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The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ May 2014

Volume 7, Number 3

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Hematology/Oncology Theme Issue EDITORIAL

Where Is the Fix? David B. Nash, MD, MBA

Payers’ Management of Oncology Drugs: Opportunities and Challenges James T. Kenney, Jr, RPh, MBA CLINICAL ™

Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study Kirk J. Wojno, MD; Frank J. Costa, MD; Robert J. Cornell, MD; Jeffrey D. Small, MD; Erik Pasin, MD; Wim Van Criekinge, PhD; Joseph W. Bigley, MSc; Leander Van Neste, PhD Stakeholder Perspective: Molecular Tests Can Help to Reduce Repeated Prostate Biopsies By Kelly Huang, PhD

Treatment Patterns, Survival, and Healthcare Costs of Patients with Malignant Gliomas in a Large US Commercially Insured Population Saurabh Ray, PhD; Machaon M. Bonafede, PhD, MPH; Nimish A. Mohile, MD Stakeholder Perspective: Treatment Decision in the Management of Malignant Gliomas By Jeffrey A. Bourret, PharmD, MS, BS, RPh, BCPS, FASHP  BUSINESS

Current Challenges in Health Economic Modeling of Cancer Therapies: A Research Inquiry Jeffrey D. Miller, MS; Kathleen A. Foley, PhD; Mason W. Russell, MAPE Stakeholder Perspective: Disruptive Innovation, Uncertain Value, and Economic Modeling in Oncology By Michael F. Murphy, MD, PhD

The Impact of 5-HT3RA Use on Cost and Utilization in Patients with ChemotherapyInduced Nausea and Vomiting: Systematic Review of the Literature Michael S. Broder, MD, MSHS; Claudio Faria, PharmD, MPH; Annette Powers, PharmD, MBA; Jehangeer Sunderji, MD; Dasha Cherepanov, PhD Stakeholder Perspective: The Value of Pharmaceuticals in the Prevention and Treatment of CINV By Atheer A. Kaddis, PharmD

©2014 Engage Healthcare Communications, LLC

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NOW

APPROVED!

First oral treatment FDA-approved for adults with active psoriatic arthritis Please see Important Safety Information on the adjacent page.


INDICATION Otezla® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Otezla is contraindicated in patients with hypersensitivity to apremilast or to components in its formulation. Depression was reported by patients taking Otezla, including serious depression. Some patients discontinued treatment due to depression. Weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, and in patients who develop such symptoms while on Otezla. Weight loss was reported in patients taking Otezla. Monitor body weight regularly. Concomitant use of Otezla with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended. The most common adverse reactions (≥5%) in clinical trials, and those most frequently leading to treatment discontinuation, were diarrhea, nausea, and headache. Otezla is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when Otezla is administered to a nursing woman. Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information. Please see Brief Summary of Full Prescribing Information on the following page.

Get the latest news at www.otezla.com

Otezla® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 04/14 USII-APR130013


Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary of the Prescribing Information; see Full Prescribing Information for complete product information. INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis. CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)]. WARNINGS AND PRECAUTIONS Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During the 0 to 16 weeks placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of patients while receiving OTEZLA, compared to none in placebo treated patients (0/495). In the clinical trials, two patients who received placebo committed suicide compared to none in OTEZLA treated patients. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. Weight Decrease: During the controlled period of the studies, weight decrease between 5-10% of body weight was reported in 10% (49/497) of patients treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse Reactions (6.1)]. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. ADVERSE REACTIONS Clinical Trials Experience in Psoriatic Arthritis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of the most common adverse reactions presented in Table 2 occurred within the first two weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.

