an RxCDS application to discover the 30 patients in
your hospital who require renal dosing if you have to type in
all the information for 300 patients! Application developers or
programmers, either external or internal to the hospital, can
map the data to an existing RxCDS or create a new RxCDS.
Ideally a pharmacist who is also an application developer or
programmer can be found.
Our RxCDS is used for pharmacokinetic (PK) dosing of
aminoglycosdies and vancomycin; automating clinical pharmacy
protocols for renal dosing, anticoagulation, and total parenteral
nutrition (TPN); government regulatory compliance; ad hoc
searches for patients on specic drugs or with recent specic
laboratory tests; and providing patient pharmacy proles, labs,
and prescription label printing during planned or unplanned
EMR downtime.
22 P&T January 2017 Vol. 42 No. 1
The RxCDS is a productivity tool. Pharmacists spend no
time typing existing data into the RxCDS, so there are no data-
entry errors. Vancomycin/aminoglycoside and heparin dosing
are both faster and accurately reect clinical protocols. TPN
patients are found quickly, nutritional metrics calculated, and
current labs displayed. Our data is ltered to discover duplicate
prescriptions or overlapping as-needed indications so that
the pharmacist can correct those orders and avoid potential
medication administration errors as well as avoid government
regulatory nes. Patients on recalled or unavailable drugs
can be found quickly. Screening to nd patients who might
require a pharmacists intervention can be done quickly; the
relevant clinical pharmacy protocol is displayed with a sug-
gested course of action. Any actual intervention made by the
pharmacist can either be recorded into the RxCDS or copied
and pasted into the EMR.
Ad hoc observational studies can be created to investigate
medication issues. As an advantage to lowering bias in stud-
ies, the application decides, based on our inclusion criteria, if
a patient is included or excluded: There is no cherry-picking
of data.
Our argatroban dosing protocol required a dose reduc-
tion for patients on continuous renal replacement therapy
(CRRT); even though the drug is not renally cleared, CRRT
was suggested as a predictor of hepatic failure. We created a
small application to search our data and collected 30 relevant
patients. In about three-quarters, the results of liver-function
tests (LFTs) were elevated, but not in the other one-quarter,
who we may have been underdosing. A good suggestion was
to order LFTs to monitor for possible dose adjustments. As a
byproduct, we were surprised to discover that CRRT patients
had a mortality rate of 70%.
Some of our pharmacists use another PK dosing model
instead of our RxCDS PK function. It was recently noted
in morbidly obese patients that vancomycin regimens were
signicantly different between the two models. We created a
small application to search our data and collected 10 relevant
patients. We determined that using an adjusted weight for
patients whose actual weight was more than 1.5 times their
ideal body weight was best for our RxCDS vancomycin PK
model; otherwise it uses actual patient weight. This change
has been completed in the RxCDS. The other model (which
we cannot change) seems to underdose by estimating a longer
half-life in obesity.
The health care work environment in general is high touch
and low tech; hospital pharmacy is no different. We love our
paper and have suffered with the introduction of new technol-
ogy. We have endured the challenges of rst-generation EMR
implementations. We prefer to stay with our current EMR to
avoid going through the pain of a conversion. The centralized
enterprise business model is very seductive.
There is another, perhaps better modelthe federated
model, a decentralized collaboration of processes. The idea
is to use best of breed processes in a modular structure.
You own the model; the model does not own you. There is no
monopoly. If one of the subprocesses fails, you replace it with
another. The entire business is not brought down; there is no
downtime. This allows competitive free enterprise to create a
new product or service.
 LETTERS TO THE EDITOR
We need to add modular computer subprocesses to hospital
pharmacy, such as RxCDS. Any vendor providing a module for
functionality not in the EMR needs to have an interface (e.g.,
HL7) to the data held captive in the EMR. Our RxCDS simply
uses data from text les. Microsoft has marketed Amalga
to hospitals as a solution to move data from the EMR into
Microsoft SQL, an RDBS. Any modern computer application,
like our RxCDS, can access data from an RDBS. In time, it is
hoped that second-generation EMRs with RDBSs will be the
norm in hospital pharmacy. But for now we all must nd a
useable source of hidden EMR data to advance our hospital
pharmacy information systems.
Albert D. Stewart, PharmD, MBA
Clinical Pharmacist
St. Joseph Health Systems
Irvine, California
Extending Patents With New Indications
To the Editor:
In your November issue, Stephen Barlas expresses his dis-
satisfaction with a Food and Drug Administration, Congress,
and court system that refused to give AstraZeneca the tools to
prevent the generic manufacturer of Crestor from selling it for
the indication of homozygous familial hypercholesterolemia.1
However, he fails to see the overarching issue here. The drug
was going off patent. The company was trying to effectively
extend that patent by coming up with a new indication and
locking out the generic. In fact, the indication is just a rare
form of high cholesterol, a disease that this product, the
generic, and all the competing drugs already treat. To effectively
prohibit the generic from being used for the same purpose as
the brand version would be a gift to the drug company, and
probably unnecessary, since I am sure this drug was already
being tried by doctors treating someone with high cholesterol.
The law is ne as it is. We dont need to allow drug
companies to shut out generics by using these sleight-of-hand
tricks.
Lorne Basskin, PharmD
Professor, Health Economics
Brown University School of Professional Studies
Providence, Rhode Island
REFERENCE
1. Barlas S. The push for additional orphan drugs. Can the FDA
do more to encourage their development? P T 2016;41(11):667.
Wed love to hear from you!
Send your letters to:
smciver@medimedia.com
MEDICATION ERRORS
continued from page 5
engage in disrespectful behaviors may be powerful in the orga-
nization, which may discourage reporting of the behavior due
to fear of retaliation and a general reluctance to confront the
individual. Organizations may also be wary of offending high-
revenue producers and therefore fail to take action. But the deep
sense of frustration threaded through many of the comments
from survey respondents suggests that now is the time for action.
In next months column, Part 2 of our report will provide
recommendations to help address this longstanding problem.
REFERENCE
1. ISMP. Intimidation: Practitioners speak up about this unresolved
problem (part I). Available at: www.ismp.org/sc?id=248. Accessed
November 21, 2016. Q
DRUG FORECAST
continued from page 21
REFERENCES
1. Territo M. Neutropenia (agranulocytosis; granulocytopenia).
Merck Manual Professional Version. July 2014. Available at: www.
merckmanuals.com/professional/hematology-and-oncology/leu-
kopenias/neutropenia. Accessed August 26, 2016.
2. BMJ Best Practice. Assessment of neutropenia. BMJ Publishing
Group. August 17, 2016. Available at: http://bestpractice.bmj.com/
best-practice/monograph/893.html. Accessed August 26, 2016.
3. American Society of Clinical Oncology Cancer.Net. Neutropenia.
August 2015. Available at: www.cancer.net/navigating-cancer-care/
side-effects/neutropenia. Accessed June 14, 2016.
4. MedlinePlus. Low white blood cell count and cancer. May 4,
2015. Available at: https://medlineplus.gov/ency/patientinstruc-
tions/000675.htm. Accessed September 6, 2016.
5. Neupogen (lgrastim) prescribing information. Thousand Oaks,
California: Amgen, Inc.; 2016.
6. Food and Drug Administration. Drugs@FDA: Neulasta (pegl-
grastim). April 28, 2016. Available at: www.accessdata.fda.gov/
scripts/cder/daf/index.cfm?event=BasicSearch.process. Accessed
November 14, 2016.
7. Traynor K. Pharmacy news: FDA approves Tevas tbo-lgrastim.
American Society of Health-System Pharmacists. October 21,
2013. Available at: www.ashp.org/menu/News/PharmacyNews/
NewsArticle.aspx?id=3775. Accessed June 14, 2016.
8. Food and Drug Administration. Information on biosimilars. May
10, 2016. Available at: www.fda.gov/Drugs/DevelopmentApprov-
alProcess/HowDrugsareDevelopedandApproved/ApprovalAp-
plications/TherapeuticBiologicApplications/Biosimilars. Accessed
February 20, 2016.
9. Food and Drug Administration. FDA approves rst biosimilar
product Zarxio. March 6, 2015. Available at: www.fda.gov/newsev-
ents/newsroom/pressannouncements/ucm436648.htm. Accessed
February 20, 2016.
10. Zarxio (lgrastim-sndz) prescribing information. Princeton, New
Jersey: Sandoz, Inc.; 2016.
11. Sandoz. Zarxio (lgrastim): Presentation to the FDA Oncologic
Drugs Advisory Committee. January 7, 2015. Available at: www.fda.
gov/downloads/advisorycommittees/ucm431119.pdf. Accessed
November 14, 2016.
12. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of
EP2006, a lgrastim biosimilar, to the reference: a phase III, ran-
domized, double-blind clinical study in the prevention of severe
neutropenia in patients with breast cancer receiving myelosuppres-
sive chemotherapy. Ann Oncol 2015;26(9):19481953.
13. Red Book Online. Ann Arbor, Michigan: Truven Health Analytics.
Accessed November 14, 2016. Q
Vol. 42 No. 1 January 2017 P&T
23
 2017 Presages Dramatic Change
For Federal Health Care Policies
Republicans Are Likely to Face Hiccups Along the Way
Stephen Barlas
onald Trumps election as president poses a real
D challenge to elements of the U.S. health care policy
framework. But it is not yet clear whether the changes
will reach seismic proportions or resemble ripples in a pond.
Despite repeated statements during the campaign that he would
repeal Obamacare immediately upon taking ofce,
the president-elect said a few days after his election,
once he had chatted with President Barack Obama,
that he wants to keep a couple of its key reforms,
such as prohibiting insurance companies from
discriminating based on existing illnesses.
Trump will have a strong ally in congressional
Republicans, who have a much broader, more com-
plete agenda that includes important changes to
Medicare and Medicaid as well as a restructuring of Stephen Barlas
health insurance. Depending on the extent to which
those changes morph into law, the new order will likely affect
every corner of health care, from hospitals to physicians to all
sectors of the pharmaceutical industry.
The pharmaceutical industry, theoretically, has a lot at stake,
having drawn Trumps reproach during the campaign. For
example, at a March GOP primary debate in Miami, Trump said,
They have a fantastic lobby. They take care of all of the senators,
the congressmen. That sounded as if it were part criticism and
part compliment. During the campaign, he supported letting
Medicare negotiate drug prices with pharmaceutical companies,
anathema to the industry. He also blessed importation of drugs
from abroad, also condemned by the industry.
Trumps presidential campaign website appears to send
veiled warnings to the industry. It includes, in the same para-
graph, these statements: Though the pharmaceutical indus-
try is in the private sector, drug companies provide a public
service, and Congress will need the courage to step away
from the special interests and do what is right for America. 1
If Trump takes on the pharmaceutical industry, he will nd
willing allies among the Democrats. At a meeting with reporters
on November 17, Senator Bernie Sanders (I-Vermont), who
caucuses with the Democrats, argued that he and Trump could
forge a common cause on drug pricing.
In September 2015, Sanders introduced legislation (S. 2023)
called the Prescription Drug Affordability Act.2 It would make
numerous changes, such as allowing Medicare to negotiate lower
drug prices in Medicare Part D, accelerating closure of the Part D
doughnut hole, requiring drug companies to issue additional
rebates under various circumstances, and more. However, that
Mr. Barlas is a freelance writer in Washington, D.C., who covers
issues inside the Beltway. Send ideas for topics and your comments
to sbarlas@verizon.net.
24 P&T January 2017 Vol. 42 No. 1
bill never received a hearing in the Senate Finance Committee,
despite high-visibility hearings in both the House and Senate
during 2016 that featured drug-pricing horror stories. Senator
Amy Klobuchar (D-Minnesota) introduced a narrower bill (S. 31)
authorizing Medicare to deal directly with drug companies on
price.3 That bill also went nowhere. Neither Sanders
nor Klobuchars press ofces responded to requests
concerning the senators chances of enlisting Trumps
support for their efforts in 2017.
Some of Trumps promises and threats will become
history once he occupies the White House; perhaps
some already have. Mary Jo Carden, Vice President
of Government and Pharmacy Affairs for the Academy
of Managed Care Pharmacy (AMCP), says Trump
appeared to backtrack during the campaign on his
support for direct negotiation between Medicare and
drug companies, morphing from that position to one supporting
importation of foreign drugs. The AMCP opposes direct negotia-
tion by the government. But drug prices are still an issue on
American minds, Carden states. She believes that value-based
purchasing of drugs is more likely to be the avenue that Congress
and the Trump administration take to ease the cost of specialty
drugs to payers such as Medicare, Medicaid, and hospitals.
Pharmaceutical companies generally dont have a problem
with value-based pricing, as long as it conforms to their formula.
They have strongly opposed the work done by the Institute for
Clinical and Economic Review (ICER), which has published a
series of monographs estimating what a reasonable price would
be for high-prole drugs such as sofosbuvir (Sovaldi, Gilead
Sciences) and the proprotein convertase subtilisin/kexin type 9
inhibitors. The reason we oppose the ICER methodology is
because it does not give enough weight to patient experience,
one industry insider explains. We do believe we need as an
industry to bring greater evidence to payers to demonstrate
they are getting value.
With a view toward congressional legislative efforts on
drug pricing in 2017, the drug industry is backing an ICER
rival called the Innovation and Value Initiative, which is a new
program of Precision Health Economics, a research consulting
rm to the health care industry. Its website states: Our view
is that ICER currently emphasizes a short-term budget impact
approach based on concepts of affordability. Our research will
focus more on the longer term, looking at health care spending
as an investment in the vitality of the system as well its cost.4
The Future of the PPACA
For Trump and congressional Republicans, the marquee
issue, of course, is repeal and replacement of the Patient
Protection and Affordable Care Act (PPACA) insurance market-
 2017 Presages Dramatic Change for Federal Health Care Policies
place, where more than 20 million individuals and employees
of small businesses not covered by employer health care have
been able to obtain insurance. The majority of those individu-
als are in the 31 states that have expanded their Medicaid
programs. About 80% of the policies purchased by individuals
(outside of Medicaid) are heavily subsidized by the federal
government. Trump and GOP allies have promised immediate
repeal, though they havent laid out a replacement except to
endorse some general solutions such as allowing consumers
to cross state lines to buy insurance policies and greater access
to health savings accounts (HSAs).
The blueprint for repeal of some key elements of the PPACA
is already in place. Last year Congress passed a budget rec-
onciliation bill (H.R. 3762) that annulled key portions of the
exchanges, such as the subsidies, the requirement to buy
insurance, and the Medicaid expansion, which is nanced
up to 90% until 2020 by the federal government.5 There was a
transition period of two years before the disappearance of the
PPACA marketplaces as presently constituted. That would
give policy-holders and insurance companies a chance to
adjust to the changes, which would likely cause a mass exodus
from marketplace policies both by consumers and insurance
companies. President Obama vetoed that bill.
But the provisions of H.R. 3762 are likely to be the starting
and perhaps ending point for a repeal bill in 2017. Unlike most
bills, a budget reconciliation bill needs only 50 votes to pass the
Senate, not 60. There will be 52 GOP members in the Senate
in 2017. House passage of a bill such as H.R. 3762 in 2017 is a
foregone conclusion. But a bill like H.R. 3762 cannot eliminate
all aspects of the PPACA exchanges, just those dealing directly
with federal spending and taxes. So that legislation can eliminate
tax penalties on those not buying policies (i.e., the individual
mandate) and subsidies for 80% of policy-holders.
Though a successor to H.R. 3762 could pass Congress
quickly and receive President Trumps signature, that will not
happen immediately. Trump has already said that President
Obama convinced him to keep the requirement that insurance
companies not discriminate in terms of premiums charged to
people with pre-existing conditions. He also wants to allow
adults 26 years of age or younger to stay on their parents poli-
cies. The GOP will have to come up with some workarounds
to last years bill to accommodate Trumps statements (unless
he repudiates them).
Negotiations between the congressional GOP and the Trump
White House should be relatively smooth given Trumps
appointment of Representative Tom Price, MD (R-Georgia), to
be Secretary of the Department of Health and Human Services.
Dr. Price was chairman of the House Budget Committee and
a senior member of the Health Subcommittee in Ways and
Means. An orthopedic surgeon, he has deep knowledge of
federal health programs and was a leading theoretician for
the House GOP in its drive to end the PPACA and reform
Medicare and Medicaid.
Its simply too soon to respond to anything that may or may
not be proposed, says Kristine Grow, Senior Vice President
for Americas Health Insurance Plans, the health insurance
industrys lobbying group. But her comments indicate the
insurance industrys desire to keep all the facets of current
PPACA policies. The demands of consumers havent changed,
she states. They want affordable coverage, the control to
choose a plan that best ts them, high-quality care that gets
them well when theyre sick and keeps them well when theyre
healthy, and nancial protection, peace of mind, and value that
insurance provides.
Trump and other Republicans have some of the same ideas
for the replace part of PPACA elimination. House Speaker
Paul Ryan (R-Wisconsin) headed an effort in 2016 to produce
a game plan called A Better Way for changes to federal
health plans.6 Trumps transition website echoes many of these
GOP ideas. A bushel of the prescriptions are long-term
Republican tenets, such as expansion of HSAs tied to high-
deductible health insurance plans. The Ryan blueprint argues
that the PPACA put a number of roadblocks in the way
of HSAs that should be ditched. Rather than subsidizing
individual health insurance plans, as the PPACA does, the
GOP would provide a universal, advanceable, refundable tax
credit for individuals and families. The new xed credit would
be large enough to purchase the typical pre-PPACA health
insurance plan. The GOP Better Way also advocates allow-
ing consumers to buy insurance across states lines, a longtime
Republican concept that Democrats have shunned whenever
it was broached.
What May Await Medicare
Changes to Medicare and Medicaid are also in the ofng.
A Better Way includes a number of prescriptions for change in
the Medicare Part B physician care, Part C Medicare Advantage,
and Part D outpatient drug benet programs. President-elect
Trump said during the campaign that he didnt want to touch
Medicare. Still, no one has ever accused him of consistency,
as he has shown by pledging adherence to a couple of PPACA
precepts.
Here again, expect the GOP members of Congress to take
the lead. A Better Way strategy would bend Medicare poli-
cies away from fee-for-service toward both a premium-support
program and Medicare Advantage, the health maintenance
organization option that has been around since 2003. In pre-
mium support, a senior would get a xed amount with which
to buy an insurance plan on the private market. Republicans
think Medicare Advantage has more cost savings built in
than fee-for-service, and from the seniors perspective has the
advantage of an annual ceiling on out-of-pocket costs, which
Part B plans do not have. Hardly anyone disputes that Medicare
costs are unsustainable over the long term. The Congressional
Budget Ofce estimates the Part A Hospital Insurance Trust
Fund will be insolvent in 2026.
The Medicare Part D outpatient drug benet, established
in 2003, has been something of a roaring success. But like
the PPACA marketplace plans and state Medicaid plans, it
has been hurt by high drug prices. Trump has advocated
for direct negotiations between the Medicare program and
drug companies. But when that kind of proposal has come up
in Congress in past years, Republicans and pharmaceutical
companies have opposed it. The industry insider says that
Part D plans negotiate rebates from drug companies on the
order of 20% off the list price, so negotiation takes place in the
program already. Moreover, Medicare has no desire to establish
a national formulary. Is Medicare going to deny every Part D
Vol. 42 No. 1 January 2017 P&T
25
 2017 Presages Dramatic Change for Federal Health Care Policies
plan the right to carry a specic drug on their formulary? he
asks. Formulary setting is not their expertise.
The Prospects for Medicaid
Republicans want to convert Medicaid into a block grant pro-
gram in which states would have more freedom to determine
what they cover, including which drugs they pay for.6 Trump has
nominated a true believer on behalf of Medicaid reform to head
the Centers for Medicare and Medicaid Services (CMS). Seema
Verma was one of the architects of Indianas Healthy Indiana
Plan (HIP) 2.0, which opened for business in February 2015. It
won a Medicaid waiver from the Obama administration, which
enabled Medicaid expansion to Indianas higher-income poor.
Recipients are required to make monthly paymentsequal to
2% of incometo an HSA in exchange for a more expansive HIP
Plus benet package. Residents with incomes under 100% of the
poverty line who cannot make those contributions are placed
in a HIP Basic plan with limited benets. A study by Lewin
Associates based on one year of the plans operation found that
upwards of 70% of members of HIP Plus and Basic were satised
with their coverage.
However, Vermas work with both Kentucky and Ohio in
2016 failed to gain a Medicaid exemption for either of those two
states. Verma is the owner of a health care consulting company
in Indianapolis. Her general philosophy ts in with the beliefs of
Dr. Price and other Republican legislators that federal dollars can
be saved by turning Medicaid into a block grant program without
sacricing access to care, all by turning Medicaid into a managed
care program where members have what Vice President-elect and
former Indiana Governor Mike Pence calls skin in the game.
Some of the 31 state Medicaid expansions created under the
PPACA may be jeopardized if federal subsidies are ended. The
100% of new enrollee costs the CMS is paying today in expan-
sion states drops in stages to 90% by 2020. Ending those sub-
sidies, which may force states to drop a large percentage of the
12 million people added under the expansion, would denitely
hurt hospitals. For hospitals, the majority of those 12 million
were formerly nonpaying customers. Pharmaceutical compa-
nies could be hurt, too, but not all of them. The impact would
depend on the extent of the rebate a drug company is paying,
with those paying high rebates not being affected as much.
Companies paying the highest rebates make less money than
drug companies paying smaller rebates. Generally, older drugs
pay higher rebates. Our new net Medicaid sales are very low,
reports one industry executive from a major manufacturer that
is among those that would not suffer, sales-wise, from the end
of the expansion.
The Medicaid rebate structure is as arcane as any policy
in Washington. It has been around for decades and is ripe for
reform, which may be on the agenda for 2017 if the National
Association of Medicaid Directors (NAMD) and others, perhaps
even the pharmaceutical industry, have their way. Last March
the NAMD sent a letter to the leaders of the Senate Finance
Committee saying: We continue to believe that the policy levers
available to state Medicaid programs are not designed to address
fundamental sustainability issues posed by high-cost, high-impact
products. Currently, there is little insight into how pharmaceuti-
cal manufacturers price new therapies entering the market and,
more specically, the potential value for Medicaid populations. 7
26 P&T January 2017 Vol. 42 No. 1
Possible Changes at the FDA
Drug companies argue that their prices reect research and
development costs, which are unnecessarily high because of
Food and Drug Administration (FDA) approval requirements.
The Trump campaign website seems to agree with this senti-
ment. It supports this step: Remove barriers to entry into free
markets for drug providers that offer safe, reliable, and cheaper
products. 1 That may or may not be a call to change FDA
rules. If it is, it ts hand-in-glove with the congressional GOPs
A Better Way, which says: Translating research into thera-
pies is an incredibly risky, cumbersome, and expensive process.
We must improve how new treatments are developed, tested,
and ultimately approved by the FDA. Our plan would stream-
line clinical trials and modernize data collection activities by
cutting through red tape, using drug development tools like
biomarkers and patient-reported outcomes, and harnessing the
wealth of information in electronic health records and other
troves of real-world data. 6
There is some regulatory relief in the 21st Century Cures bill
signed by President Obama in December 2016. But those mea-
sures were probably just a down payment on a much broader
attempt to eliminate regulatory barriers during reauthorization
of the Prescription Drug User Fee Act (PDUFA), which expires
at the end of September 2017. The PDUFA sets the fees that
drug companies pay the FDA to fund staff working on drug
approvals. It also contains FDA commitments on the speed of
application review and policy changes to the approval process.
User fees in scal year (FY) 2016 stood at $851 millionabout
two-thirds of the FDAs FY 2016 budget for human drugs, which
is $1.4 billion. The FDA has already met with interested parties
to gather input on how it can improve its approval process in
the context of the PDUFA reauthorization Congress is expected
to pass in September 2017.
In July, the FDA released its PDUFA VI Goals Letter for
FYs 2018 to 2022.8 It includes commitments in areas such as
additional stafng and post-market surveillance, which are of
prime importance to various pharmaceutical sectors. In terms
of stafng, the agency has committed, for example, to estab-
lishing a dedicated unit within the Ofce of Medical Products
and Tobacco charged with the continuous recruiting, stafng,
and retention of scientic, technical, and professional staff for
reviewing human drug applications. The agency sets specic
numbers for professional hires in each of the ve years covered
by the commitment letter.
In another area, the FDA promises to buff up its Sentinel
System, which looks at adverse reactions to drugs once they
enter the market. Improving the Sentinel System is a top
priority of pharmacy groups. The FDA says it will use user
fee funds to conduct a series of activities to systematically
implement and integrate Sentinel in FDA pharmacovigilance
practices. These activities will involve augmenting the quality
and quantity of data available through the Sentinel System,
improving methods for determining when and how that data
is utilized, and comprehensive training of review staff on the
use of Sentinel.
The Sentinel System of post-market surveillance was autho-
rized by Congress in 2008, remained a pilot program until
2014, and has only recently blossomed into a wider-ranging
drug adverse effects monitoring system. It relies on the FDAs
 2017 Presages Dramatic Change for Federal Health Care Policies
database of individuals medical claims and looks for abnormali- 4. Innovation and Value Initiative. How is IVI related to organizations
ties rather than depending, as the FDA has for decades, on like ICER? 2016. Available at: http://thevalueinitiative.org/search/
section/general/string/icer. Accessed November 29, 2016.
physicians and drug companies voluntarily reporting problems 5. Price T. H.R.3762To provide for reconciliation pursuant to
caused by drugs. Pharmacy groups sent a letter to the FDA Section 2002 of the concurrent resolution on the budget for s-
after its PDUFA VI commitment letter was published saying: cal year 2016. 114th Congress (20152016). February 2, 2016.
Our organizations commend the FDA for its commitment to Available at: www.congress.gov/bill/114th-congress/house-
bill/3762. Accessed November 29, 2016.
develop a more robust and rigorous Sentinel program. Our orga-
6. A Better Way. Health care. June 22, 2016. Available at: http://
nizations agree that performing active, diligent post-marketing abetterway.speaker.gov/_assets/pdf/ABetterWay-HealthCare-
pharmacovigilance is critical for proactively identifying possible PolicyPaper.pdf. Accessed November 29, 2016.
areas of concern for medications and ensuring the ongoing 7. Salo M. Letter to Senators Ron Wyden and Charles Grassley,
safety of medications post-approval. Senate Finance Committee. National Association of Medicaid
Directors. March 4, 2016. Available at: http://medicaiddirectors.
org/wp-content/uploads/2016/03/NAMD-Response-to-SFC-on-
Antitrust Concerns About Health Care drug-value-03-04-16.pdf. Accessed November 30, 2016.
Elsewhere in the bureaucracy, the Justice Department 8. Food and Drug Administration. PDUFA reauthorization perfor-
looms large because of its policing of mergers and other mance goals and procedures, scal years 2018 through 2022.
Available at: www.fda.gov/downloads/ForIndustry/UserFees/
antitrust issues, such as pricing agreements between phar-
PrescriptionDrugUserFee/UCM511438.pdf. Accessed November
macy benet managers (PBMs) and drug manufacturers. 30, 2016.
David Balto, a Washington attorney who specializes in health 9. Marino T. H.R.1188Preserving Our Hometown Independent
care issues, doesnt expect a Trump Justice Department to Pharmacies Act of 2013. 113th Congress (20132014). March
take a much different approach to mergers than the Obama 14, 2013. Available at: www.congress.gov/bill/113th-congress/
house-bill/1188/cosponsors. Accessed November 30, 2016. Q
Justice Department, which contested the Aetna/Humana
and Anthem/Cigna health care merger proposals. What may
get added scrutiny are complaints from pharmacies alleging
predatory practices by PBMs. Past administrations have Call for Papers
pursued such allegations. For example, Novartis and
P&T is accepting submissions. We welcome a variety
AstraZeneca have agreed to pay nes and penalties to settle
of manuscripts, including drug class reviews, disease
allegations that they had offered a quid pro quo to PBMs for
state management reviews, pharmacoeconomic analyses,
preferred formulary status.
Balto notes that Representative Tom Marino (R-Pennsylvania) strategies for coping with medication errors, P&T com-
is taking over as chairman of the House Judiciary Committees mittee experiences, and letters to the editor. While we
antitrust subcommittee. He is a foe of PBMs, Balto explains. will entertain all suggestions, readers have expressed
Marino introduced a bill called the Preserving Our Hometown interest in these topics:
Independent Pharmacies Act in past Congresses (though GENERAL
not in the last one) that would have exempted independent Biosimilars Orphan drugs
drugstores from antitrust laws prohibiting them from banding Clinical pharmacy Pharmacists
together to buy medication.9 Community pharmacies will also and medical staff challenges
have a strong supporter in Senator Jeff Sessions (R-Alabama), collaboration Pharmacy benet
nominated to be the next Attorney General. Sessions has
Electronic medical managers
advocated allowing pharmacies to collectively negotiate with
records P&T processes
PBMs, Balto adds.
Expect the Republican Congress to begin reining in health Long-term safety data Specialty drug cost
care spending in 2017 and laying out a broad selection of Medication trends
changes, many of which wont happen overnight. This time, reconciliation Transitions of care
no threatened presidential veto will stand in their way. None CLINICAL
of the GOP reforms are likely to make any sector within the Acute coronary Infectious diseases
pharmaceutical industry jump for joy. But if its any consola- syndrome Migraine
tion, hospitals, physicians, and other associated health care
Cancer, all types Multiple sclerosis
sectors wont be partying either.
Cardiac drug class Opioid addiction
REFERENCES reviews Osteoporosis
1. Donald J. Trump for President. Healthcare reform to make Amer- Diabetes Pneumonia
ica great again. Available at: www.donaldjtrump.com/positions/ Gastrointestinal Psoriasis
healthcare-reform. Accessed November 29, 2016. disorders
2. Sanders B. S.2023Prescription Drug Affordability Act of 2015.
Rheumatology
114th Congress (20152016). September 10, 2015. Available at: Hemophilia
www.congress.gov/bill/114th-congress/senate-bill/2023/text.
Accessed November 29, 2016. Please see our author guidelines at PTCommunity.com.
3. Klobuchar A. S.31Medicare Prescription Drug Price Negotia-
tion Act of 2015. 114th Congress (20152016). January 6, 2015.
You can contact the editor, J. Stephen McIver, via tele-
Available at: www.congress.gov/bill/114th-congress/senate- phone (267-685-3713) or email (smciver@medimedia.com).
bill/31/text. Accessed November 29, 2016.

