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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
P&T provides managed care and formulary management
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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
CONTENTS
January 2017
Cover: For centuries, the circulation of FEATURES

the blood has been attributed to the
heart-as-pump model. But could the
disappointing findings for drug and
Letters to the Editor 22
device remedies for the heart imply
the model may be flawed? We explore 2017 Presages Dramatic Change
an alternative autonomous circulation
theory on page 33. (Credit: Pixologic
For Federal Health Care Policies 24
Studio / Science Source) 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.
DEPARTMENTS Stephen Barlas
Medication Errors 4 HEALTH CARE & LAW

Survey reveals widespread Systemic Market and Organizational Changes:
health workplace intimidation Impact on P&T Committees 28
The authors consider market stakeholder consolidation, market-driven efficiency
Prescription: Washington 6 demands, consumerism, and legal enforcement of patient rights related to access to
Plan to settle 340B disputes appropriate drugs and posit how future P&T committees may approach these issues.
is itself the focus of a dispute
F. Randy Vogenberg, RPh, PhD; Rita Marcoux, RPh, MBA; and Martha M. Rumore,
PharmD, JD, MS, LLM, FAPhA
Drug and Device News 7
Approvals, new indications,
regulatory activities, and more
Branko Fursts Radical Alternative 33
Pharmaceutical We examine key evidence against the standard cardiac function model and describe
Approval Update 17 Branko Fursts alternative model with its implications for therapy and further exploration.
Olaratumab (Lartruvo) for Walter Alexander
the treatment of soft tissue
sarcoma; bezlotoxumab A Comparison of Medication Histories Obtained by a Pharmacy
(Zinplava) for use with Technician Versus Nurses in the Emergency Department 41
an antibiotic to reduce A study finds that medication histories obtained by the pharmacy technician in a busy
recurrence of C. difficile emergency department were much more accurate than those obtained by nurses.
infection; and doxylamine Marija Markovic, PharmD; A. Scott Mathis, PharmD; Hoytin Lee Ghin, PharmD,
succinate/pyridoxine hydro- BCPS; Michelle Gardiner, PharmD, BCGP; and Germin Fahim, PharmD, BCPS
chloride (Bonjesta) for the
treatment of nausea and Challenges and Solutions in
vomiting during pregnancy
Reducing Opioid Misuse and Abuse 47
We present some of the approaches to and challenges of the opioid crisis that
Drug Forecast 19
emerged from thought-leaders at an Academy of Managed Care Pharmacy symposium.
Zarxio (filgrastim-sndz), a
biosimilar for the treatment of Peter Sonnenreich and Linda Geisler
severe chronic neutropenia
MEETING HIGHLIGHTS
Research Briefs 54 Society for Immunotherapy of Cancer 49
And
Back issues are available on
American Heart Association 50
We review key sessions from the Society for Immunotherapy of Cancer and the
the PubMed Central archive. American Heart Association annual meetings.
Visit www.pubmedcentral.nih.gov Walter Alexander
2 P&T January 2017 Vol. 42 No. 1

Editor-in-Chief Associate Editor-in-Chief
David B. Nash, MD, MBA Karl A. Matuszewski, MS, PharmD
Dr. Raymond C. and Vice President
Doris N. Grandon Professor First Databank, Inc.
The Jefferson College of Population Health Clinical and Editorial
Philadelphia, Pennsylvania Knowledge Base Services
South San Francisco, California
EDITORIAL BOARD
Richard Afable, MD, MPH Marvin M. Goldenberg, PhD, RPh, MS Luke A. Probst, PharmD, BCPS
President and Chief Executive Ofcer President, Pharmaceutical and Scientic Director of Pharmacy Services
Hoag Memorial Hospital Presbyterian Services Upstate University Hospital/
Newport Beach, California Marvin M. Goldenberg, LLC Downtown Campus
Westeld, New Jersey Clinical Assistant Professor, Departments
Robert L. Barkin, MBA, PharmD of Pediatrics and Medicine
Professor, Faculty of Anesthesiology, Nancy Greengold, MD, MBA SUNY Upstate Medical University
Family Medicine, and Pharmacology Chief Medical Ofcer Syracuse, New York
Rush Medical College of Rush University Sharp Grossmont Hospital/Sharp
Chicago, Illinois HealthCare Sheldon M. Retchin, MD, MSPH
Clinical Pharmacologist La Mesa, California Executive Vice President of Health
North Shore University Health System
Sciences, The Ohio State University
Pain Centers
Matthew Grissinger, RPh, FASCP Chief Executive Ofcer, OSU Wexner
Skokie and Evanston, Illinois
Director, Error Reporting Programs Medical Center
Institute for Safe Medication Practices Columbus, Ohio
Mark J. Baumel, MD, MS Horsham, Pennsylvania
President/Chief Executive Ofcer
Colon Health Centers of America, LLC Vitalina Rozenfeld, PharmD, BCPS
Mendenhall, Pennsylvania Rusty Hailey, PharmD, DPh, MBA, FAMCP Medical Affairs
President, Pharmaceutical Operations AstraZeneca
Thomas Biancaniello, MD Senior Vice President, HealthSpring, Inc. Wilmington, Delaware
Clinical Professor of Pediatrics Nashville, Tennessee
Columbia University Fadia T. Shaya, PhD, MPH
College of Physicians and Surgeons Steven D. Hanks, MD, MMM, FACP Professor and Vice-Chair for Academic
Division of Pediatric Cardiology Executive Vice President Affairs
New York, New York and Chief Medical Ofcer University of Maryland School of Pharmacy
The Hospital of Central Connecticut Associate Director
Joseph E. Biskupiak, PhD, MBA New Britain, Connecticut Center on Drugs and Public Policy
Research Associate Professor Baltimore, Maryland
Department of Pharmacy Practice Michele B. Kaufman, PharmD, BCGP, RPh
Director, Pharmacotherapy Outcomes Pharmacist, New YorkPresbyterian
Research Center Arthur F. Shinn, PharmD, FASCP
Lower Manhattan Hospital, Pharmacy
College of Pharmacy, University of Utah President
Department
Salt Lake City, Utah Managed Pharmacy Consultants, LLC
New York, New York
Palm City, Florida
David A. Casey, MD Grant D. Lawless, RPh, MD
Vice Chairman, Department of Psychiatry Associate Professor of Clinical Pharmacy, Brian Swift, PharmD, MBA
University of Louisville Pharmaceutical Economics and Policy Vice President/Chief of Pharmacy
Louisville, Kentucky Director, Master of Science Program in and Accreditation
Healthcare Decision Analysis Thomas Jefferson University Hospital
Alan Caspi, PhD, PharmD, MBA School of Pharmacy Associate Dean of Professional Affairs
President, Caspi & Associates University of Southern California Jefferson College of Pharmacy
New York, New York Los Angeles, California Philadelphia, Pennsylvania
Burke A. Cunha, MD Burton Orland, BS, RPh F. Randy Vogenberg, RPh, PhD
Professor of Medicine President Partner
State University of New York at Stony Brook BioCaRe Consultants Access Market Intelligence and National
Chief, Infectious Disease Division Westport, Connecticut Institute of Collaborative Healthcare
Winthrop-University Hospital Greenville, South Carolina
Mineola, New York
Fred Joseph Pane, RPh, BS, FASHP, FABC
Joseph C. English III, MD Senior Director, Customer Engagement Scott W. Yates, MD, MBA, MS
Professor of Dermatology The Medicines Company Center for Executive Medicine
Clinical Vice Chairman Parsippany, New Jersey Plano, Texas
for Quality and Innovation
Founding Director of Teledermatology Lawrence Charles Parish, MD
University of Pittsburgh Dermatologist, Editor-in-Chief
Department of Dermatology Clinics in Dermatology
Pittsburgh, Pennsylvania Philadelphia, Pennsylvania

3
MEDICATION ERRORS
Unresolved Disrespectful
Behavior in Health Care
Practitioners Speak Up (Again)Part 1
Matthew Grissinger, RPh, FASCP
Mr. Grissinger, an editorial manager/director/administrator level behaviors were among the most frequent
board member of P&T, is were also represented (25%). Most they had encountered during the past
Director of Error Reporting respondents had more than 10 years of year. Furthermore, one of these behav-
Programs at the Institute for experience (70%) and were female (87%). iorsphysical abuseincreased from
Safe Medication Practices 4% to 7%, regardless of the source, and
(ISMP) in Horsham, Penn- Practitioners Feel the Sting from 5% to 8% when the source was a
sylvania (www.ismp.org). Regardless of the source of disrespectful physician. While respondents suggested
behavior (physicians or others), respon- that some forms of disrespectful behavior
The Institute for Safe Medication dents in 2013 reported a wide variety of have lessened in the last decade, par-
Practices (ISMP) has discussed the topic behaviors encountered during the past ticularly impatience with questions or
of bullying, incivility, intimidation, and year. When ranked by frequency of the use of condescending language and
other forms of disrespectful behavior that occurrence, the behaviors most often insults, many disrespectful behaviors con-
have run rampant in health care in past encountered included: tinue to occur at an alarming frequency,
P&T columns, while many remain silent demonstrating little improvement.
or make excuses in an attempt to minimize Negative comments about
the profound devastation that disrespectful colleagues or leaders (encountered Not Just Physicians
behavior has caused. Many years ago, by 73% at least once, by 20% often) In both 2003 and 2013, respondents
ISMP conducted a national survey regard- Reluctance or refusal to answer ques- reported that physicians and other pre-
ing intimidation in the workplace.1 Results tions or return calls (77% at least scribers engaged in disrespectful behav-
showed that disrespectful behaviors were once, 13% often) ior more often than other health care pro-
not isolated events, they were not limited to Condescending language or demean- fessionals. However, respondents in 2003
just a few practitioners, they involved both ing comments or insults (68% at least and 2013 also made it clear that its not just
lateral (peer-to-peer) and interdisciplinary once, 15% often) physicians who behave in a disrespect-
staff (and not just physicians), and they Impatience with questions or hanging ful mannerin many cases, encounters
involved both genders equally. We up the phone (69% at least once, 10% have been nearly as frequent, or some-
followed up in 2013 with a similar survey often) times more frequent, with other health
to measure progress (or lack thereof). Reluctance to follow safety practices care professionals. For example, in both
Sadly, based on recent observations and or work collaboratively (66% at least 2003 and 2013, a little more than 40% of
interactions with health care practitio- once, 13% often) respondents reported that both physicians
ners along with the results of this survey, and other health care professionals had
disrespectful behaviors continue to erode The least frequent disrespectful behav- reported (or threatened to report) them
professional communication, which is iors encountered at least once during the to their manager during the past year. To
essential to patient safety. past year included: cite another example, between 63% and
In Part 1 of this report, we present what 69% of the 2013 respondents reported
respondents had to say about disrespectful Shaming, humiliation, or spreading resistance on the part of physicians, as
behaviors in the workplace and compare malicious rumors (46%) well as other health care professionals,
the 2013 results to the 2003 survey. Reporting staff to a manager (actual to following safety practices or working
or threat) (42%) collaboratively with others.
Survey Respondents Insulting or slighting an individual Furthermore, repeated occurrences of
Our 2013 survey included 4,884 respon- due to race, religion, or appearance disrespectful behavior did not arise from
dentsmore than double the respondents (24%) a single menacing individual. Thirty-eight
in our 2003 survey. With the exception Thrown objects (18%) percent of respondents in 2003 and 36% in
of more physicians in the 2013 survey, Physical abuse (7%) 2013 reported that three to ve individuals
the respondent proles were quite similar. were involved in disrespectful behaviors,
Most respondents were nurses (68%) Although these were the least frequent while 19% and 21% respectively reported
or pharmacists (14%), but more than behaviors encountered in aggregate that more than ve individuals were
200 physicians and almost 100 quality/ by respondents, it is truly a sad state involved in occurrences during the past
risk management staff also participated. of affairs when nearly a quarter (24%) year. Respondents in 2013 also reported
Most respondents (66%) were staff- of respondentsthats 1,148 practitio- that more nonphysicians than physicians
level practitioners, but leaders at the nersreported that at least one of these were involved in disrespectful behavior.

MEDICATION ERRORS
Impact on Safety differences were reported in the fre- However, pharmacists reported more
Almost half of the 2003 (49%) and 2013 quency with which each group encoun- frequent physician reluctance to follow
(44%) respondents told us that their past tered disrespectful behaviors. For safety practices or work collaboratively
experiences with intimidation had altered example, a higher percentage of male than nurses, and less nitpicking/fault-
the way they handle order clarications respondents reported that they had, nding, shaming, thrown objects, and
or questions about medication orders. during the past year, assumed that a insults due to race, religion, gender, and
At least once during the year, 39% of medication order was correct and safe appearance than nurses. In contrast,
respondents in 2003 and 33% in 2013 rather than interact with a particular pharmacists experienced more frequent
had concerns about a medication order prescriber (2003: 48% male, 37% female; disrespectful behavior by nonphysicians
but assumed it was correct rather than 2013: 40% male, 32% female). A higher than nurses, particularly a refusal to answer
interact with an intimidating prescriber. percentage of male respondents also felt questions or return calls, impatience with
Similar results were reported when the pressured to accept an order, dispense questions, yelling and cursing, and being
prescribers stellar reputation led to a product, or administer a drug despite reported to their manager.
reluctance to question or clarify orders concerns about its safety (2003: 53% male, Pharmacists also reported more fre-
despite concerns. More than one-third 49% female; 2013: 43% male, 38% female). quent effects from disrespectful behavior
of respondents in both 2003 (39%) and In 2013, male respondents also reported than nurses in both the 2003 and 2013
2013 (38%) asked another professional more frequently being reported to a surveys. For example, in 2013, 63% of
to talk to a particularly disrespectful pre- manager (49% male, 42% female) and pharmacists and 30% of nurses reported
scriber about the safety of an order. Small being physically abused by nonphysicians that, during the past year, they had
improvements were seen between 2003 (8% male, 5% female). On the other hand, assumed a medication order was correct
and 2013 in regard to asking a colleague female respondents in 2013 reported that and safe rather than interact with a par-
to help validate the safety of an order, more individuals were engaged in disre- ticular prescriber. Pharmacists (57%)
asking a colleague to talk to a disrespect- spectful behavior than reported by male asked another professional to talk to a
ful prescriber on their behalf, or feeling respondents. particular prescriber about an order more
pressured to accept an order despite frequently than nurses (36%). Pharmacists
safety concerns. However, there was no Practitioner Type Differences (29%) also asked, suggested, or allowed
reduction between 2003 and 2013 in the In the 2013 survey, nurses and phy- a physician to give a medication himself
percent of respondents who were aware sicians encountered about the same despite concerns about the safety of an
of a medication error during the year frequency of disrespectful behavior by order more often than nurses (17%). Very
in which disrespectful behavior played physicians, although physicians reported similar ndings were reported in 2003.
a role. more nitpicking/fault-finding and While more nurses (54%) than pharma-
inappropriate joking, and less impatience cists (41%) felt that their organizations had
Not Satised With with questions than nurses. However, phy- dened an effective process for handling
Organizational Efforts sicians reported signicantly less frequent disagreements with the safety of an order,
It appears that the 2013 respondents disrespectful behavior by other health pharmacists (83%) reported greater dis-
were less satised than the 2003 respon- care professionals (nonphysicians) than satisfaction than nurses (74%) with their
dents with organizational efforts to nurses and pharmacists. Nevertheless, organizations ability to deal effectively
address disrespectful behavior. Only 60% the frequency of disrespectful behaviors with disrespectful behavior.
of respondents in 2003 and 50% of respon- toward physicians by nonphysicians was
dents in 2013 felt their organization had unexpected. More than half of the physi- Summary
clearly dened an effective process for cians reported encountering these behav- The results of our surveys expose
handling disagreements with the safety iors by nonphysicians one or more times health cares continued tolerance and
of an order. Even less (33% in 2003, 14% in during the prior year: indifference to disrespectful behavior.
2013) felt that the process allowed them These behaviors are clearly learned,
to bypass a particularly disrespectful Negative comments about tolerated, and reinforced in the health
prescriber or their supervisor if neces- colleagues (71%) care culture, and little improvement
sary. While 70% of respondents in 2003 Refusal to answer questions or return has been made in recent years. The
reported that their organization/manager calls (68%) stressful health care environment,
would support them if they reported dis- Constant nitpicking/fault-finding particularly in the presence of produc-
respectful behavior, just 52% of the 2013 (56%) tivity demands, cost containment, and
respondents felt this way. In the end, Reluctance to follow safety practices hierarchies that nurture a sense of status
only 39% in 2003 and 25% in 2013 felt that or work collaboratively (55%) and autonomy, have likely been the
their organization dealt effectively with Impatience with questions (55%) most inuential factors. This creates an
disrespectful behavior. Condescending language, demeaning environment in which victims may feel
comments, and insults (54%) they have no choice but to become
Gender Makes Little Difference perpetrators and join in the practice.
Female respondents to the survey out- Overall, nurses and pharmacists also Organizations have largely failed to
numbered male respondents in both the encountered about the same frequency address disrespectful behavior for a variety
2003 and 2013 survey, but only minor of disrespectful behavior by physicians. of reasons. First, some individuals who
continued on page 23

5
PRESCRIPTION: WASHINGTON
Plan to Settle 340B Disputes Elicits Dispute

Roadblocks Remain to Quieting Drug Pricing Controversies
Stephen Barlas
Mr. Barlas is a freelance Pharmaceutical makers dont like to authority for implementing the 340B ADR
writer in Washington, be forced to sell products at a discount, process does not permit consolidated claims
D.C., who covers issues but they must do so if they want to sell to on behalf of manufacturers by associations
inside the Beltway. Send state Medicaid programs. The discounts or organizations representing their inter-
ideas for topics and your are problematic enough for them, but the ests. There is also some question whether
comments to sbarlas@ drug companies have argued for years that the consolidation of claims by manufactur-
verizon.net. covered entities, either consciously or due ers generally is legal. Such consolidation
to faulty billing systems, divert discounted may be barred by what the HHS calls the
drugs to ineligible individuals. The hospitals operational challenges presented by the
rug companies and hospitals are and clinics, for their part, complain they do statutory requirement for a manufacturer
D warring over a proposed adminis-

trative dispute resolution (ADR)
program1 meant to settle long-running
not have access to pricing data that would
assure them the discounted prices are what
they should be.
to rst audit the covered entity.
We believe that the 340B statute does
not bar association or organization claims
allegations over pricing and diversion The purpose of the ADR process is to on behalf of manufacturers, states Wayne
of drugs in the 340B program. In this resolve: 1) claims by covered entities that Sichel, Head of U.S. Federal Policy for
federally sponsored program, drug manufacturers have overcharged them for Bristol-Myers Squibb.
manufacturers sell medications at a discovered outpatient drugs; and 2) claims by One imagines that any ADR panel will
count to qualied hospitals and clinics, manufacturers that a covered entity has have its hands full, because key manu-
allowing them to generate revenue to violated the prohibition on diversion to facturer pricing informationespecially
expand services to generally low-income ineligible patients or duplicate discounts. ceiling prices, which are closely linked
populations. Historically, the Department of Health and to the size of a rebateare not available
Sylvia Yu, Assistant General Counsel Human Services (HHS) has encouraged to covered entities. Hospitals argue that,
for Pharmaceutical Research and Man- manufacturers and covered entities to work without such data, it will be hard for them
ufacturers of America, argues that it will together to attempt to resolve disputes in to claim they were overcharged for a drug.
be impossible for drug companies to good faith. The ADR process is not meant to The HRSAs proposed rule says the agency
access the ADR program because they are replace those good-faith efforts, but would will give the panel price ceiling data. That
unable to audit hospitals to see whether be a last resort when those efforts fail. wont help hospitals develop a strong case
discounted drugs have been diverted to The Ofce of Pharmacy Affairs (OPA), that they were overcharged. We are very
ineligible patients. The existing guidelines part of the HHS Health Resources and concerned that our members do not have
for manufacturers to audit 340B entities, Services Administration (HRSA), which access to ceiling prices, and will conse-
issued in 1996, suffer from critical defects administers the 340B program, has pro- quently not be able to provide sufcient
that make manufacturer audits nearly posed ideas about how the ADR process documents to demonstrate claims for over-
infeasible, Yu states. The result is a might work,1 and various players have charge, says Debbie Johnston, Senior Vice
blocked gateway to the ADR process for voiced opinions. There would be a 340B President of Policy Development for the
manufacturers. And a one-sided ADR ADR panel with three voting members, who Arizona Hospital and Healthcare Associa-
system in which covered entities can insti- would differ from case to case. They would tion. The HHS is apparently developing a
tute ADR claims but manufacturers face be drawn from the HHS or the Department system that would let hospitals access drug
nearly insuperable barriers to instituting of Veterans Affairs. An OPA member would prices, but no one seems to know when it
ADR claims would weaken condence in serve as a nonvoting ex ofcio member. will be operational.
the integrity of the 340B program. No member of a given panel could have a Given years of controversy over the 340B
Congress created the 340B program conict of interest. program, an ironclad ADR program would
in 1992 for hospitals with high numbers A covered entity or manufacturer would be welcome to both hospitals and drug
of uninsured patients, including certain have to le a written claim within three years manufacturers. But legal roadblocks and
disproportionate-share hospitals, childrens of the date of the sale (or payment) at issue. program shortcomings dont bode well for
hospitals, freestanding cancer hospitals, Covered entities could consolidate their the effectiveness of any ADR process.
rural referral centers, sole community hos- claims, or have them submitted by a trade
pitals, and critical access hospitals. Only association, when those claims allege over- REFERENCE
certain patients are eligible to receive the charges by the same manufacturer for the 1. Health Resources and Services Admin-
discounted drugs, which can be dispensed same drug. istration. 340B drug pricing program;
administrative dispute resolution. Fed
only in hospital outpatient pharmacies and How manufacturers might consolidate
Regist 2016;81(156):5338153388. Q
some local retail pharmacies. their claims is trickier. First, the statutory

NEW DRUG APPROVALS two 12-week, placebo-controlled trials of Nuvigil (Cephalon, Inc.), a prescription
Xultophy for Type-2 Diabetes involving a total of 406 healthy post- medication indicated to improve wakeful-
The FDA has approved Xultophy menopausal women, 40 to 80 years of ness in adults with excessive sleepiness
100/3.6 (insulin degludec 100 units/mL age, who identied moderate-to-severe associated with obstructive sleep apnea,
and liraglutide 3.6 mg/mL injection, Novo pain during sexual intercourse as their narcolepsy, or shift work disorder.
Nordisk). The product, a once-daily combi- most bothersome symptom of VVA. Source: Breckenridge Pharmaceutical,
nation of Tresiba (insulin degludec injec- The women were randomly assigned to November 28, 2016
tion) and Victoza (liraglutide injection), is receive prasterone or a placebo vaginal
indicated as an adjunct to diet and exercise insert. Prasterone reduced the sever- Metaxalone Tablets
to improve glycemic control in adults with ity of pain experienced during sexual The FDA has approved metaxalone
type-2 diabetes that is inadequately con- intercourse compared with placebo. tablets USP, 800 mg (Lannett Company),
trolled on less than 50 units of basal insulin Source: Endoceutics, November 17, the therapeutic equivalent of Skelaxin
daily or on less than or equal to 1.8 mg of 2016 (King Pharmaceuticals/Pzer). Skelaxin
liraglutide daily. Xultophy 100/3.6 belongs is indicated as an adjunct to rest, physical
to a new class of diabetes treatments that Vemlidy for Hepatitis B therapy, and other measures for the relief
combine a basal insulin and a glucagon- The FDA has approved tenofovir ala- of discomforts associated with acute,
like peptide-1 receptor agonist in a single, fenamide 25 mg (Vemlidy, Gilead Sci- painful musculoskeletal conditions.
once-daily injection. ences), a prodrug of tenofovir, as a once- Source: Lannett Company, November
The approval of Xultophy 100/3.6 was daily treatment for adults with chronic 28, 2016
based on efcacy and safety data from hepatitis B virus (HBV) infection with
the DUAL clinical development program. compensated liver disease. The approval Memantine Hydrochloride Tablets
In three DUAL trials involving a total of was based on positive 48-week data from Lannett Company has secured FDA
1,393 adults with type-2 diabetes, patients two international phase 3 studies involv- approval to market memantine hydro-
who were inadequately controlled on ing 1,298 treatment-nave and treatment- chloride tablets USP, 5 mg and 10 mg
liraglutide or basal insulin therapy and experienced adults. the therapeutic equivalent to Namenda
switched to Xultophy 100/3.6 achieved A total of 425 HBeAg-negative patients tablets 5 mg and 10 mg (Forest Labo-
reductions in hemoglobin A1c (HbA1c). and 873 HBeAg-positive patients were ratories). The product is indicated for
For adults uncontrolled on basal insulin, treated with either tenofovir alafenamide the treatment of moderate-to-severe
Xultophy 100/3.6 demonstrated signi- or tenofovir disoproxil fumarate (TDF) dementia.
cant reductions in HbA1c from baseline (Viread, Gilead Sciences) in studies Source: Lannett Company, November
of 1.67% and 1.94%. 108 and 110, respectively. HBeAg, a 14, 2016
Source: Novo Nordisk, November 21, hepatitis B viral protein, indicates active
2016 viral replication. Both studies met their NEW INDICATIONS
primary endpoint of noninferiority to Avastin for Ovarian Cancer
Intrarosa for Pain During Sex TDF, based on the percentage of patients The FDA has given the nod to bevaci-
For Postmenopausal Women with plasma HBV DNA levels less than zumab (Avastin, Genentech), either in
Intrarosa (Endoceutics, Inc.) has 29 IU/mL after 48 weeks of therapy. combination with carboplatin and pacli-
received FDA approval for the treat- Source: Gilead Sciences, November taxel or in combination with carboplatin
ment of women experiencing moderate- 10, 2016 and gemcitabine chemotherapy, followed
to-severe pain during sexual intercourse by bevacizumab alone, for the treat-
(dyspareunia), a symptom of vulvar and Generic Approvals and Launches ment of patients with platinum-sensitive
vaginal atrophy (VVA) due to meno- Armodanil Tablets recurrent epithelial ovarian, fallopian
pause. Intrarosa is the rst FDA-approved Breckenridge Pharmaceutical, Inc., tube, or primary peritoneal cancer.
product containing the active ingredi- and its partner Natco Pharma Ltd. have Previously approved indications for
ent prasterone, which is also known as launched armodanil tablets (CIV) in bevacizumab include rst- or second-
dehydroepiandrosterone. 50-mg, 150-mg, and 250-mg strengths line treatment of patients with meta-
The efficacy of Intrarosa, a once- after receiving final FDA approval. static colorectal cancer in combination
daily vaginal insert, was established in Armodanil tablets are a generic version with intravenous 5uorouracil-based

7
chemotherapy; second-line treatment of Opdivo for FDA REVIEW ACTIVITIES
patients with metastatic colorectal can- Head-and-Neck Cancer Priority Review Designations
cer who have progressed on a rst-line The FDA has approved nivolumab Avelumab for Skin Cancer
bevacizumab-containing regimen, in (Opdivo, Bristol-Myers Squibb) for the The FDA has accepted for priority
combination with uoropyrimidine/iri- treatment of patients with recurrent or review a biologics license application
notecan- or fluoropyrimidine/oxaliplatin- metastatic squamous cell carcinoma of for avelumab (EMD Serono/Pzer) as
based chemotherapy; rst-line treatment the head and neck with disease progres- a proposed treatment for patients with
of patients with unresectable, locally sion on or after platinum-based therapy. metastatic Merkel cell carcinoma (MCC).
advanced, recurrent, or metastatic non- Nivolumab is the only immuno-oncology Avelumab is an investigational, fully
squamous, nonsmall-cell lung cancer treatment shown in a phase 3 study to human anti-programmed death ligand-1
in combination with carboplatin and signicantly extend overall survival (OS) immunoglobulin G1 monoclonal antibody.
paclitaxel chemotherapy; and treatment for these patients. If approved, it would be the rst treatment
of metastatic renal cell carcinoma in In the CheckMate-141 trial, nivolumab indicated for metastatic MCC in the U.S.
combination with interferon alfa. demonstrated signicantly superior OS The submission was supported by data
Source: Genentech, December 6, 2016 compared with the investigators choice from the JAVELIN Merkel 200 trial, a
of therapy (i.e., methotrexate, docetaxel, phase 2 study involving 88 patients with
Jardiance for Diabetes or cetuximab), with a 30% reduction in metastatic MCC whose disease had pro-
Patients With CVD the risk of death (hazard ratio, 0.70; gressed after at least one chemotherapy
The FDA has approved a new indica- P = 0.0101) and a median OS of 7.5 months treatment. Avelumab was administered
tion for empagliozin (Jardiance, Boeh- compared with 5.1 months, respectively. at a dose of 10 mg/kg every two weeks.
ringer Ingelheim) to reduce the risk of Nivolumab was previously approved The patients were followed for a median
cardiovascular death in adults with type-2 for use in patients with nonsmall-cell of 10.4 months. An objective response (the
diabetes (T2D) and cardiovascular dis- lung cancer, metastatic melanoma, renal trials primary endpoint) was achieved in
ease (CVD). The FDAs decision was cell carcinoma, or classic Hodgkins 28 patients (32%), including eight complete
based on a post-marketing study required lymphoma. responses and 20 partial responses.
by the agency when it approved empa- Source: Bristol-Myers Squibb, Source: Merck, November 29, 2016
gliozin in 2014 as an adjunct to diet and November 10, 2016
exercise to improve glycemic control Keytruda for MSI-H Cancer
in adults with T2D. Empagliozin was Enbrel for Pediatric The FDA has accepted for review a
assessed in more than 7,000 patients with Plaque Psoriasis supplemental biologics license application
T2D and CVD. In the study, empagliozin The FDA has approved a supple- (sBLA) for pembrolizumab (Keytruda,
was shown to reduce the risk of cardio- mental biologics license application Merck Oncology), an anti-programmed
vascular death compared with placebo for the expanded use of etanercept death-1 therapy, for the treatment of pre-
when added to standard-of-care therapies (Enbrel, Amgen), making it the rst viously treated patients with advanced
for diabetes and atherosclerotic CVD. systemic therapy to treat pediatric microsatellite instability-high (MSI-H)
Source: FDA, December 2, 2016 patients (417 years of age) with chronic cancer. The FDA granted the application
moderate-to-severe plaque psoriasis. a priority review with a target action date
FluLaval Quadrivalent Vaccine The approval was based on positive of March 8, 2017.
The FDAs Center for Biologics Evalua- efcacy results from a 48-week, phase 3 The sBLA will be reviewed under the
tion and Research has expanded the indi- study in which signicantly more patients FDAs accelerated approval program
cation for FluLaval Quadrivalent inuenza who received etanercept than those who based on the tumor response rate and
vaccine (GlaxoSmithKline) to include use received placebo achieved a Psoriasis the durability of response. The FDA pre-
in children 6 months of age and older. Area and Severity Index score of at viously granted breakthrough therapy
The vaccine was originally approved in least 75the studys primary endpoint designations to pembrolizumab for the
2013 for patients 3 years of age and older. at week 12 (57% versus 11%, respectively; treatment of patients with unresectable
Source: GlaxoSmithKline, November P < 0.001); a signicant difference was or metastatic MSI-H colorectal or non-
21, 2016 observed as early as week 4. colorectal cancer.
Source: Amgen, November 4, 2016 Source: Merck, November 28, 2016