Table 2: Adverse Reactions Reported in ≥ 2% of Patients on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Patients on Placebo For Up To Day 112 ( Week 16) Placebo

Preferred Term

OTEZLA 30 mg BID

Day 1 to 5 Day 6 to Day 112 Day 1 to 5 Day 6 to Day 112 (N=495) (N=490) (N=497) (N=493) n (%)c n (%) n (%) n (%)

Diarrhea a

6 (1.2)

8 (1.6)

46 (9.3)

38 (7.7)

Nauseaa

7 (1.4)

15 (3.1)

37 (7.4)

44 (8.9)

Headachea

9 (1.8)

11 (2.2)

24 (4.8)

29 (5.9)

Upper respiratory tract infectionb

3 (0.6)

9 (1.8)

3 (0.6)

19 (3.9)

Vomitinga

2 (0.4)

2 (0.4)

4 (0.8)

16 (3.2)

Nasopharyngitisb

1 (0.2)

8 (1.6)

1 (0.2)

13 (2.6)

Abdominal pain upperb

0 (0.0)

1 (0.2)

3 (0.6)

10 (2.0)

a

Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. b Of the reported adverse drug reactions none were serious. c n (%) indicates number of patients and percent.

Other adverse reactions reported in patients on OTEZLA were hypersensitivity, weight decrease, frequent bowel movement, gastroesophageal reflux disease, dyspepsia, decreased appetite*, migraine, cough, and rash. *1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction. DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C : OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1493 patients who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146 psoriatic arthritis patients were 65 years of age and older, including 19 patients 75 years and older. No overall differences were observed in the safety profile of elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies. Renal Impairment: OTEZLA pharmacokinetics were not characterized in subjects with mild (creatinine clearance of 60-89 mL per minute estimated by the Cockroft– Gault equation) or moderate (creatinine clearance of 30-59 mL per minute estimated by the Cockroft–Gault equation) renal impairment. The dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockroft– Gault equation) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in subjects with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients. OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose. Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademarks of Celgene Corporation. Pat. www.celgene.com ©2014 Celgene Corporation, All Rights Reserved.

OTZPBS.001 03/14


editorial board Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia Aging and Wellness

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director, Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc. Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

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May 2014

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc. New York, NY

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

Personalized medicine

SPECIALTY PHARMACY

PAYER-PROVIDER FINANCES

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia PHARMACOECONOMICs

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT

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Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

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may 2014

Volume 7, number 3 The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

Table of Contents Hematology/Oncology Theme Issue EDITORIAL

116 Where Is the Fix? David B. Nash, MD, MBA  INTRODUCTION

121 Cancer Care in 2014: Continuing Challenges, New Opportunities Dalia Buffery, MA, ABD  Perspective

123 Payers’ Management of Oncology Drugs: Opportunities and Challenges James T. Kenney, Jr, RPh, MBA CLINICAL

129 R  educed Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study Kirk J. Wojno, MD; Frank J. Costa, MD; Robert J. Cornell, MD; Jeffrey D. Small, MD; Erik Pasin, MD; Wim Van Criekinge, PhD; Joseph W. Bigley, MSc; Leander Van Neste, PhD 134 Stakeholder Perspective: Molecular Tests Can Help to Reduce Repeated Prostate Biopsies By Kelly Huang, PhD Continued on page 115

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Volume 7, number 3 The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued)

140 Treatment Patterns, Survival, and Healthcare Costs of Patients with Malignant Gliomas in a Large US Commercially Insured Population Saurabh Ray, PhD; Machaon M. Bonafede, PhD, MPH; Nimish A. Mohile, MD 149 Stakeholder Perspective: Treatment Decision in the Management of Malignant Gliomas By Jeffrey A. Bourret, PharmD, MS, BS, RPh, BCPS, FASHP BUSINESS

153 Current Challenges in Health Economic Modeling of Cancer Therapies: A Research Inquiry Jeffrey D. Miller, MS; Kathleen A. Foley, PhD; Mason W. Russell, MAPE 161 Stakeholder Perspective: Disruptive Innovation, Uncertain Value, and Economic Modeling in Oncology By Michael F. Murphy, MD, PhD 171 The Impact of 5-HT3RA Use on Cost and Utilization in Patients with ChemotherapyInduced Nausea and Vomiting: Systematic Review of the Literature Michael S. Broder, MD, MSHS; Claudio Faria, PharmD, MPH; Annette Powers, PharmD, MBA; Jehangeer Sunderji, MD; Dasha Cherepanov, PhD 181 Stakeholder Perspective: The Value of Pharmaceuticals in the Prevention and Treatment of CINV By Atheer A. Kaddis, PharmD