Vol. 42 No. 1 January 2017 P&T

27
HEALTH CARE & L AW
Systemic Market and Organizational
Changes: Impact on P&T Committees
F. Randy Vogenberg, RPh, PhD; Rita Marcoux, RPh, MBA; and
Martha M. Rumore, PharmD, JD, MS, LLM, FAPhA
Keywords: Patient Protection
and Affordable Care Act, Medicare
Access and CHIP Reauthorization Act,
P&T, value-based reimbursement,
formularies, managed care, insurance
How We Got Here
The Post-PPACA Marketplace
In 2004, Balu et al. reviewed the chang-
ing role of the P&T committee from its
beginnings in acute-care hospitals.1
Traditionally, P&T committees limited
the impact of their decisions to the popu-
lations associated with their hospital or
health plan; however, as hospitals trans-
formed into larger health systems and
even integrated payer organizations, P&T
committees had to begin to consider
inpatient, outpatient, and/or ambulatory
needs in multiple hospitals and ambula-
tory care settings. The primary function
of the P&T committee had not necessar-
ily changed, but its scope expanded to
other health care entities, such as health
plans and pharmacy benet management
(PBM) rms.
After passage of the Patient Protection
and Affordable Care Act (PPACA) and
the implementation of health reform,
Vogenberg and Gomes revisited the
landscape of changes affecting P&T
committees in 2014.2 Market and regu-
latory changes since then have resulted
in more signicant modications to
Dr. Vogenberg is Principal at the Insti-
tute for Integrated Healthcare and National
Institute of Collaborative Healthcare in Green-
ville, South Carolina, and Adjunct Professor
of Pharmacy Administration at the Univer-
sity of Rhode Island, College of Pharmacy,
in Kingston, Rhode Island. Ms. Marcoux is a
Clinical Associate Professor of Regulations
and Managed Care and Director of Pharmacy
Outreach Programs at the University of Rhode
Island College of Pharmacy. Dr. Rumore is
Associate Professor of Social, Behavioral, and
Administrative Pharmacy at Touro College
of Pharmacy in New York, New York; and Of
Counsel at Sorell, Lenna & Schmidt, LLP, in
New York, New York.
28 P&T January 2017 Vol. 42 No. 1
health care delivery models in 2016,
a short two years later.
Today, P&T committees routinely deal
with chronic drug shortages and become
involved in ethical discussions on medica-
tion rationing. Still evolving, the commit-
tees role in hospitals, payer organizations,
and other entities has to meet the needs
of a market that has further changed with
new reimbursement pressures in both
quality and cost in care delivery accel-
erated by the PPACA; the emergence
of large, robust health care systems;
and the proliferation of biotechnology-
based drugs, diagnostic tests, and
devices. While the dening task of the
P&T committee has remained intactthe
evaluation of the clinical use of medica-
tions and development of guidelines for
managing access to them to ensure safe
drug use and administrationconcerns
around decision-making independence
are more commonly heard.3 The use of
clinical effectiveness data that integrate
overall costs and offer comparisons
among therapies for the sake of public
health remains imperative for the P&T
committee;2 however, conicts of interest
in patient care when making decisions
or creating guidelines from such
comparisons have emerged as a concern.
Now it is more important than ever for
P&T committees to use these data as
they make decisions for a larger volume
of patients who have been incorporated
into larger health systems. For example,
not only does a health system have to
consider the medications that patients
need while in the hospital, it must also
consider the drugs that its patients will
need at home to sustain positive health
outcomes and avoid readmission.
Stakeholders in Care Delivery
and Decision-Making
Pharmacists, physical therapists,
nurses, and physicians are assuming new
leadership responsibilities, making them
partners with P&T committees in improv-
ing clinical care and cost performance for
health systems. The formation of formal
and informal care teams tasked with
holistic care places drug therapy at a
higher level of scrutiny and accountability.
P&T committees offer a perceived sense
of comfort and independence in protecting
patients using prescribed drugs. However,
various institutional entities may be per-
ceived as using the formulary as leverage
for economic gain. Complicit or not, health
care professionals and manufacturers can
be tainted by perceptions that question the
integrity of health care entitiesand by
extension their P&T committees.
Decision-making across the health care
spectrum is under re, and economic pres-
sures are reshaping the landscape of care
delivery. Professionals in the stakeholder
mix are closest to patients and, therefore,
have the most credibility to lose during
the rapid transitions. As members of P&T
committees, health care professionals
necessarily need to redouble efforts to
represent the interest of patients for safety
and efcacy in drug therapy.
Focus on Cost and Quality
Considerations of quality, cost (reim-
bursement), and access (accreditation)
affecting P&T committees over the past
decade will become even more important
as new drugs and biologic therapies enter
the market and the shortage of primary
care physicians intensies.
Therapy costs, having skyrocketed in
the last few years, escalate the focus of
attention on cost but also on the achieve-
ment of good outcomes. The tension
among key attributes of a health care
systemcost, quality, and accessis
reverberating rapidly, causing further
stress that impacts the care of patients.
Efforts to identify key drivers in quality
to empower decision-making are under
way in an effort to moderate the system
tension that has opened access without
consideration of cost. As seen in health
care reform efforts in Massachusetts,
addressing cost rapidly emerges as a
priority. Pharmacotherapies today will
continue to engage P&T committees in
challenging issues beyond traditional
population health.

Convergence in Care Delivery
The nancial pressures to demonstrate
revenue growth and innovation in the
post-PPACA era has resulted in an accel-
erated merger and acquisitions trend
that began in 2014 and continues even
now. Hospitals and providers merged to
address the threats by more efcient and
cost-effective outpatient facilities as well
as changes in reimbursement. Regional
hospitals and health systems also afford
greater negotiating power with insurance
companies. These acquisitions or partner-
ships offer the integration of technology,
clinical practice, and providers needed to
address the developing models of care.
In 2015, the pharmaceutical and insur-
ance sectors joined in the merger and
acquisitions activity. The pharmaceuti-
cal sectors acquisitions and divestitures
attempted to capitalize on revenue growth,
specialty pipelines, and distribution
opportunities provided by the PPACA.
Some of the higher-prole deals included
Actavis and Mylan. Actavis purchased
Allergan for $70 billion and Kythera
Biopharmaceuticals for $2.1 billion
and divested its generics line to Teva.4
Mylan purchased a division of Abbott,
then inverted to the Netherlands for tax
benets. Pzer made a bid for Allergan,
but when the Obama administration intro-
duced rule changes in 2016, the value of
this overseas purchase diminished. The
new rules limited Pzers ability to shed
corporate citizenship in an effort to move
income and avoid taxes.5
Finally, national insurance market
activity has been delayed by the federal
government. In 2014, ve companies
represented 83% of the national insur-
ance market share. In 2015, Anthem
announced plans to purchase Cigna for
$54 billion, while Aetna made a $37-billion
offer for Humana.6 The government has
argued that this consolidation to three
insurers would reduce competition,
especially in the Medicare segment, as
well as limit quality initiatives and the
control of premiums. The AnthemCigna
judicial review is under way. The Aetna
Humana merger was set for a judicial
hearing in December 2016 and a decision
is expected mid-January 2017.7
While entities in all health care sectors
work to report revenue growth and inno-
vation to nancial markets, payers are
working to redene the reimbursement
algorithms. Value-based reimburse-
ment is being driven by the Centers
for Medicare and Medicaid Services
(CMS). CMS continues its work to replace
fee-for-service with episode-of-care pay-
ments and increase quality-based pay-
ments. Hospital value-based purchasing
and physician-based value modier pro-
grams reward providers for quality of care.
The Medicare Access and CHIP Reautho-
rization Act of 2015 (MACRA) provided a
new approach that aligns payment with
quality and value of care. MACRA sup-
ports two paths: the merit-based incentive
payment system (MIPS), which adjusts
fee-for-service payments, and advanced
alternative payment models (APMs),
which include patient-centered medical
homes, accountable care organizations,
and bundled payment-of-care initiatives.
The availability of data is imperative
to manage utilization and cost within
these new paradigms of reimburse-
ment. In 2018, MIPS will consolidate
existing quality programs into a unied
reimbursement that assesses quality,
resource use, technology, and clinical
practice. Payment adjustments will be
made based on individual composite
scores. The advanced APMs require
that providers meet the criteria for tech-
nology and quality measurement, and
assume more than nominal nancial risk.
Hospitals receiving bundled payments
will be required to manage inpatient and
postacute-care costs for up to 90 days.
Since the implementation of MACRA,
CMS has proposed additional bundles
for episodes of care, including the com-
prehensive care for joint replacement
model for hip and knee replacement, the
oncology care model, and the cardiac
bundled payment model for heart attacks
and bypass surgery.8 To avoid costs shift-
ing to the private sector, private insur-
ers are monitoring and implementing
similar bundled payment programs and
quality measures. Anthem Blue Cross and
Blue Shield of Ohio introduced a reward
program for providers who received the
Joint Commissions Integrated Care
Certication.9 The Integrated Care Certi-
cation program focuses on the integra-
tion of technology, sharing of information,
and transition of care for patients, and the
best practice standards elements require
that providers must be working toward
improving outcomes through coordina-
tion of care, be accredited, and highlight
risk sharing.10
HEALTH CARE & L AW
These new models of care require
integration and collaboration among all
sectors of the industry. As health systems
and providers are pushed to assume risk,
pharmaceutical industry participation and
assumption of risk for outcomes is being
discussed. Physicians will be integral to
reducing postacute treatment and man-
aging patient behaviors to ensure posi-
tive outcomes. The integration models
must align incentives and payment while
including patients as key stakeholders.
As the burden of cost continues to shift
to the consumer in the form of premiums,
cost-sharing, and deductibles, consumers
will demand transparency in the pricing
model.
For integrated health care systems
with multiple service lines, managed
care negotiations can be complex. While
payers often focus on negotiating with
the hospital, an integrated system needs
to think about the bigger picture, says
Paula Dillon, Director of Managed Care
at Rockford Health System in Rockford,
Illinois. For example, increased rates in
certain settings can offset decreased rates
in others. By looking at the net changes
across the organization, you can negoti-
ate more effectively and realize a robust
agreement for the entire organization.
That includes incorporating other enti-
ties, such as ancillary providers and
physicians in the negotiations.11
Impact on P&T Committees
P&T committees are currently in a state
of ux with regard to commercial plans,
Medicare Part D, Medicaid, the Veterans
Health Administration/Department of
Defense, hospitals, long-term care, and
various submarkets. For example, PBMs
and their P&T committees are shifting
toward formularies that lower costs for
employers and plans while passing those
costs to employees. Over the last few
years, emerging P&T consequences of
rising drug costs have dominated the
health care landscape, affecting patient
accessibility to medications and giving
rise to concerted patient advocacy, phar-
macy benet discrimination cases, and
legislative action.
The increasing costs of most generic
and brand-name medications have
prompted concerns about future sus-
tainability for state governments and
insurers to shoulder the absolute costs
of medications. Emerging trends for
Vol. 42 No. 1 January 2017 P&T
29
HEALTH CARE & L AW
Table 1 Emerging Formulary Restriction Strategies
Tiering Adverse tiering Increasing multiple specialty tiers
Increased tier numbers Increasing number of generic drugs
(higher prices)
Utilization Increased cost-sharing Drug-specic deductibles
management Increasing use of closed formularies Increase in prior authorizations and
quantity limits
Medication Especially where no lower-cost generic alternative
exclusions
Trend to exclude rather than tier brands for therapeutic
equivalents that are chemically and pharmacologically different
The lists keep getting longer (e.g., Express Scripts
excluded 80 drugs in 2016, up from 66 in 2015)
Alignments differeach PBM is aligned with a different insulin maker
Specialty drugs Different approaches being taken by different PBMs
PBM = pharmacy benet manager
health plan strategies for medication illegal inducements of P&T formulary
formulary restrictions are detailed decisions in state hospital systems.
in Table 1. From 2006 to the present,
medication cost-sharing for brand-name Cases Allege Pharmacy
medications has increased. Such practices Benet Failure to
comport with the traditional role of P&T Provide Adequate Care
committees, where cost is a legitimate P&T formulary decisions can create
factor that can be taken into consider- possible legal dilemmas. Beginning with
ation but cannot be the only or overriding Wickline v State of California in 1986,
factor for P&T decisions. P&T commit- courts have ruled that health plans
tees cannot make formulary decisions could be liable for improper cost-control
negligently or recklessly based upon decisions.13 Courts have granted substan-
nonlegitimate criteria. Participating phy- tial awards to patients from health plans
sicians are often encouraged to conform that failed to treat patients fairly.14
their prescribing practices to align with New medications for hepatitis Cwith
health insurer policies, to consider the cure rates exceeding 90%, signicantly
cost of treatment to the health plans, and fewer side effects compared with older
to prioritize patients accordingly. Should treatments, shorter lengths of treatment,
an unfavorable result occur as a result and increased ease of administration
of a medication substitution, the patient have met with health plan restrictions due
only has to prove negligence somewhere to the high cost of these drugs over the
along the chain of responsibility for those past two years. The restrictions have gen-
who assemble the formulary. erated many consumer lawsuits against
P&T committee collusion lawsuits have insurers in California, Washington state,
emerged as plaintiffs have increasingly and New York, as well as the Medicaid
pressed a formulary inuence theory of program in Washington state and the
liability, alleging that off-label promotion Massachusetts prison system.
or kickbacks caused states to wrongfully In New York, the Attorney General
place drugs on formulary or give them sued a health insurer for denying cover-
preferred formulary status. In the high- age for hepatitis C drugs unless patients
prole Avandia (rosiglitazone maleate, had an advanced stage of disease, such
GlaxoSmithKline) case, the plaintiffs as moderate-to-severe hepatic scarring.
alleged the drug was included on formu- The lawsuit accuses the insurer of failing
laries in reliance on representations made to advise beneciaries in plan documents
by the pharmaceutical manufacturer.12 that cost was a factor in its formulary
Pharmaceutical companies have been decision-making processes for medically
forced to pay millions to resolve kick- necessary treatment.15 The complaint
back allegations related to PBM formulary states the restrictions are contrary to
placement, inappropriate inuence, or prevailing medical guidelines and gener-
30 P&T January 2017 Vol. 42 No. 1
ally accepted treatment standards and are
based exclusively on cost considerations.
The insurer claims its guidelines for
coverage were developed by an indepen-
dent P&T committee utilizing evidence-
based medicine. However, the reversal
of claim denials by external medical
reviewers during the appeal process
has provided strong evidence that
cost-based rather than evidence-based
formulary decisions are being made. The
New York case is based upon consumer
fraud, deceptive business practice, and
insurance law violations.1618 In at least
one case, the Attorney General threat-
ened to sue to a manufacturer for violating
consumer protection laws if it refuses to
lower its prices. In other cases, the health
plan has settled by loosening formulary
restrictions.
In several cases involving prisoners,
the claims involved a denial under the
states formulary for the prisoners medi-
cation. In Whipple v Schoeld, the alle-
gation was made that having the P&T
committee stacked with employees from
private contractors, which have a prot
motivation to cut costs, puts the nan-
cial needs of those contractors above the
medical needs of the prisoners.19
Legislative, Regulatory,
and Judicial Deterrents
Over the past few years, state legisla-
tures introduced and passed numerous
bills regarding drug formularies. The
PPACA requires all qualied health plans
(QHPs) to provide prescription drug
coverage as an essential health benet
(EHB) and such plans must cover at least
the greater of: 1) one drug in every United
States Pharmacopeia (USP) category and
class, or 2) the same number of prescrip-
tion drugs in each USP category and class
as the states EHB-benchmark plan.19 A
QHP that fails to meet the EHB standard
can be decertied if the plan employs a
discriminatory benets design.
Formulary rankings, known as tiers,
have traditionally been used by health
care plans. Can formularies designed by
P&T committees be considered discrimi-
natory? Over the past few years, the cost
consideration factor has transformed into
a process of structuring formularies to
discourage patients with certain disease
states from enrolling.
Adverse tieringthe placing of all
medications (including generics) for