Midostaurin for AML Velusetrag for Gastroparesis DS-8201 for Metastatic Breast Cancer
The FDA has granted priority review The FDA has given a fast-track The FDA has granted a fast-track
status to a new drug application for designation to velusetrag (Theravance designation to DS-8201 (Daiichi Sankyo
midostaurin (Novartis), an oral, multi- Biopharma) for the treatment of symp- Company), an investigational human
targeted kinase inhibitor, for the treat- toms associated with idiopathic and epidermal growth factor receptor-2
ment of newly diagnosed adults with acute diabetic gastroparesis. Velusetrag is an (HER2)-targeting antibodydrug conju-
myeloid leukemia (AML) with an FMS- oral, once-daily investigational medication gate, for the treatment of HER2-positive
like tyrosine kinase-3 (FLT3) mutation, for gastrointestinal motility disorders. It unresectable and/or metastatic breast
as well as for the treatment of patients is a highly selective agonist with high cancer in patients who have progressed
with advanced systemic mastocytosis. In intrinsic activity at the human 5-hydroxy- after treatment with HER2-targeted
addition, a premarket approval application tryptamine receptor 4. therapies, including ado-trastuzumab
for a midostaurin FLT3 companion diag- An ongoing phase 2b, multicenter, emtansine. DS-8201 consists of a human-
nostic, developed by Novartis in collabora- double-blind, randomized, placebo- ized anti-HER2 antibody attached by a
tion with Invivoscribe Technologies, was controlled, parallel-group trial is evaluat- peptide linker to a topoisomerase I inhibi-
accepted for review by the FDA. ing the efcacy and safety of velusetrag tor. This linkerpayload combination
The phase 3 RATIFY trial investigated in patients with diabetic (n = 100) or allows a higher drug-to-antibody ratio,
midostaurin plus standard chemotherapy idiopathic (n = 100) gastroparesis. Three according to the products developer.
versus placebo plus standard chemo- dosages of velusetrag (5 mg, 15 mg, and Source: Daiichi Sankyo, December 1,
therapy in adults younger than 60 years 30 mg once daily for 12 weeks) are being 2016
of age with FLT3-mutated AML. Those in evaluated. The primary endpoint is the
the midostaurin arm experienced a statis- effect of velusetrag on symptoms in Tazemetostat for B-Cell Lymphoma
tically signicant improvement in overall patients with gastroparesis. The FDA has granted fast-track
survival, with a 23% reduction in the risk Source: Theravance Biopharma, status to tazemetostat (Epizyme, Inc.)
of death compared with the placebo arm December 6, 2016 for the treatment of patients with diffuse
(hazard ratio, 0.77; P = 0.0074). large B-cell lymphoma (DLBCL) with
Source: Novartis, November 14, 2016 ASN100 for S. Aureus Pneumonia EZH2-activating mutations. Tazemetostat
The FDA has granted fast-track status inhibits EZH2, a histone methyltransfer-
Fast-Track Designations to ASN100 (Arsanis, Inc.) for the preven- ase that is increasingly understood to play
IFN Kinoid Vaccine for SLE tion of Staphylococcus aureus pneumonia a role in the growth and proliferation of
The FDA has granted fast-track sta- in mechanically ventilated patients who a number of cancers, including DLBCL,
tus to IFN Kinoid in Lupus (Neovacs), are at high risk for S. aureus pneumo- the most commonly diagnosed form of
an investigational vaccine for systemic nia. ASN100 is a combination of two fully non-Hodgkins lymphoma.
lupus erythematosus (SLE). Neovacs human monoclonal antibodies (ASN-1 Tazemetostat is being evaluated as
research activities are focused on patholo- and ASN-2) that collectively neutralize monotherapy and in combination with
gies associated with an overproduction of six important S. aureus cytotoxins asso- other agents in multiple cancer indica-
endogenous cytokines. Specically, the ciated with pneumonia pathogenesis. tions. Phase 2 studies of tazemetostat
company is developing active immuno- ASN-1 neutralizes alpha-hemolysin, a as monotherapy are ongoing.
therapy involving the administration of key S. aureus toxin responsible for lung Source: Epizyme, November 28, 2016
an immunogenic complex involving the epithelial cell damage, in addition to four
target cytokine (for example, interferon S. aureus leukocidins responsible for lysis Breakthrough Therapy Status
alfa [IFN]) to a carrier protein. The of human phagocytic (immune) cells. Brentuximab for Cutaneous Lymphoma
intramuscular injection of this kinoid ASN-2 inactivates the remaining S. aureus The FDA has granted a breakthrough
induces an immune response and leukocidin, LukGH, which is a potent therapy designation to brentuximab
stimulates the production of polyclonal human cytotoxin that is also responsible vedotin (Adcetris, Seattle Genetics, Inc.)
antibodies against the target cytokines, for the lysis of human phagocytes. for the treatment of patients with CD30-
thereby blocking cytokine overproduction Source: Arsanis, December 1, 2016 expressing mycosis fungoides (MF)
and its biologic effects. and primary cutaneous anaplastic large-
Source: Neovacs, December 7, 2016 cell lymphoma (pcALCL) who require

9
systemic therapy and have received one ated. The biocompatible scaffold contain- (including Mucor spp. and Rhizopus
prior systemic therapy. MF and pcALCL ing the stem cells is then implanted. The spp.). APX001 is a rst-in-class small-
are the most common subtypes of cutane- proprietary technology was designed to molecule drug candidate that targets
ous T-cell lymphoma (CTCL), account- improve outcomes for patients by poten- and inhibits the conserved fungal
ing for more than 75% of cases of the tially simplifying surgical techniques and enzyme Gwt1, thereby compromising
disease. Brentuximab vedotin is an anti- by prompting regeneration of the patients the growth of major fungal pathogens,
bodydrug conjugate directed to CD30, own esophagus. including Candida and Aspergillus.
which is expressed on skin lesions in Source: Biostage, December 1, 2016 Source: Amplyx Pharmaceuticals,
approximately 50% of patients with CTCL. November 16, 2016
Source: Seattle Genetics, November Risankizumab for
10, 2016 Pediatric Crohns Disease Napabucasin for Pancreatic Cancer
The FDA has granted an orphan drug Napabucasin (Boston Biomedical) has
Orphan Drug Designations designation to risankizumab (AbbVie) for received an orphan drug designation from
VK0214 for Adrenoleukodystrophy the investigational treatment of Crohns the FDA for the treatment of patients with
The FDA has granted orphan drug disease in pediatric patients. Crohns pancreatic cancer. This is the second such
status to VK0214 (Viking Therapeutics) disease is an incurable chronic inam- designation for napabucasin, an orally
for the treatment of patients with x-linked matory condition of the gastrointestinal administered agent designed to inhibit
adrenoleukodystrophy (X-ALD). VK0214 tract that can cause diarrhea, abdominal cancer stemness pathways by targeting
is an investigational, orally available pain, and weight loss. STAT3; the rst designation was for gas-
thyroid receptor-beta agonist that selec- Source: AbbVie, November 30, 2016 tric cancer, including gastroesophageal
tively modulates lipoprotein and tri- junction cancer.
glyceride levels in liver tissue. This mecha- PRX-OTC for Ornithine Source: Boston Biomedical, November
nism has been demonstrated to affect the Transcarbamylase Deciency 14, 2016
expression of the genes that are relevant PRX-OTC (PhaseRx, Inc.) has received
to the manifestation of X-ALD. In X-ALD, an orphan drug designation from the ELX-02 for Mucopolysaccharidosis
mutations in the ABCD1 gene lead to the FDA for the treatment of patients with The FDA has granted an orphan drug
accumulation of very long-chain fatty acids ornithine transcarbamylase deciency designation to ELX-02 (Eloxx Pharma-
(VLCFAs), which is believed to be a fun- (OTCD). OTCD is a rare liver disorder ceuticals) for the treatment of patients
damental cause of the disease. Research caused by an inherited single-gene with mucopolysaccharidosis type-1
has shown that increasing the expression deficiency that results in hyper- (MPS-1). ELX-02 is a synthetic amino-
of the ABCD2 gene can counteract this pro- ammonemia and can lead to irrevers- glycoside that has been developed as a
cess and lead to normalization of VLCFA ible neurological impairment, coma, translational read-through drug for the
levels. and death. PRX-OTC is an intracellular treatment of genetic diseases caused by
Source: Viking Therapeutics, December enzyme replacement therapy designed nonsense mutations.
6, 2016 to replace the missing or defective MPS-1 is a chronic, progressive genetic
enzyme in patients with OTCD, thereby disorder caused by an enzymatic de-
Cellspan Esophageal Implants correcting the disease. ciency of alpha-L-iduronidase, which dis-
The Cellspan esophageal implant Source: PhaseRx, November 28, 2016 rupts the glycosaminoglycan catabolic
(Biostage, Inc.) has received an orphan pathway, leading to an intralysosomal
drug designation from the FDA as a means APX001 for Fungal and Mold Infections accumulation of the substrates heparan
for restoring the structure and function of The FDAs Ofce of Orphan Products sulfate and dermatan sulfate. The accu-
the esophagus after damage due to can- Development has granted orphan drug mulation of these substrates disrupts the
cer, injury, or congenital abnormalities. status to APX001 (Amplyx Pharma- movement of intracellular molecules,
The patients own stem cells are taken ceuticals) for the treatment of invasive resulting in the dysfunction of cells,
from a simple adipose/fat tissue biopsy, candidiasis, invasive aspergillosis, coc- tissues, and organs.
expanded, and banked, and then seeded cidioidomycosis, and rare mold infec- Source: Eloxx Pharmaceuticals,
onto a scaffold that mimics the natural tions caused by Scedosporium spp., November 7, 2016
dimensions of the organ being regener- Fusarium spp., and Mucorales fungi

Rare Pediatric Abilify Maintena for Bipolar I Disorder application (NDA) for valbenazine
Disease Designation The FDA has determined that the (Ingrezza, Neurocrine Biosciences) for
VTS-270 for NiemannPick Disease supplemental new drug application for the treatment of patients with tardive
The FDA has granted a rare pediatric expanded labeling of Abilify Maintena dyskinesia on February 16, 2017. The
disease designation to VTS-270 (Vtesse, (Otsuka/Lundbeck) for the mainte- FDA has granted priority review status
Inc.), an investigational drug for children nance treatment of adults with bipolar I to the NDA, with a target action date of
with NiemannPick type-C1 disease disorder is sufficiently complete to April 11, 2017.
(NPC). NPC is a progressive, irreversible, permit a substantive review. The VMAT2 is a protein in the human
chronically debilitating, and ultimately agency has set a target action date of brain that is primarily responsible for
lethal genetic disease. July 28, 2017. repackaging and transporting mono-
In early 2016, the FDA granted break- Abilify Maintena, an atypical anti- amines (dopamine, norepinephrine,
through therapy status for VTS-270, psychotic, is an intramuscular depot serotonin, and histamine) in presynaptic
which is currently in a pivotal phase 2b/3 formulation of aripiprazole. It is a neurons. Valbenazine is a highly selec-
clinical trial in NPC. The FDA also previ- sterile lyophilized powder that, when tive VMAT2 inhibitor that modu-
ously granted orphan drug status to the reconstituted with sterile water for lates dopamine release during nerve
medication. injection, forms an injectable suspen- communication.
VTS-270 is a mixture of hydroxy- sion that can be administered monthly. Source: Neurocrine Biosciences,
propyl betacyclodextrin (HPCD) with The product was approved in the U.S. November 29, 2016
a specic compositional ngerprint that in 2013 for the treatment of adults with
distinguishes it from other HPCD schizophrenia. OxyContin Bioequivalent
mixtures. Source: Otsuka, December 1, 2016 Intellipharmaceutics International,
Source: Vtesse, November 29, 2016 Inc., has led a new drug application with
Abuse-Deterrent Oxaydo for Pain the FDA seeking authorization to mar-
New Applications Egalet Corporation has submitted ket Rexista abuse-deterrent oxycodone
Semaglutide for Type-2 Diabetes to the FDA a supplemental new drug hydrochloride extended-release tablets
Novo Nordisk has submitted a new application for Oxaydo (oxycodone in 10-mg, 15-mg, 20-mg, 30-mg, 40-mg,
drug application to the FDA for sema- hydrochloride, USP) tablets CII to 60-mg, and 80-mg strengths.
glutide, a glucagon-like peptide-1 (GLP-1) support an abuse-deterrent label claim Rexista is indicated for the manage-
analogue administered once weekly for for the intravenous route of abuse. ment of pain severe enough to require
the treatment of adults with type-2 dia- The application includes in vitro data daily, around-the-clock, long-term
betes (T2D). demonstrating that Oxaydo resists the opioid treatment and for which alterna-
The submission was based on results extraction of oxycodone and, based tive treatment options are inadequate.
from the SUSTAIN clinical trial program, on its gelling properties, is more dif- The submission was supported by data
which included eight phase 3a studies cult to draw into a syringe compared from pivotal pharmacokinetic studies,
involving more than 8,000 adults with with a nonabuse-deterrent immediate- which demonstrated that Rexista is bio-
T2D. In that program, once-weekly sema- release (IR) oxycodone comparator. equivalent to OxyContin (oxycodone
glutide was administered in combination Oxaydo is an IR oral formulation indi- hydrochloride extended release, Purdue
with oral antidiabetic agents and basal cated for the management of acute and Pharma).
insulin and demonstrated statistically chronic moderate-to-severe pain for Source: Intellipharmaceutics Inter-
signicant and sustained blood glucose which the use of an opioid analgesic national, November 25, 2016
control compared with that of sitagliptin, is appropriate.
extended-release exenatide, once-daily Source: Egalet Corporation, December Guselkumab for Plaque Psoriasis
insulin glargine U100, and placebo. In 1, 2016 Janssen Biotech has submitted a bio-
addition, semaglutide was associated with logics license application to the FDA
signicantly greater reductions in mean Valbenazine for Tardive Dyskinesia seeking approval of guselkumab for the
body weight than the comparators. The FDAs Psychopharmacologic treatment of adults with moderate-to-
Source: Novo Nordisk, December 5, Drugs Advisory Committee has agreed severe plaque psoriasis. Guselkumab
2016 to review data included in the new drug is a human monoclonal antibody that

11
targets interleukin-23, a protein that plays metastatic colorectal cancer or locally CLINICAL TRIAL NEWS
a key role in the development of immune- advanced, unresectable, or metastatic Tagrisso for Lung Cancer
mediated inammatory diseases. gastrointestinal stromal tumors. Promising results have been reported
Source: Janssen Biotech, November The submission was based on positive from a phase 3 study of osimertinib
17, 2016 data from the phase 3, placebo-controlled (Tagrisso, AstraZeneca) in the second-
RESORCE trial, which investigated rego- line treatment of patients with epider-
L-Glutamine for Sickle Cell Disease rafenib in 573 patients with uHCC whose mal growth factor receptor T790M
The FDA has accepted for review a disease had progressed during treat- mutation-positive locally advanced or
new drug application for orally adminis- ment with sorafenib (Nexavar, Bayer). metastatic nonsmall-cell lung cancer.
tered pharmaceutical-grade L-glutamine The patients were randomly assigned to Osimertinib improved progression-free
(Emmaus Life Sciences) for the treatment receive regorafenib or placebo plus best survival (PFS) by 5.7 months compared
of patients with sickle cell disease. Data supportive care. with standard platinum-based doublet
from a phase 3 study demonstrated a The study met its primary endpoint of chemotherapy (10.1 months versus
reduction in the frequency of sickle cell a statistically signicant improvement in 4.4 months, respectively; hazard ratio
crises and hospitalizations, a reduction overall survival (OS) with regorafenib. [HR], 0.30; P < 0.001). Moreover, in the
in cumulative days hospitalized, and a Median OS was 10.6 months for rego- 34% of patients with central nervous
lower incidence of life-threatening acute rafenib compared with 7.8 months for system metastases at baseline, PFS
chest syndrome in 230 adult and pediatric placebo. was signicantly greater with osimer-
patients. If approved, the product would Source: Bayer, November 7, 2016 tinib than with platinum-based doublet
be the rst potential new treatment for chemotherapy (8.5 months versus
adults with sickle cell disease in nearly Complete Response Letter 4.2 months, respectively; HR, 0.32).
20 years. Heplisav-B Vaccine Source: AstraZeneca, December 6,
Source: Emmaus Life Sciences, Dynavax Technologies Corporation 2016
November 8, 2016 has received a complete response letter
(CRL) from the FDA regarding its bio- Bosulif for CML
Biosimilar Herceptin logics license application for Heplisav-B Positive results have been reported
Mylan and Biocon Ltd. have sub- (hepatitis B vaccine, recombinant [adju- from a phase 3 comparison of bosutinib
mitted a biologics license application vanted]) for the immunization of adults (Bosulif, Pzer/Avillion) and imatinib
for MYL-14010, a proposed biosimilar 18 years of age and older against hepatitis as rst-line treatments in patients with
trastuzumab, to the FDA. The product B infection. The CRL seeks information chronic-phase Philadelphia chromosome-
is a proposed biosimilar to Herceptin on several topics, including clarica- positive (Ph+) chronic myeloid leuke-
(Genentech), which is indicated to treat tion of specic adverse events of special mia (CML). The study met its primary
certain human epidermal growth factor interest; a numerical imbalance in the endpoint of a superior major molecular
receptor-2-positive breast and gastric number of cardiac events in one study; response at 12 months with bosutinib
cancers. Mylan and Biocon believe it to new analyses of the integrated safety compared with imatinib. Bosutinib is cur-
be the rst submission of a proposed database across different time periods; rently indicated in the U.S. for the treat-
biosimilar trastuzumab in the U.S. and post-marketing commitments. ment of adults with Ph+ CML who were
Source: Mylan, November 8, 2016 The vaccine was previously the subject resistant to or intolerant of prior therapy.
of a CRL in 2012. Bosutinib is an oral, once-daily tyrosine
Stivarga for Liver Cancer Heplisav-B is an investigational kinase inhibitor that inhibits the Bcr-Abl
Bayer has submitted a supplemen- hepatitis B vaccine for adults that kinase, which promotes CML; it is also an
tal new drug application to the FDA to combines hepatitis B surface antigen inhibitor of Src-family kinases. Bosutinib
have its cancer medication regorafenib with a Toll-like receptor 9 agonist to was approved by the FDA in September
(Stivarga) approved for the second-line enhance the immune response. The vac- 2012 for the treatment of adults with Ph+
treatment of patients with unresectable cine is administered in two doses over CML who were resistant to or intolerant
hepatocellular carcinoma (uHCC). Rego- one month. of prior therapy.
rafenib, an oral multikinase inhibitor, Source: Dynavax Technologies, Source: Pzer, December 5, 2016
is currently indicated for patients with November 14, 2016

Jaka for Myelobrosis to the FDA, in which Shire will request the use of which requires federal waiv-
A pooled analysis of ve-year follow- an expanded indication for Vonvendi. ers because it is a banned substance
up data from the phase 3 COMFORT-I Source: Shire, December 2, 2016 brought relief from distress that lasted
and COMFORT-II trials has suggested for more than six months in 80% of the
that earlier treatment with ruxolitinib Lyrica for Pediatric Epilepsy 29 study patients monitored, based on
(Jaka, Incyte Corporation), a rst-in- Pzer has announced positive results clinical evaluation scores for anxiety and
class Janus kinase-1 (JAK1) and JAK2 from a phase 3 study that evaluated the depression.
inhibitor, may result in an improved use of pregabalin (Lyrica) capsules Source: NYU Langone Medical
survival advantage for patients with CV and oral solution CV as adjunctive Center, December 1, 2016
intermediate- or high-risk myelobrosis therapy for pediatric epilepsy patients
compared with best available therapy 4 to 16 years of age with partial-onset Pulmaquin for Lung Infection
or placebo. The ndings showed pro- seizures. Adjunctive treatment with Pulmaquin (Aradigm Corporation), a
longed survival in patients treated pregabalin 10 mg/kg per day resulted once-daily inhaled formulation of cipro-
with ruxolitinib, with the risk of death in a statistically signicant reduction in oxacin, has failed to meet the primary
reduced by 30% compared with the con- seizure frequency compared with pla- endpoint in a late-stage study involving
trol groups. Ruxolitinib also showed an cebo (the primary efcacy endpoint). patients with non-cystic brosis bronchi-
overall survival advantage in various The 12-week, double-blind, placebo- ectasis (non-CF BE) who had chronic
patient subgroup analyses, including controlled, randomized, parallel-group lung infections with Pseudomonas
age, gender, disease type, risk status, study involved 295 pediatric patients in aeruginosa. In another study, however,
JAK2V617F mutation status, baseline 18 countries. Pulmaquin was deemed to have had a
spleen length, anemia, white blood cell In the United States, pregabalin is indi- statistically significant benefit over
count, and platelet count. cated for the treatment of bromyalgia, placebo.
Source: Incyte Corporation, diabetic nerve pain, spinal cord injury The primary endpoint in both trials
December 4, 2016 nerve pain, and pain after shingles in was an increase in the median time to the
adults. The medication is also indicated rst mild, moderate, or severe pulmo-
Vonvendi for Blood for the treatment of partial-onset seizures nary exacerbation (PE). The key second-
Loss in Surgery in adults with epilepsy who take one or ary efcacy endpoint in both studies was
Positive results have been reported more drugs for seizures. Pregabalin is the frequency of PEs during the 48-week,
from a phase 3 trial of Vonvendi (von not approved as adjunctive therapy for double-blind treatment period.
Willebrand factor [recombinant], Shire) pediatric epilepsy patients with partial- In the ORBIT-3 trial, the median time
to treat bleeds in elective surgical onset seizures. to the rst PE was 221 days in the Pul-
settings for adults with severe von Source: Pzer, December 1, 2016 maquin group compared with 136 days
Willebrand disease (VWD), the most in the placebo group (P = 0.8488).
common inherited bleeding disorder. Psilocybin for Anxiety and Pulmaquin-treated patients showed a 13%
Vonvendi is an on-demand recombi- Depression in Cancer Patients reduction in the frequency of PEs during
nant treatment for adults with VWD When combined with psychological the 48-week treatment period compared
and replaces von Willebrand factor, counseling, a single dose of a mind- with those given placebo (P = 0.3125).
one of several types of proteins in the altering compound contained in psyche- In the ORBIT-4 trial, the median time
blood that are needed to facilitate proper delic mushrooms signicantly lessened to the rst PE was 230 days in the Pul-
blood clotting missing in patients with mental anguish in distressed cancer maquin group compared with 163 days in
VWD. The study met its primary end- patients for months at a time, according the placebo group (P = 0.0462). In addi-
point, indicating that Vonvendi effec- to the results of a clinical study led by tion, there was a 37% reduction in the
tively controlled bleeding and blood loss researchers at the New York University frequency of PEs during the 48-week
during an operation in adults under- Langone Medical Center. treatment period in the Pulmaquin
going major, minor, and oral elec- Published online in December in the group compared with the placebo group
tive surgical procedures. The results Journal of Psychopharmacology, the study (P = 0.0007).
from this study will form the basis of a showed that one-time treatment with Source: Aradigm Corporation,
supplemental new drug application the hallucinogenic drug psilocybin December 1, 2016

13
Herceptin Biosimilar patients age, body mass index, or previ- controlled trial of weekly and monthly
For Breast Cancer ous treatment with conventional synthetic subcutaneous injections of buprenor-
Pzer has announced that its pivotal disease-modifying antirheumatic drugs. phine (Braeburn Pharmaceuticals/
REFLECTIONS B3271002 trial, a com- At week 12, in the baricitinib 4-mg group, Camurus) for the treatment of patients
parative safety and efcacy study of 67% of patients less than than 65 years of with moderate-to-severe opioid use
PF-05280014 versus Herceptin (trastu- age and 68% of patients 65 years of age disorder. Long-acting buprenorphine
zumab, Genentech), met its primary end- or older showed at least a 20% improve- achieved the studys primary endpoint
point. PF-05280014 is a monoclonal anti- ment according to American College of statistical noninferiority compared
body that is in development as a potential of Rheumatology criteria (ACR20). In with daily sublingual buprenorphine/
biosimilar for all approved indications of the group that received placebo, 40% of naloxone (the current standard of care)
Herceptin. Currently, Herceptin is indi- patients less than 65 years of age and in terms of the response to treatment.
cated for the treatment of human epider- 43% of patients 65 years or age or older Buprenorphine maintenance therapy
mal growth factor receptor-2 (HER2)- achieved an ACR20 response. is currently considered the gold stan-
positive breast cancer and gastric cancer. Baricitinib is a once-daily oral selective dard for the treatment of opioid use
The randomized, double-blind trial Janus kinase-1 (JAK1) and JAK2 inhibi- disorder, with more than one million
demonstrated equivalence in the primary tor currently in late-stage clinical studies patients receiving buprenorphine in the
endpoint of the objective response rates for the treatment of inammatory and U.S. and Europe. Currently, most patients
for PF-05280014 and Herceptin admin- autoimmune diseases. receiving buprenorphine take daily doses.
istered in combination with paclitaxel Source: Eli Lilly, November 14, 2016 Source: Braeburn Pharmaceuticals,
in rst-line patients with HER2-positive November 14, 2016
metastatic breast cancer after 25 weeks Simponi Aria for
of treatment. Ankylosing Spondylitis Romosozumab for Decreased
Source: Pzer, November 29, 2016 A pivotal phase 3 study has demon- Bone Mineral Density in Men
strated the efcacy of the intravenous Results from the phase 3 BRIDGE
Cosentyx for Psoriatic Arthritis anti-tumor necrosis factor (TNF)-alpha trial have shown that, in men with osteo-
New data have shown that secukinu- therapy golimumab (Simponi Aria, porosis, treatment with the investiga-
mab (Cosentyx, Novartis), a fully human Janssen) in patients with active anky- tional agent romosozumab (Amgen/
interleukin-17A inhibitor, delivered losing spondylitis (AS). Data from the UCB) resulted in a signicant 12.1% gain
sustained improvements in the signs GO-ALIVE trial showed that 73% of in bone mineral density (BMD) at the
and symptoms of psoriatic arthritis patients with active AS receiving goli- lumbar spine compared with placebo
(PsA)including patient-reported mumab 2 mg/kg achieved the primary at 12 months (the studys primary end-
painduring three years of treat- endpoint of at least a 20% improve- point) (P < 0.01). Both secondary end-
ment. In the rst year of a three-year ment in the Assessment in Ankylosing points were also met, with romosozumab
open-label extension study, 77% of PsA Spondylitis criteria at week 16, compared showing a statistically signicant increase
patients achieved at least 20% improve- with 26% of patients receiving placebo in BMD at the total hip (2.5%) and the
ment in American College of Rheuma- (P 0.001). In July 2013, golimumab femoral neck (2.2%) at 12 months (both
tology response criteria. The new data received FDA approval as a 30-minute P < 0.01 compared with placebo). Romo-
also showed that response rates were infusion for the treatment of adult patients sozumab is a bone-forming monoclonal
consistent from year 1 (69%) to year 3 with moderately to severely active agent that inhibits the activity of the
(77%). rheumatoid arthritis in combination with protein sclerostin.
Source: Novartis, November 14, 2016 methotrexate. Source: Amgen, November 14, 2016
Source: Janssen, November 14, 2016
Baricitinib for RA Ibalizumab for HIV
New data analyses of two phase 3 Long-Acting Buprenorphine A 24-week phase 3 study has conrmed
studies have shown that treatment with For Opioid Addiction the safety and efcacy results with ibali-
baricitinib (Eli Lilly/Incite Corporation) Positive results have been reported zumab (Theratechnologies, Inc./TaiMed
resulted in improvements in rheumatoid from a pivotal phase 3, randomized, Biologics) observed in a previously com-
arthritis (RA) symptoms regardless of the double-blind, double-dummy, active- pleted phase 2b trial, despite the fact that

the patient population in the phase 3 characterized by the loss of motor neu- A total of 961 patients were enrolled
investigation had higher levels of multi- rons in the spinal cord and lower brain in the two trials. Patients who complete
drug-resistant human immunodeciency stem. This results in severe, progres- the 12- week double-blind portion of the
virus-1 ( HIV-1) and more advanced dis- sive muscular atrophy and weakness. studies will have the option to continue in
ease at the time of enrollment. Ibalizumab Over time, patients with the most severe a long-term open-label safety extension,
is a humanized monoclonal antibody. form of SMA can become paralyzed and which will evaluate the safety of intermit-
The results indicated that 33 of the have difculty in breathing and swallow- tent use of FMX101 for up to an additional
40 patients (83%) met the primary ending. Patients with SMA do not produce nine months.
point of a reduction of at least 0.5 log10 enough survival motor neuron (SMN) Source: Foamix Pharmaceuticals,
in the viral load after seven days of treat- protein, which is caused by a defect in November 28, 2016
ment with ibalizumab. After 24 weeks of the SMN1 gene. Spinraza is an antisense
treatment, the mean reduction in the viral oligonucleotide that alters the splicing of Daprodustat for Anemia
load was 1.6 log10, and 48% of the patients SMN2, a gene almost identical to SMN1, Associated With Renal Disease
showed a viral load reduction of more which results in the increased production GlaxoSmithKline has begun a phase 3
than 2.0 log10. of fully functional SMN protein. development program investigating
Source: Theratechnologies, November Source: Biogen, November 7, 2016 daprodustat, an oral hypoxia-inducible
10, 2016 factor prolyl hydroxylase inhibitor, as
Orkambi in Children With CF a treatment for anemia associated with
Binimetinib/Encorafenib Positive results have been reported chronic kidney disease (CKD). The
For Melanoma from a phase 3 study of Orkambi (luma- program includes two clinical trials.
A pivotal phase 3 trial of binimetinib caftor/ivacaftor, Vertex Pharmaceuticals) The rst trial, ASCEND-D, will enroll
plus encorafenib (Array BioPharma/ in children 6 through 11 years of age with approximately 3,000 dialysis-dependent
Pierre Fabre) in patients with BRAF- cystic brosis (CF) who have two copies patients with CKD-associated anemia
mutant melanoma has met its primary of the F508del mutation. The study met its who are switching from an erythropoietin-
endpoint, with the combination sig- primary endpoint of an absolute change stimulating agent (ESA). The second trial,
nicantly improving progression-free in the lung clearance index (LCI2.5) after ASCEND-ND, will enroll approximately
survival (PFS) compared with vemu- 24 weeks of treatment, demonstrating a 4,500 nondialysis-dependent patients
rafenib, a BRAF inhibitor, alone. The statistically signicant improvement in with CKD-associated anemia and will
median PFS for patients treated with bin- LCI2.5 among patients treated with Ork- include patients who are either switching
imetinib/encorafenib was 14.9 months ambi compared with those given placebo. from or nave to an ESA. For both stud-
compared with 7.3 months for patients At baseline, the mean LCI2.5 was 10.28. ies, the coprimary endpoints are the time
treated with vemurafenib (hazard ratio, Children treated with Orkambi experi- to the rst occurrence of major adverse
0.54; P < 0.001). Binimetinib is a late- enced an improvement in lung function cardiovascular events and the mean
stage small-molecule MEK inhibitor, of 1.09 compared with placebo after change in hemoglobin levels between
and encorafenib is a late-stage small- 24 weeks (P < 0.0001). baseline and the efcacy period (i.e.,
molecule BRAF inhibitor, both of which Source: Vertex Pharmaceuticals, the mean during weeks 28 to 52). The
target key enzymes in this pathway. November 7, 2016 studies will assess whether daprodus-
Source: Array BioPharma, November tat is noninferior to recombinant human
9, 2016 Minocycline Foam for Acne erythropoietin on these endpoints.
Foamix Pharmaceuticals has com- Source: GlaxoSmithKline, November
Spinraza for Spinal pleted patient enrollment in two phase 3 25, 2016
Muscular Atrophy trials designed to evaluate the efcacy
Spinraza (nusinersen, Biogen/Ionis and safety of FMX101, a topical 4% mino- DEVICE APPROVALS
Pharma) provided a signicant improve- cycline foam, in the treatment of patients TroClose1200 Trocar
ment in motor function compared with with moderate-to-severe acne. The two The FDA has cleared the TroClose1200
placebo (the primary endpoint) in a pivotal studies are being conducted simul- (Gordian Surgical), a new trocar with an
phase 3 study of patients with later-onset taneously, and results are expected in the integrated closure system for suturing
spinal muscular atrophy (SMA). SMA is rst half of 2017. abdominal-wall incisions during laparo-