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@engagehc.com Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits 1249 South River Rd, Suite 202A Cranbury, NJ 08512 The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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Editorial

Where Is the Fix? David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits Jefferson School of Population Health, Philadelphia, PA

W

hen 2 leaders in the healthcare field, coming from entirely different perspectives, arrive at the same conclusion, it’s time to pay attention. Please allow me to explain. Lawrence P. Casalino, MD, PhD, is the Livingston Farrand Associate Professor of Public Health and Chief of the Division of Outcomes and Effectiveness Research at the Weill Cornell Medical College in New York City. Dr Casalino has been a prolific contributor to the literature in health services research and our paths have crossed several times, most recently when we cohosted a Commonwealth Fund’s Harkness Fellow from the United Kingdom. Jeffrey Brenner, MD, has risen to national prominence as a recent MacArthur Fellow Genius Grant awardee, as well as the Executive Director and Founder of the Camden Coalition of Healthcare Providers, a nonprofit organization committed to delivering better care at lower costs in Camden, NJ, one of America’s poorest cities. In their separate, recent publications, they came to the identical conclusion. Dr Casalino’s article was published by the Agency for Healthcare Research and Quality (AHRQ) in February 2014, and was based on a February 2011 presentation at an AHRQ conference entitled, “The Challenge and Promise of Delivery System Research.”1 Dr Brenner’s conclusion was written in his GrantWatch blog dated February 18, 20142—within days of the publication of Dr Casalino’s article. Despite spending hundreds of billions of dollars in biomedical research, which is largely funded through the National Institutes of Health (NIH), and spending nearly 18% of the US gross domestic product (the world’s largest economic engine) on healthcare, we still have “little understanding of how to deliver better care at lower cost to every American…and we do not understand the fundamental drivers of healthcare utilization; the basic rules for designing and implementing effective interventions; the best ways to use data to plan, implement, manage, and evaluate interventions; nor how to train staff to run and lead these interventions.”2 In his AHRQ synthesis article, Dr Casalino expresses pretty much the same idea, but he obviously has to cast it in a different light, because of the support from the AHRQ. In his article, he concludes that, “the discoveries

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of basic scientific and clinical research have no impact on patients’ health unless they are used effectively by the healthcare delivery system.”1 To improve quality and to contain costs, Dr Casalino recommends that “research should focus on (1) identifying the types of organizations that are high performing; (2) identifying the types of incentives that induce these organizations to continually improve care; and (3) identifying the types of incentives likely to lead to the creation of more high-performing organizations and to physicians and other providers becoming members of high-performing organizations.”1 I think Dr Brenner and Dr Casalino would agree that it is the culture that makes the difference, and a core component of the culture is the leadership that motivates these organizations. In other words, although the awesome biomedical research engine represented by the NIH and the health services research engine represented by the AHRQ are certainly the envy of the world, what value do we have to show for this investment? When the United States ranks number 17 in the world (behind Slovenia) with regard to the quality of life of our citizenry, I would argue that we have not achieved a great return on this sizable investment.3 We need a new type of research framework. The questions become what should be the components of this research framework, and who ought to drive it? Dr Casalino eloquently describes what the components of the new research framework should be. He has gone so far as to establish the criteria for selecting the priority areas for delivery system research, and these are detailed in his article.1 It should come as no surprise to our readers that Dr Casalino considers the critical framework to involve an evaluation of accountable care organizations, patient-centered medical homes, and other components of the Affordable Care Act. I have discussed many aspects of this exact challenge in this column previously. Dr Casalino goes on to ask probing framework-like questions regarding “what effects, if any, does the structure, process, or incentive have on areas for care not directly related to it? For example, do large organizations score better on typical measures of quality but not on areas of quality that are not typically measured (eg, timely diagnosis)?”