a particular disease on a specialty or
high-cost tierhas ourished. When an
insurance plan charges more for common
human immunodeciency virus (HIV)/
acquired immunodeciency syndrome
(AIDS) medications than other insur-
ers, the company may be trying to dis-
courage high-cost patients from choos-
ing its plans on the PPACA exchange
marketplace. Adverse tiering is explicitly
prohibited under the antidiscrimination
provisions of the PPACA; a plan may not
employ marketing practices or benet
designs that have the effect of discour-
aging the enrollment in such plan by
individuals with signicant health needs.21
The PPACA also includes annual
limits on cost-sharing, which means that
patients with chronic conditions should
not pay high coinsurance once they reach
maximum out-of-pocket spending. While
the PPACA rule has been the basis for
complaints to state and federal regulators,
insurers have countered with the Safe
Harbor Provision, which protects insur-
ers in underwriting risks, classifying
risks, or administering such risks that are
not inconsistent with state laws. 22 The
Safe Harbor provision cannot be a sub-
terfuge to circumvent antidiscrimination
provisions inasmuch as limits must be
based upon actual or reasonable predict-
able risks. All that is required is the
showing of a rational nexus between
the higher tier and cost-sharing, including
copayment and coinsurance for certain
classes of medications and risks.
A 2015 study published in the New
England Journal of Medicine reported
adverse tiering for HIV and AIDS drugs
in 12 of 48 plans.23 Enrollees in adverse-
tiered plans had a yearly per-drug cost
that was almost $4,900 versus about
$1,600 for those in nonadverse-tiered
plans. About half of the adverse-tiered
plans had a deductible that was drug-
specic. CMS has issued various letters
regarding cost-sharing and adverse
tiering and its intent to conduct outlier
analysis as part of QHP certication
or recertication.2426 The Department
of Health and Human Services exam-
ples of potentially discriminatory
plan designs include: adverse tiering
of HIV prescription drugs; formularies
or services that fail to meet recognized
treatment guidelines or the standard
of care for a certain condition; applying
age limits to services found to be
effective at all ages; requiring prior
authorization for all medications in
certain classes; and whether limitations
and exclusions are based on clinical
guidelines and medical evidence.
In May 2016, CMS issued the nal
rule implementing Section 1557, the anti-
discrimination provision of the PPACA.27
The rule prohibits plan designs that place
most or all drugs that treat a specic con-
dition on highest cost tiers and charge
more for single-tablet regimens than for
treatments that require patients to take
multiple tablets. Although it will take
years for the scope of Section 1557 to
be established by the courts and provi-
sions for health plan benet design will
not take effect until January 2017, the
rule authorizes private right to action.
Increased plan benet litigation will be on
the horizon as courts are already authoriz-
ing Section 1557 lawsuits. A number of
states, such as Florida, have warned that
plans found to be discriminatory will not
be recommended as QHPs that can be
sold in the state.
Over the past two years, we have
witnessed the divergence of P&T formu-
lary trends in the new PPACA exchange
market, employer-sponsored plans, and
Medicare Part D plans. One study of the
exchange market in eight states revealed
signicant drug access and cost-sharing
differences in exchange plans versus
employer and Medicare Part D plans.
For example, exchange plans cover fewer
specialty drugs and have three times the
utilization management rates. Specialty
coinsurance is often more than 30%
for single-source drugs for HIV/AIDS,
hepatitis, cancer, and multiple sclerosis.28
One of the duties of P&T committees
is to assign products to formulary tiers.
Over the past few years, health care plan
formularies have gone from the typical
three tiers (i.e., generic, preferred brand,
nonpreferred brand) to four-, ve-, and
even eight-tier formularies. Most plans
have created two tiers for generic drugs,
and some have tiers for generic drugs
used to treat certain conditions, such as
diabetes, Parkinsons disease, and epi-
lepsy. The new tiers most often pertain
to higher-cost generics and specialty
medications. The trend toward more
tiers warrants close attention.
The Medicare Part D approach to
medication access applies to participating
health care insurers. Medicare designates
HEALTH CARE & L AW
six classes of medications as protected
and mandates at least two medications
in every drug category.29 CMS also has
a rule for the independence of P&T com-
mittee members that requires at least
two members to be independent of the
plan sponsor or manufacturer (but not
the PBM). There are now two tiers for
generic medications in most Medicare
Part D plans. The scope of formulary med-
ication coverage for these plans varies
widely; some plans list all drugs from the
CMS drug reference le, while others list
as few as 65% of these drugs. Even if on
formulary, utilization management rules,
including step therapy, prior authoriza-
tion, and quantity limits may restrict a
beneciarys access to the medication.
On average, prior authorization applies
to 22% of medications.30
Perhaps the balance between savings
and wellness has tipped too far toward
savings. A more equitable health care
system for patients with chronic disease
is required.
P&T: Dealing With Convergence
in a Transitional Marketplace
While much of what has been
discussed in this column is unlikely to
change, the post-presidential election
fallout has already begun in many eco-
nomic sectors, including health care.
During the campaign, the PPACA was
targeted for elimination. Now that the
campaign is over, it has become apparent
that incremental change is more likely,
and that not much will change in 2017.
That being said, commercial market
impacts could be felt in 2017 and are
much more likely to be seen along with
public sector shifts for the 2018 plan year.
This transitional marketplace makes
some P&T committee decisions more
difcult based upon the myriad of com-
mercial or public plans covered while
maintaining some simplicity for others
that only deal with one type of plan, such
as Medicaid or Medicare. For example,
closed or preferential-based formularies
may become less favored over more-open
formularies depending on the plan type
and progress of legal or regulatory change
being implemented around prescription
drug coverage. Other similar impacts
may result from the pricing furor in 2016
leading to fewer-to-no rebates or contract
incentives through managed care middle-
men. Such uncertainty around specics
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31
HEALTH CARE & L AW
will continue through 2017, epitomizing
the nature of transition.
With the complexity of todays health
care organizations, how can P&T commit-
tees most effectively deal with pharma-
ceutical decision-making alongside care
delivery issues over the next few years?
Understanding the purpose and actions to
be taken by a P&T committee will provide
a touchstone for examining formulary or
policy decisions. Maintaining an aware-
ness of health policy and legal trends will
be more critical for the P&T committee
and its individual members for making
decisions on drug use. Avoiding obvious
legal infringements or conicts requires
effective continuing education of P&T
committee members and support staff.
Given the pace of change and calls
for efciency, what will the future P&T
landscape look like by 2020? Based on
trends to date in market stakeholder
consolidation, market-driven efciency
demands, public and commercial plans
drive for value, consumerism, and legal
enforcement of patient rights related to
access to appropriate drugs, P&T com-
mittees will have their hands full balanc-
ing the issues when making decisions.
The rise in shared-risk arrangements,
high-deductible insurance plans, and
litigation will create an increasingly
tangled environment in which to main-
tain legitimacy, focus on clean execution
of purpose, and nd persons willing to
serve on such a high-prole committee.
Individuals who can lead P&T commit-
tees into the new decade of care will be in
high demand and can help deliver on the
promise for better outcomes, better quality
care processes, and scally responsible
action. The need for P&T committees will
only grow in urgency, but most urgent is
the authenticity, credibility, and reliability
of future P&T committees to maintain
their core mission of providing safety and
efcacy guidance to prescribers or users
of drugs in their organizations.
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15. People of the State of New York v Capital
District Physicians Health Plan, Inc., NY
Super Ct. Complaint led April 14, 2016.
Available at: www.ag.ny.gov/pdfs/Filed-
Complaint.pdf. Accessed September 5,
2016.
16. New York Executive Law 63(12).
17. New York General Business Law 349.
18. New York Insurance Law 3214-a(a)
(1), 4324(a)(1).
19. Whipple v Schofield, U.S.D.C.(M.D.
Tenn.), Case No. 1:13-cv-00109.
20. 45 CF.R. 156.125(a).
21. U.S.C. 18031 (c) (1)(a).
22. 42 U.S.C. 12201 (c) (1).
23. Jacobs DB, Sommers BD. Using drugs
to discriminateadverse selection in
the insurance marketplace. N Engl J Med
2015;372(5):399402.
24. Centers for Medicare and Medicaid
Services. 2015 letter to issuers in the
federally-facilitated marketplaces. March
14, 2014. Available at: www.cms.gov/
CCIIO/Resources/Regulations-and-
Guidance/Downloads/2015-nal-issuer-
letter-3-14-2014.pdf. Accessed September
5, 2016.
25. Centers for Medicare and Medicaid
Services. Final 2016 letter to issuers in
the federally-facilitated marketplaces.
February 20, 2015. Available at:
www.cms.gov/CCIIO/Resources/Regu-
lations-and-Guidance/Downloads/2016-
Letter-to-Issuers-2-20-2015-R.pdf.
Accessed September 5, 2016.
26. Centers for Medicare and Medicaid
Services. Draft 2017 letter to issuers in
the federally-facilitated marketplaces.
December 23, 2015. Available at:
www.cms.gov/CCIIO/Resources/Regu-
lations-and-Guidance/Downloads/Draft-
2017-Letter-to-Issuers-12-23-2015_508.pdf.
Accessed September 5, 2016.
27. HHS Office for Civil Rights. Non-
discrimination in health programs and
activities. Fed Regist 2016;81(96): 31376
31473. Available at: www.gpo.gov/fdsys/
pkg/FR-2016-05-18/pdf/2016-11458.pdf.
Accessed September 5, 2016.
28. Benet Design Trends of Exchange Market
for Formulary Market. Washington, DC:
Avalere Health; 2015.
29. Centers for Medicare and Medicaid
Services. Medicare prescription drug
benet manual. September 26, 2008.
Available at: www.cms.gov/Regulations-
and-Guidance/Guidance/Manuals/
Downloads/Pub100_18.pdf. Accessed
September 3, 2016.
30. Hoadley J, Summer L, Hargrave E. Medi-
care Part D in its Ninth Year: The 2014
Marketplace and Key Trends, 20062014.
Menlo Park, California: Henry J. Kaiser
Family Foundation; 2014:26. Q
P&T TV
P&T is accepting video clips
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free to send a short video about the
activities of your P&T committee.
You can contact the Editor,
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or smciver@medimedia.com.
 PERSPECTIVE
Branko Fursts Radical Alternative
Is the Heart Moved by the Blood, Rather Than Vice Versa?
Walter Alexander
Most heart failure trials yield results that are disappointing or
difcult to interpret, Milton Packer, MD, wrote in the April 2016
issue of Circulation: Heart Failure.1 Dr. Packer, Distinguished
Scholar in Cardiovascular Science at Baylor University Medical
Center in Dallas, has experienced this frustration rsthand as
lead investigator of more than 15 large international multicenter
heart failure trials. He pointed out that in the late-breaking clinical
trials session at the 2015 annual meeting of the American Heart
Association, every randomized trial in heart failure yielded
distressing results. Two medications failed to meet primary end-
points (the guanylate cyclase stimulator vericiguat and the beta3
adrenergic receptor agonist mirabegron [Myrbetriq, Astellas]);
another (oral nitrates) had adverse effects on daily activity; and
yet another (the GLP-1 agonist liraglutide) showed no diminution
of clinical symptoms but was linked with possible renal-function
harm and increased risk of death or heart failure hospitalization.
Such disappointing ndings hardly stand alone among research
results in heart failure and cardiac support, recent or other-
wise. Attempts to replace failing hearts permanently with fully
mechanical ones, after years of experimental and clinical trials,
have largely been abandoned because of high patient mortality
through combinations of thromboembolic, hemorrhagic, and
infectious events leading to strokes and multiple organ failure.
Despite success at adjusting cardiac outputs, matching hemo-
dynamics to organ requirements with mechanical devices has
remained elusive.2
Experience with intra-aortic balloon pumps (IABPs) serves
as a further example. A 2015 meta-analysis by Su et al. of
17 studies including 3,226 acute myocardial infarction (AMI)
patients, with or without cardiogenic shock, examined the
effect of circulatory assist with IABPs. Analysis revealed no
signicant difference between the IABP group and controls on
short-term mortality (relative risk [RR], 0.90; 95% condence
interval [CI], 0.771.06; P = 0.214) and long-term mortality
(RR, 0.91; 95% CI, 0.791.04; P = 0.155). The presence or absence
of cardiogenic shock did not affect the results.3 Based on this
and other similar accumulating evidence, the triumvirate of
the American College of Cardiology, the American Heart
Association, and the European Society of Cardiology all recently
downgraded their recommendations for the use of IABPs in the
setting of AMI associated with cardiogenic shock from class Ib
(should be used) to class IIb (may/can be used).
Commentators on another recent IABP meta-analysis4 showing
no survival advantage posited a range of explanations for the
benet that has never appeared over four decades for this seem-
ingly practical and plausible strategy: IABP effects are too weak
to counteract failed cardiac function; IABP complication harms
overwhelm benets; clinical trial methods simply fail to accu-
rately capture IABP benet; and baseline selection bias toward
sicker patients dilutes benets in active treatment groups.5
The author is a freelance writer living in New York City.
Given how deeply assumptions about heart failure are
entrenched, it is understandable that commentators did not
entertain the radical-seeming possibility that the prevailing
cardiac function paradigm does not accurately reect the reality
of heart function. The success of angiotensin-converting enzyme
inhibitors and angiotensin-receptor blockers conrmed that
chronic neurohormonal activation of mechanisms of myocardial
damage and circulatory dysfunction (including impairment of
protective mechanisms) play a role in heart failure. That success
also shifted the pathophysiological emphasis away from the
traditional hemodynamic model. But the possibility that the
dominant paradigm is deeply awed is what Branko Furst, MD,
explores in The Heart and Circulation: An Integrative Model 2 in
2014 and in The Heart: Pressure-Propulsion Pump or Organ
of Impedance in the Journal of Cardiothoracic and Vascular
Anesthesia in 2015.6 In these, he marshals the evidence against
the standard propulsion pump model and presents an alterna-
tive that may open new avenues for understanding circulation
and, ultimately, pharmacotherapy. As a vascular anesthesiolo-
gist in a tertiary care medical center, Dr. Furst holds hemo-
dynamic monitoring and support of circulation at the core of
his acute-care concerns.
To challenge the prevailing paradigm in any field is
difcult, and in the case of heart function, with its notoriously
complex dynamics, myriad of interrelated inuencing factors,
and vast diagnostic and therapeutic implications, it is a prodigious
undertaking. Dr. Furst has provided more than 800 supporting
references in his book and the journal article. It is far beyond the
scope of this article to fairly represent the range of this content.
However, we will attempt to review the basic argument and
rationale for such a challenge and give the reader a compass
for delving more deeply into the underlying research.
In what follows, we examine key evidence against the
standard cardiac function model, including failed attempts to
address cardiac pathology with pharmacotherapy and devices
based on that model. We also describe the alternative model
and its supporting research and touch upon its implications
for therapy and further exploration.
The History of the Conventional Model
The current heart-as-propulsion-pump model is traditionally
traced to William Harveys 17th century De Motu Cordis. It
took another 200 years, however, for traces of vitalism to be
eradicated from physiological understanding and for Alfred
Volkmann to precisely articulate a fully mechanical model
as follows: The heart is a pumping engine and as such has
enough power to drive the mass of the blood through the
whole vascular system. 7 Contemporary denitions of heart
failure still recognize pump malfunction as a key component,
but they also acknowledge the complexity of heart failure
diagnosis and treatment. The European Heart Journal guide-
lines in 20018 stated that while no denitions of heart failure
Vol. 42 No. 1 January 2017 P&T
33
 Branko Fursts Radical Alternative
are entirely satisfactory, a commonly used one is: Heart
failure is a pathophysiological state in which an abnormality
of cardiac function is responsible for the failure of the heart
to pump blood at a rate commensurate with the requirements
of the metabolizing tissues. The next sentence, however, is:
A simple objective denition of chronic heart failure is
currently impossible. The more recent American College of
Cardiology Foundation/American Heart Association guide-
lines (from 2013)9 dene heart failure as a complex clinical
syndrome that results from any structural or functional impair-
ment of ventricular lling or ejection of blood. While pump
function is implied, this broader description may suggest an
evolutionary direction away from reliance on so simplistic a
model as is suggested by Volkmanns strict analogy.
In his book and journal article, Dr. Furst surveys the dis-
appointing ndings for pharmacotherapeutic and device strate-
gies developed as specic remedies for the heart when seen
as a compromised and incompetent propulsion pump. Potent
sympathomimetic amines such as epinephrine, isoproterenol,
and dopamine were used widely in the 1960s and 1970s10,11 based
on the assumption that as inotropes they would strengthen the
heartbeat in patients with congestive heart failure, thereby
increasing cardiac output and ultimately prolonging survival.
Most recently among negative inotrope ndings, the ADHERE
(Acute Decompensated Heart Failure National Registry) trial,12
a 2003 registry, showed that of 150,000 patients with acute heart
failure, systolic blood pressure was lower than 90 mm Hg in
less than 3%, suggesting a harmful effect on heart function.
Mortality among those treated with inotropes was 19%, com-
pared with 14% among those not receiving inotropes. American
and European medical societies practice guidelines have since
recommended the use of vasodilators and de-emphasized
inotrope use in acute heart failure syndrome management.
While inotrope use has been largely abandoned in favor
of vasodilators to reduce blood pressure and decrease the
resistance that lowers cardiac output, the exception is inotrope
administration in a minority of patients with severe systolic dys-
function who cannot tolerate vasodilators due to hypotension.13
Of signicance is the fact that dobutamine and milrinone are
usually selected out of the range of available inotropes because
of their substantial vasodilatory effects. Applied to the con-
ventional model, vasodilators would decrease the pressure
head needed by the pump in order to drive the blood around
the circuit, Dr. Furst points out.2 Also counterintuitive to a
propulsion pump model is the proven efcacy and universal
recommendation of beta blockers for all patients with stable
mild, moderate, and severe heart failure with ischemic or non-
ischemic cardiomyopathy and reduced left ventricular ejection
fraction.14 It is suggested that by reducing catecholamines,
beta blockers promote ventricular lling and enhanced ejec-
tion fraction, but the proven efcacy of treating a failing heart
pump by weakening the force of ventricular contractions and
slowing heart rate remains puzzling.
Failing Heart, Rising Output?
Among the observations most confounding to a heart-as-
propulsion-pump model, the instances where cardiac output
rises in the presence of a compromised or disabled pump stand
out. Partially isolating the heart from the circulation through
34 P&T January 2017 Vol. 42 No. 1
aortic cross-clamping, as is typically done during aortic surgery
and in experimental settings, should lead to disastrous reduc-
tions in cardiac output. But increases in cardiac output of up to
25% in some cross-clamped aortic surgery patients and in an
animal model beg explanation.15,16 Another paradox presents
itself when children with congenital univentricular hearts are
helped by the staged Fontan repair that, in the absence of the
right ventricle, delivers venous blood directly to the pulmonary
arteries. Asking the single, often weakened left ventricle to do
double dutypumping blood for the body and for the lungs
seems extreme, yet it manages quite successfully, sending
more than normal volumes of blood to the lungs.
Paradoxical increases in cardiac output are also seen in
patients with septic shock, where cardiac output can be doubled
or tripled at the same time that cardiac function is declining.
Yet another observed example is the lack of signicant change
in blood pressure when aerobic exercise increases cardiac
output several-fold beyond the theoretical limits of the hearts
pumping capacity and peripheral resistance drops by two-thirds.
Up to 60% of increased contractility may be explained by beta-
adrenergic stimulation and improved diastolic compliance (the
Frank-Starling mechanism). But greatly increased heart rates
shorten diastolic lling time, and the maximally performing
exercising heart can account for only about half of the volume
throughput measured in high-performance athletes (more than
30 L per minute).2 The source of extra blood volume remains
a long-standing dispute among exercise physiologists, and
the concept of a muscle pumpa mechanism by which the
blood is returned to the heart by the contracting muscleshas
long been entertained. Evidence against the existence of such
a muscle pump is accumulating, however.17,18
Dr. Furst describes various animal and human studies mea-
suring or modeling heart function and compares them with
mechanical propulsion pumps engineered to maintain either
constant pressure or ow under varying loading conditions.
Dr. Fursts conclusion emerging from studies of isolated heart
preparations is that if the heart is in fact a pressure-propulsion
pump, it is a rather poorly designed one, with its thin apex and
relatively low ejection fractions of 50% to 60% (why not 100%?).
Dr. Furst, in the introduction to The Heart and Circulation,
states that, in 1920, Rudolf Steiner suggested that the heart,
rather than propelling blood ow, restrains and regulates it.2
The venous return model articulated by Arthur Guyton has been
the prevailing view since the 1970s and stands in opposition to
the pure left ventricular model.2 In it, the peripheral circulation
controls cardiac output, with elastic recoil energy from the
vessel walls squeezing blood back toward the heart. Guyton
and collaborators also reported that cardiac output is largely
unaffected by the hearts activity19 even with pacing rates up
to four times normal. The Guyton model ascribes a dual role
to the right atrial pressure. Considered from the perspective
of the heart, the right atrial pressure determines the degree
of lling of the right ventricle and therefore regulates cardiac
output. From the perspective of the peripheral circulation,
a positive right atrial pressure exerts a backpressure and
therefore impedes venous return. This ambiguous depiction
of the right atriums role, according to the models critics, is
mechanistically inconsistent and is a weakness of the model.
By assuming an impedance function for the right atrium and
 Branko Fursts Radical Alternative
emphasizing the role of the peripheral circulation, however,
Figure 1 Hydraulic Ram
Guytons model nevertheless more closely matches the actual
observed phenomena. The fact that the Guyton venous return
model still holds the heart as the ultimate source of blood
propulsion leaves many unresolved issues, which Dr. Furst C C
reviews in detail in his book and journal article. A A
In addition, Dr. Furst questions the validity of identify-
ing similarities between heart and propulsion-pump function B S B S
based on observing animal preparations with arrested hearts
and abolished vasomotor reexes. The intent of reducing the At left, water from the reservoir (A) accelerates with gravity along
number of variables to facilitate measurements and isolate the drive pipe (B) and escapes from the open spill valve (S) (red
factors for study is sound, but the applicability of compari- arrows).
sons based on the circulatory systems of nearly deceased At right, drag of the accelerating water closes the spill valve (S),
experimental animals is open to question. Also, Dr. Furst says, creating a back surge (water-hammer effect) and an increase in
identifying the causal relationships among the set of physical pressure, forcing water to ow from the delivery pipe (C). A drop
parameters of pressure, ow, and resistance as one would in a in pressure in the delivery pipe (B) opens the spill valve (S) and the
closed hydraulic system of known dimensions with rigid tubes cycle repeats.
and a homogenous uid may not be reliably analogous to a
highly dynamic circulatory system. The model insufciently two hours after cardiac arrest.23,24 Other research has shown
addresses many key variables, including the dimensions and 20% to 40% increases in canine cardiac output after occlusion
nonconstant elasticity of the vessels, the non-Newtonian uid of the thoracic aorta.15
moving within them (blood lacks a constant coefcient of
viscosity), and the bloods pulsatile ow with reected waves, Two Inevitable Questions
pulse-wave velocity, inertial factors, and mechanical, chemical, What then is impelling the blood if not the ventricular
and thermal energy conversions. contractions? And what are the ventricles doing if not providing
the motive force for the circulation? Dr. Manteuffel-Szoeges
An Alternative Model conclusion about the rst question was that blood has its
The rst instance in scientic literature refuting the heart- own kinetic energy derived from thermal conditions of the
as-pump model appeared in Germany in the 1930s at about tissues.22 Before endeavoring to answer the second question,
the same time as early discussions of the physics of open Dr. Furst explores the evidence from embryonic hemodynamics
systems.2 Hans Havlicek pointed to an analogy, both mechani- suggesting that blood does not rely on the ventricles for its
cal and morphological, between the heart and a hydraulic propulsion.
ram (Figure 1 and Figure 2).20 The key difference between
a hydraulic ram and a propulsion pump is that a hydraulic Embyronic Circulation
ram is inserted into the path of an already moving uid and The assumption has been, Dr. Furst says, that the valveless
uses the force of the stream to do its work. Hydraulic rams two-chambered embryonic heart functions like a peristaltic
are used most commonly in construction applications to raise pump, moving blood along its lumen the way the esophagus
the level of an already moving water
supply without any external power Figure 2 The Heart as a Hydraulic Ram (Right Heart Cycle)
source.21 A propulsion pump, by deni-
tion, is the provider of force to a uid
stream. Dr. Furst quotes the cardiac
surgeon Leon Manteuffel-Szoege,
who in the 1970s and 1980s published Pulmonary artery Delivery pipe
observational studies of chick embry- Venous (delivery pipe) Venous (pulmonary artery)
onic circulation and of circulation in return reservoir
patients in deep hypothermic arrest.
Pulmonic Pulmonic
Dr. Manteuffel-Szoege wrote: A pump
Atrium valveclosed Atrium valveopen
sucks in uid from a reservoir. In
the circulation, on the other hand,
Tricuspid
not only is the blood ejected from the Tricuspid
valveopened
heart, but it ows into the heart. The valveclosed
Ventricle Ventricle
heart is a mechanism inserted in the
blood circuit, and so it is a very pecu-
liar kind of pump. 22 DIASTOLE SYSTOLE
Dr. Manteuffel-Szoege repeated the
Arrows represent direction of blood ow. In diastole, blood ows from the atrium (reservoir) and
experiments of S. A. Thompson, who
lls the ventricle (drive pipe). In systole, ow reversal and build-up of pressure in the ventricle
had shown that in asphyxiated dogs,
close the tricuspid valve (spill valve) and eject the blood into the pulmonary artery (delivery pipe).
residual circulation continued for up to