15
scopic surgical procedures. The device The nonsterile water-based gel forms Ormev IV Bag
acts as both a trocar, through which surgi- a protective barrier on skin to increase The FDA has given the OK to a prior
cal instruments enter the abdomen, and moisture and to reduce water loss. Its approval supplement (PAS) for Ormev
a device to close internal incisions made contents include emollients, preserva- (acetaminophen, Mallinckrodt Pharma-
during surgery. The sutures are inserted tives, skin-conditioning agents, viscosity- ceuticals) injection available in an
into the tissue at the beginning of the increasing agents, emulsifying agents, intravenous (IV) bag, which will provide
procedure and anchored to remain in and binders. The gel is applied three health care providers with an additional
place throughout the operation, allowing times per day or as needed. delivery option. The PAS to the approved
the incisions to be closed quickly upon Source: Helsinn Integrative Care, new drug application for Ofirmev
removal of the device. December 1, 2016 included the addition of a new container
Source: Gordian, December 7, 2016 closure and manufacturer. The poly-
PolyPlex Wound Dressing propylene bags will be manufactured by
Insulia Diabetes- The FDA has approved PolyPlex wound Fresenius Kabi. Mallinckrodt anticipates
Management Software dressing (Global Health Solutions), a product availability in the second quarter
Paris-based company Voluntis has rst-of-its-kind, petrolatum-based topical of 2017.
received FDA 510(k) clearance for the gel indicated for the management of acute Ormev injection is the only IV formu-
Insulia Diabetes Management Compan- and chronic wounds. The gel provides lation of acetaminophen to be approved
ion, a global digital device for patients protection against bacteria, fungi, and and marketed in the United States. The
with type-2 diabetes who are being yeasts without irritating fragile, healing FDA approved the drug in November
treated with insulin. The prescription- tissue, according to the manufacturer. It 2010. Ormev is indicated for the man-
only medical device works with Sanos will be available in January 2017 through agement of mild-to-moderate pain; the
Lantus (insulin glargine injection) and McKesson Medical-Surgical. management of moderate-to-severe pain
Novo Nordisks Levemir (insulin detemir Source: Global Health Solutions, with adjunctive opioid analgesics; and the
[rDNA origin] injection). A patient may November 28, 2016 reduction of fever.
use the application via a Web portal, on Source: Mallinckrodt, November 8,
a smartphone, or on a tablet. The device XEN Glaucoma 2016
will be available in the rst half of 2017. Treatment System
The Insulia device provides patients The FDA has cleared the XEN glau- Propeller Platform
with insulin dose recommendations coma treatment system (Allergan), For Ellipta Inhaler
and educational coaching messages in consisting of the XEN45 gel stent and The FDA has cleared the Propeller
response to blood glucose values and the XEN injector, for use in the United platform (Propeller Health) for use
other diabetes-related data. The device States. The system reduces intraocular with the Ellipta inhaler (GlaxoSmith-
also supports a variety of treatment plans pressure (IOP) and is indicated for the Kline). The digitally guided platform
and evidence-based insulin adjustment management of refractory glaucoma for is designed to help patients and their
rules used in routine clinical practice. which previous surgical treatment has physicians better understand asthma
Source: Voluntis, December 6, 2016 failed or in patients with primary open- and chronic obstructive pulmonary
angle glaucoma, and pseudoexfoliative or disease and to help improve the symp-
Xonrid Gel for Dermatitis pigmentary glaucoma with open angles toms and outcomes of these chronic
Induced by Radiotherapy that are unresponsive to maximum toler- respiratory diseases. With proprietary
Xonrid gel (Helsinn Integrative Care), ated medical therapy. XEN is implanted sensor technology, software, and ser-
a topical gel for radiotherapy-induced through an ab-interno approach and vices, the platform integrates informa-
dermatitisclassied as a medical device reduces IOP by creating a new drainage tion from multiple sources, including
in the European Unionhas received channel with a permanent implant that connected medications, and then uses
510(k) FDA clearance. This allows the becomes exible. machine intelligence to help individuals
product to be marketed in the U.S. for Source: Allergan, November 22, 2016 manage their condition.
the management of the burning and Source: Propeller Health, November
itching associated with radiation 7, 2016 Q
dermatitis.

Pharmaceutical Approval Update
Mary Choy, PharmD, BCGP, FASHP
Olaratumab (Lartruvo) In patients who experience grade 1 or 2 IRRs, interrupt the

Manufacturer: Eli Lilly and Company, Indianapolis, Indiana olaratumuab infusion. After resolution, resume the infusion
Date of Approval: October 19, 2016 at 50% of the initial rate. In patients with neutropenic fever/
Indication: Olaratumab, a platelet-derived growth factor infection or grade 4 neutropenia lasting longer than one week,
receptor-alpha (PDGFR-)-blocking antibody, is indicated in discontinue administration of olaratumab until the absolute
combination with doxorubicin for the treatment neutrophil count recovers to 1,000/mcL or greater
of adult patients with soft tissue sarcoma (STS) and then permanently reduce the dose to 12 mg/kg.
that is not amenable to curative treatment with Commentary: The FDA approval of olaratumab
radiotherapy or surgery and that has a histologi- is based on the results of a phase 2 study that
cal subtype for which an anthracycline-containing showed a signicant improvement in patient survival
regimen is appropriate. with a combination of doxorubicin plus olaratumab
Drug Class: PDGFR- antagonist compared with doxorubicin alone (a median gain of
Uniqueness of Drug: Olaratumab was approved 11.8 months). The most common adverse reactions
by the Food and Drug Administration (FDA) under of olaratumab plus doxorubicin in 20% or more of
its accelerated program in combination with doxo- patients are nausea, fatigue, musculoskeletal pain,
Mary Choy, PharmD,
rubicin as a rst-line therapy for patients with STS. BCGP, FASHP mucositis, alopecia, vomiting, diarrhea, decreased
Continued approval for this indication will be con- appetite, abdominal pain, neuropathy, and head-
tingent upon verication and description of clinical benet in ache. The most common laboratory abnormalities occurring
the conrmatory phase 3 study, ANNOUNCE. in 20% or more of patients were lymphopenia, neutropenia,
Warnings and Precautions: thrombocytopenia, hyperglycemia, elevated activated partial
Infusion-related reactions. Infusion-related reactions thromboplastin time, hypokalemia, and hypophosphatemia.
(IRRs) occurred in 70 of 485 patients (14%) who received at Sources: Eli Lilly and Company, Lartruvo prescribing
least one dose of olaratumab across clinical trials. For 68 of information
those 70 patients (97%), the rst occurrence of an IRR was in
the rst or second cycle. Grade 3 or higher IRRs occurred in Bezlotoxumab (Zinplava)
11 of 485 patients (2.3%), with one fatality (0.2%). Manufacturer: Merck and Co., Inc., Whitehouse Station,
IRRs caused permanent discontinuation of olaratumab in New Jersey
2.3% of patients, and interruption of infusion occurred in 10% of Date of Approval: October 18, 2016
patients. All 59 patients with grade 1 or 2 IRRs resumed olara- Indication: Bezlotoxumab, a human monoclonal antibody
tumab; 12 of these patients (20%) had a grade 1 or 2 IRR with that binds to Clostridium difcile toxin B, is indicated to reduce
rechallenge. The incidence of IRRs in the overall safety database recurrence of C. difcile infection (CDI) in patients 18 years
(N = 485) was similar (18% versus 12%) between those who of age or older who are receiving antibacterial drug treatment
did (56%) and those who did not (44%) receive premedication. for CDI and are at a high risk for CDI recurrence. It is not
The symptoms of IRR included ushing, shortness of breath, indicated for the treatment of CDI and should only be used in
bronchospasm, or fever/chills. In severe IRR cases, symptoms conjunction with antibacterial drug treatment of CDI.
manifested as hypotension, anaphylactic shock, or cardiac arrest. Drug Class: Monoclonal antibody
Monitor patients during and following the infusion for signs Uniqueness of Drug: The Centers for Disease Control
and symptoms of IRRs in a setting with available resuscitation and Prevention estimated that CDI caused almost 500,000
equipment. Discontinue olaratumab for grade 3 or 4 IRRs. illnesses and 29,000 deaths within one month of initial diagnosis
Embryo-fetal toxicity. Based on animal data and its mecha- in 2011. CDI recurs in roughly 20% of people who have had the
nism of action, olaratumab can cause fetal harm when adminis- infection. Bezlotoxumab is specically indicated for adults who
tered to a pregnant woman. Advise women of the potential risk are taking an antibiotic for CDI and are at risk of becoming
to the fetus and to use effective contraception during treatment infected again. Not an antibiotic itself, bezlotoxumab binds
with olaratumab and for three months after the last dose. to and neutralizes toxin B, one of several toxins produced by
Dosage and Administration: The recommended dose of C. difcile and the one considered central to the life-threatening
olaratumab is 15 mg/kg administered as an intravenous (IV) virulence of the bacteria.
infusion over 60 minutes on days 1 and 8 of each 21-day cycle Warnings and Precautions:
until disease progression or unacceptable toxicity. Premedicate Heart failure. Heart failure was reported more commonly
with diphenhydramine (2550 mg IV) and dexamethasone in the two phase 3 clinical trials in bezlotoxumab-treated
(1020 mg IV) prior to olaratumab on day 1 of cycle 1. For the patients compared with placebo-treated patients. These adverse
rst eight cycles, olaratumab is administered with doxorubicin. reactions occurred primarily in patients with underlying con-
gestive heart failure (CHF). In patients with a history of CHF,
Dr. Choy is an Associate Professor at Touro College of Pharmacy 15 of 118 bezlotoxumab-treated patients (12.7%) and ve of
and a Clinical Pharmacist at Metropolitan Hospital in New York, 104 placebo-treated patients (4.8%) had the serious adverse reac-
New York. tion of heart failure during the 12-week study period. In addi-

17
Pharmaceutical Approval Update
tion, there were more deaths in bezlotoxumab-treated patients Concomitant medical conditions. This medication has
(23 of 118; 19.5%) than in placebo-treated patients (13 of 104; anticholinergic properties and therefore should be used with
12.5%) during the 12-week study period. The causes of death caution in women with asthma, increased intraocular pressure,
varied and included cardiac failure, infections, and respiratory narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal
failure. In patients with a history of CHF, bezlotoxumab should obstruction, or urinary bladder-neck obstruction.
be reserved for use when the benet outweighs the risk. Dosage and Administration: The initial recommended
Dosage and Administration: Administer bezlotoxumab dose is one extended-release tablet orally at bedtime (day 1).
during antibacterial drug treatment for CDI. A single dose If this dose adequately controls symptoms, the patient should
of 10 mg/kg administered as an intravenous infusion over continue taking one tablet daily at bedtime on the next day.
60 minutes is recommended. Bezlotoxumab must be diluted However, if symptoms persist on day 2, the daily dose may
prior to infusion. be increased to one tablet in the morning and one tablet at
Commentary: The Food and Drug Administration approval bedtime. The maximum recommended dose is two tablets per
of bezlotoxumab was based on two phase 3 trials, MODIFY I day, one in the morning and one at bedtime. The medication
and II. MODIFY I enrolled 1,452 patients (median age, should be taken on an empty stomach with a glass of water,
65 years) in 19 countries, and the MODIFY II study enrolled and should be swallowed whole. The tablets should not be
1,203 patients (median age, 67 years) in 17 countries. The crushed, chewed, or split.
studies were conducted in both hospital and outpatient settings, Commentary: There have been no efcacy and safety
and the primary outcome measure in each trial was the number trials conducted with Bonjesta. A double-blind, randomized,
of participants who had CDI recurrence in the 12 weeks follow- multicenter, placebo-controlled study was conducted to support
ing bezlotoxumab administration. CDI recurrence was dened the safety and efcacy of 10-mg doxylamine succinate and
as the development of a new episode of diarrhea (three or more 10-mg pyridoxine hydrochloride tablets (a different formulation
loose stools in 24 or fewer hours) and a positive lab stool test and dosage strength) in the treatment of nausea and vomit-
for toxigenic C. difcile after clinical cure of the initial episode. ing during pregnancy. Women 18 years of age or older at
Nausea, fatigue, fever, and headache were among the most seven to 14 weeks gestation (median, nine weeks) with nausea
common adverse events experienced on the day of infusion and vomiting were randomized to 14 days of 10-mg doxyl-
or within four weeks of infusion. Heart failure emerged as a amine succinate and 10-mg pyridoxine hydrochloride tablets
serious adverse reaction 12 weeks after therapy. or placebo. The primary efcacy endpoint was the change from
Sources: Merck and Co., Inc., Zinplava prescribing baseline at day 15 in the Pregnancy Unique-Quantication
information of Emesis (PUQE) score. The PUQE score incorporates the
number of daily vomiting episodes, number of daily heaves, and
Doxylamine Succinate/Pyridoxine Hydrochloride length of daily nausea in hours for an overall score of symptoms
(Bonjesta) rated from 3 (no symptoms) to 15 (most severe). At base-
Manufacturer: Duchesnay USA, Inc., Bryn Mawr, line, the mean PUQE score was 9.0 in the 10-mg doxylamine
Pennsylvania succinate and 10-mg pyridoxine hydrochloride tablets arm and
Date of Approval: November 14, 2016 8.8 in the placebo arm. There was a 0.7-point mean decrease in
Indication: Bonjesta is a xed-dose combination of nausea and vomiting symptoms from baseline in PUQE score
doxylamine succinate and pyridoxine hydrochloride indicated at day 15 with 10-mg doxylamine succinate and 10-mg pyridox-
for the treatment of nausea and vomiting during pregnancy ine hydrochloride tablets (95% condence interval, 0.21.2;
in women who do not respond to conservative management. P = 0.006) compared with placebo.
Each extended-release tablet contains 20 mg of doxyl- Sources: Duchesnay USA, Inc., Bonjesta prescribing
amine succinate, an antihistamine, and 20 mg of pyridoxine information Q
hydrochloride, a vitamin B6 analogue.
Drug Class: Antiemetic agent
Uniqueness of Drug: The combination of doxylamine
succinate and pyridoxine hydrochloride has been the subject Reprints Available
of many epidemiologic studies designed to detect possible
teratogenicity. No increased risk for congenital malformations Major articles are reviewed by appropriate members
has been reported based on these studies. of P&Ts editorial advisory board and/or other qualied
Warnings and Precautions: experts. Reprints of these articles may be a useful tool
Somnolence. This medication may cause somnolence due for your company.
to the anticholinergic properties of doxylamine succinate, an To obtain information concerning the purchase of
antihistamine. Women should avoid engaging in activities professionally printed reprints, please contact:
requiring complete mental alertness, such as driving or operat-
ing heavy machinery, while using this medication until cleared
Dawn Flook
to do so by their health care provider. Doxylamine succinate
and pyridoxine hydrochloride use is not recommended if a Phone: 267-685-3422
woman is concurrently using central nervous system depres- Email: dook@medimedia.com
sants, including alcohol. The combination may result in severe
drowsiness leading to falls or accidents.

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 EVOLUTION OF G-CSF endothelial cells. It regulates the pro-

Leukocytes are the bodys main defense Myeloid growth factor therapy has duction of neutrophils within the bone
against infection. The most abundant now become the standard of care in the marrow and affects neutrophil progenitor
leukocytes are neutrophils, also called treatment of severe chronic neutropenia proliferation differentiation, and selected
granulocytes, which are important in (SCN).2,4 The myeloid-specic cytokine end-cell functions (including enhanced
ghting various microorganisms. There- granulocyte-colony simulating factor phagocytic ability priming of the cellular
fore, a decline in neutrophilsa condition (G-CSF) is the primary growth factor metabolism associated with respiratory
called neutropeniamay predispose an used to increase neutrophil produc- burst antibody-dependent killing, and the
individual to a host of illnesses.1 tion. The gene for human G-CSF was increased expression of some cell surface
Absolute neutrophil count (ANC) is transduced and incorporated through antigens). G-CSF is not species-specic
generally used to grade the severity recombinant DNA technology into and has been shown to have minimal
of neutropenia, although there is no Escherichia coli and developed into the direct in vivo or in vitro effects on the pro-
standard classication system.2 Neutro- drug filgrastim (Neupogen, Amgen, duction or activity of hematopoietic cell
penia is dened as an ANC of less than Inc.), which was approved by the Food types other than the neutrophil lineage.10
1.5 x 109/L, and its presentation may and Drug Administration (FDA) in
be mild (11.5 x 10 9/L), moderate 1991.5 Pegylated G-CSF, developed as INDICATIONS
(0.50.99 x 109/L), or severe (less than peglgrastim (Neulasta, Amgen, Inc.), Zarxio is approved for several indica-
0.5 x 109/L).2 In addition, neutropenia is another alternative used in patients tions, the rst of which is to decrease
can be acute (occurring over hours to with SCN since its initial FDA approval the incidence of infection in patients
a few days) or chronic (lasting months in 2002.6 In 2012, the FDA approved with nonmyeloid malignancies receiv-
to years).1 another G-CSF, tbo-lgrastim (Granix, ing myelosuppressive chemotherapy
The most common causes of neutro- Teva, Inc.).7 associated with a signicant incidence
penia in adults are infections, followed The Patient Protection and Affordable of febrile neutropenia. It is approved
by drug-induced neutropenia.2 Acquired Care Act (PPACA), signed into law by to reduce the time to neutrophil recov-
bone marrow diseases (e.g., leukemia, President Obama in 2010, paved the way ery and the duration of fever following
lymphoma, aplastic anemia) are relatively for the expedited development of less induction or consolidation chemotherapy
common causes of neutropenia in adults, costly alternatives to FDA-approved bio- treatment of patients with acute myeloid
as are certain nutritional deciencies.2 logics. The biosimilars provision in the leukemia (AML); and to reduce the
Approximately half of cancer patients PPACA creates an abbreviated licensure duration of neutropenia and neutropenia-
receiving chemotherapy experience some pathway for biologics that are demon- related clinical sequelae (e.g. febrile
type of neutropenia and are at increased strated to be biosimilar to or inter- neutropenia) in patients with nonmyeloid
risk for infection.3 Other risk factors changeable with an already-approved malignancies undergoing myeloablative
for neutropenia include bone marrow biologic in terms of efcacy, safety, purity, chemotherapy followed by BMT. In
transplantation (BMT) and autologous and potency. (Minor differences in clini- addition, Zarxio is indicated to mobilize
peripheral blood progenitor cell (PBPC) cally inactive components are permitted.) autologous hematopoietic progenitor
collection and therapy. The latter is usu- The biosimilar is bound to the same regu- cells into the peripheral blood for collec-
ally performed in patients undergoing lations as the reference entity and must tion by leukapheresis; and for chronic
chemotherapy.3 also adhere to FDA standards.8 administration to reduce the incidence
The FDA approved lgrastim-sndz and duration of sequelae of neutropenia
(Zarxio, Sandoz, Inc.), the rst biosimilar (e.g. fever infections oropharyngeal
Mina Awad and Pavit Singh are PharmD product available in the United States, in ulcers) in symptomatic patients with
Candidates (2017) at St. Johns University in March 2015. Zarxio has the same mecha- congenital cyclic or idiopathic
Queens, New York. Dr. Hilas is an Associate nism of action, route of administration, neutropenia.10
Professor at St. Johns University. Drug strength, and dosage form as Amgens
Forecast is a regular column coordinated by Neupogen.9 DOSAGE AND ADMINISTRATION
Alan Caspi, PhD, PharmD, MBA, President of Zarxio may be administered as a sub-
Caspi and Associates in New York, New York. MECHANISM OF ACTION cutaneous injection, a short intravenous
Endogenous G-CSF is a lineage- (IV) infusion over 1530 minutes, or a
Disclosure: The authors report no nancial or specic colony-stimulating factor pro- continuous IV infusion, dependent on the
commercial relationships in regard to this article. duced by monocytes broblasts, and indication.10

19
DRUG FORECAST
For patients with cancer receiving recommended starting dosage in patients number of consecutive days with grade 4
myelosuppressive chemotherapy and/or with idiopathic or cyclic neutropenia is neutropenia (ANC less than 0.5 x 109/L).
consolidation chemotherapy for AML, 5 mcg/kg as a single daily subcutaneous Secondary efcacy endpoints included
the recommended dose is 5 mcg/kg per injection.10 incidence of febrile neutropenia by cycle
day by any of the three approved routes and across all cycles; the number of days
of administration. A complete blood PIVOTAL PHASE 3 STUDY of fever for each cycle; depth of ANC
count (CBC) and platelet count should A rigorous program of clinical trials nadir; time to ANC recovery; frequency of
be performed before the patient begins that demonstrates no clinically meaning- infections by cycle and across all cycles;
treatment. During treatment, monitor the ful differences between the biosimilar and incidence and duration of hospital-
patient twice weekly for changes in ANC product and the reference product must ization due to febrile neutropenia. Safety
and platelet count. Zarxio is not recom- be completed for a biosimilar to receive endpoints included incidence, occur-
mended in patients with an ANC greater FDA approval.8 The totality of evidence rence, and severity of serious adverse
than 10,000/mm3.10 presented to the FDA for Zarxio com- events, local tolerability at the injection
Zarxio should not be administered pared with Neupogen showed no clinically site, and systemic tolerability.12
within the 24-hour period before chemo- meaningful differences between them.11 The mean duration of grade 4 neutro-
therapy and should be administered at The phase 3 PIONEER trial, a ran- penia in cycle 1 was approximately
least 24 hours after cytotoxic chemo- domized, double-blind, parallel-group, 1.2 days (range, zero to four days) in both
therapy. ANC levels will increase tran- multicenter study, was conducted to groups. The mean difference in duration
siently one to two days after the rst treat- demonstrate the noninferiority of Zarxio of neutropenia was 0.04 days. The inci-
ment. To ensure a sustained response, to Neupogen in the prevention of neutro- dence of febrile neutropenia was low in
administer Zarxio daily for up to penic complications in 218 breast cancer both groups, with no clinically relevant
two weeks or until the ANC has reached patients treated with myelosuppressive differences for cycle 1. The mean time to
10000/mm3 following the expected chemotherapy.12 The study also pro- ANC recovery in cycle 1 was also similar
chemotherapy-induced neutrophil nadir.10 vided safety and efcacy outcomes for for Zarxio compared with Neupogen. In
For patients with cancer who have Zarxio compared with Neupogen. Key all, there were no substantial differences
undergone BMT, the recommended dos- inclusion criteria encompassed patients between the treatment arms.12
age is 10 mcg/kg daily, which should with histologically proven breast cancer The data assessed from cycle 2, which
be administered as an IV infusion for no approved for neoadjuvant or adjuvant represented switching the therapies about
longer than 24 hours. Administer the rst chemotherapy; women 18 years of age halfway through the trial, also showed
dose of Zarxio at least 24 hours after cyto- and older; estimated life expectancy of similar results for all treatment arms. The
toxic chemotherapy and at least 24 hours more than six months; an Eastern Coop- incidence of febrile neutropenia in the
after bone marrow infusion.10 erative Oncology Group performance group that received the same treatment
For patients with cancer undergoing score of 2 or less; adequate bone marrow throughout the study was 2.3%, while
autologous PBPC collection and therapy, function prior to chemotherapy admin- the incidence in the group that switched
the recommended dosage is 10 mcg/kg istration; and an ANC of 1.5 x 109/L or therapies was 6.7%, which did not exceed
per day given by subcutaneous injection. greater, a platelet count of 100 x 109/L the noninferiority margin of 15%.12
Administer Zarxio for at least four days or greater, and a hemoglobin level of The safety analysis included a total
before the rst leukapheresis procedure 10 g/dL or greater.12 of 214 patients, approximately 96.3% of
and continue until the last leukapher- Patients were initially randomized to whom experienced one adverse event.
esis procedure. Although the optimal either Zarxio or Neupogen. Half of the Most adverse events were related to
duration of Zarxio administration and patients remained on the therapy started chemotherapy, and the safety proles
leukapheresis schedule have not been in the rst treatment cycle for the dura- of Zarxio and Neupogen were similar.
established administration of lgrastim tion of the trial, while the other half of the No statistically signicant difference in
for six to seven days with leukapheresis patients received alternating treatment safety was reported.12
on days 5 6 and 7 was found to be safe with either Zarxio or Neupogen starting The most frequent treatment-emergent
and effective.10 with the second cycle of chemotherapy. adverse events for the two therapies were
For patients with suspected SCN, con- This design was used to assess whether alopecia, nausea, asthenia, fatigue, and
rm the diagnosis by evaluating serial switching the therapies during the treat- bone pain. The most notable adverse drug
CBCs with differential and platelet counts, ment period had any impact on safety, reactions were bone pain (Zarxio, 23%, ver-
and by evaluating bone marrow morphol- efcacy, and immunogenicity.12 sus Neupogen, 33%) and musculoskeletal
ogy and karyotype. If Zarxio is used before Patients in the study received pain (Zarxio, 7%, versus Neupogen, 2%).12
conrming the correct diagnosis, diagnos- 5 mcg/kg of Zarxio or Neupogen daily
tic efforts may be impaired, thus impairing starting on day 2 of each chemotherapy ADVERSE DRUG REACTIONS
or delaying the evaluation and treatment cycle and continued until ANC levels Adverse drug reactions vary according
of an underlying condition (other than recovered to 10 x 109/L or for a maxi- to the indication for which Zarxio is used.
SCN) causing the neutropenia.10 mum of 14 days of treatment, whichever The most common adverse reactions in
The starting dose for patients with occurred rst. The primary endpoint was patients with nonmyeloid malignancies
congenital neutropenia is 6 mcg/kg as a duration of chemotherapy-induced severe receiving myelosuppressive anticancer
twice-daily subcutaneous injection. The neutropenia, which was dened as the drugs are pyrexia, pain, rash, cough, and