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Editorial

I concur with most of the framework discussion articulated by Dr Casalino. So where should this new work occur, and who should support it? Dr Brenner is seeking a “scientific revolution of better care at lower cost,” and he declares that the revolution will not be led by academic health centers alone, because they are at risk of losing too much.2 He believes that “the underpinnings of their financial model would collapse if their unneeded bed capacity went occupied.” Finally, Dr Brenner proposes that the creation and support of industrial population health research laboratories in disparate locations across the country be funded by private foundations. This industrial population health resource, as he describes it, would be led by community-wide, nonprofit organizations with broad stakeholder and community support. Local hospitals may be participants in this process.2 I have tremendous respect for both Dr Casalino and Dr Brenner. I believe that they have come, largely, to the same conclusion—it is the system. We desperately need more insight as to what will deliver the greatest care at the highest level of value to the largest number of patients. However, I do not agree with Dr Brenner that a local coalition of not-for-profit organizations is going to make it work. Nor do I agree with Dr Casalino that more AHRQ funding is the answer to gaining a better understanding of the culture and leadership. I think they are both off the mark in this regard. My own view is to “let 1000 flowers bloom.” Let the private sector, driven by powerful and inexorable market forces, recreate the healthcare system. Let private organizations build the platforms to create population

Although the awesome biomedical research engine represented by the NIH and the health services research engine represented by the AHRQ are certainly the envy of the world, what value do we have to show for this investment? When the United States ranks number 17 in the world (behind Slovenia) with regard to the quality of life of our citizenry, I would argue that we have not achieved a great return on this sizable investment. health registries, create the companies that will deliver economic incentives for patients to change their behavior, and ultimately, and perhaps in a messy way, we will get to a population health agenda that our nation so desperately deserves. As always, I am interested in your views, and you can reach me via e-mail at david.nash@jefferson.edu. n

References

1. Casalino LP. Identifying key areas for delivery system research. AHRQ Publication No. 14-0024-EF. February 2014. www.ahrq.gov/professionals/systems/system/deliverysystem-initiative/casalino/paper/casalino_idkeydsr.pdf. Accessed April 29, 2014. 2. Brenner J. A world of darkness: what if Thomas Edison had to write grant proposals to invent the light bulb? GrantWatch. February 18, 2014. http://healthaffairs.org/ blog/2014/02/18/a-world-of-darkness-what-if-thomas-edison-had-to-write-grantproposals-to-invent-the-light-bulb/?cat=grantwatch. Accessed April 29, 2014. 3. National Research Council (US); Institute of Medicine (US); Woolf SH, Aron L, eds. U.S. Health in International Perspective: Shorter Lives, Poorer Health. Washington, DC: National Academies Press (US); 2013. www.ncbi.nlm.nih.gov/books/NBK115854/ pdf/TOC.pdf. Accessed April 29, 2014.

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MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

Jakafi is a registered trademark of Incyte Corporation. © 2014, Incyte Corporation. All rights reserved. RUX-1329c 01/14

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Tuberculosis (TB) has been reported; attention should be given to the possibility of latent or active TB. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate


The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

50

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

40

Patients (%)

50

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30

10

0.7

Placebo (n = 152)

20

5.3

P < 0.0001

0

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2 V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus-associated kinase.

• Advise patients about early signs and symptoms of herpes zoster and to seek early treatment • The three most frequent non‐hematologic adverse reactions were bruising, dizziness and headache • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.


Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Jakafi is a registered trademark of Incyte Corporation. All rights reserved. U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved. Issued: November 2013 RUX-1326


INTRODUCTION

Cancer Care in 2014: Continuing

Challenges, New Opportunities Dalia Buffery, MA, ABD Editorial Director, American Health & Drug Benefits