Vol. 42 No. 1 January 2017 P&T 35

 Branko Fursts Radical Alternative
pushes ingested food as a bolus
Figure 3 Evolutionary Stages of Circulation2
to the stomach. The observation
that the velocity of the blood in the
EARLY FISH AMPHIBIAN MAMMAL
embryonic heart lumen exceeds the
VERTEBRATE
speed of the peristaltic wave moving
through the lumen contradicts that
GILLS GILLS LUNG LUNG
interpretation and supports the
notion that the blood is already in atria
ventricle atria
motion before a functionally com-
petent heart has developed.25 In atrium
primitive vertebrates, like the lancet- ventricle
sh, circulation occurs without a ventricles
central propulsive organ (Figure 3).
The embryonic heart, rather than SC SC SC SC
moving the blood, rhythmically
interrupts its ow, Dr. Furst states.
How would demand for oxygen-
rich blood in the tissues lead to and
regulate blood circulation without
Systemic Capillaries (SC)
reliance on propulsive force from
the ventricles? How does blood
Circulatory systems in early vertebrates, sh, amphibians, and mammals: The lancetsh, a
move itself if it is not being driven
primitive vertebrate, has no heart as a central organ of circulation. The blood moves autonomously
mechanically?
within the vessels without endothelial lining. The sh have a single-loop, predominantly venous
Of course, if it were mechani-
circulation with a two-chamber heart, a single atrium and a single ventricle, placed in series with
cally driving itself, that would be
the gill and systemic circulations. Transition from water to land calls for development of a new
perpetual motion in deance of the
organ, the lung, and for metamorphosis of the heart into a three-chamber organ consisting of two
second law of thermodynamics. But
atria and a single ventricle. In amphibians, arterial blood from the lung and venous blood from
by being in a responsive relationship
the body mix in the ventricle, which subserves low-pressure pulmonary and systemic circulations
with its environment at the level of
now placed in parallel. The circulatory system undergoes further development in warm-blooded
the microcirculation at the vascu-
mammals with high metabolic rates and greater demands for oxygen. This is achieved by a
lar beds, such behavior of blood
complete separation of the pulmonary and systemic circulations. In addition to the existing
may be quite in accord with what
ventricle serving the pulmonary circulation, a new chamber, the left ventricle, develops to serve
is predicted when an organism is
high-pressure systemic (arterial) circulation. The two circulations are placed in series.
considered as a far-from-equilibrium
living system, as it is in Dr. Fursts Adapted from The Heart and Circulation (Springer 2014).
proposed model.
Self-regulation of vessel walls in response to shear stress regions toward those with higher oxygen levels. Although
through release of nitric oxide, a potent vasodilator, has long nitric oxide is produced continuously by the pulmonary vas-
been recognized.26 Beyond shear stress, vascular tone is affected cular epithelium and the respiratory epithelium inhibiting
by intraluminal pressure and local metabolite concentrations.27 pulmonary hypoxic vasoconstrictionirreversible binding of
The newer insight, however, is that red blood cells may play nitric oxide to hemoglobin in red blood cells counteracts its
a more direct role than has been suspected in relation to local vasodilatory effects.30 Gladwin et al. estimated that 25% to 30%
biochemical and mechanical factors affecting tissue metabolism. of basal human blood ow can be attributed to red blood cell-
Ellsworth et al. and others have shown that erythrocytes induced production of nitric oxide by vascular endothelium.31
are not mere suppliers of oxygen; they are also sensors That may be a substantial underestimate, Dr. Furst suggests.
and regulators of tissue oxygen saturation.28 Ellsworth and Others have proposed that the common denominator in various
colleagues also demonstrated that when erythrocytes perfuse forms of distributive and cardiogenic shock is this red blood
a poorly oxygen-saturated (SpO2) region of tissue, they release cell-induced release of nitric oxide.32 This feature of the micro-
adenosine triphosphate (ATP), which in turn stimulates produc- circulation has led to its being called the motor of sepsis
tion of nitric oxide. In that manner, low Sp02 opens the vessel because it is there that a short-circuiting (shunting) of the
in a retrograde direction, inducing greater ow of oxygen-rich capillaries takes placewith blood moving from arterioles to
blood to where it is needed (Figure 4).29 venules without supplying oxygen to the tissues and causing
Importantly, the pulmonary vessels react in a polar-opposite increased cardiac output as a downstream result.33
fashion, complementing the pivotal role that erythrocytes In mature circulation, Dr. Furst suggests, rhythmic inter-
play in supplying oxygen to the metabolically active systemic ruption of blood ow by the ventricles pressurizes a pulsatile
vascular beds. The systemic vascular smooth muscle reacts ow. But this pressure is not the primary engine of systemic
to hypoxemia with vasodilation and increased blood ow, but circulation. Instead, it is the force behind the rhythmic operation
when levels of inspired oxygen in the lung are low, pulmonary of the heart valves. The pressure sustained by the heart in its
vessels constrict, diverting blood away from hypoxic lung joining of the pulmonary and systemic circulations is essential

36 P&T January 2017 Vol. 42 No. 1

 Branko Fursts Radical Alternative
Figure 4 Erythrocytes as Oxygen Sensors and Modulators of Vascular Tone
Endothelial cells
Low SO2
High SO2
Body tissue Capillary lumen
Conducted
vasodilation
Physical deformation of erythrocytes and their entry into tissues with low oxygen saturation
stimulate release of ATP from the erythrocytes. The released ATP reacts with endothelial purinergic
receptors that stimulate release of vasodilators, including nitric oxide and products of arachidonic
acid metabolism. ATP also elicits vascular smooth muscle-dependent vasodilation conducted
opposite to the direction of blood ow.
ATP = adenosine triphosphate; PR = purinergic receptor; RBCs = red blood cells; SO2 = oxygen saturation.
for maintenance of normal physiology, but it is not the primary
cause of the moving circulation. Locally, the immediate meta-
bolic demands at the level of the tissues and microcirculation
self-regulate blood ow, and, globally, a polarity persists in a
dynamic tension between the lungs supplying of oxygen and
the peripheral tissues consumption of it. The heart, in this
model, is a feedback organ of impedance that maintains a 1:1
balance in ow between the pulmonary and systemic circula-
tions. Its function is ram-like, converting kinetic energy into
pressure and maintaining it in the systemic and pulmonary
arterial compartments.
An important difference between the pump model of left
ventricular propulsion and Dr. Fursts proposed model is that
the former treats the blood as an inert uid transported by
mechanical force, while the latter sees it as a dynamic uid
organ that gains movement through its essential mediating
of metabolic processes via reciprocal relationships with the
physiological life of the tissues it supplies with oxygen and
nutrients (Figure 5).
Implications for Therapy
The recently discovered autoregulatory ATP response of red
blood cells to the metabolic needs of the tissues, according to
Dr. Furst, has been insufciently appreciated because of the
entrenched pressure-propulsion cardiac model. Recognition of
its potentially pivotal role in critical illness, however, has grown
with the development of techniques for intravital microscopy.
The capacity to image the activity of microvascular beds with
orthogonal polarization spectral imaging and sidestream dark-
eld imaging in animal models and in patients has revealed
not only that microvascular hemodynamics are altered in
patients with sepsis, hemorrhage, cardiogenic shock, and
multiple trauma and during cardiopulmonary bypass, but
has also uncovered hemodynamic
incoherence after usual treatment
strategies are carried out in these
conditions. Hemodynamic coher-
ence is consistency between the
monitored parameters of the sys-
temic macrocirculation and the
microcirculation. Resuscitation
measures, for example, can
succeed in normalizing systemic
hemodynamic variables such as
blood pressure, cardiac output,
Direction of stroke volume, and mixed venous
blood ow oxygen hemoglobin saturation
(SvO2) without leading to a paral-
Arteriole
lel normalization of capillary per-
fusion and tissue oxygenation,34
according to Ince et al. They point
out that morbidity and mortality
were increased in several studies in
patients in whom videomicroscopy
identied a lack of hemodynamic
coherence in sublingual micro-
circulation. They observed, States
of shock, reperfusion, inammation,
and infections can damage the cel-
lular sensing mechanisms needed to regulate blood ow, and
Dr. Furst described animal models in which endotoxin admin-
istration produced endothelial injury, capillary leakage, and
interstitial edema with progressing reductions in functional
capillary density.
Reduced capillary function implies lowered perfusion with
shunting: Blood ow increases from the left to the right side
of the circulatory loop, but bypasses the tissues in need of
oxygenation. When this blood with higher-than-normal SvO2
returns to the lungs, it triggers accelerated ow through the
mechanism stated earlier. In this proposed manner, micro-
circulatory dysfunction may underlie the perplexing hyper-
dynamic circulation (high cardiac output with low systemic
vascular resistance) observed in conditions associated with
impaired myocardial function.
Dr. Furst notes that microcirculatory dysfunction, as is
now widely recognized, is one of the most sensitive pre-
dictors of outcome in critical illness,35 and restoration of
microcirculatory function has become the principal focus
of goal-directed therapy. Indeed, the assumed link between
microcirculatory function and global hemodynamics has come
into question, and a relative independence for the former has
been proposed.36 The recent therapeutic trend, according
to Dr. Furst, is to recruit the microvascular beds by using
vasodilators such as nitroglycerin to open the underperfused
capillaries rather than forcing them open with increased
used of vasopressors, the current standard of care. In spite of
improvement in macrocirculatory parameters, such as blood
pressure, cardiac index, and left ventricular ejection fraction,
vasopressors have limited effect at the level of the microcircu-
lation, and they may cause adverse patient outcomes.37 Ince
et al. offered examples of hemodynamic incoherence, where
therapeutic strategies based on the conventional assumption