DRUG FORECAST
dyspnea (5% or greater difference in inci- CONTRAINDICATIONS treatment. The relationship of these events
dence compared to placebo). In patients Zarxio is contraindicated in patients to lgrastim administration is unknown.10
with AML, adverse reactions include pain, with a history of serious allergic reactions
epistaxis, and rash (2% or greater differ- to human G-CSF, such as lgrastim or Geriatric Use
ence in incidence compared to placebo). peglgrastim.10 In three randomized, placebo-
Patients with nonmyeloid malignancies controlled trials of a total of 855 lgrastim-
undergoing myeloablative chemotherapy SPECIAL POPULATIONS treated patients receiving myelo-
followed by BMT most often experience Pregnancy and Lactation suppressive chemotherapy, 232 patients
rash (5% or greater difference in inci- There are no adequate and well- were age 65 years or older and 22 were
dence compared to placebo). In patients controlled studies of lgrastim products age 75 years or older. No overall differ-
undergoing PBPC mobilization and col- in pregnant women; studies in rats and ences in safety or effectiveness were
lection, the most common adverse effects rabbits revealed no fetal malformations, observed between these patients and
are bone pain, pyrexia, and headache although rabbits administered two to the younger population. Clinical studies
(5% or greater difference in incidence 10 times the human dose experienced of lgrastim in other approved indica-
compared to placebo). Pain, anemia, maternal toxicity, reduced embryo- tions (i.e., BMT recipients, PBPC mobi-
epistaxis, diarrhea, hypoesthesia, and fetal survival, and increased abortions. lization, and SCN) did not include suf-
alopecia may occur (5% or greater differ- Because the risk to humans is unknown, cient numbers of patients 65 years of age
ence in incidence compared to placebo) lgrastim products should be used during and older to determine whether elderly
in patients with SCN.10 pregnancy only if the potential benet people respond differently than those
justies the potential risk to the fetus.10 who are younger.10
WARNINGS AND PRECAUTIONS It is unknown if lgrastim products
Splenic ruptures and sickle cell are excreted in human milk; therefore, COST
crises, including fatal cases, have caution should be exercised if they Zarxio is provided in prelled syringes
been reported after treatment with are administered to women who are in dosage strengths of 300 mcg/0.5 mL
lgrastim products. In addition, treat- breastfeeding.10 and 480 mcg/0.8 mL. The average
ment may cause acute respiratory wholesale prices (AWPs) of Zarxio are
distress syndrome; serious allergic Pediatric Use $331 and $527 for 300 mcg/0.5 mL and
reactions, including anaphylaxis; glo- Because the Zarxio prelled syringe 480 mcg/0.8 mL, respectively.13 In
merulonephritis; alveolar hemorrhage may not accurately measure volumes less contrast, the AWPs of Neupogen in
and hemoptysis; thrombocytopenia; than 0.3 mL, the direct administration of the same dosages, also provided in
leukocytosis; and cutaneous vasculi- a volume less than 0.3 mL is not recom- prelled syringes, are $389 and $620,
tis. Symptomatic patients should be mended due to the potential for dosing respectively.13
monitored for capillary leak syndrome.10 errors.10
Cytogenetic abnormalities and trans- Several studies have established the P&T COMMITTEE
formation to myelodysplastic syndromes pharmacokinetics, safety, and effective- CONSIDERATIONS
(MDS) and AML have been reported in ness of lgrastim in pediatric patients. A biosimilar product is identical in
patients with SCN treated with lgrastim Additional information is available from a function to its reference biologic drug,
products.10 post-marketing surveillance study, which but offers a lower-cost alternative. Zarxio,
Because the G-CSF receptor through includes long-term follow-up of patients in the rst biosimilar approved by the FDA,
which Zarxio acts has also been found the clinical studies and information from offers lower costs, potentially greater
on tumor cell lines, the possibility that additional patients who entered directly accessibility to treatment, and increased
the treatment acts as a growth factor for into the post-marketing study. Of the exibility in prescribing, which makes it
any tumor type cannot not be excluded.10 731 patients in the surveillance study, a landmark agent for future biosimilars.
Simultaneous use of Zarxio with chemo- 429 were pediatric patients less than P&T committees can consider adding
therapy or radiation therapy has not been 18 years of age (range, 0.917 years). Long- Zarxio to their formularies alongside or
evaluated and is not recommended.10 term follow-up data suggest that height in place of Neupogen to treat neutropenia.
Growth factor therapy has been and weight are not adversely affected in
associated with transient positive bone- patients who received up to ve years of CONCLUSION
imaging changes, which should be taken lgrastim treatment. Limited data from Neutropenia is a condition that, if left
into account when interpreting nuclear patients who were followed for 1.5 years untreated, can result in signicant health
imaging results.10 did not suggest alterations in sexual matu- consequences. With its FDA approval,
ration or endocrine function.10 Zarxio is the rst biosimilar to provide an
DRUG INTERACTIONS Pediatric patients with congenital types alternative to Neupogen that is similar in
Zarxio administration is not recom- of neutropenia (Kostmanns syndrome, safety and efcacy. This allows providers
mended within 24 hours of cytotoxic congenital agranulocytosis, or Schwach- and the market more than one option in
chemotherapy because of the increased manDiamond syndrome) have devel- treating the various forms of neutropenia
risk of sensitivity of rapidly dividing oped cytogenetic abnormalities and have at a lower cost.
myeloid progenitor cells in response to undergone transformation to MDS and continued on page 23
chemotherapy.10 AML while receiving chronic lgrastim

21
LETTERS TO THE EDITOR
Transition From Paper to Computerized The RxCDS is a productivity tool. Pharmacists spend no
time typing existing data into the RxCDS, so there are no data-
Pharmacist Clinical Decision Support entry errors. Vancomycin/aminoglycoside and heparin dosing
To the Editor: are both faster and accurately reect clinical protocols. TPN
The progress of electronic pharmacy clinical decision patients are found quickly, nutritional metrics calculated, and
support has been limited because of problems of interoperability current labs displayed. Our data is ltered to discover duplicate
between and within electronic medical records (EMRs). EMRs prescriptions or overlapping as-needed indications so that
in use in hospitals are predominantly rst-generation EMRs the pharmacist can correct those orders and avoid potential
with 1970-style hierarchical databases that predate the advent medication administration errors as well as avoid government
of relational database systems (RDBSs). These non-RDBSs regulatory nes. Patients on recalled or unavailable drugs
require the creation of computer applications, application can be found quickly. Screening to nd patients who might
program interfaces, for an external application to access the require a pharmacists intervention can be done quickly; the
data stored in these non-RDBSs. relevant clinical pharmacy protocol is displayed with a sug-
This is the root cause of the data silos and data islands gested course of action. Any actual intervention made by the
problem, where data are isolated to a single organization or pharmacist can either be recorded into the RxCDS or copied
abandoned to a single unit within an organization. Hospital and pasted into the EMR.
pharmacy faces this issue as data are trapped in the EMR. Ad hoc observational studies can be created to investigate
First-generation EMR providers adopted the enterprise busi- medication issues. As an advantage to lowering bias in stud-
ness model, where the customer relies on that single EMR for ies, the application decides, based on our inclusion criteria, if
all its information. Thus the very design of the rst-generation a patient is included or excluded: There is no cherry-picking
EMRs supports the lack of interoperability; there was never of data.
any intention to share the data with any outside entity. This Our argatroban dosing protocol required a dose reduc-
is a shrewd business model to maintain a local monopoly on tion for patients on continuous renal replacement therapy
the data. (CRRT); even though the drug is not renally cleared, CRRT
Most computer applications providing pharmacist clinical was suggested as a predictor of hepatic failure. We created a
decision support (RxCDS) require the user to type in the data small application to search our data and collected 30 relevant
because the EMR will not share them. Fortunately, EMRs are patients. In about three-quarters, the results of liver-function
good at generating printed reports. Where there are printed tests (LFTs) were elevated, but not in the other one-quarter,
paper reports, there was once a text le, e.g., MyReport.txt. who we may have been underdosing. A good suggestion was
Most hospital pharmacies periodically have a pharmacist to order LFTs to monitor for possible dose adjustments. As a
patient prole report generated to be used in the event of EMR byproduct, we were surprised to discover that CRRT patients
downtime. Likewise, most hospital nursing departments have had a mortality rate of 70%.
something to use for patient data as a backup to EMR failure. Some of our pharmacists use another PK dosing model
We electronically mined EMR pharmacy downtime reports instead of our RxCDS PK function. It was recently noted
intended as printed paper reports to collect patient-specic in morbidly obese patients that vancomycin regimens were
data for use in an RxCDS application. The data automatically signicantly different between the two models. We created a
populate into the RxCDS. small application to search our data and collected 10 relevant
First, we found a pharmacist patient prole le and a prior patients. We determined that using an adjusted weight for
12-hour patient lab le on our local area network. Next, we patients whose actual weight was more than 1.5 times their
had our Information Technology Department increase the ideal body weight was best for our RxCDS vancomycin PK
frequency of the reports to generate them every two hours, model; otherwise it uses actual patient weight. This change
so we are never more than two hours behind in the data. has been completed in the RxCDS. The other model (which
This eliminates the largest obstacle to the progress of an we cannot change) seems to underdose by estimating a longer
RxCDS application: A data source is now available. Why half-life in obesity.
create an RxCDS application to discover the 30 patients in The health care work environment in general is high touch
your hospital who require renal dosing if you have to type in and low tech; hospital pharmacy is no different. We love our
all the information for 300 patients! Application developers or paper and have suffered with the introduction of new technol-
programmers, either external or internal to the hospital, can ogy. We have endured the challenges of rst-generation EMR
map the data to an existing RxCDS or create a new RxCDS. implementations. We prefer to stay with our current EMR to
Ideally a pharmacist who is also an application developer or avoid going through the pain of a conversion. The centralized
programmer can be found. enterprise business model is very seductive.
Our RxCDS is used for pharmacokinetic (PK) dosing of There is another, perhaps better modelthe federated
aminoglycosdies and vancomycin; automating clinical pharmacy model, a decentralized collaboration of processes. The idea
protocols for renal dosing, anticoagulation, and total parenteral is to use best of breed processes in a modular structure.
nutrition (TPN); government regulatory compliance; ad hoc You own the model; the model does not own you. There is no
searches for patients on specic drugs or with recent specic monopoly. If one of the subprocesses fails, you replace it with
laboratory tests; and providing patient pharmacy proles, labs, another. The entire business is not brought down; there is no
and prescription label printing during planned or unplanned downtime. This allows competitive free enterprise to create a
EMR downtime. new product or service.

LETTERS TO THE EDITOR MEDICATION ERRORS
We need to add modular computer subprocesses to hospital continued from page 5
pharmacy, such as RxCDS. Any vendor providing a module for engage in disrespectful behaviors may be powerful in the orga-
functionality not in the EMR needs to have an interface (e.g., nization, which may discourage reporting of the behavior due
HL7) to the data held captive in the EMR. Our RxCDS simply to fear of retaliation and a general reluctance to confront the
uses data from text les. Microsoft has marketed Amalga individual. Organizations may also be wary of offending high-
to hospitals as a solution to move data from the EMR into revenue producers and therefore fail to take action. But the deep
Microsoft SQL, an RDBS. Any modern computer application, sense of frustration threaded through many of the comments
like our RxCDS, can access data from an RDBS. In time, it is from survey respondents suggests that now is the time for action.
hoped that second-generation EMRs with RDBSs will be the In next months column, Part 2 of our report will provide
norm in hospital pharmacy. But for now we all must nd a recommendations to help address this longstanding problem.
useable source of hidden EMR data to advance our hospital
pharmacy information systems. REFERENCE
1. ISMP. Intimidation: Practitioners speak up about this unresolved
Albert D. Stewart, PharmD, MBA problem (part I). Available at: www.ismp.org/sc?id=248. Accessed
Clinical Pharmacist November 21, 2016. Q
St. Joseph Health Systems
Irvine, California
DRUG FORECAST
continued from page 21
Extending Patents With New Indications REFERENCES
To the Editor: 1. Territo M. Neutropenia (agranulocytosis; granulocytopenia).
Merck Manual Professional Version. July 2014. Available at: www.
In your November issue, Stephen Barlas expresses his dis- merckmanuals.com/professional/hematology-and-oncology/leu-
satisfaction with a Food and Drug Administration, Congress, kopenias/neutropenia. Accessed August 26, 2016.
and court system that refused to give AstraZeneca the tools to 2. BMJ Best Practice. Assessment of neutropenia. BMJ Publishing
prevent the generic manufacturer of Crestor from selling it for Group. August 17, 2016. Available at: http://bestpractice.bmj.com/
the indication of homozygous familial hypercholesterolemia.1 best-practice/monograph/893.html. Accessed August 26, 2016.
3. American Society of Clinical Oncology Cancer.Net. Neutropenia.
However, he fails to see the overarching issue here. The drug August 2015. Available at: www.cancer.net/navigating-cancer-care/
was going off patent. The company was trying to effectively side-effects/neutropenia. Accessed June 14, 2016.
extend that patent by coming up with a new indication and 4. MedlinePlus. Low white blood cell count and cancer. May 4,
locking out the generic. In fact, the indication is just a rare 2015. Available at: https://medlineplus.gov/ency/patientinstruc-
tions/000675.htm. Accessed September 6, 2016.
form of high cholesterol, a disease that this product, the 5. Neupogen (lgrastim) prescribing information. Thousand Oaks,
generic, and all the competing drugs already treat. To effectively California: Amgen, Inc.; 2016.
prohibit the generic from being used for the same purpose as 6. Food and Drug Administration. Drugs@FDA: Neulasta (pegl-
the brand version would be a gift to the drug company, and grastim). April 28, 2016. Available at: www.accessdata.fda.gov/
probably unnecessary, since I am sure this drug was already scripts/cder/daf/index.cfm?event=BasicSearch.process. Accessed
November 14, 2016.
being tried by doctors treating someone with high cholesterol. 7. Traynor K. Pharmacy news: FDA approves Tevas tbo-lgrastim.
The law is ne as it is. We dont need to allow drug American Society of Health-System Pharmacists. October 21,
companies to shut out generics by using these sleight-of-hand 2013. Available at: www.ashp.org/menu/News/PharmacyNews/
tricks. 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-
Lorne Basskin, PharmD alProcess/HowDrugsareDevelopedandApproved/ApprovalAp-
Professor, Health Economics plications/TherapeuticBiologicApplications/Biosimilars. Accessed
Brown University School of Professional Studies February 20, 2016.
Providence, Rhode Island 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
REFERENCE February 20, 2016.
1. Barlas S. The push for additional orphan drugs. Can the FDA 10. Zarxio (lgrastim-sndz) prescribing information. Princeton, New
do more to encourage their development? P T 2016;41(11):667. 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.
Wed love to hear from you! 12. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of
EP2006, a lgrastim biosimilar, to the reference: a phase III, ran-
Send your letters to: domized, double-blind clinical study in the prevention of severe
neutropenia in patients with breast cancer receiving myelosuppres-
smciver@medimedia.com sive chemotherapy. Ann Oncol 2015;26(9):19481953.
13. Red Book Online. Ann Arbor, Michigan: Truven Health Analytics.
Accessed November 14, 2016. Q

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 bill never received a hearing in the Senate Finance Committee,
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 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)
Despite repeated statements during the campaign that he would authorizing Medicare to deal directly with drug companies on
repeal Obamacare immediately upon taking ofce, price.3 That bill also went nowhere. Neither Sanders
the president-elect said a few days after his election, nor Klobuchars press ofces responded to requests
once he had chatted with President Barack Obama, concerning the senators chances of enlisting Trumps
that he wants to keep a couple of its key reforms, support for their efforts in 2017.
such as prohibiting insurance companies from Some of Trumps promises and threats will become
discriminating based on existing illnesses. history once he occupies the White House; perhaps
Trump will have a strong ally in congressional some already have. Mary Jo Carden, Vice President
Republicans, who have a much broader, more com- of Government and Pharmacy Affairs for the Academy
plete agenda that includes important changes to of Managed Care Pharmacy (AMCP), says Trump
Medicare and Medicaid as well as a restructuring of Stephen Barlas
appeared to backtrack during the campaign on his
health insurance. Depending on the extent to which support for direct negotiation between Medicare and
those changes morph into law, the new order will likely affect drug companies, morphing from that position to one supporting
every corner of health care, from hospitals to physicians to all importation of foreign drugs. The AMCP opposes direct negotia-
sectors of the pharmaceutical industry. tion by the government. But drug prices are still an issue on
The pharmaceutical industry, theoretically, has a lot at stake, American minds, Carden states. She believes that value-based
having drawn Trumps reproach during the campaign. For purchasing of drugs is more likely to be the avenue that Congress
example, at a March GOP primary debate in Miami, Trump said, and the Trump administration take to ease the cost of specialty
They have a fantastic lobby. They take care of all of the senators, drugs to payers such as Medicare, Medicaid, and hospitals.
the congressmen. That sounded as if it were part criticism and Pharmaceutical companies generally dont have a problem
part compliment. During the campaign, he supported letting with value-based pricing, as long as it conforms to their formula.
Medicare negotiate drug prices with pharmaceutical companies, They have strongly opposed the work done by the Institute for
anathema to the industry. He also blessed importation of drugs Clinical and Economic Review (ICER), which has published a
from abroad, also condemned by the industry. series of monographs estimating what a reasonable price would
Trumps presidential campaign website appears to send be for high-prole drugs such as sofosbuvir (Sovaldi, Gilead
veiled warnings to the industry. It includes, in the same para- Sciences) and the proprotein convertase subtilisin/kexin type 9
graph, these statements: Though the pharmaceutical indus- inhibitors. The reason we oppose the ICER methodology is
try is in the private sector, drug companies provide a public because it does not give enough weight to patient experience,
service, and Congress will need the courage to step away one industry insider explains. We do believe we need as an
from the special interests and do what is right for America. 1 industry to bring greater evidence to payers to demonstrate
If Trump takes on the pharmaceutical industry, he will nd they are getting value.
willing allies among the Democrats. At a meeting with reporters With a view toward congressional legislative efforts on
on November 17, Senator Bernie Sanders (I-Vermont), who drug pricing in 2017, the drug industry is backing an ICER
caucuses with the Democrats, argued that he and Trump could rival called the Innovation and Value Initiative, which is a new
forge a common cause on drug pricing. program of Precision Health Economics, a research consulting
In September 2015, Sanders introduced legislation (S. 2023) rm to the health care industry. Its website states: Our view
called the Prescription Drug Affordability Act.2 It would make is that ICER currently emphasizes a short-term budget impact
numerous changes, such as allowing Medicare to negotiate lower approach based on concepts of affordability. Our research will
drug prices in Medicare Part D, accelerating closure of the Part D focus more on the longer term, looking at health care spending
doughnut hole, requiring drug companies to issue additional as an investment in the vitality of the system as well its cost.4
rebates under various circumstances, and more. However, that
The Future of the PPACA
Mr. Barlas is a freelance writer in Washington, D.C., who covers For Trump and congressional Republicans, the marquee
issues inside the Beltway. Send ideas for topics and your comments issue, of course, is repeal and replacement of the Patient
to sbarlas@verizon.net. 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 she states. They want affordable coverage, the control to
of small businesses not covered by employer health care have choose a plan that best ts them, high-quality care that gets
been able to obtain insurance. The majority of those individu- them well when theyre sick and keeps them well when theyre
als are in the 31 states that have expanded their Medicaid healthy, and nancial protection, peace of mind, and value that
programs. About 80% of the policies purchased by individuals insurance provides.
(outside of Medicaid) are heavily subsidized by the federal Trump and other Republicans have some of the same ideas
government. Trump and GOP allies have promised immediate for the replace part of PPACA elimination. House Speaker
repeal, though they havent laid out a replacement except to Paul Ryan (R-Wisconsin) headed an effort in 2016 to produce
endorse some general solutions such as allowing consumers a game plan called A Better Way for changes to federal
to cross state lines to buy insurance policies and greater access health plans.6 Trumps transition website echoes many of these
to health savings accounts (HSAs). GOP ideas. A bushel of the prescriptions are long-term
The blueprint for repeal of some key elements of the PPACA Republican tenets, such as expansion of HSAs tied to high-
is already in place. Last year Congress passed a budget rec- deductible health insurance plans. The Ryan blueprint argues
onciliation bill (H.R. 3762) that annulled key portions of the that the PPACA put a number of roadblocks in the way
exchanges, such as the subsidies, the requirement to buy of HSAs that should be ditched. Rather than subsidizing
insurance, and the Medicaid expansion, which is nanced individual health insurance plans, as the PPACA does, the
up to 90% until 2020 by the federal government.5 There was a GOP would provide a universal, advanceable, refundable tax
transition period of two years before the disappearance of the credit for individuals and families. The new xed credit would
PPACA marketplaces as presently constituted. That would be large enough to purchase the typical pre-PPACA health
give policy-holders and insurance companies a chance to insurance plan. The GOP Better Way also advocates allow-
adjust to the changes, which would likely cause a mass exodus ing consumers to buy insurance across states lines, a longtime
from marketplace policies both by consumers and insurance Republican concept that Democrats have shunned whenever
companies. President Obama vetoed that bill. it was broached.
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 What May Await Medicare
bills, a budget reconciliation bill needs only 50 votes to pass the Changes to Medicare and Medicaid are also in the ofng.
Senate, not 60. There will be 52 GOP members in the Senate A Better Way includes a number of prescriptions for change in
in 2017. House passage of a bill such as H.R. 3762 in 2017 is a the Medicare Part B physician care, Part C Medicare Advantage,
foregone conclusion. But a bill like H.R. 3762 cannot eliminate and Part D outpatient drug benet programs. President-elect
all aspects of the PPACA exchanges, just those dealing directly Trump said during the campaign that he didnt want to touch
with federal spending and taxes. So that legislation can eliminate Medicare. Still, no one has ever accused him of consistency,
tax penalties on those not buying policies (i.e., the individual as he has shown by pledging adherence to a couple of PPACA
mandate) and subsidies for 80% of policy-holders. precepts.
Though a successor to H.R. 3762 could pass Congress Here again, expect the GOP members of Congress to take
quickly and receive President Trumps signature, that will not the lead. A Better Way strategy would bend Medicare poli-
happen immediately. Trump has already said that President cies away from fee-for-service toward both a premium-support
Obama convinced him to keep the requirement that insurance program and Medicare Advantage, the health maintenance
companies not discriminate in terms of premiums charged to organization option that has been around since 2003. In pre-
people with pre-existing conditions. He also wants to allow mium support, a senior would get a xed amount with which
adults 26 years of age or younger to stay on their parents poli- to buy an insurance plan on the private market. Republicans
cies. The GOP will have to come up with some workarounds think Medicare Advantage has more cost savings built in
to last years bill to accommodate Trumps statements (unless than fee-for-service, and from the seniors perspective has the
he repudiates them). advantage of an annual ceiling on out-of-pocket costs, which
Negotiations between the congressional GOP and the Trump Part B plans do not have. Hardly anyone disputes that Medicare
White House should be relatively smooth given Trumps costs are unsustainable over the long term. The Congressional
appointment of Representative Tom Price, MD (R-Georgia), to Budget Ofce estimates the Part A Hospital Insurance Trust
be Secretary of the Department of Health and Human Services. Fund will be insolvent in 2026.
Dr. Price was chairman of the House Budget Committee and The Medicare Part D outpatient drug benet, established
a senior member of the Health Subcommittee in Ways and in 2003, has been something of a roaring success. But like
Means. An orthopedic surgeon, he has deep knowledge of the PPACA marketplace plans and state Medicaid plans, it
federal health programs and was a leading theoretician for has been hurt by high drug prices. Trump has advocated
the House GOP in its drive to end the PPACA and reform for direct negotiations between the Medicare program and
Medicare and Medicaid. drug companies. But when that kind of proposal has come up
Its simply too soon to respond to anything that may or may in Congress in past years, Republicans and pharmaceutical
not be proposed, says Kristine Grow, Senior Vice President companies have opposed it. The industry insider says that
for Americas Health Insurance Plans, the health insurance Part D plans negotiate rebates from drug companies on the
industrys lobbying group. But her comments indicate the order of 20% off the list price, so negotiation takes place in the
insurance industrys desire to keep all the facets of current program already. Moreover, Medicare has no desire to establish
PPACA policies. The demands of consumers havent changed, a national formulary. Is Medicare going to deny every Part D

25
plan the right to carry a specic drug on their formulary? he Possible Changes at the FDA
asks. Formulary setting is not their expertise. Drug companies argue that their prices reect research and
development costs, which are unnecessarily high because of
The Prospects for Medicaid Food and Drug Administration (FDA) approval requirements.
Republicans want to convert Medicaid into a block grant pro- The Trump campaign website seems to agree with this senti-
gram in which states would have more freedom to determine ment. It supports this step: Remove barriers to entry into free
what they cover, including which drugs they pay for.6 Trump has markets for drug providers that offer safe, reliable, and cheaper
nominated a true believer on behalf of Medicaid reform to head products. 1 That may or may not be a call to change FDA
the Centers for Medicare and Medicaid Services (CMS). Seema rules. If it is, it ts hand-in-glove with the congressional GOPs
Verma was one of the architects of Indianas Healthy Indiana A Better Way, which says: Translating research into thera-
Plan (HIP) 2.0, which opened for business in February 2015. It pies is an incredibly risky, cumbersome, and expensive process.
won a Medicaid waiver from the Obama administration, which We must improve how new treatments are developed, tested,
enabled Medicaid expansion to Indianas higher-income poor. and ultimately approved by the FDA. Our plan would stream-
Recipients are required to make monthly paymentsequal to line clinical trials and modernize data collection activities by
2% of incometo an HSA in exchange for a more expansive HIP cutting through red tape, using drug development tools like
Plus benet package. Residents with incomes under 100% of the biomarkers and patient-reported outcomes, and harnessing the
poverty line who cannot make those contributions are placed wealth of information in electronic health records and other
in a HIP Basic plan with limited benets. A study by Lewin troves of real-world data. 6
Associates based on one year of the plans operation found that There is some regulatory relief in the 21st Century Cures bill
upwards of 70% of members of HIP Plus and Basic were satised signed by President Obama in December 2016. But those mea-
with their coverage. sures were probably just a down payment on a much broader
However, Vermas work with both Kentucky and Ohio in attempt to eliminate regulatory barriers during reauthorization
2016 failed to gain a Medicaid exemption for either of those two of the Prescription Drug User Fee Act (PDUFA), which expires
states. Verma is the owner of a health care consulting company at the end of September 2017. The PDUFA sets the fees that
in Indianapolis. Her general philosophy ts in with the beliefs of drug companies pay the FDA to fund staff working on drug
Dr. Price and other Republican legislators that federal dollars can approvals. It also contains FDA commitments on the speed of
be saved by turning Medicaid into a block grant program without application review and policy changes to the approval process.
sacricing access to care, all by turning Medicaid into a managed User fees in scal year (FY) 2016 stood at $851 millionabout
care program where members have what Vice President-elect and two-thirds of the FDAs FY 2016 budget for human drugs, which
former Indiana Governor Mike Pence calls skin in the game. is $1.4 billion. The FDA has already met with interested parties
Some of the 31 state Medicaid expansions created under the to gather input on how it can improve its approval process in
PPACA may be jeopardized if federal subsidies are ended. The the context of the PDUFA reauthorization Congress is expected
100% of new enrollee costs the CMS is paying today in expan- to pass in September 2017.
sion states drops in stages to 90% by 2020. Ending those sub- In July, the FDA released its PDUFA VI Goals Letter for
sidies, which may force states to drop a large percentage of the FYs 2018 to 2022.8 It includes commitments in areas such as
12 million people added under the expansion, would denitely additional stafng and post-market surveillance, which are of
hurt hospitals. For hospitals, the majority of those 12 million prime importance to various pharmaceutical sectors. In terms
were formerly nonpaying customers. Pharmaceutical compa- of stafng, the agency has committed, for example, to estab-
nies could be hurt, too, but not all of them. The impact would lishing a dedicated unit within the Ofce of Medical Products
depend on the extent of the rebate a drug company is paying, and Tobacco charged with the continuous recruiting, stafng,
with those paying high rebates not being affected as much. and retention of scientic, technical, and professional staff for
Companies paying the highest rebates make less money than reviewing human drug applications. The agency sets specic
drug companies paying smaller rebates. Generally, older drugs numbers for professional hires in each of the ve years covered
pay higher rebates. Our new net Medicaid sales are very low, by the commitment letter.
reports one industry executive from a major manufacturer that In another area, the FDA promises to buff up its Sentinel
is among those that would not suffer, sales-wise, from the end System, which looks at adverse reactions to drugs once they
of the expansion. enter the market. Improving the Sentinel System is a top
The Medicaid rebate structure is as arcane as any policy priority of pharmacy groups. The FDA says it will use user
in Washington. It has been around for decades and is ripe for fee funds to conduct a series of activities to systematically
reform, which may be on the agenda for 2017 if the National implement and integrate Sentinel in FDA pharmacovigilance
Association of Medicaid Directors (NAMD) and others, perhaps practices. These activities will involve augmenting the quality
even the pharmaceutical industry, have their way. Last March and quantity of data available through the Sentinel System,
the NAMD sent a letter to the leaders of the Senate Finance improving methods for determining when and how that data
Committee saying: We continue to believe that the policy levers is utilized, and comprehensive training of review staff on the
available to state Medicaid programs are not designed to address use of Sentinel.
fundamental sustainability issues posed by high-cost, high-impact The Sentinel System of post-market surveillance was autho-
products. Currently, there is little insight into how pharmaceuti- rized by Congress in 2008, remained a pilot program until
cal manufacturers price new therapies entering the market and, 2014, and has only recently blossomed into a wider-ranging
more specically, the potential value for Medicaid populations. 7 drug adverse effects monitoring system. It relies on the FDAs

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.