C

ancer continues to be a major clinical area attracting investment in research and development for new therapeutics and new diagnostics, as well as a significant driver for innovation in care delivery and a patient-focused, value-based approach to care. Immunotherapies are rapidly becoming an enhanced focus for research, as better understanding of the biology of cancer is increasing the pool of patients who can benefit from these new developments. In tandem, patient navigation and survivorship programs are providing opportunities for improved quality of life for patients with cancer, as many now live longer through improved therapies, and as tumor remission and extended periods of disease-free survival are becoming a reality for an ever-growing number of patients. The rapid discovery of new biomarkers and advancements in molecular sequencing and diagnostic modalities are gradually encouraging cancer researchers to focus on subpopulations of patients, charting a clear pathway for personalized medicine, despite ongoing doubts about the applicability of this approach in the real world. But all this new energy and increased innovations do not come “cheap.” The cost of cancer care continues to be a top concern for patients, payers, and policymakers, while reimbursement issues are taking center stage for the entire cancer care team. The growing economic challenges in the face of great strides in oncology management might have led the American Society of Clinical Oncology (ASCO) to issue its first-ever comprehensive report on the current state of cancer to the nation in a publication titled “The State of Cancer Care in America, 2014.”1 In addition to its “recommendations for addressing the cancer care delivery system’s most pressing concerns, this landmark ASCO report also examines the rapid expansion of health information technology and the growing emphasis on quality measurement and value.”2 The present annual oncology/hematology theme issue from American Health & Drug Benefits highlights some of these top concerns, addressing issues facing the oncology community in 2014 from a variety of perspectives. The rapid approvals of new therapies and novel diagnostics for cancer by the US Food and Drug Administration (FDA)—as evidenced by the growing number of so-called breakthrough therapies for cancer approved by

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the FDA, and the agency’s frequent use of the priority review process to accelerate patient access to new and improved drugs— have shifted the focus of cancer drug management from traditional pharmacy benefit management to specialty pharmacy, where the majority of new oncolytics are increasingly being managed. This growth in oncology specialty pharmaceuticals has created a significant management challenge for health plans and an opportunity for innovation, says James T. Kenney, Jr, RPh, MBA, in his perspective in this issue. Innovation is also the focus of the article by Jeffrey D. Miller, MS, and his team of health economics researchers. They issue a call to action for the health economics community, noting that as innovative, yet high-cost, therapies for cancer continue to come to market, the need for economic modeling is growing as a way of providing better insight into the meaning of “value”—perhaps the most prevalent word in 2014 used to define the current focus on quality and cost in cancer care. However, Mr Miller and his colleagues suggest that serious methodologic and policy challenges are facing modeling-­ based analyses as a decision-making tool in oncology; the team is inviting researchers and other members of the oncology community to take part in this discussion and to help promote these complex pharmacoeconomic concerns in an attempt to chart new directions toward improved decision-making based on cost, quality, and value considerations. Saurabh Ray, PhD, and colleagues offer insight into the treatment and cost of glioblastoma multiforme—the most common and malignant brain tumor in adults—a malignancy associated with challenging treatment issues and poor survival, leaving much room for innovation and further research. The authors raise questions about the cost-effectiveness of the current standard of therapy for this disease, which involves radiotherapy in combination with temozolomide. As can be expected, the use of this expensive drug in the treatment regimen adds significant costs, but, as Dr Saurabh and colleagues show, the median survival time is highest in patients who receive neither temozolomide nor radiation therapy. Additional cost-­ effectiveness and quality-of-life analyses, the authors suggest, are critical to better understand the role of temozolomide in this patient population and to improve outcomes.

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INTRODUCTION

Kirk J. Wojno, MD, and colleagues discuss the issue of repeated biopsies that are often used in connection with the diagnosis of prostate cancer. As an invasive procedure, a prostate biopsy places the patient at risk for complications and is subject to significant sampling errors. Dr Wojno and his team provide data from a small study in a real-world setting investigating the use of an epigenetic test—which is currently being used in clinical practice— as a means to assess the need for repeated biopsy in men with no history of prostate cancer. Based on the data from several urology groups in the United States, men who had a negative result on the epigenetic test had a <5% rate of repeated prostate biopsies, suggesting a potential 10-fold reduction in repeated biopsies compared with the current rates. This type of epigenetic testing, the authors conclude, can help to reduce the number of unnecessary repeated biopsies for the diagnosis of prostate cancer, the most common type of cancer in men. Finally, Michael S. Broder, MD, MSHS, and his colleagues conducted the first systematic review of the published literature to investigate the economic burden of prophylactic therapy for chemotherapy-induced nausea and vomiting (CINV), an ongoing topic of concern with any type of chemotherapy, despite new developments in oncology drugs. The risk for CINV continues even with new therapies, and proper management is key to improved patient quality of life and the control of significant side effects associated with current chemotherapy. Based on the data from clinical studies, Dr Broder and colleagues suggest that significant differences exist among the different therapies available for the prevention and management of CINV. Furthermore, the costs of these therapies vary signifi-