Vol. 42 No. 1 January 2017 P&T

37
 Branko Fursts Radical Alternative
Figure 5 A Comparison of Circulation Models6
Guytons VR Left Ventricular Biological
Model Model Model
Flow impeded Power source Systemic and
pulmonary
capillaries
A dening feature of both the classical pressure-propulsion and
Guyton models is that the pressure gradient created by the heart
is the source of blood propulsion. In Guytons venous return
(VR) model, cardiac output (CO) is predominantly regulated by
the circuit parameters, that is, elastic and resistive properties of
the blood vessels and blood volume. The right atrial pressure
(Pra) plays a dual role; viewed from the heart, increased Pra
promotes ventricular lling, thereby increasing CO. Viewed from
the circulation, increased Pra exerts back pressure, impedes
venous return, and reduces CO.
The left ventricular model assumes that the ow (CO) is limited
by the pumps output and is proportional to the gradient
between the mean aortic and right atrial pressures, and
inversely proportional to peripheral resistance. The blood is
considered an inert, incompressible uid, and the amount
pumped into the arterial side of the circuit is equal to the
amount of blood returning at the venous side.
The biological model assumes the existence of dynamic
tension between the source of oxygen in the lung and its
sink in the metabolically active tissues. The blood, a liquid
self-moving organ, bridges this tension and plays a dual role
by delivering oxygen and nutrients to the peripheral tissues, and
also to itself. The forces for blood propulsion originate at the
level of the microcirculation. The heart plays a secondary role
and exerts a negative feedback to the metabolic demands of the
tissues by rhythmic interruption of the blood ow. Its ram-like
function maintains pressure in the systemic and pulmonary
arterial compartment and carries the rhythm of life.
Used with permission from the Journal of Cardiothoracic and Vascular
Anesthesia (December 2015).
that what is good for the macrocirculation is good for the
microcirculation can misre. In septic (endotoxic) shock,
excessive use of uids can produce tissue edema; after cardio-
pulmonary bypass, excessive uid administration to raise mean
arterial pressure can cause hemodilution and tissue edema;
and use of vasopressors (inotropic agents) in cardiogenic
shock, despite normalizing cardiac index, can lead to increased
mortality. Attention to microcirculatory ow is necessary, and
38 P&T January 2017 Vol. 42 No. 1
the problem, Dr. Furst said in a personal conversation in
September 2016, is that there is as yet no consensus on treatment
of these complex hemodynamic states. But what Ince et al.33,34
have offered, based on numerous published phenomenological
observations and quantications of capillary function, is the
rst rational treatment strategy for these conditions.
Schematic Versions
Given the limited scope of this article, we have neces-
sarily presented schematic versions of Dr. Fursts hypo-
theses. Dr. Furst traces the parallel-running evolutionary and
embryonic courses of cardiac development, where in the embryo
and in sh it is clearly evident that venous-type low-pressure
blood ow predominates. In gradually emerging sh-amphibian-
mammalian/two-to-four chamber stages, progress leads to
arterialization and separation of pulmonary and systemic cir-
cuits. Only later in warm-blooded mammalian species is a thick
left ventricle required to maintain the same basic function of
rhythmic ow interruption at signicantly higher pressures
(to work the valves and eject blood into the respective com-
partments). The movement of the circulation is created and
regulated locally at the level of the tissues through metabolic
demand and globally through a dynamic tension between the
lungs supplying of oxygen and its consumption in the tissues.
The idea of autonomous movement of blood is seemingly
radical, but Dr. Furst points out, Conceptually, autonomous
movement of the blood is no different than autonomous con-
traction of the heart, the enterohepatic circulation of bile salts,
or the circulation of cerebrospinal uid.2
If this model of autonomous blood ow is conrmed by con-
tinuing research, it may drive the understanding of circulatory
and cardiac function further along in a direction it has been
taking gradually for some time, at least in the eld of pharmaco-
therapy of heart failure. By superseding the propulsion-pump
model, it may steer researchers away from pharmacological
and device blind alleys and lead them instead to wide avenues
of discovery and progress in therapy.
REFERENCES
1. Packer M. Unbelievable folly of clinical trials in heart failure:
the inconvenient truth about how investigators and guidelines
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CIRCHEARTFAILURE.116.002837.
2. Furst B. The Heart and Circulation: An Integrative Model. London,
United Kingdom: Springer-Verlag; 2014.
3. Su D, Yan B, Guo L, et al. Intra-aortic balloon pump may grant no
benet to improve the mortality of patients with acute myocar-
dial infarction in short and long term: an updated meta-analysis.
Medicine (Baltimore) 2015;94(19):e876.
4. Doll JA, Sketch MH Jr. ECMO and the intra-aortic balloon pump:
in search of the ideal mechanical circulatory support device.
J Invasive Cardiol 2015;27(10):459460.
5. OConnor CM, Rogers JG. Evidence for overturning the guidelines
in cardiogenic shock. N Engl J Med 2012;367(14):13491350. doi:
10.1056/NEJMe1209601.
6. Furst B. The heart: pressure-propulsion pump or organ of
impedance? J Cardiothorac Vasc Anesth 2015;29(6):16881701.
doi: 10.1053/j.jvca.2015.02.022.
7. Volkmann AW. Die Hmodynamik. Leipzig, Germany: Breitkopf
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8. Remme WJ, Swedberg K; Task Force for the Diagnosis and Treat-
ment of Chronic Heart Failure, European Society of Cardiology.
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Eur Heart J 2001;22(17):15271560.
 Branko Fursts Radical Alternative
9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline
for the management of heart failure: a report of the American
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ciation Task Force on Practice Guidelines. J Am Coll Cardiol
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10. Goldberg LI. Use of sympathomimetic amines in heart failure.
Am J Cardiol 1968;22(2):177182.
11. Elliott WC, Gorlin R. Isoproterenol in treatment of heart disease
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12. Fonarow G. The Acute Decompensated Heart Failure National
Registry (ADHERE): opportunities to improve care of
patients hospitalized with acute decompensated heart failure.
Rev Cardiovasc Med 2003;(4)(suppl 7):S21S30.
13. Bayram M, De Luca L, Massie MB, et al. Reassessment of
dobutamine, dopamine, and milrinone in the management of acute
heart failure syndromes. Am J Cardiol 2005;19;96(6A):47G58G.
14. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the
diagnosis and treatment of chronic heart failure: Executive
summary (update 2005): The Task Force for the Diagnosis and
Treatment of Chronic Heart Failure of the European Society of
Cardiology. Eur Heart J 2005;26(11):11151140.
15. Gelman S. The pathophysiology of aortic cross-clamping and
unclamping. Anesthesiology 1995;82(4):10261060.
16. Stene JK, Burns B, Permutt S, et al. Increased cardiac output
following occlusion of the descending thoracic aorta in dogs.
Am J Physiol 1982;243(1):R152-R158.
17. Hamann JJ, Valic Z, Buckwalter JB, Clifford PS. Muscle pump
does not enhance blood ow in exercising skeletal muscle. J Appl
Physiol (1985) 2003;94(1):610.
18. Clifford PS, Hamann JJ, Valic Z, Buckwalter JB. Counterpoint: The
muscle pump is not an important determinant of muscle blood
ow during exercise. J Appl Physiol (1985) 2005;99(1):372374;
discussion 374375.
19. Guyton AC, Jones CE, Coleman TG. Circulatory Physiology: Cardiac
Output and Its Regulation, 2nd ed. Philadelphia, Pennsylvania:
WB Saunders; 1973:137146.
20. Havlicek H. Does the heart work as a pressure pump or as a
hydraulic ram? Basic Research in Cardiology 1937;1:188224
[in German].
21. U.S. Department of Agriculture, Natural Resources Conservation
Service. Technical Notes: hydraulic ram pumps. September 2007.
Available at: www.nrcs.usda.gov/Internet/FSE_DOCUMENTS/
nrcs142p2_041913.pdf. Accessed October 5, 2016.
22. Manteuffel-Szoege L. Energy sources of blood circulation and the
mechanical action of the heart. Thorax 1960;15(1):4753.
23. Thompson SA. The effect of pulmonary ination and deation upon
the circulation. J Thorac Surg 1948;17(3):323334.
24. Manteuffel-Szoege L, Michalowski J, Grundman J, Pacocha W. On
the possibility of blood circulation continuing after stopping the
heart. J Cardiovasc Surg (Torino) 1966;7(3):201208.
25. Forouhar AS, Liebling M, Hickerson A, et al. The embryonic
vertebrate heart tube is a dynamic suction pump. Science
2006;312(5774):751753.
26. Sherman TF. On connecting large vessels to small. The meaning
of Murrays law. J Gen Physiol 1981;78(4):431453.
27. Carlson BE, Arciero JC, Secomb TW. Theoretical model
of blood flow autoregulation: roles of myogenic, shear-
dependent, and metabolic responses. Am J Physiol Heart
Circ Physiol 2008;295(4):H1572H1579. doi: 10.1152/ajp-
heart.00262.2008.
28. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The eryth-
rocyte as a regulator of vascular tone. Am J Physiol 1995;269
(6 Pt 2):H2155H2161.
29. Ellsworth ML. Red blood cell-derived ATP as a regulator of skeletal
muscle perfusion. Med Sci Sports Exerc 2004;36(1):3541.
30. Deem S. Nitric oxide scavenging by hemoglobin regulates hypoxic
pulmonary vasoconstriction. Free Radic Biol Med 2004;36(6):
698706.
31. Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric
oxide, nitrite, and hemoglobin: Role in blood ow regulation. Free
Radic Biol Med 2004;36(6):707717.
32. Klijn E, Den Uil CA, Bakker J, Ince C. The heterogeneity of the
microcirculation in critical illness. Clin Chest Med 2008;29(4):
643654, viii. doi: 10.1016/j.ccm.2008.06.008.
33. Ince C. The microcirculation is the motor of sepsis. Crit Care
2005;(9)(suppl 4):S13S19.
34. Ince C. Hemodynamic coherence and the rationale for monitoring
the microcirculation. Crit Care 2015;(9)(suppl 3):S8. doi: 10.1186/
cc14726.
35. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory
alterations are associated with organ failure and death in patients
with septic shock. Crit Care Med 2004;32(9):18251831.
36. De Backer D, Ortiz JA, Salgado D. Coupling microcirculation to
systemic hemodynamics. Curr Opin Crit Care 2010;16(3):250254.
doi: 10.1097/MCC.0b013e3283383621.
37. Dnser MW, Ruokonen E, Pettil V, et al. Association of arterial
blood pressure and vasopressor load with septic shock mortality: a
post hoc analysis of a multicenter trial. Crit Care 2009;13(6):R181.
doi: 10.1186/cc8167. Q
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Experts Provide a Glimpse of the New
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Susan Worley
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Address Unmet Clinical Needs
Chris Fellner
MEETING HIGHLIGHTS
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Annual Meeting
Walter Alexander
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 A Comparison of Medication Histories
Obtained by a Pharmacy Technician Versus
Nurses in the Emergency Department
Marija Markovic, PharmD; A. Scott Mathis, PharmD; Hoytin Lee Ghin, PharmD, BCPS;
Michelle Gardiner, PharmD, BCGP; and Germin Fahim, PharmD, BCPS
ABSTRACT
Purpose: To compare the medication history error rate of
the emergency department (ED) pharmacy technician with
that of nursing staff and to describe the workow environment.
Methods: Fifty medication histories performed by an ED
nurse followed by the pharmacy technician were evaluated for
discrepancies (RN-PT group). A separate 50 medication histo-
ries performed by the pharmacy technician and observed with
necessary intervention by the ED pharmacist were evaluated
for discrepancies (PT-RPh group). Discrepancies were totaled
and categorized by type of error and therapeutic category of
the medication. The workow description was obtained by
observation and staff interview.
Results: A total of 474 medications in the RN-PT group and
521 in the PT-RPh group were evaluated. Nurses made at least
one error in all 50 medication histories (100%), compared to
18 medication histories for the pharmacy technician (36%).
In the RN-PT group, 408 medications had at least one error,
corresponding to an accuracy rate of 14% for nurses. In the
PT-RPh group, 30 medications had an error, correspond-
ing to an accuracy rate of 94.4% for the pharmacy technician
(P < 0.0001). The most common error made by nurses was a
missing medication (n = 109), while the most common error
for the pharmacy technician was a wrong medication frequency
(n = 19). The most common drug class with documented
errors for ED nurses was cardiovascular medications
(n = 100), while the pharmacy technician made the most errors
in gastrointestinal medications (n = 11).
Conclusion: Medication histories obtained by the pharmacy
technician were signicantly more accurate than those obtained
by nurses in the emergency department.
Keywords: pharmacy technician, medication history,
emergency department
INTRODUCTION
The Joint Commission denes the process of medication
reconciliation as the comparison of the medications a patient
is currently taking (and should be taking) with newly ordered
medications.1 The process consists of two phases in which a
Dr. Markovic is a PGY-2 Neuropsychiatry Pharmacy Resident at
Rutgers University in New Brunswick, New Jersey. Dr. Mathis
is Regional Director of Pharmacy and Medication Use,
Dr. Lee Ghin is Assistant Pharmacy Director and PGY-1 Residency
Program Director, Dr. Gardiner is a Clinical Specialist in Emergency
Medicine and Geriatrics, and Dr. Fahim is an Internal Medicine
Pharmacist at Monmouth Medical Center in Long Branch, New
Jersey. Dr. Fahim is also a Clinical Assistant Professor at Rutgers
University.
complete and accurate patient medication list must rst be
obtained, followed by a comparison (or reconciliation) of the
obtained history to the list of medications that patients will
either continue or discontinue during their stay in the hospi-
tal or as they move through the continuum of care.2 It is well
established that the process of obtaining an accurate medication
history and subsequent medication reconciliation is complex,
with numerous opportunities to create discrepancies. These
discrepancies may include omissions, duplications, discrepant
doses or frequencies, and incorrect drugs or formulations.3,4
Obtaining an accurate medication list is particularly essential
during patient transitions of care. The emergency department
(ED) stands at a critical crossroads for obtaining an accurate
medication list, as many patients who visit the ED may be
admitted. At that point, an accurate medication history becomes
crucial for maintaining continuity of care. In the demanding
and often hectic ED environment, there are numerous barriers
to obtaining an accurate medication history that continue to
frustrate clinicians. Such barriers include patients who may
be obtunded or who present with impaired memory, outdated
information from patients or hospital records, patients use
of multiple pharmacies, restrictive access to patient records,
time constraints, and language barriers.5 As a result, a crucial
role exists for skilled pharmacy personnel participating in the
medication history process.
The American Society of Health-System Pharmacists
supports the idea that every hospital pharmacy department
should provide its ED with pharmacy services.6 While the role
of a clinical pharmacist in the ED cannot be understated, it is
the role of the pharmacy technician that has been evolving to
encompass patient care activities, such as obtaining the medica-
tion history. Pharmacy technicians are in a unique position to
fulll this critical role, as they have a working knowledge of
commonly prescribed medications at a signicantly decreased
personnel cost compared with other health care professionals,
such as pharmacists or nurses.
The purpose of this study was to perform a descriptive
analysis of the ED workow for obtaining medication histories
after the addition of a pharmacy technician to the staff and to
compare the accuracy of the pharmacy technician to that of
ED nursing staff and an ED clinical pharmacist. The primary
outcome was the evaluation of the number and types of medica-
tion history discrepancies resolved by the pharmacy technician.
Secondary outcomes included the classes of medications with
an intervention and the time it took for various personnel to
complete tasks associated with medication reconciliation when
a patient presented to the ED.
Disclosures: The authors report no commercial or nancial interests
in regard to this article.
Vol. 42 No. 1 January 2017 P&T
41
 Accuracy of Medication Histories Obtained by a Pharmacy Technician in the ED
PROGRAM DESCRIPTION
Rationale for the Program
Prior to placing a pharmacy technician in the ED, the docu-
mentation of patient medication histories was largely driven by
ED nurses. The ED clinical pharmacist participated in obtain-
ing some medication histories; however, the primary focus
for the pharmacist was clinical evaluation and interventions.
An interview of the nursing staff revealed that given the high
patient turnover in the ED and the number of patients and
tasks to which they are assigned, most nurses are not able to
prioritize obtaining an accurate medication history due to time
constraints. Moreover, nurses revealed that they had no time
to utilize outside resources, such as contacting the patients
outpatient pharmacy or speaking with primary care physician
ofces. As a result, many medication histories were inaccurate,
incomplete, imported from the patients prior admission and
therefore outdated, or simply not done. When the medication
history was incomplete or inaccurate, the medical resident
admitting the patient assumed responsibility for obtaining the
medication history and completing the medication reconcilia-
tion. Interviews with the medical residents showed that they
too were unable to efciently prioritize obtaining an accurate
medication history due to time constraints and other admis-
sion responsibilities. Therefore, inaccurate or only partially
complete medication histories were frequently being used as
the basis for physicians medication reconciliation.
Prior to implementing the pharmacy technician program,
the ED clinical pharmacist conducted a study in which she
performed a thorough medication history on 24 patients in
the ED after a nurse had already documented the medication
history as complete. Of the 24 documented medication histories,
22 (91.7%) had at least one error. Of a total of 261 medications,
there were 116 errors (44.4%), the majority of which were either
medication omissions or errors in documenting the medica-
tion dose. Therefore, it was evident that the current process of
obtaining medication histories was inaccurate and unreliable,
indicating a clear need for a process change.
Implementation
The ED pharmacy technician program was implemented
in April 2015 as part of a pilot program across a large health
system to optimize the medication history and reconciliation
process. Prior to starting work in the ED, the pharmacy tech-
nician had been employed for approximately two years in the
main inpatient pharmacy, where she did not perform medica-
tion reconciliation. The pharmacy technician is registered with
the state of New Jersey but not nationally certied. Prior to
employment at our facility, she worked as a pharmacy liaison
for a different hospital for approximately one year, gathering
and processing prescriptions from inpatients and delivering
them before discharge. The technician received one week
of training from the emergency medicine pharmacist before
independently collecting and documenting medication histories.
Throughout the course of this study, the pharmacy technicians
work hours shifted to coincide with hours of peak volume in
the ED. The initial work hours were 8 A.M. to 4:30 P.M. but
gradually transitioned to the current 1 P.M. to 9:30 P.M. schedule.
42 P&T January 2017 Vol. 42 No. 1
Job Description and Workow
The workow for a patient arriving at the ED by ambu-
lance is depicted in Figure 1. After the patient is triaged and
assigned a bed in the ED, the pharmacy technician initiates
the medication history process, usually after the nurse has
imported an outdated medication history from the patients
past admission. This process consists of asking the patient or
caregiver if they know which medications the patient is taking
or whether there is a list of medications; utilizing an electronic
database of prescriptions lled through insurance; calling the
patients pharmacy, insurance company, and/or primary care
provider; and comparing the newly obtained list to the history
documented in the patients electronic health record (EHR).
The pharmacy technician follows up with the patient to ask
whether he or she is taking any over-the-counter medications,
such as vitamins or aspirin. The pharmacy technician also
updates the patients preferred pharmacy in the EHR.
When the patient is unable to provide a medication history
or a medication list or the caregiver is unavailable, the techni-
cian will compile a list as accurately as possible using avail-
able resources. These resources may include past medica-
tion histories if available, electronic databases, calling the
patients pharmacy, or asking the ED pharmacist to generate a
New Jersey prescription-monitoring program report when
appropriate. In these cases, the pharmacy technician will
indicate in the medication history that she is not able to
assess adherence to the documented regimen and will alert
the physician.
By mutual agreement given the high patient volume, the
nurse will generally independently complete the medication
history when the patient has four or fewer medications. If
the patient has more than four medications or if the medica-
tion history is complex or time consuming (such as patients
coming from long-term-care facilities, who tend to have long
medication histories), the nurse will reach out to the pharmacy
technician by phone or in person or will record the term MAR
(medication administration record) in the notes eld on the
electronic ED patient-tracking queue to alert the technician that
a medication history needs to be completed. In the meantime,
the technician independently looks at new patient records
between documentations to proactively identify patients who
will need medication histories.
In the daily workow, multiple patients may simultaneously
require a medication history to be completed by the pharmacy
technician. In these instances, the pharmacy technician will
triage patients with physician and nursing assistance, taking
into account the disease state that precipitated the ED visit. For
example, a stroke patient being assessed for administration of
tissue plasminogen activator will take precedence over other
patients. The technician will also prioritize medication histories
for patients who are being admitted so that the admitting physi-
cians can quickly reconcile and order the medications to ensure
smooth continuity of care. Often, the technician will speak to
multiple patients who need medication histories in one trip,
make copies of medication lists, and bring the documentation
back to her workstation to complete the medication histories
as efciently as possible.
During one work shift, the pharmacy technician is able to
complete approximately 20 medication histories. The duration
 Accuracy of Medication Histories Obtained by a Pharmacy Technician in the ED
Figure 1 Medication Reconciliation Flow for Patient Arriving to Emergency Department by Ambulance
Phase
Patient

Patient arrives
from ambulance

Obtain medication
Charge Nurse

4 history: Ask patient/

Yes medications caregiver, import Typically
Number of from prior admis- 1015 minutes
Available? sion, patient medi-
medications
cation list, nursing
>4 home MAR. Does
medications not call pharmacy,
insurance or PCP
No due to time
Pharmacy Technician

Obtain medication Typically

history: Ask patient/ 530 minutes
Yes (average 2024)
caregiver, copies
Available? medication list or
MAR if available,
calls pharmacy,
PCP, insurance if
needed to verify
No

Obtain medication If history not done

history: Ask patient/ by this point,
caregiver, import often old history is
Yes from prior admis- imported in system
Nurse

sion, patient medi- due to time

Available? cation list, nursing Review medication history constraints.
home MAR. Does Inaccurate process.
not call pharmacy, Often left for the
insurance, or PCP physician or LIP
due to time
No

Obtain medication If history not done

history: Ask patient/ by this point,
caregiver, import often old history is
Yes from prior admis- imported in system
sion, patient medi- Admit or due to time
ED LIP

Available? Review medication history Discharge: Complete

cation list, nursing discharge? medication reconciliation constraints.
home MAR. Does Inaccurate process.
not call pharmacy, Often left for the
insurance, or PCP admitting physician
due to time

No
Attending Physician

Obtain medication If history not

Review medication history Admit: Complete performed by this
history: Ask patient/ medication reconciliation
caregiver, import point, admitting
from prior admis- physician or
sion, patient medi- bedside nurse will
cation list, nursing have to complete,
home MAR. Does usually after ad-
not call pharmacy, mission orders are
insurance, or PCP already written
due to time

ED = emergency department; LIP = licensed independent practitioner; MAR = medication administration record; PCP = primary care physician.

of time spent on each medication history varies based on the assisting patients who have questions or elding them to the
complexity of the medication list and the available resources. appropriate nurse. The pharmacy technician also attends codes
Generally, each history takes about ve to 30 minutes to com- in the ED in case she might be able to help the medical staff
plete, with an average of 20 to 24 minutes. It is important to obtain a medication.
note that the pharmacy technicians workspace is located in
the high-trafc geriatric ED. As a result, the pharmacy techni-
cian frequently interacts with patients and family members,