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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 health care delivery models in 2016, holistic care places drug therapy at a
and Affordable Care Act, Medicare a short two years later. higher level of scrutiny and accountability.
Access and CHIP Reauthorization Act, Today, P&T committees routinely deal P&T committees offer a perceived sense
P&T, value-based reimbursement, with chronic drug shortages and become of comfort and independence in protecting
formularies, managed care, insurance involved in ethical discussions on medica- patients using prescribed drugs. However,
tion rationing. Still evolving, the commit- various institutional entities may be per-
How We Got Here tees role in hospitals, payer organizations, ceived as using the formulary as leverage
The Post-PPACA Marketplace and other entities has to meet the needs for economic gain. Complicit or not, health
In 2004, Balu et al. reviewed the chang- of a market that has further changed with care professionals and manufacturers can
ing role of the P&T committee from its new reimbursement pressures in both be tainted by perceptions that question the
beginnings in acute-care hospitals.1 quality and cost in care delivery accel- integrity of health care entitiesand by
Traditionally, P&T committees limited erated by the PPACA; the emergence extension their P&T committees.
the impact of their decisions to the popu- of large, robust health care systems; Decision-making across the health care
lations associated with their hospital or and the proliferation of biotechnology- spectrum is under re, and economic pres-
health plan; however, as hospitals trans- based drugs, diagnostic tests, and sures are reshaping the landscape of care
formed into larger health systems and devices. While the dening task of the delivery. Professionals in the stakeholder
even integrated payer organizations, P&T P&T committee has remained intactthe mix are closest to patients and, therefore,
committees had to begin to consider evaluation of the clinical use of medica- have the most credibility to lose during
inpatient, outpatient, and/or ambulatory tions and development of guidelines for the rapid transitions. As members of P&T
needs in multiple hospitals and ambula- managing access to them to ensure safe committees, health care professionals
tory care settings. The primary function drug use and administrationconcerns necessarily need to redouble efforts to
of the P&T committee had not necessar- around decision-making independence represent the interest of patients for safety
ily changed, but its scope expanded to are more commonly heard.3 The use of and efcacy in drug therapy.
other health care entities, such as health clinical effectiveness data that integrate
plans and pharmacy benet management overall costs and offer comparisons Focus on Cost and Quality
(PBM) rms. among therapies for the sake of public Considerations of quality, cost (reim-
After passage of the Patient Protection health remains imperative for the P&T bursement), and access (accreditation)
and Affordable Care Act (PPACA) and committee;2 however, conicts of interest affecting P&T committees over the past
the implementation of health reform, in patient care when making decisions decade will become even more important
Vogenberg and Gomes revisited the or creating guidelines from such as new drugs and biologic therapies enter
landscape of changes affecting P&T comparisons have emerged as a concern. the market and the shortage of primary
committees in 2014.2 Market and regu- Now it is more important than ever for care physicians intensies.
latory changes since then have resulted P&T committees to use these data as Therapy costs, having skyrocketed in
in more signicant modications to they make decisions for a larger volume the last few years, escalate the focus of
of patients who have been incorporated attention on cost but also on the achieve-
Dr. Vogenberg is Principal at the Insti- into larger health systems. For example, ment of good outcomes. The tension
tute for Integrated Healthcare and National not only does a health system have to among key attributes of a health care
Institute of Collaborative Healthcare in Green- consider the medications that patients systemcost, quality, and accessis
ville, South Carolina, and Adjunct Professor need while in the hospital, it must also reverberating rapidly, causing further
of Pharmacy Administration at the Univer- consider the drugs that its patients will stress that impacts the care of patients.
sity of Rhode Island, College of Pharmacy, need at home to sustain positive health Efforts to identify key drivers in quality
in Kingston, Rhode Island. Ms. Marcoux is a outcomes and avoid readmission. to empower decision-making are under
Clinical Associate Professor of Regulations way in an effort to moderate the system
and Managed Care and Director of Pharmacy Stakeholders in Care Delivery tension that has opened access without
Outreach Programs at the University of Rhode and Decision-Making consideration of cost. As seen in health
Island College of Pharmacy. Dr. Rumore is Pharmacists, physical therapists, care reform efforts in Massachusetts,
Associate Professor of Social, Behavioral, and nurses, and physicians are assuming new addressing cost rapidly emerges as a
Administrative Pharmacy at Touro College leadership responsibilities, making them priority. Pharmacotherapies today will
of Pharmacy in New York, New York; and Of partners with P&T committees in improv- continue to engage P&T committees in
Counsel at Sorell, Lenna & Schmidt, LLP, in ing clinical care and cost performance for challenging issues beyond traditional
New York, New York. health systems. The formation of formal population health.
and informal care teams tasked with

HEALTH CARE & L AW
Convergence in Care Delivery ment is being driven by the Centers These new models of care require
The nancial pressures to demonstrate for Medicare and Medicaid Services integration and collaboration among all
revenue growth and innovation in the (CMS). CMS continues its work to replace sectors of the industry. As health systems
post-PPACA era has resulted in an accel- fee-for-service with episode-of-care pay- and providers are pushed to assume risk,
erated merger and acquisitions trend ments and increase quality-based pay- pharmaceutical industry participation and
that began in 2014 and continues even ments. Hospital value-based purchasing assumption of risk for outcomes is being
now. Hospitals and providers merged to and physician-based value modier pro- discussed. Physicians will be integral to
address the threats by more efcient and grams reward providers for quality of care. reducing postacute treatment and man-
cost-effective outpatient facilities as well The Medicare Access and CHIP Reautho- aging patient behaviors to ensure posi-
as changes in reimbursement. Regional rization Act of 2015 (MACRA) provided a tive outcomes. The integration models
hospitals and health systems also afford new approach that aligns payment with must align incentives and payment while
greater negotiating power with insurance quality and value of care. MACRA sup- including patients as key stakeholders.
companies. These acquisitions or partner- ports two paths: the merit-based incentive As the burden of cost continues to shift
ships offer the integration of technology, payment system (MIPS), which adjusts to the consumer in the form of premiums,
clinical practice, and providers needed to fee-for-service payments, and advanced cost-sharing, and deductibles, consumers
address the developing models of care. alternative payment models (APMs), will demand transparency in the pricing
In 2015, the pharmaceutical and insur- which include patient-centered medical model.
ance sectors joined in the merger and homes, accountable care organizations, For integrated health care systems
acquisitions activity. The pharmaceuti- and bundled payment-of-care initiatives. with multiple service lines, managed
cal sectors acquisitions and divestitures The availability of data is imperative care negotiations can be complex. While
attempted to capitalize on revenue growth, to manage utilization and cost within payers often focus on negotiating with
specialty pipelines, and distribution these new paradigms of reimburse- the hospital, an integrated system needs
opportunities provided by the PPACA. ment. In 2018, MIPS will consolidate to think about the bigger picture, says
Some of the higher-prole deals included existing quality programs into a unied Paula Dillon, Director of Managed Care
Actavis and Mylan. Actavis purchased reimbursement that assesses quality, at Rockford Health System in Rockford,
Allergan for $70 billion and Kythera resource use, technology, and clinical Illinois. For example, increased rates in
Biopharmaceuticals for $2.1 billion practice. Payment adjustments will be certain settings can offset decreased rates
and divested its generics line to Teva.4 made based on individual composite in others. By looking at the net changes
Mylan purchased a division of Abbott, scores. The advanced APMs require across the organization, you can negoti-
then inverted to the Netherlands for tax that providers meet the criteria for tech- ate more effectively and realize a robust
benets. Pzer made a bid for Allergan, nology and quality measurement, and agreement for the entire organization.
but when the Obama administration intro- assume more than nominal nancial risk. That includes incorporating other enti-
duced rule changes in 2016, the value of Hospitals receiving bundled payments ties, such as ancillary providers and
this overseas purchase diminished. The will be required to manage inpatient and physicians in the negotiations.11
new rules limited Pzers ability to shed postacute-care costs for up to 90 days.
corporate citizenship in an effort to move Since the implementation of MACRA, Impact on P&T Committees
income and avoid taxes.5 CMS has proposed additional bundles P&T committees are currently in a state
Finally, national insurance market for episodes of care, including the com- of ux with regard to commercial plans,
activity has been delayed by the federal prehensive care for joint replacement Medicare Part D, Medicaid, the Veterans
government. In 2014, ve companies model for hip and knee replacement, the Health Administration/Department of
represented 83% of the national insur- oncology care model, and the cardiac Defense, hospitals, long-term care, and
ance market share. In 2015, Anthem bundled payment model for heart attacks various submarkets. For example, PBMs
announced plans to purchase Cigna for and bypass surgery.8 To avoid costs shift- and their P&T committees are shifting
$54 billion, while Aetna made a $37-billion ing to the private sector, private insur- toward formularies that lower costs for
offer for Humana.6 The government has ers are monitoring and implementing employers and plans while passing those
argued that this consolidation to three similar bundled payment programs and costs to employees. Over the last few
insurers would reduce competition, quality measures. Anthem Blue Cross and years, emerging P&T consequences of
especially in the Medicare segment, as Blue Shield of Ohio introduced a reward rising drug costs have dominated the
well as limit quality initiatives and the program for providers who received the health care landscape, affecting patient
control of premiums. The AnthemCigna Joint Commissions Integrated Care accessibility to medications and giving
judicial review is under way. The Aetna Certication.9 The Integrated Care Certi- rise to concerted patient advocacy, phar-
Humana merger was set for a judicial cation program focuses on the integra- macy benet discrimination cases, and
hearing in December 2016 and a decision tion of technology, sharing of information, legislative action.
is expected mid-January 2017.7 and transition of care for patients, and the The increasing costs of most generic
While entities in all health care sectors best practice standards elements require and brand-name medications have
work to report revenue growth and inno- that providers must be working toward prompted concerns about future sus-
vation to nancial markets, payers are improving outcomes through coordina- tainability for state governments and
working to redene the reimbursement tion of care, be accredited, and highlight insurers to shoulder the absolute costs
algorithms. Value-based reimburse- risk sharing.10 of medications. Emerging trends for

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ally accepted treatment standards and are

Table 1 Emerging Formulary Restriction Strategies
based exclusively on cost considerations.
Tiering Adverse tiering Increasing multiple specialty tiers The insurer claims its guidelines for
Increased tier numbers Increasing number of generic drugs coverage were developed by an indepen-
(higher prices) dent P&T committee utilizing evidence-
based medicine. However, the reversal
Utilization Increased cost-sharing Drug-specic deductibles
of claim denials by external medical
management Increasing use of closed formularies Increase in prior authorizations and reviewers during the appeal process
quantity limits has provided strong evidence that
Medication Especially where no lower-cost generic alternative cost-based rather than evidence-based
exclusions formulary decisions are being made. The
Trend to exclude rather than tier brands for therapeutic New York case is based upon consumer
equivalents that are chemically and pharmacologically different fraud, deceptive business practice, and
The lists keep getting longer (e.g., Express Scripts insurance law violations.1618 In at least
excluded 80 drugs in 2016, up from 66 in 2015) one case, the Attorney General threat-
ened to sue to a manufacturer for violating
Alignments differeach PBM is aligned with a different insulin maker
consumer protection laws if it refuses to
Specialty drugs Different approaches being taken by different PBMs lower its prices. In other cases, the health
PBM = pharmacy benet manager plan has settled by loosening formulary
restrictions.
health plan strategies for medication illegal inducements of P&T formulary In several cases involving prisoners,
formulary restrictions are detailed decisions in state hospital systems. the claims involved a denial under the
in Table 1. From 2006 to the present, states formulary for the prisoners medi-
medication cost-sharing for brand-name Cases Allege Pharmacy cation. In Whipple v Schoeld, the alle-
medications has increased. Such practices Benet Failure to gation was made that having the P&T
comport with the traditional role of P&T Provide Adequate Care committee stacked with employees from
committees, where cost is a legitimate P&T formulary decisions can create private contractors, which have a prot
factor that can be taken into consider- possible legal dilemmas. Beginning with motivation to cut costs, puts the nan-
ation but cannot be the only or overriding Wickline v State of California in 1986, cial needs of those contractors above the
factor for P&T decisions. P&T commit- courts have ruled that health plans medical needs of the prisoners.19
tees cannot make formulary decisions could be liable for improper cost-control
negligently or recklessly based upon decisions.13 Courts have granted substan- Legislative, Regulatory,
nonlegitimate criteria. Participating phy- tial awards to patients from health plans and Judicial Deterrents
sicians are often encouraged to conform that failed to treat patients fairly.14 Over the past few years, state legisla-
their prescribing practices to align with New medications for hepatitis Cwith tures introduced and passed numerous
health insurer policies, to consider the cure rates exceeding 90%, signicantly bills regarding drug formularies. The
cost of treatment to the health plans, and fewer side effects compared with older PPACA requires all qualied health plans
to prioritize patients accordingly. Should treatments, shorter lengths of treatment, (QHPs) to provide prescription drug
an unfavorable result occur as a result and increased ease of administration coverage as an essential health benet
of a medication substitution, the patient have met with health plan restrictions due (EHB) and such plans must cover at least
only has to prove negligence somewhere to the high cost of these drugs over the the greater of: 1) one drug in every United
along the chain of responsibility for those past two years. The restrictions have gen- States Pharmacopeia (USP) category and
who assemble the formulary. erated many consumer lawsuits against class, or 2) the same number of prescrip-
P&T committee collusion lawsuits have insurers in California, Washington state, tion drugs in each USP category and class
emerged as plaintiffs have increasingly and New York, as well as the Medicaid as the states EHB-benchmark plan.19 A
pressed a formulary inuence theory of program in Washington state and the QHP that fails to meet the EHB standard
liability, alleging that off-label promotion Massachusetts prison system. can be decertied if the plan employs a
or kickbacks caused states to wrongfully In New York, the Attorney General discriminatory benets design.
place drugs on formulary or give them sued a health insurer for denying cover- Formulary rankings, known as tiers,
preferred formulary status. In the high- age for hepatitis C drugs unless patients have traditionally been used by health
prole Avandia (rosiglitazone maleate, had an advanced stage of disease, such care plans. Can formularies designed by
GlaxoSmithKline) case, the plaintiffs as moderate-to-severe hepatic scarring. P&T committees be considered discrimi-
alleged the drug was included on formu- The lawsuit accuses the insurer of failing natory? Over the past few years, the cost
laries in reliance on representations made to advise beneciaries in plan documents consideration factor has transformed into
by the pharmaceutical manufacturer.12 that cost was a factor in its formulary a process of structuring formularies to
Pharmaceutical companies have been decision-making processes for medically discourage patients with certain disease
forced to pay millions to resolve kick- necessary treatment.15 The complaint states from enrolling.
back allegations related to PBM formulary states the restrictions are contrary to Adverse tieringthe placing of all
placement, inappropriate inuence, or prevailing medical guidelines and gener- medications (including generics) for

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a particular disease on a specialty or effective at all ages; requiring prior six classes of medications as protected
high-cost tierhas ourished. When an authorization for all medications in and mandates at least two medications
insurance plan charges more for common certain classes; and whether limitations in every drug category.29 CMS also has
human immunodeciency virus (HIV)/ and exclusions are based on clinical a rule for the independence of P&T com-
acquired immunodeciency syndrome guidelines and medical evidence. mittee members that requires at least
(AIDS) medications than other insur- In May 2016, CMS issued the nal two members to be independent of the
ers, the company may be trying to dis- rule implementing Section 1557, the anti- plan sponsor or manufacturer (but not
courage high-cost patients from choos- discrimination provision of the PPACA.27 the PBM). There are now two tiers for
ing its plans on the PPACA exchange The rule prohibits plan designs that place generic medications in most Medicare
marketplace. Adverse tiering is explicitly most or all drugs that treat a specic con- Part D plans. The scope of formulary med-
prohibited under the antidiscrimination dition on highest cost tiers and charge ication coverage for these plans varies
provisions of the PPACA; a plan may not more for single-tablet regimens than for widely; some plans list all drugs from the
employ marketing practices or benet treatments that require patients to take CMS drug reference le, while others list
designs that have the effect of discour- multiple tablets. Although it will take as few as 65% of these drugs. Even if on
aging the enrollment in such plan by years for the scope of Section 1557 to formulary, utilization management rules,
individuals with signicant health needs.21 be established by the courts and provi- including step therapy, prior authoriza-
The PPACA also includes annual sions for health plan benet design will tion, and quantity limits may restrict a
limits on cost-sharing, which means that not take effect until January 2017, the beneciarys access to the medication.
patients with chronic conditions should rule authorizes private right to action. On average, prior authorization applies
not pay high coinsurance once they reach Increased plan benet litigation will be on to 22% of medications.30
maximum out-of-pocket spending. While the horizon as courts are already authoriz- Perhaps the balance between savings
the PPACA rule has been the basis for ing Section 1557 lawsuits. A number of and wellness has tipped too far toward
complaints to state and federal regulators, states, such as Florida, have warned that savings. A more equitable health care
insurers have countered with the Safe plans found to be discriminatory will not system for patients with chronic disease
Harbor Provision, which protects insur- be recommended as QHPs that can be is required.
ers in underwriting risks, classifying sold in the state.
risks, or administering such risks that are Over the past two years, we have P&T: Dealing With Convergence
not inconsistent with state laws. 22 The witnessed the divergence of P&T formu- in a Transitional Marketplace
Safe Harbor provision cannot be a sub- lary trends in the new PPACA exchange While much of what has been
terfuge to circumvent antidiscrimination market, employer-sponsored plans, and discussed in this column is unlikely to
provisions inasmuch as limits must be Medicare Part D plans. One study of the change, the post-presidential election
based upon actual or reasonable predict- exchange market in eight states revealed fallout has already begun in many eco-
able risks. All that is required is the signicant drug access and cost-sharing nomic sectors, including health care.
showing of a rational nexus between differences in exchange plans versus During the campaign, the PPACA was
the higher tier and cost-sharing, including employer and Medicare Part D plans. targeted for elimination. Now that the
copayment and coinsurance for certain For example, exchange plans cover fewer campaign is over, it has become apparent
classes of medications and risks. specialty drugs and have three times the that incremental change is more likely,
A 2015 study published in the New utilization management rates. Specialty and that not much will change in 2017.
England Journal of Medicine reported coinsurance is often more than 30% That being said, commercial market
adverse tiering for HIV and AIDS drugs for single-source drugs for HIV/AIDS, impacts could be felt in 2017 and are
in 12 of 48 plans.23 Enrollees in adverse- hepatitis, cancer, and multiple sclerosis.28 much more likely to be seen along with
tiered plans had a yearly per-drug cost One of the duties of P&T committees public sector shifts for the 2018 plan year.
that was almost $4,900 versus about is to assign products to formulary tiers. This transitional marketplace makes
$1,600 for those in nonadverse-tiered Over the past few years, health care plan some P&T committee decisions more
plans. About half of the adverse-tiered formularies have gone from the typical difcult based upon the myriad of com-
plans had a deductible that was drug- three tiers (i.e., generic, preferred brand, mercial or public plans covered while
specic. CMS has issued various letters nonpreferred brand) to four-, ve-, and maintaining some simplicity for others
regarding cost-sharing and adverse even eight-tier formularies. Most plans that only deal with one type of plan, such
tiering and its intent to conduct outlier have created two tiers for generic drugs, as Medicaid or Medicare. For example,
analysis as part of QHP certication and some have tiers for generic drugs closed or preferential-based formularies
or recertication.2426 The Department used to treat certain conditions, such as may become less favored over more-open
of Health and Human Services exam- diabetes, Parkinsons disease, and epi- formularies depending on the plan type
ples of potentially discriminatory lepsy. The new tiers most often pertain and progress of legal or regulatory change
plan designs include: adverse tiering to higher-cost generics and specialty being implemented around prescription
of HIV prescription drugs; formularies medications. The trend toward more drug coverage. Other similar impacts
or services that fail to meet recognized tiers warrants close attention. may result from the pricing furor in 2016
treatment guidelines or the standard The Medicare Part D approach to leading to fewer-to-no rebates or contract
of care for a certain condition; applying medication access applies to participating incentives through managed care middle-
age limits to services found to be health care insurers. Medicare designates men. Such uncertainty around specics

31
HEALTH CARE & L AW
committees. Part 2: beyond managed 21. U.S.C. 18031 (c) (1)(a).

will continue through 2017, epitomizing
care. P T 2004;29;(12):780783. 22. 42 U.S.C. 12201 (c) (1).
the nature of transition. 4. Wieczner J. The real reasons for the 23. Jacobs DB, Sommers BD. Using drugs
With the complexity of todays health pharma merger boom. Fortune. July to discriminateadverse selection in
care organizations, how can P&T commit- 28, 2015. Available at: http://fortune. the insurance marketplace. N Engl J Med
tees most effectively deal with pharma- com/2015/07/28/why-pharma-mergers- 2015;372(5):399402.
are-booming. Accessed August 20, 2016. 24. Centers for Medicare and Medicaid
ceutical decision-making alongside care 5. Thomas K, Bray C. Pzer faces limited Services. 2015 letter to issuers in the
delivery issues over the next few years? options after its dead deal with Allergan. federally-facilitated marketplaces. March
Understanding the purpose and actions to The New York Times. April 6, 2016. Avail- 14, 2014. Available at: www.cms.gov/
be taken by a P&T committee will provide able at: www.nytimes.com/2016/04/07/ CCIIO/Resources/Regulations-and-
business/dealbook/pzer-allergan-merg- Guidance/Downloads/2015-nal-issuer-
a touchstone for examining formulary or
er.html?_r=0 Accessed August 29, 2016. letter-3-14-2014.pdf. Accessed September
policy decisions. Maintaining an aware- 6. Vaida B, Wess A. Health care consolida- 5, 2016.
ness of health policy and legal trends will tion. Alliance for Health Reform. Novem- 25. Centers for Medicare and Medicaid
be more critical for the P&T committee ber 2015. Available at: www.allhealth.org/ Services. Final 2016 letter to issuers in
and its individual members for making publications/Consolidation-Toolkit_169. the federally-facilitated marketplaces.
pdf. Accessed September 9, 2016. February 20, 2015. Available at:
decisions on drug use. Avoiding obvious 7. Teichert E. Aetna-Humana merger chal- www.cms.gov/CCIIO/Resources/Regu-
legal infringements or conicts requires lenge to be decided in January. Modern lations-and-Guidance/Downloads/2016-
effective continuing education of P&T Healthcare. August 10, 2016. Avail- Letter-to-Issuers-2-20-2015-R.pdf.
committee members and support staff. able at: www.modernhealthcare.com/ Accessed September 5, 2016.
article/20160810/NEWS/160819986. 26. Centers for Medicare and Medicaid
Given the pace of change and calls
Accessed November 28, 2016. Services. Draft 2017 letter to issuers in
for efciency, what will the future P&T 8. McClellan M, McStay F, Saunders R. The the federally-facilitated marketplaces.
landscape look like by 2020? Based on roadmap to physician payment reform: December 23, 2015. Available at:
trends to date in market stakeholder what it will take for all clinicians to succeed www.cms.gov/CCIIO/Resources/Regu-
consolidation, market-driven efciency under MACRA. Health Affairs Blog. August lations-and-Guidance/Downloads/Draft-
30, 2016. Available at: http://healthaffairs. 2017-Letter-to-Issuers-12-23-2015_508.pdf.
demands, public and commercial plans org/blog/2016/08/30/the-roadmap-to- Accessed September 5, 2016.
drive for value, consumerism, and legal physician-payment-reform-what-it-will-take- 27. HHS Office for Civil Rights. Non-
enforcement of patient rights related to for-all-clinicians-to-succeed-under-macra. discrimination in health programs and
access to appropriate drugs, P&T com- Accessed August 20, 2016. activities. Fed Regist 2016;81(96): 31376
9. Whitman E. Anthem offers incentives to 31473. Available at: www.gpo.gov/fdsys/
mittees will have their hands full balanc-
providers certied for integrated care. pkg/FR-2016-05-18/pdf/2016-11458.pdf.
ing the issues when making decisions. Modern Healthcare. August 31, 2016. Accessed September 5, 2016.
The rise in shared-risk arrangements, Available at: www.modernhealthcare.com/ 28. Benet Design Trends of Exchange Market
high-deductible insurance plans, and article/20160831/NEWS/160839973/ for Formulary Market. Washington, DC:
litigation will create an increasingly anthem-offers-incentives-to-providers- Avalere Health; 2015.
certied-for-integrated-care. Accessed 29. Centers for Medicare and Medicaid
tangled environment in which to main- September 1, 2016. Services. Medicare prescription drug
tain legitimacy, focus on clean execution 10. The Joint Commission. Integrated care benet manual. September 26, 2008.
of purpose, and nd persons willing to certication. Available at: www.joint- Available at: www.cms.gov/Regulations-
serve on such a high-prole committee. commission.org/certication/integrat- and-Guidance/Guidance/Manuals/
ed_care_certification.aspx. Accessed Downloads/Pub100_18.pdf. Accessed
Individuals who can lead P&T commit-
August 26, 2016. September 3, 2016.
tees into the new decade of care will be in 11. Vega K. Successfully negotiating 30. Hoadley J, Summer L, Hargrave E. Medi-
high demand and can help deliver on the managed contracts. Healthcare Financial care Part D in its Ninth Year: The 2014
promise for better outcomes, better quality Management Association. Available at: Marketplace and Key Trends, 20062014.
care processes, and scally responsible www.hfma.org/Content.aspx?id=16658. Menlo Park, California: Henry J. Kaiser
Accessed August 26, 2016. Family Foundation; 2014:26. Q
action. The need for P&T committees will 12. MDL 1871 In re: Avandia marketing, sales
only grow in urgency, but most urgent is practices and products liability litigation.
the authenticity, credibility, and reliability 804 F3d 633 (2015).
of future P&T committees to maintain 13. Wickline v State of California, 228 Cal Rptr
their core mission of providing safety and
14.
661 (Cal App 1986).
Fox v Health Net of California, Case No.
P&T TV
efcacy guidance to prescribers or users 219692 (Cal. Super. C., Riverside Cty, Dec P&T is accepting video clips
of drugs in their organizations. 23, 1993). from readers, and we might
15. People of the State of New York v Capital post yours on our website
REFERENCES District Physicians Health Plan, Inc., NY
Super Ct. Complaint led April 14, 2016. (www.PTCommunity.com). Feel
1. Balu S, OConnor P, Vogenberg FR. Available at: www.ag.ny.gov/pdfs/Filed- free to send a short video about the
Contemporary issues affecting P&T Complaint.pdf. Accessed September 5, activities of your P&T committee.
committees. Part 1: the evolution. P T 2016.
2004;29(11):709711. You can contact the Editor,
16. New York Executive Law 63(12).
2. Vogenberg FR, Gomes J. The changing 17. New York General Business Law 349. J. Stephen McIver, at 267-685-3713
roles of P&T committees: A look back 18. New York Insurance Law 3214-a(a) or smciver@medimedia.com.
at the last decade and a look forward to (1), 4324(a)(1).
2020. P T 2014;39(11):760761, 768772. 19. Whipple v Schofield, U.S.D.C.(M.D.
3. Balu S, OConnor P, Vogenberg FR. Tenn.), Case No. 1:13-cv-00109.
Contemporary issues affecting P&T 20. 45 CF.R. 156.125(a).