cantly, but cost alone cannot determine the selection of the prophylactic agent, because a more expensive therapy may actually result in lower overall costs when considering the cost of uncontrolled CINV side effects. This first systematic analysis of the impact of prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for CINV on cost and utilization shows that the use of palonosetron for CINV prophylaxis is indeed associated with higher total acquisition costs but also with lower use of rescue medications and lower outpatient and inpatient utilization compared with other 5-HT3RAs in the United States. In addition, they note that the use of palonosetron is recommended as the preferred 5-HT3RA agent by the majority of oncology societies and organizations in the United States and Europe, reflecting its superior outcomes, which therefore result in reduced utilization and lower costs overall. This sample of articles offers insight into the type of challenges, some old and some new, facing the oncology team today—all indicating a need for innovation in the search for new solutions. Applying the results and implications of health economics research in oncology into everyday patient care can provide new opportunities to improve patient outcomes and reduce healthcare costs. We invite your comments, perspectives, and letters related to this collection of articles. Submit your correspondence at www.AHDBonline.com. n

References

1. American Society of Clinical Oncology. The state of cancer care in America, 2014: a report by the American Society of Clinical Oncology. J Oncol Pract. 2014;10: 119-143. 2. American Society of Clinical Oncology. The state of cancer care in America. www.asco.org/practice-research/cancer-care-america. Accessed May 14, 2014.

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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perspective

Payersâ&#x20AC;&#x2122; Management of Oncology Drugs: Opportunities

and Challenges

By James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

T

he increased approvals and rising costs of specialty pharmacy drugs have created a significant management challenge for health plans. The 3 primary disease areas that account for the majority of the specialty drug spending include autoimmune disorders, multiple sclerosis, and cancer.1 The category of oncology has seen exponential growth over the past few years, with more than 900 products currently in clinical trials for oncology, including a large number of oral agents.2 Traditionally, health plans have not applied utilization management approaches to cancer care; however, over the past 1 to 2 years, health plans have begun to focus on opportunities to manage oncology drugs in the outpatient setting.3 The implementation of federal healthcare reform, combined with increased pressure on plans to reduce costs to remain competitive in the market, comply with state and federal regulations, and achieve improved clinical outcomes, have prompted this shift in focus. A key factor influencing the management of oncology treatments has been the development of targeted therapies for many cancers, including chronic myelogenous leukemia and multiple myeloma.3 Although the number of patients with these cancers is relatively small compared with more prevalent cancersâ&#x20AC;&#x201D;such as breast, prostate, lung, and colorectalâ&#x20AC;&#x201D;the drugs used to treat these smaller populations have a high cost and have prompted health plans to take a more active role in their management. Diagnostic testing in oncology is becoming more common to identify patients who are appropriate candidates for a specific drug, as well as to measure efficacy and determine whether a drug should continue to be used for the individual patient, or if the patient should be switched to a different treatment regimen.3 Health plans can therefore incorporate diagnostic testing requirements into oncology management programs to achieve more predictable results while not compromising clinical value. The coverage for oncology drugs is administered via the medical and the pharmacy benefits, and each health plan applies coverage criteria based on its unique benefit de-