Vol. 42 No. 1 January 2017 P&T 43

 Accuracy of Medication Histories Obtained by a Pharmacy Technician in the ED
METHODS
Study Setting
This study was conducted between July 2015 and March 2016
at a 520-bed community academic hospital that had 48,544 ED
visits in 2015. The 47-bed ED consists of three triage beds,
six overow beds, 19 adult beds, six express care beds, a
six-bed geriatric emergency medicine unit, and a seven-
bed pediatric ED. The average daily volume in the ED is
approximately 115 patients.
Inclusion and Exclusion Criteria
The study patients were chosen consecutively during the
study period by the pharmacy resident based on manual review
of paper medication history logs retained by the pharmacy
technician, followed by a review of the electronic documenta-
tion in the medical chart. To be included in the study, patients
had to have a medication history rst documented electroni-
cally by an ED nurse, followed by the pharmacy technician,
so that a comparison could be performed. Due to the nature
of the patient population the pharmacy technician targets
(see Program Description and Figure 1), patients were included
if they were at least 18 years of age, taking at least one medi-
cation, and were seen in the ED for a medical condition (and
subsequently discharged from the ED, placed on observation
status, or admitted to the hospital). We excluded patients
younger than 18 years of age, patients seen in the psychiatric
emergency screening service, and patients seen in the ED
outside of the pharmacy technicians scheduled work shift.
Study Design
This study was approved by the institutional review board
(IRB) and comprised three separate components, including
two medication history discrepancy analyses and a workow
description. The rst analysis was based on a retrospective
chart review by the PGY-1 pharmacy resident of 50 patients
visiting the ED at our facility between July and October 2015.
To be included in the rst analysis, patients had to rst have a
medication history documented in the electronic medical record
by a nurse, and a follow-up medication history electronically
documented by the pharmacy technician. The second analysis
was a real-time observational study in March 2016, in which
the emergency medicine clinical pharmacist accompanied
the pharmacy technician in the collection of 50 medication
histories, observed the technicians routine in obtaining the
medication history, and intervened as necessary to complete
the best possible medication history. Pharmacist interventions
were documented as medication discrepancies. The third
component of the study consisted of a workow diagram that
was established by the PGY-1 pharmacy
resident through interviews of the nursing Table 1 Baseline Characteristics of Study Groups
staff, pharmacy technician, ED pharma-
cist, resident physicians, and attending
physicians. Medications per patient, mean ( SD)
The IRB waived the need for patient Mean age, years ( SD)
consent in the rst analysis because of the
retrospective nature of the study design Male, n (%)
and in the second analysis because the ED Admitted to hospital from ED, n (%)
pharmacist, by observing the pharmacy PT = pharmacy technician; RN = registered nurse; RPh = registered pharmacist; SD = standard deviation.
technician, was acting within her usual
44 P&T January 2017 Vol. 42 No. 1
scope of practice in overseeing the pharmacy technicians
work. Additionally, we felt that patients and caregivers might
respond differently to standard questions about their medica-
tion history and adherence if they knew the process was being
monitored for a study.
Data Collection
Baseline characteristics, including the patients admission
status after being seen in the ED, were collected for both dis-
crepancy analyses. It is important to note that the total number
of medications was based on each subjects nal medication
list, so medication duplicates or additional medications were
not included in this list.
Possible discrepancies recorded included a medication omis-
sion (failure to document a medication that the patient is actively
taking), medication commission (addition of a medication that
the patient is not taking), duplicate medication, incorrect or
missing doses, incorrect or missing frequencies, and incorrect
or missing formulations (when necessary). It was possible for
one medication to have more than one documented discrepancy
(for example, an entry of atenolol would be documented as
a missing dose as well as a missing frequency). The discrep-
ant medications were categorized by therapeutic drug class,
which included: pain, gastrointestinal, cardiovascular, neuro-
logical or psychiatric, immune, diabetic, asthma or chronic
obstructive pulmonary disease, topical, herbal supplements
or vitamins, ophthalmic, antibiotic or antiviral, endocrine,
or other. Each medication was categorized only once by
therapeutic drug class.
Statistical Analysis
Students t-tests were used to compare the medications per
patient and ages. Fischers exact tests were used to compare
the number of histories with an error, the number of medica-
tions with an error, and the gender of the patients. Results
were considered statistically signicant if the alpha was less
than 0.05. Descriptive statistics were calculated using Microsoft
Windows Excel (version 2011) and GraphPad QuickCalcs.
RESULTS
Error Rate Analysis
During the study period, 36,409 patients were seen in the ED;
the pharmacy technician saw 2,840 of them. Fifty medication
histories were evaluated in each of the two analysis groups.
Baseline characteristics (Table 1) between the two groups
were similar, with a mean of nine medications per patient in
the nurse-pharmacy technician group (RN-PT) and 10 medica-
tions in the pharmacy technician-pharmacist group (PT-RPh).
RN-PT PT-RPh P Value
9 (4.0) 10 (7.1) 0.416
66 (15.9) 61 (14.6) 0.154
22 (44) 20 (40) 0.840
20 (40) 35 (70) 0.0046
 Accuracy of Medication Histories Obtained by a Pharmacy Technician in the ED
tion list compared with ED nurses. The
Table 2 Number of Medications and Errors
ndings of this study are congruent with
RN-PT PT-RPh P value other studies examining the impact of
Total medications 474 521 NA pharmacy technicians on the medication
history and reconciliation process.5,7,8 For
Number of histories with error, n (%) 50 (100) 18 (36) < 0.0001 example, a prospective study by Johnston
Medications with error, n (%) 408 (86) 30 (5.6) < 0.0001 et al. showed that well-trained pharmacy
NA = not applicable; PT = pharmacy technician; RN = registered nurse; RPh = registered pharmacist. technicians are able to obtain a medication
history with as much accuracy and com-
However, signicantly more patients in the PT-RPh group were pleteness as pharmacists, without a requirement for additional
admitted to the hospital after being seen in the ED compared time.7 A retrospective 720-chart review by Smith et al. revealed
with the RN-PT group (70% versus 40%, respectively; P = 0.0046). that accuracy of the medication history was 45.8% versus 95%
There were 474 medications evaluated in the RN-PT group using a multidisciplinary process versus a pharmacy-based
and 521 medications in the PT-RPh group (Table 2). Of process, respectively.8 Additional studies have documented the
50 completed medication histories in each group, nurses utility of pharmacy technicians in obtaining the best possible
documented a medication history with at least one discrepancy medication histories in surgical patients, hemodialysis patients,
for all 50 medication histories (100%), while the pharmacy tech- hospitalized patients infected with human immunodeciency
nician documented a discrepancy that needed to be corrected virus, psychiatric patients, and pediatric cardiology patients.914
by the pharmacist in 18 of 50 medication histories (36%). Of In our study, we found the pharmacy technician had an
the 474 total medications in the RN-PT group, 408 medications accuracy rate of 94.4%, compared with an accuracy rate of
had an error, corresponding to an error rate of 86% for nurses. 14% for ED nurses. While we did not formally analyze the
In the PT-RPh group, 30 of 521 medications had an error, pharmacy technicians areas of error, it appeared that many
corresponding to an error rate of 5.6% (P < 0.0001). frequency errors pertained to scheduled versus unsched-
Of 502 documented discrepancies across all of the medi- uled dosing (i.e., whether a medication was to be taken on a
cations (Table 3), the three most common types of medi- scheduled basis or only as needed, such as bowel regimens).
cation discrepancies made by nurses included missing a This overall error rate correlates with the ndings of several
medication (21.7%), including an additional medication the other studies evaluating the efcacy of pharmacy technicians
patient was not taking (17.9%), and failing to document the performing medication histories. For example, Hart et al. found
dose of a medication (17.9%). The pharmacy technician had that medication histories obtained by pharmacy technicians
30 documented discrepancies, the three most common being in the ED were accurate without any identiable errors 88% of
a wrong frequency (63.3%), a wrong dose (16.7%), and a wrong the time, compared with 57% of medication histories obtained
formulation (13.3%). With regard to the therapeutic drug class by nursing staff.5 Leung et al. found that pharmacy technicians
of discrepant medications, nurses most commonly made errors and pharmacists had an agreement rate of 98.9% on medication
with cardiovascular medications, vitamins, and neurological/ histories performed for 99 hemodialysis outpatients.11 Cooper
psychiatric medications, while the pharmacy technician most et al. established a pharmacy technician medication history
often made errors with gastrointestinal and neurological/ program in a ve-hospital community health system, with the
psychiatric medications and vitamins (Table 4).
Table 4 Errors by Therapeutic Drug Class
DISCUSSION Number of Errors
This study demonstrated improved accuracy when the
pharmacy technician obtained and documented a medica- Drug Class RN-PT, n (%) PT-RPh, n (%)
Cardiovascular 100 (24.5) 2 (6.7)
Table 3 Classication by Discrepancy Type
Vitamins 75 (18.4) 4 (13.3)
Type Number of Discrepancies
Neurological/psychiatric 57 (14.0) 6 (20.0)
RN-PT, n (%) PT-RPh, n (%)
Gastrointestinal 51 (12.5) 11 (36.7)
Missing medication 109 (21.7) 2 (6.7)
Diabetes 21 (5.1) 1 (3.3)
Additional medication 90 (17.9) 0
Other 16 (3.9) 1 (3.3)
Missing dose 90 (17.9) 0
Antibiotic/antiviral 13 (3.2) 0
Missing frequency 69 (13.7) 0
Immune 10 (2.5) 0
Wrong frequency 54 (10.8) 19 (63.3)
Ophthalmic 9 (2.2) 1 (3.3)
Wrong dose 42 (8.4) 5 (16.7)
Asthma/COPD 6 (1.5) 0
Duplicate medication 21 (4.2) 0
Endocrine 6 (1.5) 0
Wrong formulation 15 (3.0) 4 (13.3)
Topical 4 (1.0) 1 (3.3)
Missing formulation 12 (2.4) 0 COPD = chronic obstructive pulmonary disease; PT = pharmacy technician;
PT = pharmacy technician; RN = registered nurse; RPh = registered pharmacist. RN = registered nurse; RPh = registered pharmacist.