PERSPECTIVE
Walter Alexander
Most heart failure trials yield results that are disappointing or Given how deeply assumptions about heart failure are
difcult to interpret, Milton Packer, MD, wrote in the April 2016 entrenched, it is understandable that commentators did not
issue of Circulation: Heart Failure.1 Dr. Packer, Distinguished entertain the radical-seeming possibility that the prevailing
Scholar in Cardiovascular Science at Baylor University Medical cardiac function paradigm does not accurately reect the reality
Center in Dallas, has experienced this frustration rsthand as of heart function. The success of angiotensin-converting enzyme
lead investigator of more than 15 large international multicenter inhibitors and angiotensin-receptor blockers conrmed that
heart failure trials. He pointed out that in the late-breaking clinical chronic neurohormonal activation of mechanisms of myocardial
trials session at the 2015 annual meeting of the American Heart damage and circulatory dysfunction (including impairment of
Association, every randomized trial in heart failure yielded protective mechanisms) play a role in heart failure. That success
distressing results. Two medications failed to meet primary end- also shifted the pathophysiological emphasis away from the
points (the guanylate cyclase stimulator vericiguat and the beta3 traditional hemodynamic model. But the possibility that the
adrenergic receptor agonist mirabegron [Myrbetriq, Astellas]); dominant paradigm is deeply awed is what Branko Furst, MD,
another (oral nitrates) had adverse effects on daily activity; and explores in The Heart and Circulation: An Integrative Model 2 in
yet another (the GLP-1 agonist liraglutide) showed no diminution 2014 and in The Heart: Pressure-Propulsion Pump or Organ
of clinical symptoms but was linked with possible renal-function of Impedance in the Journal of Cardiothoracic and Vascular
harm and increased risk of death or heart failure hospitalization. Anesthesia in 2015.6 In these, he marshals the evidence against
Such disappointing ndings hardly stand alone among research the standard propulsion pump model and presents an alterna-
results in heart failure and cardiac support, recent or other- tive that may open new avenues for understanding circulation
wise. Attempts to replace failing hearts permanently with fully and, ultimately, pharmacotherapy. As a vascular anesthesiolo-
mechanical ones, after years of experimental and clinical trials, gist in a tertiary care medical center, Dr. Furst holds hemo-
have largely been abandoned because of high patient mortality dynamic monitoring and support of circulation at the core of
through combinations of thromboembolic, hemorrhagic, and his acute-care concerns.
infectious events leading to strokes and multiple organ failure. To challenge the prevailing paradigm in any field is
Despite success at adjusting cardiac outputs, matching hemo- difcult, and in the case of heart function, with its notoriously
dynamics to organ requirements with mechanical devices has complex dynamics, myriad of interrelated inuencing factors,
remained elusive.2 and vast diagnostic and therapeutic implications, it is a prodigious
Experience with intra-aortic balloon pumps (IABPs) serves undertaking. Dr. Furst has provided more than 800 supporting
as a further example. A 2015 meta-analysis by Su et al. of references in his book and the journal article. It is far beyond the
17 studies including 3,226 acute myocardial infarction (AMI) scope of this article to fairly represent the range of this content.
patients, with or without cardiogenic shock, examined the However, we will attempt to review the basic argument and
effect of circulatory assist with IABPs. Analysis revealed no rationale for such a challenge and give the reader a compass
signicant difference between the IABP group and controls on for delving more deeply into the underlying research.
short-term mortality (relative risk [RR], 0.90; 95% condence In what follows, we examine key evidence against the
interval [CI], 0.771.06; P = 0.214) and long-term mortality standard cardiac function model, including failed attempts to
(RR, 0.91; 95% CI, 0.791.04; P = 0.155). The presence or absence address cardiac pathology with pharmacotherapy and devices
of cardiogenic shock did not affect the results.3 Based on this based on that model. We also describe the alternative model
and other similar accumulating evidence, the triumvirate of and its supporting research and touch upon its implications
the American College of Cardiology, the American Heart for therapy and further exploration.
Association, and the European Society of Cardiology all recently
downgraded their recommendations for the use of IABPs in the The History of the Conventional Model
setting of AMI associated with cardiogenic shock from class Ib The current heart-as-propulsion-pump model is traditionally
(should be used) to class IIb (may/can be used). traced to William Harveys 17th century De Motu Cordis. It
Commentators on another recent IABP meta-analysis4 showing took another 200 years, however, for traces of vitalism to be
no survival advantage posited a range of explanations for the eradicated from physiological understanding and for Alfred
benet that has never appeared over four decades for this seem- Volkmann to precisely articulate a fully mechanical model
ingly practical and plausible strategy: IABP effects are too weak as follows: The heart is a pumping engine and as such has
to counteract failed cardiac function; IABP complication harms enough power to drive the mass of the blood through the
overwhelm benets; clinical trial methods simply fail to accu- whole vascular system. 7 Contemporary denitions of heart
rately capture IABP benet; and baseline selection bias toward failure still recognize pump malfunction as a key component,
sicker patients dilutes benets in active treatment groups.5 but they also acknowledge the complexity of heart failure
diagnosis and treatment. The European Heart Journal guide-
The author is a freelance writer living in New York City. lines in 20018 stated that while no denitions of heart failure

33
are entirely satisfactory, a commonly used one is: Heart aortic cross-clamping, as is typically done during aortic surgery
failure is a pathophysiological state in which an abnormality and in experimental settings, should lead to disastrous reduc-
of cardiac function is responsible for the failure of the heart tions in cardiac output. But increases in cardiac output of up to
to pump blood at a rate commensurate with the requirements 25% in some cross-clamped aortic surgery patients and in an
of the metabolizing tissues. The next sentence, however, is: animal model beg explanation.15,16 Another paradox presents
A simple objective denition of chronic heart failure is itself when children with congenital univentricular hearts are
currently impossible. The more recent American College of helped by the staged Fontan repair that, in the absence of the
Cardiology Foundation/American Heart Association guide- right ventricle, delivers venous blood directly to the pulmonary
lines (from 2013)9 dene heart failure as a complex clinical arteries. Asking the single, often weakened left ventricle to do
syndrome that results from any structural or functional impair- double dutypumping blood for the body and for the lungs
ment of ventricular lling or ejection of blood. While pump seems extreme, yet it manages quite successfully, sending
function is implied, this broader description may suggest an more than normal volumes of blood to the lungs.
evolutionary direction away from reliance on so simplistic a Paradoxical increases in cardiac output are also seen in
model as is suggested by Volkmanns strict analogy. patients with septic shock, where cardiac output can be doubled
In his book and journal article, Dr. Furst surveys the dis- or tripled at the same time that cardiac function is declining.
appointing ndings for pharmacotherapeutic and device strate- Yet another observed example is the lack of signicant change
gies developed as specic remedies for the heart when seen in blood pressure when aerobic exercise increases cardiac
as a compromised and incompetent propulsion pump. Potent output several-fold beyond the theoretical limits of the hearts
sympathomimetic amines such as epinephrine, isoproterenol, pumping capacity and peripheral resistance drops by two-thirds.
and dopamine were used widely in the 1960s and 1970s10,11 based Up to 60% of increased contractility may be explained by beta-
on the assumption that as inotropes they would strengthen the adrenergic stimulation and improved diastolic compliance (the
heartbeat in patients with congestive heart failure, thereby Frank-Starling mechanism). But greatly increased heart rates
increasing cardiac output and ultimately prolonging survival. shorten diastolic lling time, and the maximally performing
Most recently among negative inotrope ndings, the ADHERE exercising heart can account for only about half of the volume
(Acute Decompensated Heart Failure National Registry) trial,12 throughput measured in high-performance athletes (more than
a 2003 registry, showed that of 150,000 patients with acute heart 30 L per minute).2 The source of extra blood volume remains
failure, systolic blood pressure was lower than 90 mm Hg in a long-standing dispute among exercise physiologists, and
less than 3%, suggesting a harmful effect on heart function. the concept of a muscle pumpa mechanism by which the
Mortality among those treated with inotropes was 19%, com- blood is returned to the heart by the contracting muscleshas
pared with 14% among those not receiving inotropes. American long been entertained. Evidence against the existence of such
and European medical societies practice guidelines have since a muscle pump is accumulating, however.17,18
recommended the use of vasodilators and de-emphasized Dr. Furst describes various animal and human studies mea-
inotrope use in acute heart failure syndrome management. suring or modeling heart function and compares them with
While inotrope use has been largely abandoned in favor mechanical propulsion pumps engineered to maintain either
of vasodilators to reduce blood pressure and decrease the constant pressure or ow under varying loading conditions.
resistance that lowers cardiac output, the exception is inotrope Dr. Fursts conclusion emerging from studies of isolated heart
administration in a minority of patients with severe systolic dys- preparations is that if the heart is in fact a pressure-propulsion
function who cannot tolerate vasodilators due to hypotension.13 pump, it is a rather poorly designed one, with its thin apex and
Of signicance is the fact that dobutamine and milrinone are relatively low ejection fractions of 50% to 60% (why not 100%?).
usually selected out of the range of available inotropes because Dr. Furst, in the introduction to The Heart and Circulation,
of their substantial vasodilatory effects. Applied to the con- states that, in 1920, Rudolf Steiner suggested that the heart,
ventional model, vasodilators would decrease the pressure rather than propelling blood ow, restrains and regulates it.2
head needed by the pump in order to drive the blood around The venous return model articulated by Arthur Guyton has been
the circuit, Dr. Furst points out.2 Also counterintuitive to a the prevailing view since the 1970s and stands in opposition to
propulsion pump model is the proven efcacy and universal the pure left ventricular model.2 In it, the peripheral circulation
recommendation of beta blockers for all patients with stable controls cardiac output, with elastic recoil energy from the
mild, moderate, and severe heart failure with ischemic or non- vessel walls squeezing blood back toward the heart. Guyton
ischemic cardiomyopathy and reduced left ventricular ejection and collaborators also reported that cardiac output is largely
fraction.14 It is suggested that by reducing catecholamines, unaffected by the hearts activity19 even with pacing rates up
beta blockers promote ventricular lling and enhanced ejec- to four times normal. The Guyton model ascribes a dual role
tion fraction, but the proven efcacy of treating a failing heart to the right atrial pressure. Considered from the perspective
pump by weakening the force of ventricular contractions and of the heart, the right atrial pressure determines the degree
slowing heart rate remains puzzling. of lling of the right ventricle and therefore regulates cardiac
output. From the perspective of the peripheral circulation,
Failing Heart, Rising Output? a positive right atrial pressure exerts a backpressure and
Among the observations most confounding to a heart-as- therefore impedes venous return. This ambiguous depiction
propulsion-pump model, the instances where cardiac output of the right atriums role, according to the models critics, is
rises in the presence of a compromised or disabled pump stand mechanistically inconsistent and is a weakness of the model.
out. Partially isolating the heart from the circulation through By assuming an impedance function for the right atrium and

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

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

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

37
Figure 5 A Comparison of Circulation Models6 the problem, Dr. Furst said in a personal conversation in
September 2016, is that there is as yet no consensus on treatment
Guytons VR Left Ventricular Biological of these complex hemodynamic states. But what Ince et al.33,34
Model Model Model 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-
Flow impeded Power source Systemic and cuits. Only later in warm-blooded mammalian species is a thick
pulmonary left ventricle required to maintain the same basic function of
capillaries
rhythmic ow interruption at signicantly higher pressures
A dening feature of both the classical pressure-propulsion and (to work the valves and eject blood into the respective com-
Guyton models is that the pressure gradient created by the heart partments). The movement of the circulation is created and
is the source of blood propulsion. In Guytons venous return regulated locally at the level of the tissues through metabolic
(VR) model, cardiac output (CO) is predominantly regulated by demand and globally through a dynamic tension between the
the circuit parameters, that is, elastic and resistive properties of lungs supplying of oxygen and its consumption in the tissues.
the blood vessels and blood volume. The right atrial pressure The idea of autonomous movement of blood is seemingly
(Pra) plays a dual role; viewed from the heart, increased Pra radical, but Dr. Furst points out, Conceptually, autonomous
promotes ventricular lling, thereby increasing CO. Viewed from movement of the blood is no different than autonomous con-
the circulation, increased Pra exerts back pressure, impedes traction of the heart, the enterohepatic circulation of bile salts,
venous return, and reduces CO. or the circulation of cerebrospinal uid.2
The left ventricular model assumes that the ow (CO) is limited If this model of autonomous blood ow is conrmed by con-
by the pumps output and is proportional to the gradient tinuing research, it may drive the understanding of circulatory
between the mean aortic and right atrial pressures, and and cardiac function further along in a direction it has been
inversely proportional to peripheral resistance. The blood is taking gradually for some time, at least in the eld of pharmaco-
considered an inert, incompressible uid, and the amount therapy of heart failure. By superseding the propulsion-pump
pumped into the arterial side of the circuit is equal to the model, it may steer researchers away from pharmacological
amount of blood returning at the venous side. and device blind alleys and lead them instead to wide avenues
of discovery and progress in therapy.
The biological model assumes the existence of dynamic
tension between the source of oxygen in the lung and its REFERENCES
sink in the metabolically active tissues. The blood, a liquid
1. Packer M. Unbelievable folly of clinical trials in heart failure:
self-moving organ, bridges this tension and plays a dual role the inconvenient truth about how investigators and guidelines
by delivering oxygen and nutrients to the peripheral tissues, and weigh evidence. Circ Heart Fail 2016;9(4):e002837. doi: 10.1161/
also to itself. The forces for blood propulsion originate at the CIRCHEARTFAILURE.116.002837.
level of the microcirculation. The heart plays a secondary role 2. Furst B. The Heart and Circulation: An Integrative Model. London,
United Kingdom: Springer-Verlag; 2014.
and exerts a negative feedback to the metabolic demands of the 3. Su D, Yan B, Guo L, et al. Intra-aortic balloon pump may grant no
tissues by rhythmic interruption of the blood ow. Its ram-like benet to improve the mortality of patients with acute myocar-
function maintains pressure in the systemic and pulmonary dial infarction in short and long term: an updated meta-analysis.
arterial compartment and carries the rhythm of life. Medicine (Baltimore) 2015;94(19):e876.
4. Doll JA, Sketch MH Jr. ECMO and the intra-aortic balloon pump:
Used with permission from the Journal of Cardiothoracic and Vascular in search of the ideal mechanical circulatory support device.
Anesthesia (December 2015). 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:
that what is good for the macrocirculation is good for the 10.1056/NEJMe1209601.
microcirculation can misre. In septic (endotoxic) shock, 6. Furst B. The heart: pressure-propulsion pump or organ of
excessive use of uids can produce tissue edema; after cardio- impedance? J Cardiothorac Vasc Anesth 2015;29(6):16881701.
pulmonary bypass, excessive uid administration to raise mean doi: 10.1053/j.jvca.2015.02.022.
7. Volkmann AW. Die Hmodynamik. Leipzig, Germany: Breitkopf
arterial pressure can cause hemodilution and tissue edema;
und Hrtel; 1850.
and use of vasopressors (inotropic agents) in cardiogenic 8. Remme WJ, Swedberg K; Task Force for the Diagnosis and Treat-
shock, despite normalizing cardiac index, can lead to increased ment of Chronic Heart Failure, European Society of Cardiology.
mortality. Attention to microcirculatory ow is necessary, and Guidelines for the diagnosis and treatment of chronic heart failure.
Eur Heart J 2001;22(17):15271560.

9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline 32. Klijn E, Den Uil CA, Bakker J, Ince C. The heterogeneity of the
for the management of heart failure: a report of the American microcirculation in critical illness. Clin Chest Med 2008;29(4):
College of Cardiology Foundation/American Heart Asso- 643654, viii. doi: 10.1016/j.ccm.2008.06.008.
ciation Task Force on Practice Guidelines. J Am Coll Cardiol 33. Ince C. The microcirculation is the motor of sepsis. Crit Care
2013;62(16):e147239. doi: 10.1016/j.jacc.2013.05.019. 2005;(9)(suppl 4):S13S19.
10. Goldberg LI. Use of sympathomimetic amines in heart failure. 34. Ince C. Hemodynamic coherence and the rationale for monitoring
Am J Cardiol 1968;22(2):177182. the microcirculation. Crit Care 2015;(9)(suppl 3):S8. doi: 10.1186/
11. Elliott WC, Gorlin R. Isoproterenol in treatment of heart disease cc14726.
hemodynamic effects in circulatory failure. JAMA 1966;197(5): 35. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory
315320. alterations are associated with organ failure and death in patients
12. Fonarow G. The Acute Decompensated Heart Failure National with septic shock. Crit Care Med 2004;32(9):18251831.
Registry (ADHERE): opportunities to improve care of 36. De Backer D, Ortiz JA, Salgado D. Coupling microcirculation to
patients hospitalized with acute decompensated heart failure. systemic hemodynamics. Curr Opin Crit Care 2010;16(3):250254.
Rev Cardiovasc Med 2003;(4)(suppl 7):S21S30. doi: 10.1097/MCC.0b013e3283383621.
13. Bayram M, De Luca L, Massie MB, et al. Reassessment of 37. Dnser MW, Ruokonen E, Pettil V, et al. Association of arterial
dobutamine, dopamine, and milrinone in the management of acute blood pressure and vasopressor load with septic shock mortality: a
heart failure syndromes. Am J Cardiol 2005;19;96(6A):47G58G. post hoc analysis of a multicenter trial. Crit Care 2009;13(6):R181.
14. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the doi: 10.1186/cc8167. Q
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 COMING SOON
unclamping. Anesthesiology 1995;82(4):10261060.
16. Stene JK, Burns B, Permutt S, et al. Increased cardiac output New Pharmacotherapies in
following occlusion of the descending thoracic aorta in dogs.
Am J Physiol 1982;243(1):R152-R158. Chronic Lymphocytic Leukemia
17. Hamann JJ, Valic Z, Buckwalter JB, Clifford PS. Muscle pump Jacqueline L. Olin, PharmD, BCPS, CDE, FASHP,
does not enhance blood ow in exercising skeletal muscle. J Appl FCCP; Katherine Canupp, PharmD Candidate;
Physiol (1985) 2003;94(1):610.
18. Clifford PS, Hamann JJ, Valic Z, Buckwalter JB. Counterpoint: The
and Morgan B. Smith, PharmD, BCOP
muscle pump is not an important determinant of muscle blood
ow during exercise. J Appl Physiol (1985) 2005;99(1):372374; Experts Provide a Glimpse of the New
discussion 374375. Post-SPRINT Era of Hypertension Therapy
19. Guyton AC, Jones CE, Coleman TG. Circulatory Physiology: Cardiac
Output and Its Regulation, 2nd ed. Philadelphia, Pennsylvania: Susan Worley
WB Saunders; 1973:137146.
20. Havlicek H. Does the heart work as a pressure pump or as a Effect of Intravenous Acetaminophen on
hydraulic ram? Basic Research in Cardiology 1937;1:188224
[in German].
Postanesthesia Care Unit Length of Stay,
21. U.S. Department of Agriculture, Natural Resources Conservation Opioid Consumption, Pain, and Analgesic
Service. Technical Notes: hydraulic ram pumps. September 2007. Drug Costs After Ambulatory Surgery
Available at: www.nrcs.usda.gov/Internet/FSE_DOCUMENTS/ Moteb A. Khobrani, PharmD; James M. Camamo,
nrcs142p2_041913.pdf. Accessed October 5, 2016.
22. Manteuffel-Szoege L. Energy sources of blood circulation and the PharmD; and Asad E. Patanwala, PharmD
mechanical action of the heart. Thorax 1960;15(1):4753.
23. Thompson SA. The effect of pulmonary ination and deation upon DRUG FORECAST
the circulation. J Thorac Surg 1948;17(3):323334.
24. Manteuffel-Szoege L, Michalowski J, Grundman J, Pacocha W. On
Brivaracetam (Briviact): A Novel Adjunctive
the possibility of blood circulation continuing after stopping the Therapy for Partial-Onset Seizures
heart. J Cardiovasc Surg (Torino) 1966;7(3):201208. Farbod Khaleghi, PharmD Candidate;
25. Forouhar AS, Liebling M, Hickerson A, et al. The embryonic and Eric C. Nemec II, PharmD, BCPS
vertebrate heart tube is a dynamic suction pump. Science
2006;312(5774):751753.
26. Sherman TF. On connecting large vessels to small. The meaning PIPELINE PLUS
of Murrays law. J Gen Physiol 1981;78(4):431453. New Schizophrenia Treatments
27. Carlson BE, Arciero JC, Secomb TW. Theoretical model
of blood flow autoregulation: roles of myogenic, shear-
Address Unmet Clinical Needs
dependent, and metabolic responses. Am J Physiol Heart Chris Fellner
Circ Physiol 2008;295(4):H1572H1579. doi: 10.1152/ajp-
heart.00262.2008. MEETING HIGHLIGHTS
28. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The eryth-
rocyte as a regulator of vascular tone. Am J Physiol 1995;269 American Society of Hematology
(6 Pt 2):H2155H2161. Annual Meeting
29. Ellsworth ML. Red blood cell-derived ATP as a regulator of skeletal Walter Alexander
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): PRESCRIPTION: WASHINGTON
698706. The 21st Century Cures Act
31. Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric Stephen Barlas
oxide, nitrite, and hemoglobin: Role in blood ow regulation. Free
Radic Biol Med 2004;36(6):707717.

39
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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 complete and accurate patient medication list must rst be

Purpose: To compare the medication history error rate of obtained, followed by a comparison (or reconciliation) of the
the emergency department (ED) pharmacy technician with obtained history to the list of medications that patients will
that of nursing staff and to describe the workow environment. either continue or discontinue during their stay in the hospi-
Methods: Fifty medication histories performed by an ED tal or as they move through the continuum of care.2 It is well
nurse followed by the pharmacy technician were evaluated for established that the process of obtaining an accurate medication
discrepancies (RN-PT group). A separate 50 medication histo- history and subsequent medication reconciliation is complex,
ries performed by the pharmacy technician and observed with with numerous opportunities to create discrepancies. These
necessary intervention by the ED pharmacist were evaluated discrepancies may include omissions, duplications, discrepant
for discrepancies (PT-RPh group). Discrepancies were totaled doses or frequencies, and incorrect drugs or formulations.3,4
and categorized by type of error and therapeutic category of Obtaining an accurate medication list is particularly essential
the medication. The workow description was obtained by during patient transitions of care. The emergency department
observation and staff interview. (ED) stands at a critical crossroads for obtaining an accurate
Results: A total of 474 medications in the RN-PT group and medication list, as many patients who visit the ED may be
521 in the PT-RPh group were evaluated. Nurses made at least admitted. At that point, an accurate medication history becomes
one error in all 50 medication histories (100%), compared to crucial for maintaining continuity of care. In the demanding
18 medication histories for the pharmacy technician (36%). and often hectic ED environment, there are numerous barriers
In the RN-PT group, 408 medications had at least one error, to obtaining an accurate medication history that continue to
corresponding to an accuracy rate of 14% for nurses. In the frustrate clinicians. Such barriers include patients who may
PT-RPh group, 30 medications had an error, correspond- be obtunded or who present with impaired memory, outdated
ing to an accuracy rate of 94.4% for the pharmacy technician information from patients or hospital records, patients use
(P < 0.0001). The most common error made by nurses was a of multiple pharmacies, restrictive access to patient records,
missing medication (n = 109), while the most common error time constraints, and language barriers.5 As a result, a crucial
for the pharmacy technician was a wrong medication frequency role exists for skilled pharmacy personnel participating in the
(n = 19). The most common drug class with documented medication history process.
errors for ED nurses was cardiovascular medications The American Society of Health-System Pharmacists
(n = 100), while the pharmacy technician made the most errors supports the idea that every hospital pharmacy department
in gastrointestinal medications (n = 11). should provide its ED with pharmacy services.6 While the role
Conclusion: Medication histories obtained by the pharmacy of a clinical pharmacist in the ED cannot be understated, it is
technician were signicantly more accurate than those obtained the role of the pharmacy technician that has been evolving to
by nurses in the emergency department. encompass patient care activities, such as obtaining the medica-
tion history. Pharmacy technicians are in a unique position to
Keywords: pharmacy technician, medication history, fulll this critical role, as they have a working knowledge of
emergency department commonly prescribed medications at a signicantly decreased
personnel cost compared with other health care professionals,
INTRODUCTION such as pharmacists or nurses.
The Joint Commission denes the process of medication The purpose of this study was to perform a descriptive
reconciliation as the comparison of the medications a patient analysis of the ED workow for obtaining medication histories
is currently taking (and should be taking) with newly ordered after the addition of a pharmacy technician to the staff and to
medications.1 The process consists of two phases in which a compare the accuracy of the pharmacy technician to that of
ED nursing staff and an ED clinical pharmacist. The primary
Dr. Markovic is a PGY-2 Neuropsychiatry Pharmacy Resident at outcome was the evaluation of the number and types of medica-
Rutgers University in New Brunswick, New Jersey. Dr. Mathis tion history discrepancies resolved by the pharmacy technician.
is Regional Director of Pharmacy and Medication Use, Secondary outcomes included the classes of medications with
Dr. Lee Ghin is Assistant Pharmacy Director and PGY-1 Residency an intervention and the time it took for various personnel to
Program Director, Dr. Gardiner is a Clinical Specialist in Emergency complete tasks associated with medication reconciliation when
Medicine and Geriatrics, and Dr. Fahim is an Internal Medicine a patient presented to the ED.
Pharmacist at Monmouth Medical Center in Long Branch, New
Jersey. Dr. Fahim is also a Clinical Assistant Professor at Rutgers Disclosures: The authors report no commercial or nancial interests
University. in regard to this article.

41
Accuracy of Medication Histories Obtained by a Pharmacy Technician in the ED
PROGRAM DESCRIPTION Job Description and Workow
Rationale for the Program The workow for a patient arriving at the ED by ambu-
Prior to placing a pharmacy technician in the ED, the docu- lance is depicted in Figure 1. After the patient is triaged and
mentation of patient medication histories was largely driven by assigned a bed in the ED, the pharmacy technician initiates
ED nurses. The ED clinical pharmacist participated in obtain- the medication history process, usually after the nurse has
ing some medication histories; however, the primary focus imported an outdated medication history from the patients
for the pharmacist was clinical evaluation and interventions. past admission. This process consists of asking the patient or
An interview of the nursing staff revealed that given the high caregiver if they know which medications the patient is taking
patient turnover in the ED and the number of patients and or whether there is a list of medications; utilizing an electronic
tasks to which they are assigned, most nurses are not able to database of prescriptions lled through insurance; calling the
prioritize obtaining an accurate medication history due to time patients pharmacy, insurance company, and/or primary care
constraints. Moreover, nurses revealed that they had no time provider; and comparing the newly obtained list to the history
to utilize outside resources, such as contacting the patients documented in the patients electronic health record (EHR).
outpatient pharmacy or speaking with primary care physician The pharmacy technician follows up with the patient to ask
ofces. As a result, many medication histories were inaccurate, whether he or she is taking any over-the-counter medications,
incomplete, imported from the patients prior admission and such as vitamins or aspirin. The pharmacy technician also
therefore outdated, or simply not done. When the medication updates the patients preferred pharmacy in the EHR.
history was incomplete or inaccurate, the medical resident When the patient is unable to provide a medication history
admitting the patient assumed responsibility for obtaining the or a medication list or the caregiver is unavailable, the techni-
medication history and completing the medication reconcilia- cian will compile a list as accurately as possible using avail-
tion. Interviews with the medical residents showed that they able resources. These resources may include past medica-
too were unable to efciently prioritize obtaining an accurate tion histories if available, electronic databases, calling the
medication history due to time constraints and other admis- patients pharmacy, or asking the ED pharmacist to generate a
sion responsibilities. Therefore, inaccurate or only partially New Jersey prescription-monitoring program report when
complete medication histories were frequently being used as appropriate. In these cases, the pharmacy technician will
the basis for physicians medication reconciliation. indicate in the medication history that she is not able to
Prior to implementing the pharmacy technician program, assess adherence to the documented regimen and will alert
the ED clinical pharmacist conducted a study in which she the physician.
performed a thorough medication history on 24 patients in By mutual agreement given the high patient volume, the
the ED after a nurse had already documented the medication nurse will generally independently complete the medication
history as complete. Of the 24 documented medication histories, history when the patient has four or fewer medications. If
22 (91.7%) had at least one error. Of a total of 261 medications, the patient has more than four medications or if the medica-
there were 116 errors (44.4%), the majority of which were either tion history is complex or time consuming (such as patients
medication omissions or errors in documenting the medica- coming from long-term-care facilities, who tend to have long
tion dose. Therefore, it was evident that the current process of medication histories), the nurse will reach out to the pharmacy
obtaining medication histories was inaccurate and unreliable, technician by phone or in person or will record the term MAR
indicating a clear need for a process change. (medication administration record) in the notes eld on the
electronic ED patient-tracking queue to alert the technician that
Implementation a medication history needs to be completed. In the meantime,
The ED pharmacy technician program was implemented the technician independently looks at new patient records
in April 2015 as part of a pilot program across a large health between documentations to proactively identify patients who
system to optimize the medication history and reconciliation will need medication histories.
process. Prior to starting work in the ED, the pharmacy tech- In the daily workow, multiple patients may simultaneously
nician had been employed for approximately two years in the require a medication history to be completed by the pharmacy
main inpatient pharmacy, where she did not perform medica- technician. In these instances, the pharmacy technician will
tion reconciliation. The pharmacy technician is registered with triage patients with physician and nursing assistance, taking
the state of New Jersey but not nationally certied. Prior to into account the disease state that precipitated the ED visit. For
employment at our facility, she worked as a pharmacy liaison example, a stroke patient being assessed for administration of
for a different hospital for approximately one year, gathering tissue plasminogen activator will take precedence over other
and processing prescriptions from inpatients and delivering patients. The technician will also prioritize medication histories
them before discharge. The technician received one week for patients who are being admitted so that the admitting physi-
of training from the emergency medicine pharmacist before cians can quickly reconcile and order the medications to ensure
independently collecting and documenting medication histories. smooth continuity of care. Often, the technician will speak to
Throughout the course of this study, the pharmacy technicians multiple patients who need medication histories in one trip,
work hours shifted to coincide with hours of peak volume in make copies of medication lists, and bring the documentation
the ED. The initial work hours were 8 A.M. to 4:30 P.M. but back to her workstation to complete the medication histories
gradually transitioned to the current 1 P.M. to 9:30 P.M. schedule. as efciently as possible.
During one work shift, the pharmacy technician is able to
complete approximately 20 medication histories. The duration

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,

METHODS scope of practice in overseeing the pharmacy technicians
Study Setting work. Additionally, we felt that patients and caregivers might
This study was conducted between July 2015 and March 2016 respond differently to standard questions about their medica-
at a 520-bed community academic hospital that had 48,544 ED tion history and adherence if they knew the process was being
visits in 2015. The 47-bed ED consists of three triage beds, monitored for a study.
six overow beds, 19 adult beds, six express care beds, a
six-bed geriatric emergency medicine unit, and a seven- Data Collection
bed pediatric ED. The average daily volume in the ED is Baseline characteristics, including the patients admission
approximately 115 patients. status after being seen in the ED, were collected for both dis-
crepancy analyses. It is important to note that the total number
Inclusion and Exclusion Criteria of medications was based on each subjects nal medication
The study patients were chosen consecutively during the list, so medication duplicates or additional medications were
study period by the pharmacy resident based on manual review not included in this list.
of paper medication history logs retained by the pharmacy Possible discrepancies recorded included a medication omis-
technician, followed by a review of the electronic documenta- sion (failure to document a medication that the patient is actively
tion in the medical chart. To be included in the study, patients taking), medication commission (addition of a medication that
had to have a medication history rst documented electroni- the patient is not taking), duplicate medication, incorrect or
cally by an ED nurse, followed by the pharmacy technician, missing doses, incorrect or missing frequencies, and incorrect
so that a comparison could be performed. Due to the nature or missing formulations (when necessary). It was possible for
of the patient population the pharmacy technician targets one medication to have more than one documented discrepancy
(see Program Description and Figure 1), patients were included (for example, an entry of atenolol would be documented as
if they were at least 18 years of age, taking at least one medi- a missing dose as well as a missing frequency). The discrep-
cation, and were seen in the ED for a medical condition (and ant medications were categorized by therapeutic drug class,
subsequently discharged from the ED, placed on observation which included: pain, gastrointestinal, cardiovascular, neuro-
status, or admitted to the hospital). We excluded patients logical or psychiatric, immune, diabetic, asthma or chronic
younger than 18 years of age, patients seen in the psychiatric obstructive pulmonary disease, topical, herbal supplements
emergency screening service, and patients seen in the ED or vitamins, ophthalmic, antibiotic or antiviral, endocrine,
outside of the pharmacy technicians scheduled work shift. or other. Each medication was categorized only once by
therapeutic drug class.
Study Design
This study was approved by the institutional review board Statistical Analysis
(IRB) and comprised three separate components, including Students t-tests were used to compare the medications per
two medication history discrepancy analyses and a workow patient and ages. Fischers exact tests were used to compare
description. The rst analysis was based on a retrospective the number of histories with an error, the number of medica-
chart review by the PGY-1 pharmacy resident of 50 patients tions with an error, and the gender of the patients. Results
visiting the ED at our facility between July and October 2015. were considered statistically signicant if the alpha was less
To be included in the rst analysis, patients had to rst have a than 0.05. Descriptive statistics were calculated using Microsoft
medication history documented in the electronic medical record Windows Excel (version 2011) and GraphPad QuickCalcs.
by a nurse, and a follow-up medication history electronically
documented by the pharmacy technician. The second analysis RESULTS
was a real-time observational study in March 2016, in which Error Rate Analysis
the emergency medicine clinical pharmacist accompanied During the study period, 36,409 patients were seen in the ED;
the pharmacy technician in the collection of 50 medication the pharmacy technician saw 2,840 of them. Fifty medication
histories, observed the technicians routine in obtaining the histories were evaluated in each of the two analysis groups.
medication history, and intervened as necessary to complete Baseline characteristics (Table 1) between the two groups
the best possible medication history. Pharmacist interventions were similar, with a mean of nine medications per patient in
were documented as medication discrepancies. The third the nurse-pharmacy technician group (RN-PT) and 10 medica-
component of the study consisted of a workow diagram that tions in the pharmacy technician-pharmacist group (PT-RPh).
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-
RN-PT PT-RPh P Value
cist, resident physicians, and attending
physicians. Medications per patient, mean ( SD) 9 (4.0) 10 (7.1) 0.416
The IRB waived the need for patient Mean age, years ( SD) 66 (15.9) 61 (14.6) 0.154
consent in the rst analysis because of the
retrospective nature of the study design Male, n (%) 22 (44) 20 (40) 0.840
and in the second analysis because the ED Admitted to hospital from ED, n (%) 20 (40) 35 (70) 0.0046
pharmacist, by observing the pharmacy PT = pharmacy technician; RN = registered nurse; RPh = registered pharmacist; SD = standard deviation.
technician, was acting within her usual

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.

nding that pharmacy technicians are capable of completing CONCLUSION
medication histories accurately and completely at a rate of In this study, medication histories obtained by the pharmacy
consistently more than 90%.15 technician were signicantly more complete and accurate than
A compelling nding of our study was that the pharmacy those obtained by emergency department nurses.
technicians practice of obtaining accurate medication histories
often includes the time-consuming tasks of calling pharmacies, ACKNOWLEDGEMENT
insurance companies, and physicians ofces. In the study of the The authors would like to thank their pharmacy technician,
ED workow, we were unable to compare the time that the ED Ashley OKeefe, for her contributions to this work.
nurses spent performing these tasks with that of the pharmacy
technician because nurses do not have time to engage in these REFERENCES
activities. Simply speaking, when the pharmacy technician is 1. The Joint Commission. Hospital: 2016 national patient safety goals.
not there, nurses will use readily available information (such as Available at: www.jointcommission.org/standards_information/
a verbal history or a medication list provided by the patient) or npsgs.aspx. Accessed February 14, 2016.
2. Porcelli PJ, Waitman LR, Brown SH. A review of medication recon-
they will import an already documented medication list if avail- ciliation issues and experiences with clinical staff and information
able, regardless of whether the list is outdated or not. At this systems. Appl Clin Inform 2010;1(4):442461.
point, it is up to the physicians whether to trust that the existing 3. Cornish PL, Knowles SR, Marchesano R, et al. Unintended medica-
medication history is current or whether to start obtaining the tion discrepancies at the time of hospital admission. Arch Intern
medication history themselves if the patient is admitted to the Med 2005;165(4):424429.
4. Pippins JR, Gandhi TK, Hamann C, et al. Classifying and predict-
hospital. ing errors of inpatient medication reconciliation. J Gen Intern Med
In addition, it is interesting to note that in the error rate 2008;23(9):14141422.
analyses, we found that the pharmacy technician performed 5. Hart C, Price C, Graziose G, Grey J. A program using pharmacy
medication histories for signicantly more patients who were technicians to collect medication histories in the emergency
department. P T 2015;40(1):5661.
subsequently admitted to the hospital in the PT-RPh group than 6. American Society of Health-System Pharmacists. ASHP state-
in the RN-PT group (70% versus 40%, respectively, P = 0.0046). ment on pharmacy services to the emergency department. Am J
We hypothesize that this may reect the growing ability of the Health-Syst Pharm 2008;65:23802383. Available at: www.ashp.org/
pharmacy technician to identify and target patients who are more DocLibrary/BestPractices/SpecicStEmergDept.aspx. Accessed
January 18, 2016.
likely to be admitted to the hospital (for example, elderly or
7. Johnston R, Saulnier L, Gould O. Best possible medication history
acutely ill patients, or those with complex medication regimens), in the emergency department: comparing pharmacy technicians
as approximately six months passed between these two data sets. and pharmacists. Can J Hosp Pharm 2010;63(5):359365.
There are a few limitations to our study. One is a lack of gen- 8. Smith SB, Mango MD. Pharmacy-based medication reconciliation
eralizability, given that this study evaluated the process of one program utilizing pharmacists and technicians: a process improve-
ment initiative. Hosp Pharm 2013;48(2):112119.
technician in one facility. The ED pharmacy technician is part 9. Michels RD, Meisel SB. Program using pharmacy techni-
of a new program, and there is no formal process for targeting cians to obtain medication histories. Am J Health-Syst Pharm
patients or documenting interventions. In addition, the different 2003;60(19):19821986.
design between the two study groups in the error rate analysis 10. van den Bemt PM, van den Broek S, van Nunen AK, et al. Medica-
tion reconciliation performed by pharmacy technicians at the time
may lend itself to potentially skewed results, particularly when
of preoperative screening. Ann Pharmacother 2009;43(5):868874.
accounting for the Hawthorne effect in the group in which the 11. Leung M, Jung J, Lau W, et al. Best possible medication history
clinical pharmacist observed the pharmacy technician. for hemodialysis patients obtained by a pharmacy technician. Can
At this time, the pharmacy technician is able to see about J Hosp Pharm 2009;62(5):386391.
20 patients per shift, which accounts for only about 17% of 12. Siemianowski LA, Sen S, George JM. Impact of a pharmacy
technician-centered medication reconciliation on optimization
patients seen daily in the ED. While we did not formally measure of antiretroviral therapy and opportunistic infection prophy-
staff satisfaction before and after the study, it is noteworthy laxis in hospitalized patients with HIV/AIDS. J Pharm Pract
that the ED staff appears quite receptive to the utility of the 2013;26(4):428433.
pharmacy technician and often independently seeks out her 13. Brownlie K, Schneider C, Culliford R, et al. Medication reconcilia-
service during her shift. This study did not include a nancial tion by a pharmacy technician in a mental health assessment unit.
Int J Clin Pharm 2014;36(2):303309.
analysis, but available hourly pay averages for the health care 14. Chan C, Woo R, Seto W, et al. Medication reconciliation in pediatric
system indicate that pharmacy technicians are compensated cardiology performed by a pharmacy technician: a prospective
at approximately 45% and 29% of the average salary of a staff cohort comparison study. Can J Hosp Pharm 2015;68(1):815.
nurse and a staff pharmacist, respectively. From a monetary 15. Cooper JB, Lilliston M, Brooks D, Swords B. Experience with a
pharmacy technician medication history program. Am J Health-Syst
perspective, hiring a pharmacy technician to perform medica- Pharm 2014;71(18):15671574. Q
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.

Challenges and Solutions in
Reducing Opioid Misuse and Abuse
Peter Sonnenreich and Linda Geisler
Initiatives aimed at reducing opioid misuse and abuse include dependence, and alcohol abuse and dependence. Medical costs
mining claims data to identify patients at high risk for substance started to increase six months before a diagnosis of abuse and
abuse, promoting wearable technologies to improve monitor- continued to accumulate over the next 18 months. Compared
ing of patients with chronic pain, placing limitations on the with the control group, patients in the abuse group incurred
prescribing and dispensing of opioids, and increasing patient costs of $1,000 more a month. Costs arose from inpatient
and provider awareness of alternative pain management options. settings, emergency departments, rehabilitation facilities,
A variety of approachesand a variety of challenges outpatient settings, and prescription drugs. Interestingly, these
emerged from an Academy of Managed Care Pharmacy patients were in treatment for alcohol- and nonopioid-related
(AMCP) Foundation symposium in October 2016 entitled substance abuse but do not appear to have been properly
Balancing Access and Use of Opioid Therapy in National evaluated for opioid use.
Harbor, Maryland. Panelists later recounted some of the ideas If somebody had any prior history of alcohol or any other
they heard that might have the most effect. David Calabrese, substance abuse, Dr. Mayne says, that patient is at high
RPh, MHP, Chief Pharmacy Ofcer for OptumRx, summed risk. And we should think twice about giving that patient an
up the takeaway from the symposium: This is going to take opioid. If they do need an opioid, monitor that patient very, very
a well-coordinated, multidimensional type of solution to truly carefully. And the truth is, we know physicians are not going
impact, in a positive way, this epidemic. to their claims or medical record and looking for that history.
Predicting Opioid Use Disorder Pain Practice Analyzers

One approach focuses on identifying the patients at highest Purdue is working in partnership with a chronic pain clinic and
risk for problems. Using Truven Health Analytics nationally companies that provide wearable health technologies to offer the
representative database, Purdue Pharma researchers evaluated device to new patients in the clinic over the course of a year. The
treatment patterns among noncancer patients and identied device will track pain, physical activity, sleep, depression, and
patterns of opioid prescribing that fell outside the standard for other measures important in chronic pain and provide a two-way
normal and could be considered a risk for patients. exchange of data. These data will go to dashboards for the patient
Researchers followed 71,000 patients who initiated an and the physician, but the device will also interface with electronic
extended-release (ER) opioid over a two-year period to better medical records. The device can give physicians a window into the
understand how these drugs are being used. Tracy Mayne, patients daily function, and they may be able to intervene sooner,
PhD, Executive Medical Director for Purdue Pharma, a panel- Dr. Mayne says.
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% Total Opioid Management for Managed Care
used two opioids, and just 0.7% (520 patients) used three or At the conference, Calabrese described a Five for Life
more. These data show that a practice known as opioid rota- approach to Total Opioid Management, an initiative he is helping
tion is very rare and not a standard practice among physicians to spearhead at OptumRx. This ve-step approach includes
who prescribe these drugs. Among patients who took a long- up-front education and prevention strategies to increase public
acting opioid for the full two years, only 72 patients had more awareness and encourage appropriate opioid use and promote
than two dose increases after the initial 90-day titration period; alternatives where clinically warranted. The program limits
this, Dr. Mayne says, is the most worrisome group, showing a individual exposure to opioid therapy through what Calabrese
pattern of continuous dose escalation. Fortunately, this practice describes as disruptive yet highly warranted dose and dura-
was also uncommon. tion limitations on the dispensing of these drugs, particularly
in patients who may be nave to opioid therapy. He explains
Opioid-Related Costs that limiting indiscriminate prescribing by the physician and
Another Purdue study examined the costs of opioid abuse, dispensing by the pharmacy is where we are likely to drive the
dependence, overdose, and poisoning over a three-year period. greatest benets with regard to decreasing the prevalence of
Researchers used a propensity score match on 200 variables dependence, addiction, and overdose in this country.
during a seven- to 12-month period for two cohorts: one with Another important component is high-risk patient identica-
opioid misuse and one without. The primary drivers of excess tion and intervention. This involves employment of a much
cost in this population were opioid dependence and poisoning, more forensic approach to uncovering patterns of patient-
but this was closely followed by nonopioid drug abuse and specic drug utilization that might be indicative of current
or future misuse, abuse, or diversion, he says. Then there is
Peter Sonnenreich is a freelance health care writer in Bethesda, prescriber and pharmacy surveillance, which amplies how we
Maryland. Linda Geisler is a freelance health care writer in Weston, are monitoring physician prescribing and pharmacy dispensing
Connecticut. patterns and shutting down any disproportionate or potentially

47
Challenges and Solutions in Reducing Opioid Misuse and Abuse
abusive opioid prescribing by physicians. We will be deploy- accident, injury, or disease may fear that it will happen again.
ing much more comprehensive and sophisticated analytics to They may feel vulnerable, helpless, and ashamed that somehow
identify outliers, those physicians and pharmacies that may be its their fault. Some get caught in an angerdepression loop.
contributing to the crisis through high-risk clinical practice and Chronic pain can constrict social activities, can interfere with
potentially unethical behaviors that we know are occurring all sleep, and can lead to isolation. The painand the emotional
too frequently in the marketplace. The fth step is appropri- turmoil that comes with itcan bring about unemployment,
ately supporting those who have already been afictedthose addiction, and early death.
who have had a previous overdose, are actively in substance
abuse treatment, or have formally completed substance abuse Alternatives to Opioids
treatmentto ensure that they have proper access to the right Many patients and providers do not know about the non-
resources, properly accredited treatment centers, behavioral pharmaceutical treatment options for both acute and chronic
health support services, and medication-assisted treatment. pain. In some instances, access to these alternative pain manage-
Calabrese says its important to remember how this problem ment strategies may be limited. Dr. Crooks acknowledges that
started. Excessive marketing and promotion of opioids in the nding a treatment that works requires a persons willingness
late 1980s and early 1990s was a main driver of the situation and ability to keep looking. Her career in government and
our country faces todaythe excess prescribing of these the pharmaceutical industry gave her access to experts and
products in noncancer-related chronic pain, where evidence information about nondrug alternatives to pain management
is signicantly lacking to support the value of these drugs and the nancial stability to pay out-of-pocket for them.
versus therapeutic alternatives. The particular promotional To avoid opioids, she tried yoga, massage, nutrition
campaign of Pain as the Fifth Vital Sign by the American Pain solutions, wellness, a Zen practice known as BigMind, and
Society that coincidentally coincided with the FDA approval of the Canyon Ranch Health Resort. She studied neuroscience to
Oxycontin has been identied by industry experts as potentially learn how to use her brain to manage her pain and has seen a
one of the biggest mistakes in modern medicine, Calabrese psychiatrist specializing in trauma because much of her pain
says. The numbers speak for themselves in terms of growth has been caused by a traumatic event. Another pain-relieving
in opioid prescriptions since that time and how that directly strategy for her is staying active mentally and working.
parallels with trends in inpatient admissions, ED visits, and Dr. Crooks was recently in a clinical study examining the
death tolls due to overdose. effects of the Spire and Muse apps, which track breathing and
While a contributing factor is certainly managed cares facilitate meditation, respectively. Another FDA-approved over-
insufcient surveillance and intervention to date with the the-counter device she uses, Quell, ts around the leg below
bad guys, it must be recognized that the bulk of the problem the knee and delivers an electrical signal directly into the brain
leading up to this crisis has been the well-intentioned, but for chronic, widespread pain. After wearing the device for a
signicantly misguided, efforts of physicians across the country, short period, she says, she experienced better sleep quality
who were simply trying to do the right thing for their patients and a lot less pain.
based on what they were taught and what the consensus was As with all of the other treatments Dr. Crooks has tried,
at the time, Calabrese says. Now it is time for us all to take however, she acknowledges that eventually, Quell, like other
accountability for the situation we nd ourselves in by re- methods, may no longer help. That for her is part of the journey
educating providers and patients and taking a more aggressive, through the labyrinth. For people with chronic pain, like
well-rounded approach to limiting indiscriminate use of these me, she says, when it comes to the point where something
meds while still ensuring proper care for those with chronic doesnt work anymore, you just have to keep going and try
pain management needs. something different. Q
The Path of Pain: Maze or Labyrinth

During Patient Perspective panel discussions at the AMCP For the Latest News
Foundation meeting, Glenna Crooks, PhD, Founder and CEO of ... Visit PTcommunity.com. At this online resource
Strategic Health Policy International, Inc., described a patients for P&T decision-makers, youll nd breaking-news
experience of pain as being like a maze or labyrinth. A maze, coverage of all of these topics:
she explained, has blind alleys and dead ends. Its possible to
get lost in a maze and even die there. Many people would say Clinical Trials Approvals, Launches,
that is their experience of pain. For others, their path of pain is Research News and New Indications
like a labyrinthif they keep going, they eventually come out Industry Trends Health Care Reform
the other side. That was her experience of dealing with acute Agency Actions Guidelines
surgical pain and long-term chronic pain from traumatic injury. Drug Safety Issues Pipeline Plus
Frankly, many people experience pain but are not dealing Youll also nd recent issues, a free digital app, formu-
with it, Dr. Crooks says. I think we all are in denial about lary kits, P&T TV, industry announcements via Globe
pain. She adds that even the language we use to describe NewsWire, PharmD Corner, and many other resources.
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

MEETING HIGHLIGHTS
Society for Immunotherapy of Cancer

And
American Heart Association
Walter Alexander
In the monotherapy trial, drug-induced liver injury in

Society for Immunotherapy of Cancer (SITC) one patient led to discontinuation of the 0.3-mg/kg dose of
The 31st annual SITC meeting hosted 2,700 urelumab. No treatment-related deaths were reported, and
medical professionals November 913 in National only three of 70 patients withdrew due to treatment-related
Harbor, Maryland. The record-setting attendance was adverse events.
reective of the intense current interest in immuno- The monotherapy overall response rate (ORR) was 10%
therapies. We review below two key sessions on the (5% complete and 5% partial remission), with all responses
checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers occurring in those with B-cell non-Hodgkins lymphoma
Squibb) in antitumor combinations for the treatment of (B-NHL). The conrmed disease control rates (DCR) for
solid malignancies. B-NHL, colorectal cancer (CRC), SCCHN, and other solid
tumors were 28%, 18%, 20%, and 39%, respectively.
Among the 128 combination-therapy patients receiving
Urelumab Is Safe and Active as Monotherapy at-dose urelumab (8 mg every four weeks) and nivolumab
(240 mg every two weeks), adverse events led to dis-
And in Combination With Nivolumab in continuation in 10% of patients (seven of 128 patients any grade;
Hematologic and Solid Malignancies six of 128 patients grades 34). Fatigue was the most commonly
Erminia Massarelli, MD, Associate Clinical Professor, reported adverse event (31% any grade; 0% grades 34). This
University of Texas MD Anderson Cancer Center, Houston, indicates that these two agents can be safely administered
Texas together, Dr. Massarelli said.
The ORR (conrmed and unconrmed) was 50% among
Preclinical models of combined urelumab and nivolumab 46 melanoma anti-programmed cell death-1 (PD-1)/
have demonstrated robust antitumor activity with increased programmed death ligand-1 (PD-L1) nave patients and the DCR
interferon gamma (IFN) production versus monotherapy. rate (conrmed and unconrmed) was 70%. DCRs were 21%
Because each enhances immune cell activity through distinctly for DLBCL, 21% for NSCLC (anti-PD-1/PD-L1) progressors,
different mechanisms, their activity in patients with advanced 35% for NSCLC (anti-PD-1/PD-L1 nave), 23% for SCCHN, and
cancers may be synergistic, Dr. Massarelli said. Urelumab is 33% for other solid tumors.
a fully human IgG4 monoclonal antibody that binds to and PD-L1 status (1% or greater or less than 1%) had no effect
activates CD137-expressing cytotoxic T cells. on ORR in melanoma patients receiving the urelumab plus
A monotherapy study evaluated urelumab in patients with nivolumab combination who were anti-PD-1/PD-L1 nave, with
advanced malignancies (0.1 or 0.3 mg/kg every three weeks) rates of 50% (1% or greater) and 47% (less than 1%).
or advanced non-Hodgkins lymphoma (8 mg every three Among patients receiving combination therapy with ure-
or six weeks). The combination study evaluated urelumab lumab and nivolumab, safety was manageable at all evaluated
(3 mg or 8 mg every four weeks) plus nivolumab (3 mg/kg doses. Dr. Massarelli concluded that in the urelumab mono-
or 240 mg every two weeks) in patients with advanced solid therapy trial, the 0.1-mg/kg and 8-mg doses demonstrated
tumors or B-cell lymphoma or patients with diffuse large manageable safety proles and peripheral pharmacodynamic
B-cell lymphoma (DLBCL), melanoma, nonsmall-cell lung activity. Promising antitumor activity was observed in
cancer (NSCLC), or squamous cell carcinoma of the head and melanoma patients.
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 Greater Benet for Nivolumab 1 mg/
the monotherapy study, all patients had been treated previously. Ipilimumab 3 mg in Previously Treated
With the urelumab plus nivolumab combination, increases Metastatic Urothelial Cancer
in IFN-induced peripheral cytokine expression (CXCL9/
Padmanee Sharma, MD, University of Texas MD Anderson
CXCL10) following treatment were larger than those that
Cancer Center, Houston, Texas
occurred with urelumab monotherapy. In a small sample of
melanoma tumors, greater numbers of CD8-positive T cells In previously treated patients with metastatic urothelial
and increased CXCL9 gene expression (and a trend toward carcinoma (mUC), chemotherapy efcacy is poor and associ-
increased IFN gene expression) were observed. ated with signicant toxicity, Dr. Sharma said. Monotherapy
trials (phase 1/2 and 2) of nivolumab have shown notable
The author is a freelance writer living in New York City. antitumor activity in patients previously treated for mUC,

49
MEETING HIGHLIGHTS: Society for Immunotherapy of Cancer
with overall response rates (ORR) of 19.6% and median overall While the cohort size is small, she said the ndings are
survival (OS) of 8.7 months. Both preclinical and clinical data very promising. Dr. Sharma noted that the nivolumab 1-mg/
with the combination of nivolumab, a programmed cell death-1 ipilimumab 3-mg cohort is being expanded to 92 patients.
blockade, and ipilimumab (Yervoy, Bristol-Myers Squibb), a Commenting on a question raised after her presentation
cytotoxic T-lymphocyteassociated antigen-4 blockade, have regarding the possibility of using ipilimumab at 10 mg/kg,
shown improved antitumor activity in advanced melanoma, Dr. Sharma responded, With ipilimumab 3 mg/kg you get
nonsmall-cell lung cancer, and metastatic renal cell carcinoma. the same T-cell activation as with ipilimumab 10 mg/kg.
Dr. Sharma presented rst results from Checkmate 032, Our monitoring showed, however, that ipilimumab 1 mg/kg
the rst trial of combination immunotherapy in mUC. The does not give you the same level of T-cell activation as with
phase 1/2 study compared two dosing strategies of nivolumab 3 mg/kgwhich would not give you the same level of
combined with ipilimumab in patients with previously antitumor response.
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
American Heart Association (AHA)
received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg This years AHA meeting, held November 1216
(IV every three weeks for four cycles), with all receiving main- in New Orleans, attracted approximately 18,000
tenance with nivolumab 3 mg/kg IV every two weeks. The medical professionals from nearly 100 countries. We
primary endpoint was investigator-assessed conrmed ORR. review below key sessions focusing on anticoagulation
Median age was greater in patients in the nivolumab 1-mg/ for peripheral artery disease and for stroke protection in
ipilimumab 3-mg group (50.0% versus 45.2% were 65 years of atrial brillation, cholesterol-lowering strategies, COX-2
age or older). Both groups had approximately 60% of patients inhibitors, and cognitive decline.
treated with two or more prior regimens. Programmed death
ligand-1 expression was higher than 1% in more patients in the Effects of Ticagrelor Compared With Clopidogrel
nivolumab 1-mg/ipilimumab 3-mg group (38.5% versus 28.8%). In Patients With Peripheral Artery Disease
More patients are continuing treatment in the nivolumab
1-mg/ipilimumab 3-mg group (46.2% versus 14.4%). Also in Manesh R. Patel, MD, Associate Professor of Medicine,
that group, discontinuation for disease progression was lower Duke University Medical Center, Durham, North Carolina
(38.5% versus 64.4%). Elevation of alanine aminotransferase and
aspartate aminotransferase levels was greater with the higher EUCLID, a trial designed to test whether long-term
nivolumab dose (17.3%/11.5% versus 0%/0%, respectively). monotherapy for symptomatic peripheral artery disease
Treatment discontinuation rates were 7.7% for nivolumab (PAD) with ticagrelor (Brilinta, AstraZeneca) is superior to
1 mg/ipilimumab 3 mg and 13.5% for nivolumab 3 mg/ clopidogrel in preventing cardiovascular death, myocardial
ipilimumab 1 mg. infarction, or ischemic stroke, found identical combined event
Dr. Sharma said, Grade 34 adverse event rates were around rates for both agents.
30% and very similar for both groups. PAD is associated with both cardiovascular and limb
Its very important to note the overall response rate com- morbidity and mortality, Dr. Patel noted in an AHA press
pared to the 19% with nivolumab monotherapy reported in brieng. He also said that composite cardiovascular death,
Lancet Oncology and the 15% rate previously reported for myocardial infarction, or ischemic stroke with clopidogrel in
atezolizumab, Dr. Sharma said, stating that conrmed ORR the CAPRIE trial (1996) was reduced by 8.7% (P = 0.043) versus
was 38.5% in the nivolumab 1-mg/ipilimumab 3-mg group aspirin. In further research among patients with acute coronary
(95% condence interval [CI], 20.259.4) and 26.0% in the syndromes (ACS), chronic therapy with the antiplatelet agent
nivolumab 3-mg/ipilimumab 1-mg group (95% CI, 17.935.5). ticagrelor demonstrated superiority over clopidogrel for the
Historical controls, she added, are 10% or less. same composite endpoint.
Complete response (3.8% versus 2.9%) and partial response EUCLID investigators enrolled 13,885 symptomatic PAD
rates (34.6% versus 23.1%) were higher with the higher ipilim- patients (811 sites, 28 countries) double-blind to ticagrelor
umab dose regimen. The progressive disease rate, however, 90 mg twice daily or clopidogrel 75 mg once daily. Median
was higher with the lower ipilimumab dose regimen (26.9% age was 66 years, and approximately 28% of the patients were
versus 41.3%). Median tumor change from baseline in the women. Eight percent of the patients had prior stroke, approxi-
target lesion was 27.8% in the nivolumab 1-mg/ipilimumab mately 29% had coronary artery disease, and about 18% had a
3-mg group and 0% in the nivolumab 3-mg/ipilimumab 1-mg prior myocardial infarction. Claudication was mild or moderate
group. While median time to response was similar for both in approximately 53% of patients.
groups (1.4 months), ongoing response rates were higher Reporting the combined primary endpoint, Dr. Patel said
for the higher ipilimumab dose group (80% versus 70%), as that 36-month cardiovascular death, myocardial infarction, or
were the median progression-free survival (4.3 months versus ischemic stroke occurred at an identical rate of 12.5% with both
2.6 months) and median OS rates (10.2 versus 7.3 months). ticagrelor and clopidogrel. While individual components of the
Efcacy with nivolumab 3 mg plus ipilimumab 1 mg did not endpoint were generally similar between groups, ischemic
appear to differentiate from that with nivolumab monotherapy, stroke was more common among patients receiving clopidogrel
Dr. Sharma observed. Nivolumab monotherapy ndings had compared with ticagrelor (2.4% versus 1.9%; P = 0.03). The
been reported previously. rate for major bleeding (measured with the Thrombolysis in