Vol. 42 No. 1 January 2017 P&T 45

 Accuracy of Medication Histories Obtained by a Pharmacy Technician in the ED
nding that pharmacy technicians are capable of completing
medication histories accurately and completely at a rate of
consistently more than 90%.15
A compelling nding of our study was that the pharmacy
technicians practice of obtaining accurate medication histories
often includes the time-consuming tasks of calling pharmacies,
insurance companies, and physicians ofces. In the study of the
ED workow, we were unable to compare the time that the ED
nurses spent performing these tasks with that of the pharmacy
technician because nurses do not have time to engage in these
activities. Simply speaking, when the pharmacy technician is
not there, nurses will use readily available information (such as
a verbal history or a medication list provided by the patient) or
they will import an already documented medication list if avail-
able, regardless of whether the list is outdated or not. At this
point, it is up to the physicians whether to trust that the existing
medication history is current or whether to start obtaining the
medication history themselves if the patient is admitted to the
hospital.
In addition, it is interesting to note that in the error rate
analyses, we found that the pharmacy technician performed
medication histories for signicantly more patients who were
subsequently admitted to the hospital in the PT-RPh group than
in the RN-PT group (70% versus 40%, respectively, P = 0.0046).
We hypothesize that this may reect the growing ability of the
pharmacy technician to identify and target patients who are more
likely to be admitted to the hospital (for example, elderly or
acutely ill patients, or those with complex medication regimens),
as approximately six months passed between these two data sets.
There are a few limitations to our study. One is a lack of gen-
eralizability, given that this study evaluated the process of one
technician in one facility. The ED pharmacy technician is part
of a new program, and there is no formal process for targeting
patients or documenting interventions. In addition, the different
design between the two study groups in the error rate analysis
may lend itself to potentially skewed results, particularly when
accounting for the Hawthorne effect in the group in which the
clinical pharmacist observed the pharmacy technician.
At this time, the pharmacy technician is able to see about
20 patients per shift, which accounts for only about 17% of
patients seen daily in the ED. While we did not formally measure
staff satisfaction before and after the study, it is noteworthy
that the ED staff appears quite receptive to the utility of the
pharmacy technician and often independently seeks out her
service during her shift. This study did not include a nancial
analysis, but available hourly pay averages for the health care
system indicate that pharmacy technicians are compensated
at approximately 45% and 29% of the average salary of a staff
nurse and a staff pharmacist, respectively. From a monetary
perspective, hiring a pharmacy technician to perform medica-
tion histories is more cost-effective than hiring an additional
nurse or ED pharmacist. It would be interesting for future
studies to explore the cost savings in terms of medication
errors or adverse events prevented, or even high-risk hospital
readmissions prevented. We hope to expand this service with
the use of electronic databases to collect outside pharmacy
prescription information, which will allow a more streamlined
and efcient process. Ultimately, we hope that the sustained
success of this program will justify its expansion.
46 P&T January 2017 Vol. 42 No. 1
CONCLUSION
In this study, medication histories obtained by the pharmacy
technician were signicantly more complete and accurate than
those obtained by emergency department nurses.
ACKNOWLEDGEMENT
The authors would like to thank their pharmacy technician,
Ashley OKeefe, for her contributions to this work.
REFERENCES
1. The Joint Commission. Hospital: 2016 national patient safety goals.
Available at: www.jointcommission.org/standards_information/
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ciliation issues and experiences with clinical staff and information
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3. Cornish PL, Knowles SR, Marchesano R, et al. Unintended medica-
tion discrepancies at the time of hospital admission. Arch Intern
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4. Pippins JR, Gandhi TK, Hamann C, et al. Classifying and predict-
ing errors of inpatient medication reconciliation. J Gen Intern Med
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5. Hart C, Price C, Graziose G, Grey J. A program using pharmacy
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DocLibrary/BestPractices/SpecicStEmergDept.aspx. Accessed
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7. Johnston R, Saulnier L, Gould O. Best possible medication history
in the emergency department: comparing pharmacy technicians
and pharmacists. Can J Hosp Pharm 2010;63(5):359365.
8. Smith SB, Mango MD. Pharmacy-based medication reconciliation
program utilizing pharmacists and technicians: a process improve-
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2003;60(19):19821986.
10. van den Bemt PM, van den Broek S, van Nunen AK, et al. Medica-
tion reconciliation performed by pharmacy technicians at the time
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11. Leung M, Jung J, Lau W, et al. Best possible medication history
for hemodialysis patients obtained by a pharmacy technician. Can
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12. Siemianowski LA, Sen S, George JM. Impact of a pharmacy
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13. Brownlie K, Schneider C, Culliford R, et al. Medication reconcilia-
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Int J Clin Pharm 2014;36(2):303309.
14. Chan C, Woo R, Seto W, et al. Medication reconciliation in pediatric
cardiology performed by a pharmacy technician: a prospective
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pharmacy technician medication history program. Am J Health-Syst
Pharm 2014;71(18):15671574. Q
 Challenges and Solutions in
Reducing Opioid Misuse and Abuse
Peter Sonnenreich and Linda Geisler
Initiatives aimed at reducing opioid misuse and abuse include
mining claims data to identify patients at high risk for substance
abuse, promoting wearable technologies to improve monitor-
ing of patients with chronic pain, placing limitations on the
prescribing and dispensing of opioids, and increasing patient
and provider awareness of alternative pain management options.
A variety of approachesand a variety of challenges
emerged from an Academy of Managed Care Pharmacy
(AMCP) Foundation symposium in October 2016 entitled
Balancing Access and Use of Opioid Therapy in National
Harbor, Maryland. Panelists later recounted some of the ideas
they heard that might have the most effect. David Calabrese,
RPh, MHP, Chief Pharmacy Ofcer for OptumRx, summed
up the takeaway from the symposium: This is going to take
a well-coordinated, multidimensional type of solution to truly
impact, in a positive way, this epidemic.
Predicting Opioid Use Disorder
One approach focuses on identifying the patients at highest
risk for problems. Using Truven Health Analytics nationally
representative database, Purdue Pharma researchers evaluated
treatment patterns among noncancer patients and identied
patterns of opioid prescribing that fell outside the standard for
normal and could be considered a risk for patients.
Researchers followed 71,000 patients who initiated an
extended-release (ER) opioid over a two-year period to better
understand how these drugs are being used. Tracy Mayne,
PhD, Executive Medical Director for Purdue Pharma, a panel-
ist at the meeting, shared ndings of the study. Of the 71,000
patients, 72% used one ER opioid over the two-year period, 21%
used two opioids, and just 0.7% (520 patients) used three or
more. These data show that a practice known as opioid rota-
tion is very rare and not a standard practice among physicians
who prescribe these drugs. Among patients who took a long-
acting opioid for the full two years, only 72 patients had more
than two dose increases after the initial 90-day titration period;
this, Dr. Mayne says, is the most worrisome group, showing a
pattern of continuous dose escalation. Fortunately, this practice
was also uncommon.
Opioid-Related Costs
Another Purdue study examined the costs of opioid abuse,
dependence, overdose, and poisoning over a three-year period.
Researchers used a propensity score match on 200 variables
during a seven- to 12-month period for two cohorts: one with
opioid misuse and one without. The primary drivers of excess
cost in this population were opioid dependence and poisoning,
but this was closely followed by nonopioid drug abuse and
Peter Sonnenreich is a freelance health care writer in Bethesda,
Maryland. Linda Geisler is a freelance health care writer in Weston,
Connecticut.
dependence, and alcohol abuse and dependence. Medical costs
started to increase six months before a diagnosis of abuse and
continued to accumulate over the next 18 months. Compared
with the control group, patients in the abuse group incurred
costs of $1,000 more a month. Costs arose from inpatient
settings, emergency departments, rehabilitation facilities,
outpatient settings, and prescription drugs. Interestingly, these
patients were in treatment for alcohol- and nonopioid-related
substance abuse but do not appear to have been properly
evaluated for opioid use.
If somebody had any prior history of alcohol or any other
substance abuse, Dr. Mayne says, that patient is at high
risk. And we should think twice about giving that patient an
opioid. If they do need an opioid, monitor that patient very, very
carefully. And the truth is, we know physicians are not going
to their claims or medical record and looking for that history.
Pain Practice Analyzers
Purdue is working in partnership with a chronic pain clinic and
companies that provide wearable health technologies to offer the
device to new patients in the clinic over the course of a year. The
device will track pain, physical activity, sleep, depression, and
other measures important in chronic pain and provide a two-way
exchange of data. These data will go to dashboards for the patient
and the physician, but the device will also interface with electronic
medical records. The device can give physicians a window into the
patients daily function, and they may be able to intervene sooner,
Dr. Mayne says.
Total Opioid Management for Managed Care
At the conference, Calabrese described a Five for Life
approach to Total Opioid Management, an initiative he is helping
to spearhead at OptumRx. This ve-step approach includes
up-front education and prevention strategies to increase public
awareness and encourage appropriate opioid use and promote
alternatives where clinically warranted. The program limits
individual exposure to opioid therapy through what Calabrese
describes as disruptive yet highly warranted dose and dura-
tion limitations on the dispensing of these drugs, particularly
in patients who may be nave to opioid therapy. He explains
that limiting indiscriminate prescribing by the physician and
dispensing by the pharmacy is where we are likely to drive the
greatest benets with regard to decreasing the prevalence of
dependence, addiction, and overdose in this country.
Another important component is high-risk patient identica-
tion and intervention. This involves employment of a much
more forensic approach to uncovering patterns of patient-
specic drug utilization that might be indicative of current
or future misuse, abuse, or diversion, he says. Then there is
prescriber and pharmacy surveillance, which amplies how we
are monitoring physician prescribing and pharmacy dispensing
patterns and shutting down any disproportionate or potentially
Vol. 42 No. 1 January 2017 P&T
47
 Challenges and Solutions in Reducing Opioid Misuse and Abuse
abusive opioid prescribing by physicians. We will be deploy-
ing much more comprehensive and sophisticated analytics to
identify outliers, those physicians and pharmacies that may be
contributing to the crisis through high-risk clinical practice and
potentially unethical behaviors that we know are occurring all
too frequently in the marketplace. The fth step is appropri-
ately supporting those who have already been afictedthose
who have had a previous overdose, are actively in substance
abuse treatment, or have formally completed substance abuse
treatmentto ensure that they have proper access to the right
resources, properly accredited treatment centers, behavioral
health support services, and medication-assisted treatment.
Calabrese says its important to remember how this problem
started. Excessive marketing and promotion of opioids in the
late 1980s and early 1990s was a main driver of the situation
our country faces todaythe excess prescribing of these
products in noncancer-related chronic pain, where evidence
is signicantly lacking to support the value of these drugs
versus therapeutic alternatives. The particular promotional
campaign of Pain as the Fifth Vital Sign by the American Pain
Society that coincidentally coincided with the FDA approval of
Oxycontin has been identied by industry experts as potentially
one of the biggest mistakes in modern medicine, Calabrese
says. The numbers speak for themselves in terms of growth
in opioid prescriptions since that time and how that directly
parallels with trends in inpatient admissions, ED visits, and
death tolls due to overdose.
While a contributing factor is certainly managed cares
insufcient surveillance and intervention to date with the
bad guys, it must be recognized that the bulk of the problem
leading up to this crisis has been the well-intentioned, but
signicantly misguided, efforts of physicians across the country,
who were simply trying to do the right thing for their patients
based on what they were taught and what the consensus was
at the time, Calabrese says. Now it is time for us all to take
accountability for the situation we nd ourselves in by re-
educating providers and patients and taking a more aggressive,
well-rounded approach to limiting indiscriminate use of these
meds while still ensuring proper care for those with chronic
pain management needs.
The Path of Pain: Maze or Labyrinth
During Patient Perspective panel discussions at the AMCP
Foundation meeting, Glenna Crooks, PhD, Founder and CEO of
Strategic Health Policy International, Inc., described a patients
experience of pain as being like a maze or labyrinth. A maze,
she explained, has blind alleys and dead ends. Its possible to
get lost in a maze and even die there. Many people would say
that is their experience of pain. For others, their path of pain is
like a labyrinthif they keep going, they eventually come out
the other side. That was her experience of dealing with acute
surgical pain and long-term chronic pain from traumatic injury.
Frankly, many people experience pain but are not dealing
with it, Dr. Crooks says. I think we all are in denial about
pain. She adds that even the language we use to describe
pain, the scale of 1 to 10, is insufcient and should be revised
to deal with the opioid crisis.
Dr. Crooks calls pain that in your face existential
challenge. Patients who have experienced pain from an
48 P&T January 2017 Vol. 42 No. 1
accident, injury, or disease may fear that it will happen again.
They may feel vulnerable, helpless, and ashamed that somehow
its their fault. Some get caught in an angerdepression loop.
Chronic pain can constrict social activities, can interfere with
sleep, and can lead to isolation. The painand the emotional
turmoil that comes with itcan bring about unemployment,
addiction, and early death.
Alternatives to Opioids
Many patients and providers do not know about the non-
pharmaceutical treatment options for both acute and chronic
pain. In some instances, access to these alternative pain manage-
ment strategies may be limited. Dr. Crooks acknowledges that
nding a treatment that works requires a persons willingness
and ability to keep looking. Her career in government and
the pharmaceutical industry gave her access to experts and
information about nondrug alternatives to pain management
and the nancial stability to pay out-of-pocket for them.
To avoid opioids, she tried yoga, massage, nutrition
solutions, wellness, a Zen practice known as BigMind, and
the Canyon Ranch Health Resort. She studied neuroscience to
learn how to use her brain to manage her pain and has seen a
psychiatrist specializing in trauma because much of her pain
has been caused by a traumatic event. Another pain-relieving
strategy for her is staying active mentally and working.
Dr. Crooks was recently in a clinical study examining the
effects of the Spire and Muse apps, which track breathing and
facilitate meditation, respectively. Another FDA-approved over-
the-counter device she uses, Quell, ts around the leg below
the knee and delivers an electrical signal directly into the brain
for chronic, widespread pain. After wearing the device for a
short period, she says, she experienced better sleep quality
and a lot less pain.
As with all of the other treatments Dr. Crooks has tried,
however, she acknowledges that eventually, Quell, like other
methods, may no longer help. That for her is part of the journey
through the labyrinth. For people with chronic pain, like
me, she says, when it comes to the point where something
doesnt work anymore, you just have to keep going and try
something different. Q
For the Latest News
... Visit PTcommunity.com. At this online resource
for P&T decision-makers, youll nd breaking-news
coverage of all of these topics:
Clinical Trials Approvals, Launches,
Research News and New Indications
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Youll also nd recent issues, a free digital app, formu-
lary kits, P&T TV, industry announcements via Globe
NewsWire, PharmD Corner, and many other resources.
 MEETING HIGHLIGHTS
Society for Immunotherapy of Cancer
And
American Heart Association
Walter Alexander
Society for Immunotherapy of Cancer (SITC)
The 31st annual SITC meeting hosted 2,700
medical professionals November 913 in National
Harbor, Maryland. The record-setting attendance was
reective of the intense current interest in immuno-
therapies. We review below two key sessions on the
checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers
Squibb) in antitumor combinations for the treatment of
solid malignancies.
Urelumab Is Safe and Active as Monotherapy
And in Combination With Nivolumab in
Hematologic and Solid Malignancies
Erminia Massarelli, MD, Associate Clinical Professor,
University of Texas MD Anderson Cancer Center, Houston,
Texas
Preclinical models of combined urelumab and nivolumab
have demonstrated robust antitumor activity with increased
interferon gamma (IFN) production versus monotherapy.
Because each enhances immune cell activity through distinctly
different mechanisms, their activity in patients with advanced
cancers may be synergistic, Dr. Massarelli said. Urelumab is
a fully human IgG4 monoclonal antibody that binds to and
activates CD137-expressing cytotoxic T cells.
A monotherapy study evaluated urelumab in patients with
advanced malignancies (0.1 or 0.3 mg/kg every three weeks)
or advanced non-Hodgkins lymphoma (8 mg every three
or six weeks). The combination study evaluated urelumab
(3 mg or 8 mg every four weeks) plus nivolumab (3 mg/kg
or 240 mg every two weeks) in patients with advanced solid
tumors or B-cell lymphoma or patients with diffuse large
B-cell lymphoma (DLBCL), melanoma, nonsmall-cell lung
cancer (NSCLC), or squamous cell carcinoma of the head and
neck (SCCHN; cohort expansion). Mean age was approximately
65 years. In the combination study, 28% of patients had no
prior treatment, and 70% had one or more prior lines of therapy. In
the monotherapy study, all patients had been treated previously.
With the urelumab plus nivolumab combination, increases
in IFN-induced peripheral cytokine expression (CXCL9/
CXCL10) following treatment were larger than those that
occurred with urelumab monotherapy. In a small sample of
melanoma tumors, greater numbers of CD8-positive T cells
and increased CXCL9 gene expression (and a trend toward
increased IFN gene expression) were observed.
The author is a freelance writer living in New York City.
In the monotherapy trial, drug-induced liver injury in
one patient led to discontinuation of the 0.3-mg/kg dose of
urelumab. No treatment-related deaths were reported, and
only three of 70 patients withdrew due to treatment-related
adverse events.
The monotherapy overall response rate (ORR) was 10%
(5% complete and 5% partial remission), with all responses
occurring in those with B-cell non-Hodgkins lymphoma
(B-NHL). The conrmed disease control rates (DCR) for
B-NHL, colorectal cancer (CRC), SCCHN, and other solid
tumors were 28%, 18%, 20%, and 39%, respectively.
Among the 128 combination-therapy patients receiving
at-dose urelumab (8 mg every four weeks) and nivolumab
(240 mg every two weeks), adverse events led to dis-
continuation in 10% of patients (seven of 128 patients any grade;
six of 128 patients grades 34). Fatigue was the most commonly
reported adverse event (31% any grade; 0% grades 34). This
indicates that these two agents can be safely administered
together, Dr. Massarelli said.
The ORR (conrmed and unconrmed) was 50% among
46 melanoma anti-programmed cell death-1 (PD-1)/
programmed death ligand-1 (PD-L1) nave patients and the DCR
rate (conrmed and unconrmed) was 70%. DCRs were 21%
for DLBCL, 21% for NSCLC (anti-PD-1/PD-L1) progressors,
35% for NSCLC (anti-PD-1/PD-L1 nave), 23% for SCCHN, and
33% for other solid tumors.
PD-L1 status (1% or greater or less than 1%) had no effect
on ORR in melanoma patients receiving the urelumab plus
nivolumab combination who were anti-PD-1/PD-L1 nave, with
rates of 50% (1% or greater) and 47% (less than 1%).
Among patients receiving combination therapy with ure-
lumab and nivolumab, safety was manageable at all evaluated
doses. Dr. Massarelli concluded that in the urelumab mono-
therapy trial, the 0.1-mg/kg and 8-mg doses demonstrated
manageable safety proles and peripheral pharmacodynamic
activity. Promising antitumor activity was observed in
melanoma patients.
Greater Benet for Nivolumab 1 mg/
Ipilimumab 3 mg in Previously Treated
Metastatic Urothelial Cancer
Padmanee Sharma, MD, University of Texas MD Anderson
Cancer Center, Houston, Texas
In previously treated patients with metastatic urothelial
carcinoma (mUC), chemotherapy efcacy is poor and associ-
ated with signicant toxicity, Dr. Sharma said. Monotherapy
trials (phase 1/2 and 2) of nivolumab have shown notable
antitumor activity in patients previously treated for mUC,
Vol. 42 No. 1 January 2017 P&T
49
 MEETING HIGHLIGHTS: Society for Immunotherapy of Cancer
with overall response rates (ORR) of 19.6% and median overall
survival (OS) of 8.7 months. Both preclinical and clinical data
with the combination of nivolumab, a programmed cell death-1
blockade, and ipilimumab (Yervoy, Bristol-Myers Squibb), a
cytotoxic T-lymphocyteassociated antigen-4 blockade, have
shown improved antitumor activity in advanced melanoma,
nonsmall-cell lung cancer, and metastatic renal cell carcinoma.
Dr. Sharma presented rst results from Checkmate 032,
the rst trial of combination immunotherapy in mUC. The
phase 1/2 study compared two dosing strategies of nivolumab
combined with ipilimumab in patients with previously
treated metastatic disease. Twenty-eight patients received
nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (intravenously
[IV] every three weeks for four cycles) and 104 patients
received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg
(IV every three weeks for four cycles), with all receiving main-
tenance with nivolumab 3 mg/kg IV every two weeks. The
primary endpoint was investigator-assessed conrmed ORR.
Median age was greater in patients in the nivolumab 1-mg/
ipilimumab 3-mg group (50.0% versus 45.2% were 65 years of
age or older). Both groups had approximately 60% of patients
treated with two or more prior regimens. Programmed death
ligand-1 expression was higher than 1% in more patients in the
nivolumab 1-mg/ipilimumab 3-mg group (38.5% versus 28.8%).
More patients are continuing treatment in the nivolumab
1-mg/ipilimumab 3-mg group (46.2% versus 14.4%). Also in
that group, discontinuation for disease progression was lower
(38.5% versus 64.4%). Elevation of alanine aminotransferase and
aspartate aminotransferase levels was greater with the higher
nivolumab dose (17.3%/11.5% versus 0%/0%, respectively).
Treatment discontinuation rates were 7.7% for nivolumab
1 mg/ipilimumab 3 mg and 13.5% for nivolumab 3 mg/
ipilimumab 1 mg.
Dr. Sharma said, Grade 34 adverse event rates were around
30% and very similar for both groups.
Its very important to note the overall response rate com-
pared to the 19% with nivolumab monotherapy reported in
Lancet Oncology and the 15% rate previously reported for
atezolizumab, Dr. Sharma said, stating that conrmed ORR
was 38.5% in the nivolumab 1-mg/ipilimumab 3-mg group
(95% condence interval [CI], 20.259.4) and 26.0% in the
nivolumab 3-mg/ipilimumab 1-mg group (95% CI, 17.935.5).
Historical controls, she added, are 10% or less.
Complete response (3.8% versus 2.9%) and partial response
rates (34.6% versus 23.1%) were higher with the higher ipilim-
umab dose regimen. The progressive disease rate, however,
was higher with the lower ipilimumab dose regimen (26.9%
versus 41.3%). Median tumor change from baseline in the
target lesion was 27.8% in the nivolumab 1-mg/ipilimumab
3-mg group and 0% in the nivolumab 3-mg/ipilimumab 1-mg
group. While median time to response was similar for both
groups (1.4 months), ongoing response rates were higher
for the higher ipilimumab dose group (80% versus 70%), as
were the median progression-free survival (4.3 months versus
2.6 months) and median OS rates (10.2 versus 7.3 months).
Efcacy with nivolumab 3 mg plus ipilimumab 1 mg did not
appear to differentiate from that with nivolumab monotherapy,
Dr. Sharma observed. Nivolumab monotherapy ndings had
been reported previously.
50 P&T January 2017 Vol. 42 No. 1
While the cohort size is small, she said the ndings are
very promising. Dr. Sharma noted that the nivolumab 1-mg/
ipilimumab 3-mg cohort is being expanded to 92 patients.
Commenting on a question raised after her presentation
regarding the possibility of using ipilimumab at 10 mg/kg,
Dr. Sharma responded, With ipilimumab 3 mg/kg you get
the same T-cell activation as with ipilimumab 10 mg/kg.
Our monitoring showed, however, that ipilimumab 1 mg/kg
does not give you the same level of T-cell activation as with
3 mg/kgwhich would not give you the same level of
antitumor response.
American Heart Association (AHA)
This years AHA meeting, held November 1216
in New Orleans, attracted approximately 18,000
medical professionals from nearly 100 countries. We
review below key sessions focusing on anticoagulation
for peripheral artery disease and for stroke protection in
atrial brillation, cholesterol-lowering strategies, COX-2
inhibitors, and cognitive decline.
Effects of Ticagrelor Compared With Clopidogrel
In Patients With Peripheral Artery Disease
Manesh R. Patel, MD, Associate Professor of Medicine,
Duke University Medical Center, Durham, North Carolina
EUCLID, a trial designed to test whether long-term
monotherapy for symptomatic peripheral artery disease
(PAD) with ticagrelor (Brilinta, AstraZeneca) is superior to
clopidogrel in preventing cardiovascular death, myocardial
infarction, or ischemic stroke, found identical combined event
rates for both agents.
PAD is associated with both cardiovascular and limb
morbidity and mortality, Dr. Patel noted in an AHA press
brieng. He also said that composite cardiovascular death,
myocardial infarction, or ischemic stroke with clopidogrel in
the CAPRIE trial (1996) was reduced by 8.7% (P = 0.043) versus
aspirin. In further research among patients with acute coronary
syndromes (ACS), chronic therapy with the antiplatelet agent
ticagrelor demonstrated superiority over clopidogrel for the
same composite endpoint.
EUCLID investigators enrolled 13,885 symptomatic PAD
patients (811 sites, 28 countries) double-blind to ticagrelor
90 mg twice daily or clopidogrel 75 mg once daily. Median
age was 66 years, and approximately 28% of the patients were
women. Eight percent of the patients had prior stroke, approxi-
mately 29% had coronary artery disease, and about 18% had a
prior myocardial infarction. Claudication was mild or moderate
in approximately 53% of patients.
Reporting the combined primary endpoint, Dr. Patel said
that 36-month cardiovascular death, myocardial infarction, or
ischemic stroke occurred at an identical rate of 12.5% with both
ticagrelor and clopidogrel. While individual components of the
endpoint were generally similar between groups, ischemic
stroke was more common among patients receiving clopidogrel
compared with ticagrelor (2.4% versus 1.9%; P = 0.03). The
rate for major bleeding (measured with the Thrombolysis in
 MEETING HIGHLIGHTS: American Heart Association
Myocardial Infarction score) was also identical for the ticagrelor
and clopidogrel groups at 1.6% (P = 0.49).
The ndings demonstrated that the active comparator in
EUCLID, clopidogrel, is an effective antiplatelet therapy
in PAD. Ticagrelor was not superior to clopidogrel for the
reduction of cardiovascular events, Dr. Patel said. A further
message from EUCLID, he added, is that caution needs to
be exercised in extrapolating evidence from coronary artery
disease patients to peripheral artery disease.
A possible explanation for the discrepancy between
CAPRIE and EUCLID results, commented AHA discussant
Carl Pepine, MD, from the University of Florida, could be
that clopidogrel is a prodrug that needs to be metabolized to
exert its antiplatelet action. EUCLID excluded patients who
were poor metabolizers of clopidogrel, perhaps accounting
for the equivalent effectiveness with ticagrelor. The signal
for reduced stroke with ticagrelor may also be explained by
concomitant blood pressure reduction, as was demonstrated
for ticagrelor versus clopidogrel in the DISPERSE-2 trial,
Dr. Pepine said.
Clearly many knowledge gaps remain relative to PAD,
he said, noting that PAD, which occurs in 10% of Americans
older than 60 years of age, is associated with higher risk for
adverse outcomes, ostensibly through large atherosclerosis
risk factor burden, more diffuse atherosclerosis, enhanced
platelet activation, and inammation.
Inhibition of PCSK9 Synthesis via
RNA Interference: 90-Day Data From
Orion-1A Multicenter, Phase 2,
Randomized, Controlled Trial
Kausik K. Ray, MD, Imperial College, London, United
Kingdom
LDL-C [low-density lipoprotein-cholesterol] reduction is
a proven strategy to prevent atherosclerotic cardiovascular
disease, Dr. Ray stated at an AHA press conference. While
monoclonal antibodies that block proprotein convertase
subtilisin/kexin type 9 (PCSK9) have demonstrated signif-
icant LDL-C lowering with or without statins, the needed
12 to 24 subcutaneous (SC) injections per year remain
logistically and economically difcult. RNA interference,
Dr. Ray said, is a highly efcient approach to inhibiting
PCSK9 synthesis in the liver, and in a phase 1 trial of 300 mg of
SC inclisiran in 69 patients, LDL-C was reduced by about 50%
for four to six months. Inclisiran is a synthetic double-strand
2123mer oligonucleotide.
The ORION-1 trial included 501 patients (mean age,
approximately 63 years) with atherosclerotic cardiovascular
disease or high atherosclerotic cardiovascular disease
risk with LDL-C greater than 70 mg/dL or 100 mg/dL,
respectively, despite maximally tolerated statin therapy. About
69% of patients had atherosclerotic cardiovascular disease,
and 24% had diabetes. Thirteen percent were being treated for
primary prevention, and the rest had familial hyper-
cholesterolemia (5%). At baseline, 81% of patients were on
statins, and 31.7% were on the cholesterol-lowering drug
ezetimibe (Zetia, Merck).
ORION investigators compared six different SC dosing
regimens of inclisiran to SC placebo. The primary endpoint
was percent change in LDL-C levels from baseline at day 180.
A single dose of inclisiran produced durable PCSK9 and
LDL-C lowering (P < 0.0001 versus placebo for all inclisiran
doses) at 90 days. A second inclisiran dose at 90 days sus-
tained these reductions to day 180. The mean absolute change
in LDL-C from baseline in the placebo group was 3.1%;
for inclisiran, it was 64.9% (two doses). Looking at the
300-mg dose, Dr. Ray said that a single dose achieved a mean
LDL-C reduction of 51%, while two 300-mg doses achieved a
57% LDL-C reduction.
Treatment-emergent adverse events at day 90 were reported
at similar levels for placebo (54%) and pooled inclisiran doses
(54%; 100 mg [62%], 200 mg [52%], 300 mg [56%], 500 mg
[43%]). Severe adverse event rates were 4% for placebo and
3% for inclisiran. Myalgia was reported in 4.7% and 5.7% of
placebo and inclisiran patients, respectively. Injection site
adverse event (erythema, pruritus, rash, or reaction) rates
were 0% for placebo and 3.2% for the pooled inclisiran groups.
The ndings, Dr. Ray commented, afrm potential for
biannual or triannual dosing and warrant continued evaluation
of inclisiran in a phase 3 trial. RNA interference with incli-
siran would be less expensive and has potential for sustained
suppression of hepatic PCSK9 production with fewer injections.
The efcacy, safety, and dosing prole of inclisiran are likely
to ensure signicant and durable reductions in LDL-C and,
thus, potentially impact cardiovascular outcomes.
Cardiovascular Outcomes With Celecoxib Versus
Ibuprofen or Naproxen: The PRECISION Trial
Steven E. Nissen, MD, Cleveland Clinic, Cleveland, Ohio
Nonsteroidal anti-inammatory drugs (NSAIDs) and cele-
coxib (Celebrex, Pzer), a cyclooxygenase type-2 (COX-2)
selective inhibitor, reduce pain and inammation through the
inhibition of prostaglandins in osteoarthritis and rheumatoid
arthritis patients. When rofecoxib, another COX-2 selective
inhibitor, was withdrawn from the market in 2004 because of
increased risks of heart attack and stroke associated with its
long-term, high-dosage use, the Food and Drug Administration
required a post-marketing cardiovascular safety trial comparing
the only remaining COX-2 selective inhibitor, celecoxib, with
traditional nonselective NSAIDs.
To meet that requirement and to address doubts about the
cardiovascular safety of COX-2 inhibitors, the PRECISION
trial was designed to evaluate the effects of celecoxib
(100200 mg twice daily) and ibuprofen (600800 mg three
times daily) compared with naproxen (375500 mg twice
daily) on the rst occurrence of an Antiplatelet Trialists
Collaboration (APTC) composite cardiovascular endpoint
(cardiovascular death, nonfatal myocardial infarction, or non-
fatal stroke). PRECISION included 24,081 patients at 924 sites in
13 countries with osteoarthritis or rheumatoid arthritis and
with or at high risk for concomitant cardiovascular disease.
Administration of aspirin 75100 mg daily was allowed accord-
ing to local guidelines. Patients were provided with daily
esomeprazole for gastrointestinal protection.
Vol. 42 No. 1 January 2017 P&T
51
 MEETING HIGHLIGHTS: American Heart Association
The mean patient age was 63 9.4 years, 74.3% were white,
and 64.1% were female. Aspirin was administered at baseline
to 51.1% of patients. The primary diagnosis was rheumatoid
arthritis in 10.1% of patients and osteoarthritis in 89.9%. Drug
discontinuation rates were similar for all agents (approximately
69%).
Dr. Nissen reported that for the APTC endpoint, celecoxib
was noninferior to ibuprofen and naproxen in both intention-
to-treat and in on-treatment analyses. Superiority analyses
showed a borderline benet for celecoxib versus ibuprofen
for time to major adverse cardiovascular events (15%; P = 0.06)
and for celecoxib versus naproxen for time from randomiza-
tion to all-cause mortality (25%; P = 0.052). Intention-to-treat
benets for celecoxib in time to major gastrointestinal event
were signicant compared with ibuprofen (54%; P = 0.002) and
with naproxen (41%; P = 0.01). Also, analysis of the time from
randomization to a serious renal event showed a highly signi-
cant benet for celecoxib versus ibuprofen (64%; P = 0.004).
Dr. Nissen commented, Numerically fewer APTC events occurred
with celecoxib than with naproxen or ibuprofen, meeting all
four noninferiority criteria (P < 0.001).
These ndings challenge the widely held view that naproxen
provides superior cardiovascular safety, Dr. Nissen con-
cluded. He added that between-drug differences should be
viewed as hypothesis-generating rather than conclusive given
a multiplicity of issues and the challenges of adherence and
retention in the trial.
No Cognitive Decline Benet for
Cholesterol or Blood Pressure
Lowering Among the Elderly in HOPE-3
Jackie Bosch, PhD, McMaster University, Hamilton, Ontario,
Canada
Dementia, vascular cognitive impairment, vascular demen-
tia, and cognitive aging are some of the biggest concerns of our
elderly and aging populations. Unfortunately, we dont have
any treatments or approaches that actually alter that risk,
said Ralph Sacco, MD, University of Miami Health System and
former AHA President, the AHA-appointed discussant for this
trial. Despite many smaller studies showing strong relation-
ships between blood pressure, diabetes, and cholesterol control
and decreases in cognitive decline, randomized trials have not
shown signicant reductions in cognitive decline. HOPE-3, evolocumab (420 mg monthly) or placebo for 78 weeks.
he said, is important because it uses a randomized clinical
trial design to address this question.
HOPE-3 randomized moderate-risk individuals from
228 centers in 21 countries to receive either candesartan/
hydrochlorothiazide or placebo and rosuvastatin or placebo.
Dr. Boschs HOPE-3 trial substudy examined the effect of
cholesterol and blood pressure lowering on cognitive decline
in the subset of 1,626 patients 70 years of age or older.
Participants answered questions relative to decline in
processing speed (primary outcome measured by the
Digit Symbol Substitution Test [DSST]), executive
function, psychomotor speed, functional changes, and
global activity.
Cognitive and functional decline were observed over the
52 P&T January 2017 Vol. 42 No. 1
5.6 years of follow-up. Blood pressurelowering agents and
rosuvastatin, however, did not signicantly prevent cogni-
tive or functional decline. Study end DSST scores were simi-
lar for individuals receiving blood pressure medications or
placebo (P = 0.86), statin lowering with rosuvastatin or placebo
(P = 0.38), and the combination of blood pressure and cho-
lesterol lowering versus double placebo (P = 0.63). A post hoc
analysis among 93 patients revealed a positive trend toward
reduced cognitive decline in those in the highest tertile of
blood pressure and LDL cholesterol (greater than 145 mm Hg
and greater than 140 mg/dL, respectively) at baseline. Longer
duration of blood pressure lowering was also associated with
less cognitive decline. Both of these ndings, Dr. Bosch
emphasized, require further conrmation.
While anecdotal and observational studies have raised con-
cerns that statins may adversely affect cognition and have
led to black box warnings in statin labeling, she said, in this
trial, administration of rosuvastatin had no adverse effects on
cognitive function.
Effect of Evolocumab on Progression of Coronary
Atherosclerosis in Statin-Treated Patients: A
Placebo-Controlled Intravascular Ultrasound Trial
Steven E. Nissen, MD, Cleveland Clinic, Cleveland, Ohio
Statins have been shown to slow progression or induce
regression of coronary disease in proportion to the magnitude
of low-density lipoprotein-cholesterol (LDL-C) reduction in
intravascular ultrasound (IVUS) trials. The lowest LDL-C
in these trials has been about 60 mg/dL, Dr. Nissen said in
an AHA press conference. He further noted that proprotein
convertase subtilisin/kexin type 9 (PCSK9) targets LDL
receptors for degradation, reducing hepatic removal of LDL-C
from blood. PCSK9 inhibitors induce large LDL-C reduc-
tions and, when added to statins, allow very low LDL-C levels
to be reached. Effects on atheroma burden are unknown,
however.
Evolocumab (Repatha, Amgen), a monoclonal antibody, is
a PCSK9 inhibitor administered by subcutaneous injection. In
the Global Assessment of Plaque Regression With a PCSK9
Antibody as Measured by Intravascular Ultrasound (GLAGOV)
trial, 968 statin-treated patients with established coronary
heart disease at 226 sites in 32 countries were randomized to
GLAGOV is the rst intravascular outcome trial testing the
effects of a PCSK9 inhibitor on the regression or progression
of coronary atherosclerosis as measured by intravascular
ultrasound. All patients in GLAGOV underwent an IVUS exami-
nation of a single coronary artery during a clinically indicated
angiogram at baseline and at study end. The primary efcacy
endpoint was the nominal change in percent atheroma volume
from baseline to the poststudy IVUS.
Mean patient age was 59.8 9.2 years, and 72% of
patients were male. Rates of current smoking and diabe-
tes were 24.3% and 20.6%, respectively. Mean LDL-C was
92.6 27.2 mg/dL, mean high-density lipoprotein-cholesterol was
46.0 12.8 mg/dL, and median high sensitivity C-reactive
protein was 1.61 mg/L.
 MEETING HIGHLIGHTS: American Heart Association
Analysis showed steep reductions in LDL-C levels in the
PCSK9 inhibitor arm after 78 weeks (from 90 mg/dL to
29 mg/dL; 59.8%). LDL-C levels in the placebo arm increased
by 3.9%. The primary endpoint of percent atheroma
volume increased by 0.05% in the statin plus placebo arm
and decreased by 0.95% in the statin plus evolocumab arm
(P < 0.0001). Similarly, total atheroma volume decreased by
0.9 (P = NS) with statin monotherapy and by 5.8 in the statin
plus evolocumab arm (P < 0.0001). More patients in the statin
plus evolocumab arm had atheroma regression than in the
statin plus placebo arm (64% versus 47%; P < 0.0001).
GLAGOV provides intriguing evidence that clinical
benets may extend to LDL-C levels as low as 20 mg/dL,
Dr. Nissen said, and no safety issues were identied at the mean
LDL-C level of 36.6 mg/dL. He cautioned, however, that the
modest sample size precludes rm safety conclusions, and
large outcome trials for PCSK9 inhibitors are awaited.
Benets of combination therapy in GLAGOV were observed
in patients with baseline LDL-C below the lowest levels
recommended by global guidelines (less than 70 mg/dL),
Dr. Nissen said.
Rivaroxaban and Dose-Adjusted Oral
Vitamin K Antagonist Treatment Strategies
In Patients With Atrial Fibrillation Who
Undergo Percutaneous Coronary Intervention
C. Michael Gibson, MD, Beth Israel Deaconess Medical
Center, Boston, Massachusetts
Coronary artery disease and atrial brillation often occur
together because of the strong association of both conditions
with aging and overlapping risk factors, Dr. Gibson said at an
AHA press brieng. He further noted that among the more than
18,000 atrial brillation patients enrolled in the ARISTOTLE
trial, 24.9% had undergone prior percutaneous coronary
interventions (PCIs). Optimal management of atrial brillation
and acute coronary syndromes differ, however. While warfarin
is more effective for atrial brillation, the combination of aspirin
and a thienopyridine is more effective in patients who have had
coronary stents implanted, Dr. Gibson said.
Rivaroxaban (Xarelto, Janssen) has demonstrated ef-
cacy in both acute coronary syndromes and atrial brilla-
tion. Rivaroxaban dosing for atrial brillation, however, is
four times that used in PCI, where triple therapy using an oral
anticoagulant plus dual antiplatelet therapy (DAPT) is typi-
cally administered. Prior randomized studies have suggested
that a dual-pathway therapeutic approach using a factor Xa
inhibitor and a single antiplatelet agent may be superior. The
potential risk for clinically signicant bleeding from combin-
ing DAPT with rivaroxaban remains uncertain, and the opti-
mal combination and duration of therapy remain uncertain,
Dr. Gibson observed.
The PIONEER AF-PCI trial was an open-label, random-
ized, controlled, multicenter study exploring two treatment
strategies of rivaroxaban and a dose-adjusted oral vitamin K
antagonist in patients with atrial brillation who underwent
PCI. The trial tested whether rivaroxaban plus either a thi-
enopyridine or DAPT would be associated with an increase in
bleeding rates compared with standard-of-care triple therapy
including a vitamin K antagonist among nonvalvular atrial
brillation patients who undergo PCI with stent placement.
The 12-month xed-duration trial enrolled 2,124 patients in
26 countries at 426 sites. All had paroxysmal, persistent, or
permanent nonvalvular atrial brillation and were undergoing
PCI with stent placement. They were randomized in a 1:1:1
ratio to rivaroxaban 15 mg every day plus a thienopyridine for
12 months, rivaroxaban 2.5 mg twice daily (with stratication
to a prespecied duration of DAPT for one, six, or 12 months),
or dose-adjusted warfarin every day (with stratication to a
prespecied duration of DAPT for one, six, or 12 months).
The primary safety endpoint was clinically signicant bleeding
(measured by the Thrombolysis in Myocardial Infarction scale
[major and minor bleeding] and whether bleeding required
medical attention).
Dr. Gibson reported that clinically signicant bleeding
occurred in 26.7% of patients receiving warfarin plus DAPT.
In rivaroxaban plus DAPT patients, the bleeding rate was 18.0%
(P < 0.001 versus DAPT plus warfarin). For those receiving
rivaroxaban plus a thienopyridine, the rate was 16.8%. The
number needed to treat (NNT) to prevent one bleeding event
for the latter versus warfarin was 11. Major bleeding rates for
rivaroxaban plus a thienopyridine and warfarin plus DAPT
were 2.1% and 3.3%, respectively (P = 0.234).
For the secondary endpoint of combined rst occurrence of
cardiovascular death, myocardial infarction, or stroke, rates
were not signicantly different among the three treatment arms
(6.5% for rivaroxaban plus thienopyridine, 5.6% for rivaroxaban
plus DAPT, and 6.0% for warfarin plus DAPT).
The rivaroxaban arms had reduced rates of all-cause
death or hospitalization, with low NNTs to prevent one event
(rivaroxaban plus thienopyridine, NNT = 15; rivaroxaban plus
DAPT, NNT = 10).
Among stented atrial brillation participants, administra-
tion of either rivaroxaban 15 mg daily plus a thienopyridine
for one year or rivaroxaban 2.5 mg twice daily plus one, six, or
12 months of DAPT reduced the risk of clinically signicant
bleeding as compared with standard of care warfarin plus
one, six, or 12 months of DAPT with comparable efcacy,
Dr. Gibson concluded. Q
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53
 RESEARCH BRIEFS
Novel Screening Test Sparks
New Ideas About Old Drugs
Repurposing standard drugs and rethinking drug combinations
may lead to more effective ways to combat drug-resistant bacteria,
according to ndings from a National Institutes of Health study.
The researchers developed an assay to screen for effective-
ness and used it on 5,170 drugs and other biologically active
compounds. They identied 25 that suppress the growth of
two strains of Klebsiella pneumoniae that are resistant to most
antibiotics: 11 FDA-approved drugs and 14 drugs still under
investigation, including antibiotics, antifungals, and antiseptics,
and an antiviral, antimalarial, and anticancer drug/compound.
They also looked for combinations of drugs and paired newly
identied drugs from the repurposing screen with a standard-of-
care antibiotic that did not work by itself. They found four two-
drug combinations that work against K. pneumoniae, meaning
ineffective antibiotics became active again in the presence of the
second drug. For instance, combining colistin with doxycycline,
both antibiotics, reversed drug resistance.
They also tested three-drug combinations against 10 common
strains of multidrug-resistant bacteria and found three different
combinations of broad-acting antibiotics that were effective. For
example, colistin/auranon/ceftazidime and colistin/auranon/
rifabutin suppressed more than 80% of growth for all 10 strains.
Rifabutin/colistin/imipenem inhibited more than 75% of growth
in all of the strains except two Acinetobacter baumannii isolates.
These results demonstrate that this assay has potential as
a real-time clinical tool: The results are very promising, said
Wei Zheng, PhD, one of the study authors. We think the test
can eventually help repurpose approved drugs and other com-
pounds and nd clinically relevant drug combinations that can
be approved for use in different ways that we have never used
before.
Source: National Institutes of Health, November 2016
Assessing Addiction From Multiple Perspectives
Its time to change addiction assessment and build on
advances in neuroscience, say scientists at the National Institute
on Alcohol Abuse and Alcoholism (NIAAA). Theyve proposed
an assessment tool to diagnose addictive disorders that takes
into account addiction-related behaviors, brain imaging, and
genetic data. The Addictions Neuroclinical Assessment could
lead to more effective individualized treatments, they say.
We currently approach addiction diagnosis as a yes or no
proposition, said Laura Kwako, PhD, lead author of a review
article on the subject. Addictive disorders are typically classi-
ed by the substance of abuse and the presence or absence of
symptoms, such as difculty controlling consumption. By lever-
aging knowledge of the neuroscience to identify a package
of assessments, the researchers hope to more precisely iden-
tify different subtypes of addictive disorders. They compare
the new assessment tool with those used to tailor cancer
54 P&T January 2017 Vol. 42 No. 1
diagnoses, which combine cellular, genetic, molecular, and
imaging information with clinical history.
The behavioral assessment would include three functional
processes most relevant to addiction: altered perception of
an object or event or incentive salience (where drug-taking
makes something seem more attractive or important); negative
emotionality (increased negative responses when drugs are
no longer available); and executive functioning (e.g., decits
in organizing behavior toward goals).
The assessment framework that we describe recognizes the
great advances that continue to be made in our understand-
ing of the neuroscience of addiction, said NIAAA Director
George Koob, PhD, a co-author of the review. These advances
underscore how much we know about the core neurobiological
manifestations of addiction in people.
Source: National Institutes of Health, October 2016
Flu Vaccine Offers Substantial
Benets to Diabetes Patients
Is it safe to give u vaccinations to patients with an impaired
immune response, such as those with diabetes? The evidence
was both sparse and inconclusive, say researchers from Imperial
College London. But their seven-year study of 124,503 patients
with type-2 diabetes suggests substantial benets.
The study covered four periods in each cohort year: pre-
inuenza, inuenza season, postinuenza, and summer. The
outcome measures were hospital admissions for acute myocar-
dial infarction (MI), stroke, pneumonia, inuenza, and heart
failure, as well as all-cause death.
During the study, there were 5,142 admissions for acute MI;
4,515 for stroke; 14,154 for pneumonia or inuenza; 12,915 for
heart failure; and 21,070 deaths.
Vaccine recipients were older and generally more ill; they
had more coexisting conditions and were taking more medi-
cations than nonrecipients. However, vaccination was associ-
ated with signicant reductions in all of the outcomes during
the u season. After adjusting for residual confounding, the
researchers found 19% lower rates of admissions for acute MI,
30% for stroke, 22% for heart failure, and 15% for pneumonia
or inuenza. The death rate for vaccinated patients was 24%
lower than for nonrecipients.
That was during u seasonbut vaccination was also asso-
ciated with signicantly fewer events during the pre- and
postinuenza seasons for all outcomes except for acute MI
and pneumonia/inuenza in the preinuenza period.
Concerns about the benets of inuenza vaccination in older
adults and patients with chronic illnesses affect the acceptance
and uptake of vaccination, the researchers note. But their
ndings, they add, underline the importance of inuenza
vaccination as part of comprehensive secondary prevention
in this high-risk population.
Source: Canadian Medical Association Journal, October 2016
 RESEARCH BRIEFS
Which Cancer Patients Can Best Survive the ICU?
Because cancer is so complex, admitting a patient with cancer
to the intensive care unti (ICU) can be challenging triage. Often
the reason for the admission is acute complications related to
the cancer or its treatment. Understanding how those complica-
tions might affect the patients outcome is critical to planning
care, gauging use of ICU resources, and counseling patients
and their families.
Some studies have identied important determinants of mortal-
ity, but the existing literature is scarce, say researchers who
studied outcomes in ICU patients with cancer.
The researchers analyzed data from two cohort studies of
1,737 patients with solid tumors and 291 with hematological
malignancies. Of those, 456 (23%) had cancer-related compli-
cations at ICU admission, most frequently chemotherapy and
radiation therapy toxicity, venous thromboembolism (VTE),
and respiratory failure by tumor.
Patients with complications tended to have worse performance
status scores and active disease. They also were more likely to
have more severe organ dysfunction, greater need for invasive
support, and infection at ICU admission.
Complications were more frequent in patients with metastatic
solid tumors, particularly lung and breast cancer (although less
common in patients with gastrointestinal [GI] tumors), and in
patients with more aggressive hematological malignancies, espe-
cially acute leukemia and aggressive non-Hodgkins lymphoma.
The study had several major ndings, the researchers say.
First, one in four patients with cancer admitted to the ICU has
acute complications related to the underlying cancer or treatment
side effects. However, while there were many cancer-related
complications and their prognostic impact was quite variable,
and despite high mortality rates, outcome in these patients was
better than perceived a priori, the researchers say.
High sequential organ failure assessment score on the rst day
of ICU stay, worse performance status, and need for mechanical
ventilation were all independent predictors of mortality, which is
in accord with current literature. However, among the individual
cancer-related complications studied, only vena cava syndrome,
GI involvement, and respiratory failure were independently
associated with in-hospital mortality. A substantial mortality
rate (73%) among patients with GI involvement emphasizes the
importance of discussing the appropriateness of ICU admission
in these patients, the researchers caution. Although VTE was
one of the most common complications, it was not a major
determinant of outcome.
Another important point, the researchers note, was the high
frequency of chemotherapy- and radiation therapy-induced
toxicity. Treatment-related neutropenia is not a good predictor
of outcome, they say, because research has found it is not a
relevant predictor of mortality.
Source: PLOS One, October 2016
A Better Way to Predict
Colorectal Cancer Relapse?
Carcinoembryonic antigen (CEA) is often used as a marker
for relapse in colorectal cancer (CRC). But in as many as 40%
of recurrences, the serum CEA shows unmeasurable eleva-
tions. And some patients with resected CRC have transient
elevations of CEA levels; the false-positive rate during follow-
up has been as high as 16%, say researchers from Kaohsiung
Medical University in Taiwan. They propose a more powerful
tool: a membrane array-based multigene biomarker assay,
or biomarker chip, that detects circulating tumor cells in the
peripheral blood.
The researchers conducted a study in 298 patients with CRC
to test that alternative. The patients were enrolled after radical
curative resection for primary CRC tumor: 82 were stage I, 102
were stage II, and 114 were stage III. Patients were followed
for a median of 28.4 months, every three months for three
years, then every six months. At each follow-up visit, labora-
tory studies included serum CEA levels. Elevated CEA levels
were dened as two consecutive measurements greater than
5 ng/mL at a three-month interval.
During the study period, 48 patients (16.1%) had postopera-
tive relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%)
had a total biomarker chip score higher than the cutoff value.
Of the 48 who relapsed, 42 (87.5%) showed positive biochip
results prior to relapse.
The positive biochip results were signicantly associated with
postoperative relapse. In fact, the biomarker chip was better
all around than postoperative serum CEA levels for predicting
relapse: with higher sensitivity (87.5% versus 60.4%), specicity
(92.0% versus 83.2%), positive predictive value (67.7% versus
40.8%), negative predictive value (97.5% versus 91.6%), and
accuracy (91.3% versus 79.5%).
Moreover, the biochip predicted relapse considerably
earlier than did CEA levels (10.7 versus 2.8 months). The
researchers note that CRC-related deaths are largely attribut-
able to clinical relapse. The sooner a relapse is diagnosed, the
more amenable the tumor may be to resection, increasing the
likelihood of long-term survival.
In sum, the biomarker chip would be a more accurate tool
for predicting relapse, the researchers say. They also suggest
that, in clinical practice, combining the two tests could enhance
condence in the diagnosis.
Source: PLOS One, October 2016
Vol. 42 No. 1 January 2017 P&T
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RAPIVAB (peramivir injection), for intravenous use
Initial U.S. Approval: 2014
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RAPIVAB
safely and effectively. See full prescribing information for RAPIVAB.
----------------------------------INDICATIONS AND USAGE--------------------------------
RAPIVAB is an inuenza virus neuraminidase inhibitor indicated for the treatment
of acute uncomplicated inuenza in patients 18 years and older who have been
symptomatic for no more than two days.
Limitations of Use:
Efcacy based on clinical trials in which the predominant inuenza virus type was
inuenza A; a limited number of subjects infected with inuenza B virus were
enrolled.
Consider available information on inuenza drug susceptibility patterns and
treatment effects when deciding whether to use.
Efcacy could not be established in patients with serious inuenza requiring
hospitalization.
---------------------------------DOSAGE AND ADMINISTRATION------------------------
Administer as a single dose within 2 days of onset of inuenza symptoms.
Recommended dose is 600 mg, administered by intravenous infusion for a minimum
of 15 minutes.
Renal Impairment: Recommended dose for patients with creatinine clearance 30-49
mL/min is 200 mg and the recommended dose for patients with creatinine clearance
10-29 mL/min is 100 mg.
Hemodialysis: Administer after dialysis.
RAPIVAB must be diluted prior to administration.
See the Full Prescribing Information for drug compatibility information.
Seqirus USA Inc.
King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc.
-------------------------------DOSAGE FORMS AND STRENGTHS------------------------
Injection: 200 mg in 20 mL (10 mg/mL) in a single-use vial.
------------------------------------CONTRAINDICATIONS-----------------------------------
Patients with known serious hypersensitivity or anaphylaxis to peramivir or any
component of RAPIVAB.
--------------------------------WARNINGS AND PRECAUTIONS---------------------------
Cases of anaphylaxis and serious skin/hypersensitivity reactions such as Stevens-
Johnson syndrome and erythema multiforme have occurred with RAPIVAB.
Discontinue RAPIVAB and initiate appropriate treatment if anaphylaxis or serious
skin reaction occurs or is suspected.
Neuropsychiatric events: Patients with influenza may be at an increased risk of
hallucinations, delirium and abnormal behavior early in their illness. Monitor for signs
of abnormal behavior.
---------------------------------ADVERSE REACTIONS--------------------------------------
Most common adverse reaction (incidence >2%) is diarrhea.
To report SUSPECTED ADVERSE REACTIONS, call 1-844-273-2327 or contact
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
---------------------------------------DRUG INTERACTIONS---------------------------------
Live attenuated inuenza vaccine (LAIV), intranasal: Avoid use of LAIV within 2 weeks
before or 48 hours after administration of RAPIVAB, unless medically indicated.
--------------------------------USE IN SPECIFIC POPULATIONS---------------------------
Pregnancy: Use if benet outweighs risk.
Nursing mothers: Caution should be exercised when administered to a nursing
woman.
Revised: 8/2016
September 2016 US/RIV/0816/0069
 For flu patients in the emergency department who may not be appropriate for oral treatment 1,2