MEETING HIGHLIGHTS: American Heart Association
Myocardial Infarction score) was also identical for the ticagrelor ORION investigators compared six different SC dosing
and clopidogrel groups at 1.6% (P = 0.49). regimens of inclisiran to SC placebo. The primary endpoint
The ndings demonstrated that the active comparator in was percent change in LDL-C levels from baseline at day 180.
EUCLID, clopidogrel, is an effective antiplatelet therapy A single dose of inclisiran produced durable PCSK9 and
in PAD. Ticagrelor was not superior to clopidogrel for the LDL-C lowering (P < 0.0001 versus placebo for all inclisiran
reduction of cardiovascular events, Dr. Patel said. A further doses) at 90 days. A second inclisiran dose at 90 days sus-
message from EUCLID, he added, is that caution needs to tained these reductions to day 180. The mean absolute change
be exercised in extrapolating evidence from coronary artery in LDL-C from baseline in the placebo group was 3.1%;
disease patients to peripheral artery disease. for inclisiran, it was 64.9% (two doses). Looking at the
A possible explanation for the discrepancy between 300-mg dose, Dr. Ray said that a single dose achieved a mean
CAPRIE and EUCLID results, commented AHA discussant LDL-C reduction of 51%, while two 300-mg doses achieved a
Carl Pepine, MD, from the University of Florida, could be 57% LDL-C reduction.
that clopidogrel is a prodrug that needs to be metabolized to Treatment-emergent adverse events at day 90 were reported
exert its antiplatelet action. EUCLID excluded patients who at similar levels for placebo (54%) and pooled inclisiran doses
were poor metabolizers of clopidogrel, perhaps accounting (54%; 100 mg [62%], 200 mg [52%], 300 mg [56%], 500 mg
for the equivalent effectiveness with ticagrelor. The signal [43%]). Severe adverse event rates were 4% for placebo and
for reduced stroke with ticagrelor may also be explained by 3% for inclisiran. Myalgia was reported in 4.7% and 5.7% of
concomitant blood pressure reduction, as was demonstrated placebo and inclisiran patients, respectively. Injection site
for ticagrelor versus clopidogrel in the DISPERSE-2 trial, adverse event (erythema, pruritus, rash, or reaction) rates
Dr. Pepine said. were 0% for placebo and 3.2% for the pooled inclisiran groups.
Clearly many knowledge gaps remain relative to PAD, The ndings, Dr. Ray commented, afrm potential for
he said, noting that PAD, which occurs in 10% of Americans biannual or triannual dosing and warrant continued evaluation
older than 60 years of age, is associated with higher risk for of inclisiran in a phase 3 trial. RNA interference with incli-
adverse outcomes, ostensibly through large atherosclerosis siran would be less expensive and has potential for sustained
risk factor burden, more diffuse atherosclerosis, enhanced suppression of hepatic PCSK9 production with fewer injections.
platelet activation, and inammation. The efcacy, safety, and dosing prole of inclisiran are likely
to ensure signicant and durable reductions in LDL-C and,
Inhibition of PCSK9 Synthesis via thus, potentially impact cardiovascular outcomes.
RNA Interference: 90-Day Data From
Orion-1A Multicenter, Phase 2, Cardiovascular Outcomes With Celecoxib Versus
Randomized, Controlled Trial Ibuprofen or Naproxen: The PRECISION Trial
Kausik K. Ray, MD, Imperial College, London, United Steven E. Nissen, MD, Cleveland Clinic, Cleveland, Ohio
Kingdom
Nonsteroidal anti-inammatory drugs (NSAIDs) and cele-
LDL-C [low-density lipoprotein-cholesterol] reduction is coxib (Celebrex, Pzer), a cyclooxygenase type-2 (COX-2)
a proven strategy to prevent atherosclerotic cardiovascular selective inhibitor, reduce pain and inammation through the
disease, Dr. Ray stated at an AHA press conference. While inhibition of prostaglandins in osteoarthritis and rheumatoid
monoclonal antibodies that block proprotein convertase arthritis patients. When rofecoxib, another COX-2 selective
subtilisin/kexin type 9 (PCSK9) have demonstrated signif- inhibitor, was withdrawn from the market in 2004 because of
icant LDL-C lowering with or without statins, the needed increased risks of heart attack and stroke associated with its
12 to 24 subcutaneous (SC) injections per year remain long-term, high-dosage use, the Food and Drug Administration
logistically and economically difcult. RNA interference, required a post-marketing cardiovascular safety trial comparing
Dr. Ray said, is a highly efcient approach to inhibiting the only remaining COX-2 selective inhibitor, celecoxib, with
PCSK9 synthesis in the liver, and in a phase 1 trial of 300 mg of traditional nonselective NSAIDs.
SC inclisiran in 69 patients, LDL-C was reduced by about 50% To meet that requirement and to address doubts about the
for four to six months. Inclisiran is a synthetic double-strand cardiovascular safety of COX-2 inhibitors, the PRECISION
2123mer oligonucleotide. trial was designed to evaluate the effects of celecoxib
The ORION-1 trial included 501 patients (mean age, (100200 mg twice daily) and ibuprofen (600800 mg three
approximately 63 years) with atherosclerotic cardiovascular times daily) compared with naproxen (375500 mg twice
disease or high atherosclerotic cardiovascular disease daily) on the rst occurrence of an Antiplatelet Trialists
risk with LDL-C greater than 70 mg/dL or 100 mg/dL, Collaboration (APTC) composite cardiovascular endpoint
respectively, despite maximally tolerated statin therapy. About (cardiovascular death, nonfatal myocardial infarction, or non-
69% of patients had atherosclerotic cardiovascular disease, fatal stroke). PRECISION included 24,081 patients at 924 sites in
and 24% had diabetes. Thirteen percent were being treated for 13 countries with osteoarthritis or rheumatoid arthritis and
primary prevention, and the rest had familial hyper- with or at high risk for concomitant cardiovascular disease.
cholesterolemia (5%). At baseline, 81% of patients were on Administration of aspirin 75100 mg daily was allowed accord-
statins, and 31.7% were on the cholesterol-lowering drug ing to local guidelines. Patients were provided with daily
ezetimibe (Zetia, Merck). esomeprazole for gastrointestinal protection.

51
The mean patient age was 63 9.4 years, 74.3% were white, 5.6 years of follow-up. Blood pressurelowering agents and
and 64.1% were female. Aspirin was administered at baseline rosuvastatin, however, did not signicantly prevent cogni-
to 51.1% of patients. The primary diagnosis was rheumatoid tive or functional decline. Study end DSST scores were simi-
arthritis in 10.1% of patients and osteoarthritis in 89.9%. Drug lar for individuals receiving blood pressure medications or
discontinuation rates were similar for all agents (approximately placebo (P = 0.86), statin lowering with rosuvastatin or placebo
69%). (P = 0.38), and the combination of blood pressure and cho-
Dr. Nissen reported that for the APTC endpoint, celecoxib lesterol lowering versus double placebo (P = 0.63). A post hoc
was noninferior to ibuprofen and naproxen in both intention- analysis among 93 patients revealed a positive trend toward
to-treat and in on-treatment analyses. Superiority analyses reduced cognitive decline in those in the highest tertile of
showed a borderline benet for celecoxib versus ibuprofen blood pressure and LDL cholesterol (greater than 145 mm Hg
for time to major adverse cardiovascular events (15%; P = 0.06) and greater than 140 mg/dL, respectively) at baseline. Longer
and for celecoxib versus naproxen for time from randomiza- duration of blood pressure lowering was also associated with
tion to all-cause mortality (25%; P = 0.052). Intention-to-treat less cognitive decline. Both of these ndings, Dr. Bosch
benets for celecoxib in time to major gastrointestinal event emphasized, require further conrmation.
were signicant compared with ibuprofen (54%; P = 0.002) and While anecdotal and observational studies have raised con-
with naproxen (41%; P = 0.01). Also, analysis of the time from cerns that statins may adversely affect cognition and have
randomization to a serious renal event showed a highly signi- led to black box warnings in statin labeling, she said, in this
cant benet for celecoxib versus ibuprofen (64%; P = 0.004). trial, administration of rosuvastatin had no adverse effects on
Dr. Nissen commented, Numerically fewer APTC events occurred cognitive function.
with celecoxib than with naproxen or ibuprofen, meeting all
four noninferiority criteria (P < 0.001).
These ndings challenge the widely held view that naproxen
Effect of Evolocumab on Progression of Coronary
provides superior cardiovascular safety, Dr. Nissen con- Atherosclerosis in Statin-Treated Patients: A
cluded. He added that between-drug differences should be Placebo-Controlled Intravascular Ultrasound Trial
viewed as hypothesis-generating rather than conclusive given
Steven E. Nissen, MD, Cleveland Clinic, Cleveland, Ohio
a multiplicity of issues and the challenges of adherence and
retention in the trial. 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
No Cognitive Decline Benet for intravascular ultrasound (IVUS) trials. The lowest LDL-C
Cholesterol or Blood Pressure in these trials has been about 60 mg/dL, Dr. Nissen said in
Lowering Among the Elderly in HOPE-3 an AHA press conference. He further noted that proprotein
convertase subtilisin/kexin type 9 (PCSK9) targets LDL
Jackie Bosch, PhD, McMaster University, Hamilton, Ontario, receptors for degradation, reducing hepatic removal of LDL-C
Canada from blood. PCSK9 inhibitors induce large LDL-C reduc-
Dementia, vascular cognitive impairment, vascular demen- tions and, when added to statins, allow very low LDL-C levels
tia, and cognitive aging are some of the biggest concerns of our to be reached. Effects on atheroma burden are unknown,
elderly and aging populations. Unfortunately, we dont have however.
any treatments or approaches that actually alter that risk, Evolocumab (Repatha, Amgen), a monoclonal antibody, is
said Ralph Sacco, MD, University of Miami Health System and a PCSK9 inhibitor administered by subcutaneous injection. In
former AHA President, the AHA-appointed discussant for this the Global Assessment of Plaque Regression With a PCSK9
trial. Despite many smaller studies showing strong relation- Antibody as Measured by Intravascular Ultrasound (GLAGOV)
ships between blood pressure, diabetes, and cholesterol control trial, 968 statin-treated patients with established coronary
and decreases in cognitive decline, randomized trials have not heart disease at 226 sites in 32 countries were randomized to
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 GLAGOV is the rst intravascular outcome trial testing the
trial design to address this question. effects of a PCSK9 inhibitor on the regression or progression
HOPE-3 randomized moderate-risk individuals from of coronary atherosclerosis as measured by intravascular
228 centers in 21 countries to receive either candesartan/ ultrasound. All patients in GLAGOV underwent an IVUS exami-
hydrochlorothiazide or placebo and rosuvastatin or placebo. nation of a single coronary artery during a clinically indicated
Dr. Boschs HOPE-3 trial substudy examined the effect of angiogram at baseline and at study end. The primary efcacy
cholesterol and blood pressure lowering on cognitive decline endpoint was the nominal change in percent atheroma volume
in the subset of 1,626 patients 70 years of age or older. from baseline to the poststudy IVUS.
Participants answered questions relative to decline in Mean patient age was 59.8 9.2 years, and 72% of
processing speed (primary outcome measured by the patients were male. Rates of current smoking and diabe-
Digit Symbol Substitution Test [DSST]), executive tes were 24.3% and 20.6%, respectively. Mean LDL-C was
function, psychomotor speed, functional changes, and 92.6 27.2 mg/dL, mean high-density lipoprotein-cholesterol was
global activity. 46.0 12.8 mg/dL, and median high sensitivity C-reactive
Cognitive and functional decline were observed over the protein was 1.61 mg/L.

Analysis showed steep reductions in LDL-C levels in the bleeding rates compared with standard-of-care triple therapy
PCSK9 inhibitor arm after 78 weeks (from 90 mg/dL to including a vitamin K antagonist among nonvalvular atrial
29 mg/dL; 59.8%). LDL-C levels in the placebo arm increased brillation patients who undergo PCI with stent placement.
by 3.9%. The primary endpoint of percent atheroma The 12-month xed-duration trial enrolled 2,124 patients in
volume increased by 0.05% in the statin plus placebo arm 26 countries at 426 sites. All had paroxysmal, persistent, or
and decreased by 0.95% in the statin plus evolocumab arm permanent nonvalvular atrial brillation and were undergoing
(P < 0.0001). Similarly, total atheroma volume decreased by PCI with stent placement. They were randomized in a 1:1:1
0.9 (P = NS) with statin monotherapy and by 5.8 in the statin ratio to rivaroxaban 15 mg every day plus a thienopyridine for
plus evolocumab arm (P < 0.0001). More patients in the statin 12 months, rivaroxaban 2.5 mg twice daily (with stratication
plus evolocumab arm had atheroma regression than in the to a prespecied duration of DAPT for one, six, or 12 months),
statin plus placebo arm (64% versus 47%; P < 0.0001). or dose-adjusted warfarin every day (with stratication to a
GLAGOV provides intriguing evidence that clinical prespecied duration of DAPT for one, six, or 12 months).
benets may extend to LDL-C levels as low as 20 mg/dL, The primary safety endpoint was clinically signicant bleeding
Dr. Nissen said, and no safety issues were identied at the mean (measured by the Thrombolysis in Myocardial Infarction scale
LDL-C level of 36.6 mg/dL. He cautioned, however, that the [major and minor bleeding] and whether bleeding required
modest sample size precludes rm safety conclusions, and medical attention).
large outcome trials for PCSK9 inhibitors are awaited. Dr. Gibson reported that clinically signicant bleeding
Benets of combination therapy in GLAGOV were observed occurred in 26.7% of patients receiving warfarin plus DAPT.
in patients with baseline LDL-C below the lowest levels In rivaroxaban plus DAPT patients, the bleeding rate was 18.0%
recommended by global guidelines (less than 70 mg/dL), (P < 0.001 versus DAPT plus warfarin). For those receiving
Dr. Nissen said. rivaroxaban plus a thienopyridine, the rate was 16.8%. The
number needed to treat (NNT) to prevent one bleeding event
Rivaroxaban and Dose-Adjusted Oral for the latter versus warfarin was 11. Major bleeding rates for
rivaroxaban plus a thienopyridine and warfarin plus DAPT
Vitamin K Antagonist Treatment Strategies were 2.1% and 3.3%, respectively (P = 0.234).
In Patients With Atrial Fibrillation Who For the secondary endpoint of combined rst occurrence of
Undergo Percutaneous Coronary Intervention cardiovascular death, myocardial infarction, or stroke, rates
were not signicantly different among the three treatment arms
C. Michael Gibson, MD, Beth Israel Deaconess Medical
(6.5% for rivaroxaban plus thienopyridine, 5.6% for rivaroxaban
Center, Boston, Massachusetts
plus DAPT, and 6.0% for warfarin plus DAPT).
Coronary artery disease and atrial brillation often occur The rivaroxaban arms had reduced rates of all-cause
together because of the strong association of both conditions death or hospitalization, with low NNTs to prevent one event
with aging and overlapping risk factors, Dr. Gibson said at an (rivaroxaban plus thienopyridine, NNT = 15; rivaroxaban plus
AHA press brieng. He further noted that among the more than DAPT, NNT = 10).
18,000 atrial brillation patients enrolled in the ARISTOTLE Among stented atrial brillation participants, administra-
trial, 24.9% had undergone prior percutaneous coronary tion of either rivaroxaban 15 mg daily plus a thienopyridine
interventions (PCIs). Optimal management of atrial brillation for one year or rivaroxaban 2.5 mg twice daily plus one, six, or
and acute coronary syndromes differ, however. While warfarin 12 months of DAPT reduced the risk of clinically signicant
is more effective for atrial brillation, the combination of aspirin bleeding as compared with standard of care warfarin plus
and a thienopyridine is more effective in patients who have had one, six, or 12 months of DAPT with comparable efcacy,
coronary stents implanted, Dr. Gibson said. Dr. Gibson concluded. Q
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 Search for P&T
anticoagulant plus dual antiplatelet therapy (DAPT) is typi- [Pharmacy and
cally administered. Prior randomized studies have suggested Attention Therapeutics]
that a dual-pathway therapeutic approach using a factor Xa
inhibitor and a single antiplatelet agent may be superior. The
Readers:
potential risk for clinically signicant bleeding from combin- P&T is on
ing DAPT with rivaroxaban remains uncertain, and the opti- @PTJournal780
mal combination and duration of therapy remain uncertain,
Facebook,
Dr. Gibson observed. Twitter, and
The PIONEER AF-PCI trial was an open-label, random- LinkedIn.
ized, controlled, multicenter study exploring two treatment Search for
strategies of rivaroxaban and a dose-adjusted oral vitamin K P&T in Groups
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

53
RESEARCH BRIEFS
Novel Screening Test Sparks diagnoses, which combine cellular, genetic, molecular, and
New Ideas About Old Drugs imaging information with clinical history.
Repurposing standard drugs and rethinking drug combinations The behavioral assessment would include three functional
may lead to more effective ways to combat drug-resistant bacteria, processes most relevant to addiction: altered perception of
according to ndings from a National Institutes of Health study. an object or event or incentive salience (where drug-taking
The researchers developed an assay to screen for effective- makes something seem more attractive or important); negative
ness and used it on 5,170 drugs and other biologically active emotionality (increased negative responses when drugs are
compounds. They identied 25 that suppress the growth of no longer available); and executive functioning (e.g., decits
two strains of Klebsiella pneumoniae that are resistant to most in organizing behavior toward goals).
antibiotics: 11 FDA-approved drugs and 14 drugs still under The assessment framework that we describe recognizes the
investigation, including antibiotics, antifungals, and antiseptics, great advances that continue to be made in our understand-
and an antiviral, antimalarial, and anticancer drug/compound. ing of the neuroscience of addiction, said NIAAA Director
They also looked for combinations of drugs and paired newly George Koob, PhD, a co-author of the review. These advances
identied drugs from the repurposing screen with a standard-of- underscore how much we know about the core neurobiological
care antibiotic that did not work by itself. They found four two- manifestations of addiction in people.
drug combinations that work against K. pneumoniae, meaning Source: National Institutes of Health, October 2016
ineffective antibiotics became active again in the presence of the
second drug. For instance, combining colistin with doxycycline, Flu Vaccine Offers Substantial
both antibiotics, reversed drug resistance. Benets to Diabetes Patients
They also tested three-drug combinations against 10 common Is it safe to give u vaccinations to patients with an impaired
strains of multidrug-resistant bacteria and found three different immune response, such as those with diabetes? The evidence
combinations of broad-acting antibiotics that were effective. For was both sparse and inconclusive, say researchers from Imperial
example, colistin/auranon/ceftazidime and colistin/auranon/ College London. But their seven-year study of 124,503 patients
rifabutin suppressed more than 80% of growth for all 10 strains. with type-2 diabetes suggests substantial benets.
Rifabutin/colistin/imipenem inhibited more than 75% of growth The study covered four periods in each cohort year: pre-
in all of the strains except two Acinetobacter baumannii isolates. inuenza, inuenza season, postinuenza, and summer. The
These results demonstrate that this assay has potential as outcome measures were hospital admissions for acute myocar-
a real-time clinical tool: The results are very promising, said dial infarction (MI), stroke, pneumonia, inuenza, and heart
Wei Zheng, PhD, one of the study authors. We think the test failure, as well as all-cause death.
can eventually help repurpose approved drugs and other com- During the study, there were 5,142 admissions for acute MI;
pounds and nd clinically relevant drug combinations that can 4,515 for stroke; 14,154 for pneumonia or inuenza; 12,915 for
be approved for use in different ways that we have never used heart failure; and 21,070 deaths.
before. Vaccine recipients were older and generally more ill; they
Source: National Institutes of Health, November 2016 had more coexisting conditions and were taking more medi-
cations than nonrecipients. However, vaccination was associ-
Assessing Addiction From Multiple Perspectives ated with signicant reductions in all of the outcomes during
Its time to change addiction assessment and build on the u season. After adjusting for residual confounding, the
advances in neuroscience, say scientists at the National Institute researchers found 19% lower rates of admissions for acute MI,
on Alcohol Abuse and Alcoholism (NIAAA). Theyve proposed 30% for stroke, 22% for heart failure, and 15% for pneumonia
an assessment tool to diagnose addictive disorders that takes or inuenza. The death rate for vaccinated patients was 24%
into account addiction-related behaviors, brain imaging, and lower than for nonrecipients.
genetic data. The Addictions Neuroclinical Assessment could That was during u seasonbut vaccination was also asso-
lead to more effective individualized treatments, they say. ciated with signicantly fewer events during the pre- and
We currently approach addiction diagnosis as a yes or no postinuenza seasons for all outcomes except for acute MI
proposition, said Laura Kwako, PhD, lead author of a review and pneumonia/inuenza in the preinuenza period.
article on the subject. Addictive disorders are typically classi- Concerns about the benets of inuenza vaccination in older
ed by the substance of abuse and the presence or absence of adults and patients with chronic illnesses affect the acceptance
symptoms, such as difculty controlling consumption. By lever- and uptake of vaccination, the researchers note. But their
aging knowledge of the neuroscience to identify a package ndings, they add, underline the importance of inuenza
of assessments, the researchers hope to more precisely iden- vaccination as part of comprehensive secondary prevention
tify different subtypes of addictive disorders. They compare in this high-risk population.
the new assessment tool with those used to tailor cancer Source: Canadian Medical Association Journal, October 2016

RESEARCH BRIEFS
Which Cancer Patients Can Best Survive the ICU? A Better Way to Predict
Because cancer is so complex, admitting a patient with cancer Colorectal Cancer Relapse?
to the intensive care unti (ICU) can be challenging triage. Often Carcinoembryonic antigen (CEA) is often used as a marker
the reason for the admission is acute complications related to for relapse in colorectal cancer (CRC). But in as many as 40%
the cancer or its treatment. Understanding how those complica- of recurrences, the serum CEA shows unmeasurable eleva-
tions might affect the patients outcome is critical to planning tions. And some patients with resected CRC have transient
care, gauging use of ICU resources, and counseling patients elevations of CEA levels; the false-positive rate during follow-
and their families. up has been as high as 16%, say researchers from Kaohsiung
Some studies have identied important determinants of mortal- Medical University in Taiwan. They propose a more powerful
ity, but the existing literature is scarce, say researchers who tool: a membrane array-based multigene biomarker assay,
studied outcomes in ICU patients with cancer. or biomarker chip, that detects circulating tumor cells in the
The researchers analyzed data from two cohort studies of peripheral blood.
1,737 patients with solid tumors and 291 with hematological The researchers conducted a study in 298 patients with CRC
malignancies. Of those, 456 (23%) had cancer-related compli- to test that alternative. The patients were enrolled after radical
cations at ICU admission, most frequently chemotherapy and curative resection for primary CRC tumor: 82 were stage I, 102
radiation therapy toxicity, venous thromboembolism (VTE), were stage II, and 114 were stage III. Patients were followed
and respiratory failure by tumor. for a median of 28.4 months, every three months for three
Patients with complications tended to have worse performance years, then every six months. At each follow-up visit, labora-
status scores and active disease. They also were more likely to tory studies included serum CEA levels. Elevated CEA levels
have more severe organ dysfunction, greater need for invasive were dened as two consecutive measurements greater than
support, and infection at ICU admission. 5 ng/mL at a three-month interval.
Complications were more frequent in patients with metastatic During the study period, 48 patients (16.1%) had postopera-
solid tumors, particularly lung and breast cancer (although less tive relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%)
common in patients with gastrointestinal [GI] tumors), and in had a total biomarker chip score higher than the cutoff value.
patients with more aggressive hematological malignancies, espe- Of the 48 who relapsed, 42 (87.5%) showed positive biochip
cially acute leukemia and aggressive non-Hodgkins lymphoma. results prior to relapse.
The study had several major ndings, the researchers say. The positive biochip results were signicantly associated with
First, one in four patients with cancer admitted to the ICU has postoperative relapse. In fact, the biomarker chip was better
acute complications related to the underlying cancer or treatment all around than postoperative serum CEA levels for predicting
side effects. However, while there were many cancer-related relapse: with higher sensitivity (87.5% versus 60.4%), specicity
complications and their prognostic impact was quite variable, (92.0% versus 83.2%), positive predictive value (67.7% versus
and despite high mortality rates, outcome in these patients was 40.8%), negative predictive value (97.5% versus 91.6%), and
better than perceived a priori, the researchers say. accuracy (91.3% versus 79.5%).
High sequential organ failure assessment score on the rst day Moreover, the biochip predicted relapse considerably
of ICU stay, worse performance status, and need for mechanical earlier than did CEA levels (10.7 versus 2.8 months). The
ventilation were all independent predictors of mortality, which is researchers note that CRC-related deaths are largely attribut-
in accord with current literature. However, among the individual able to clinical relapse. The sooner a relapse is diagnosed, the
cancer-related complications studied, only vena cava syndrome, more amenable the tumor may be to resection, increasing the
GI involvement, and respiratory failure were independently likelihood of long-term survival.
associated with in-hospital mortality. A substantial mortality In sum, the biomarker chip would be a more accurate tool
rate (73%) among patients with GI involvement emphasizes the for predicting relapse, the researchers say. They also suggest
importance of discussing the appropriateness of ICU admission that, in clinical practice, combining the two tests could enhance
in these patients, the researchers caution. Although VTE was condence in the diagnosis.
one of the most common complications, it was not a major Source: PLOS One, October 2016
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

55
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RAPIVAB (peramivir injection), for intravenous use
Initial U.S. Approval: 2014 -------------------------------DOSAGE FORMS AND STRENGTHS------------------------
Injection: 200 mg in 20 mL (10 mg/mL) in a single-use vial.
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RAPIVAB ------------------------------------CONTRAINDICATIONS-----------------------------------
safely and effectively. See full prescribing information for RAPIVAB. Patients with known serious hypersensitivity or anaphylaxis to peramivir or any
component of RAPIVAB.
----------------------------------INDICATIONS AND USAGE-------------------------------- --------------------------------WARNINGS AND PRECAUTIONS---------------------------

RAPIVAB is an inuenza virus neuraminidase inhibitor indicated for the treatment Cases of anaphylaxis and serious skin/hypersensitivity reactions such as Stevens-
of acute uncomplicated inuenza in patients 18 years and older who have been Johnson syndrome and erythema multiforme have occurred with RAPIVAB.
symptomatic for no more than two days. Discontinue RAPIVAB and initiate appropriate treatment if anaphylaxis or serious
skin reaction occurs or is suspected.
Limitations of Use: Neuropsychiatric events: Patients with influenza may be at an increased risk of
Efcacy based on clinical trials in which the predominant inuenza virus type was hallucinations, delirium and abnormal behavior early in their illness. Monitor for signs
inuenza A; a limited number of subjects infected with inuenza B virus were of abnormal behavior.
enrolled.
Consider available information on inuenza drug susceptibility patterns and ---------------------------------ADVERSE REACTIONS--------------------------------------
treatment effects when deciding whether to use. Most common adverse reaction (incidence >2%) is diarrhea.
Efcacy could not be established in patients with serious inuenza requiring
hospitalization. To report SUSPECTED ADVERSE REACTIONS, call 1-844-273-2327 or contact
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
---------------------------------DOSAGE AND ADMINISTRATION------------------------
Administer as a single dose within 2 days of onset of inuenza symptoms. ---------------------------------------DRUG INTERACTIONS---------------------------------
Recommended dose is 600 mg, administered by intravenous infusion for a minimum Live attenuated inuenza vaccine (LAIV), intranasal: Avoid use of LAIV within 2 weeks
of 15 minutes. before or 48 hours after administration of RAPIVAB, unless medically indicated.
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 --------------------------------USE IN SPECIFIC POPULATIONS---------------------------
10-29 mL/min is 100 mg. Pregnancy: Use if benet outweighs risk.
Hemodialysis: Administer after dialysis. Nursing mothers: Caution should be exercised when administered to a nursing
RAPIVAB must be diluted prior to administration. woman.
See the Full Prescribing Information for drug compatibility information. Revised: 8/2016
Seqirus USA Inc.

King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc. 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 Patients with influenza may be at an increased risk of hallucinations,
Rapivab (peramivir injection) is indicated for the treatment of acute delirium, and abnormal behavior early in their illness. There have
uncomplicated influenza in patients 18 years and older who have been been postmarketing reports (from Japan) of delirium and abnormal
symptomatic for no more than 2 days. behavior leading to injury in patients with influenza who were receiving
neuraminidase inhibitors, including Rapivab. Because these events were
Efficacy of Rapivab was based on clinical trials in which the predominant reported voluntarily during clinical practice, estimates of frequency
influenza virus type was influenza A; a limited number of subjects cannot be made, but they appear to be uncommon. These events were
infected with influenza B virus were enrolled. reported primarily among pediatric patients. The contribution of Rapivab
Influenza viruses change over time. Emergence of resistance to these events has not been established. Patients with influenza should
substitutions could decrease drug effectiveness. Other factors (for be closely monitored for signs of abnormal behavior.
example, changes in viral virulence) might also diminish clinical benefit Serious bacterial infections may begin with influenza-like symptoms
of antiviral drugs. Prescribers should consider available information or may coexist with or occur as complications during the course of
on influenza drug susceptibility patterns and treatment effects when influenza. Rapivab has not been shown to prevent such complications.
deciding whether to use Rapivab.
Efficacy could not be established in patients with serious influenza Adverse Reactions
requiring hospitalization. The most common adverse reaction was diarrhea (8% Rapivab vs
Contraindications 7% placebo).
Rapivab is contraindicated in patients with known serious hypersensitivity Lab abnormalities (incidence * 2%) occurring more commonly with Rapivab
or anaphylaxis to peramivir or any component of the product. Severe than placebo were elevated ALT 2.5 times the upper limit of normal (3% vs
allergic reactions have included anaphylaxis, erythema multiforme, and 2%), elevated serum glucose greater than 160 mg/dL (5% vs 3%), elevated
Stevens-Johnson syndrome. 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%).
Warnings and Precautions
Concurrent use with Live Attenuated Influenza Vaccine
Rare cases of serious skin reactions, including erythema multiforme, have been
reported with Rapivab in clinical studies and in postmarketing experience. Antiviral drugs may inhibit viral replication of a live attenuated influenza
Cases of anaphylaxis and Stevens-Johnson syndrome have been reported vaccine (LAIV). The concurrent use of Rapivab with LAIV intranasal has not
in postmarketing experience with Rapivab. Discontinue Rapivab and been evaluated. Because of the potential for interference between these
institute appropriate treatment if anaphylaxis or a serious skin reaction two products, avoid use of Rapivab within 2 weeks after or 48 hours before
occurs or is suspected. The use of Rapivab is contraindicated in patients administration of LAIV unless medically indicated.
with known serious hypersensitivity or anaphylaxis to Rapivab.
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

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

A Comparison of Medication Histories

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Olaratumab (Lartruvo) In patients who experience grade 1 or 2 IRRs, interrupt the

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INTRODUCTION EVOLUTION OF G-CSF endothelial cells. It regulates the pro-

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