It only takes

to be

treating the flu with

1
Rapivab (peramivir)
The first and only full course of antiviral flu therapy in a single dose1,2
Only one 15- to 30-minute IV infusion required
Treats acute uncomplicated influenza in patients 18+ who have been
symptomatic for no more than 2 days
Appropriate for many patients, including those who cannot tolerate or may
be noncompliant with oral flu treatment and those requiring IV hydration
Can be used with OTC supportive therapies

Go to www.rapivab.com to learn more and view full Prescribing Information.

Important Safety Information
Rapivab (peramivir injection) is indicated for the treatment of acute
uncomplicated influenza in patients 18 years and older who have been
symptomatic for no more than 2 days.
Efficacy of Rapivab was based on clinical trials in which the predominant
influenza virus type was influenza A; a limited number of subjects
infected with influenza B virus were enrolled.
Influenza viruses change over time. Emergence of resistance
substitutions could decrease drug effectiveness. Other factors (for
example, changes in viral virulence) might also diminish clinical benefit
of antiviral drugs. Prescribers should consider available information
on influenza drug susceptibility patterns and treatment effects when
deciding whether to use Rapivab.
Efficacy could not be established in patients with serious influenza
requiring hospitalization.
Contraindications
Rapivab is contraindicated in patients with known serious hypersensitivity
or anaphylaxis to peramivir or any component of the product. Severe
allergic reactions have included anaphylaxis, erythema multiforme, and
Stevens-Johnson syndrome.
Warnings and Precautions
Rare cases of serious skin reactions, including erythema multiforme, have been
reported with Rapivab in clinical studies and in postmarketing experience.
Cases of anaphylaxis and Stevens-Johnson syndrome have been reported
in postmarketing experience with Rapivab. Discontinue Rapivab and
institute appropriate treatment if anaphylaxis or a serious skin reaction
occurs or is suspected. The use of Rapivab is contraindicated in patients
with known serious hypersensitivity or anaphylaxis to Rapivab.
Patients with influenza may be at an increased risk of hallucinations,
delirium, and abnormal behavior early in their illness. There have
been postmarketing reports (from Japan) of delirium and abnormal
behavior leading to injury in patients with influenza who were receiving
neuraminidase inhibitors, including Rapivab. Because these events were
reported voluntarily during clinical practice, estimates of frequency
cannot be made, but they appear to be uncommon. These events were
reported primarily among pediatric patients. The contribution of Rapivab
to these events has not been established. Patients with influenza should
be closely monitored for signs of abnormal behavior.
Serious bacterial infections may begin with influenza-like symptoms
or may coexist with or occur as complications during the course of
influenza. Rapivab has not been shown to prevent such complications.
Adverse Reactions
The most common adverse reaction was diarrhea (8% Rapivab vs
7% placebo).
Lab abnormalities (incidence * 2%) occurring more commonly with Rapivab
than placebo were elevated ALT 2.5 times the upper limit of normal (3% vs
2%), elevated serum glucose greater than 160 mg/dL (5% vs 3%), elevated
CPK at least 6 times the upper limit of normal (4% vs 2%) and neutrophils less
than 1.0 x 109/L (8% vs 6%).
Concurrent use with Live Attenuated Influenza Vaccine
Antiviral drugs may inhibit viral replication of a live attenuated influenza
vaccine (LAIV). The concurrent use of Rapivab with LAIV intranasal has not
been evaluated. Because of the potential for interference between these
two products, avoid use of Rapivab within 2 weeks after or 48 hours before
administration of LAIV unless medically indicated.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
References: 1. Rapivab [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc; 2014. 2. Kohno S, Kida H, Mizuguchi M, Shimada J; S-021812 Clinical Study
Group. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010;54(11):4568-4574.
doi:10.1128/AAC.00474-10.
RAPIVAB is a registered trademark of BioCryst Pharmaceuticals, Inc. All other trademarks herein are the property of their respective owners.

Seqirus USA Inc.

King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc. September 2016 US/RIV/0816/0069