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signs and health insurance products.4 Pharmacy benefits have been well-defined, and traditional utilization management controls have been effectively applied across the majority of therapeutic classes and disease areas, with oncology as a primary exception. Medical benefits that include coverage for physician-administered drugs have been largely unmanaged and often are provided with little or no out-of-pocket drug cost to the patient. Recent trends in the market have suggested that health plans should move physician-administered drugs covered under the medical benefit to the pharmacy benefit, where greater controls can be applied, and real-time utilization management can be applied to maximize cost control and limit inappropriate use. However, it is important to understand that in such a case, the drugs do not change their benefit classification, but rather the drugs under the medical benefit are moving to a pharmacy management model that may include specialty pharmacy distribution, while the costs continue to be applied to the medical benefit.4 Benefit designs are evolving to assist in the management of drugs across the medical and pharmacy benefits, with increased out-of-pocket costs to patients for drugs under both benefits.3 Oncology drugs may be covered by state oral chemotherapy parity legislation that requires equal treatment of drugs under the medical and pharmacy benefits. Patients cannot pay more for drugs covered with one benefit than with the other. Additional state mandates that require coverage for the off-label use of oncology drugs place more pressure on pharmacy managers to control costs and to limit exposure for unproved therapies.3 Health plans must now manage select cancers as chronic diseases with long-term treatment requirements and exclusive sole-source branded agents as the standard of care. Specialty pharmacies play a key role in managing the distribution of oncology drugs under the pharmacy benefit and in promoting their appropriate use and offering compliance and adherence programs. According to Atheer A. Kaddis, PharmD, Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, several health plans that use

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perspective

Diplomat Specialty Pharmacy as one of their providers have implemented a cycle control or a split-fill program, in which the patient receives a small, 7- to 14-day supply of an oral cancer medication to determine whether the patient can tolerate it. Patients who tolerate the oral drug are then given the remaining monthly supply, without any additional copay requirement, and subsequent fills can be provided in 30-day quantities.

The extensive development of new drugs, increased availability of diagnostics, and the level of competition in cancer types will drive plans to make difficult and prudent choices to achieve cost-effective outcomes across many cancers while striving for the best clinical outcomes. Another area of interest in cancer drugs management involves the use of clinical pathways to drive utilization to a preferred sequence of drugs for a particular cancer. This involves coordination among the health plan, the oncologist, and the pharmacy to ensure that patients receive the right mix of drugs to comply with the pathway. Providers can be paid under a global cap or on a case-mix basis, with incentives to expeditiously treat the patient and lower overall costs, and the net savings shared be-

tween the provider and the health plan. Utilization management by health plans is driven by the desire to encourage appropriate use, promote preferred medications, and limit financial exposure to the most cost-effective therapies. Many options for drug utilization management are used today, including prior authorization, step therapy, case management, quantity limits, split-fill programs, and increased cost-sharing by the patients. The need to apply utilization management to drug therapy must be balanced with the importance of achieving the best outcomes while maintaining quality and reducing medical resource utilization. Although oncology is not heavily managed by health plans today, the extensive development of new drugs, increased availability of diagnostics, and the level of competition in cancer types will drive plans to make difficult and prudent choices to achieve cost-effective outcomes across many cancers while striving for the best clinical outcomes. n

References

1. Express Scripts. The 2013 Drug Trend Report. April 2014. http://lab.express-scripts. com/~/media/pdfs/drug%20trend%20report/express%20scripts%202013%20 drug%20trend%20report.ashx. Accessed May 8, 2014. 2. Pharmaceutical Research and Manufacturers of America. Medicines in Development: Cancer. May 31, 2012. www.phrma.org/sites/default/files/pdf/phrmamedicines indevelopmentcancer2012.pdf. Accessed May 8, 2014. 3. Magellan Rx Management. Medical Pharmacy Trend Report 2013. Fourth Edition. 2014. http://magellanrxinsights.com/wp-content/uploads/dlm_uploads/2014/04 Magellan-Rx-Management_Trend-Report_2013.pdf. Accessed May 8, 2014. 4. CVS Caremark. Specialty trend management: where to go next. Insights 2013. http:// info.cvscaremark.com/sites/default/files/Insights%202013.pdf. Accessed May 8, 2014.

Call for Papers American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Employers, Manufacturers, Patients, Payers, Policymakers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations.

Areas of High Interest: • • • • • • • •

Adherence Concerns Benefit Design Case Studies Comorbidities and Cost Issues Comparative Effectiveness Research Decision-Making Tools Ethics in Medicine Health Economics Research

• • • • • • • •

Health Information Exchange Health Plan Initiatives Innovations in Healthcare Literature Reviews Managed Care Medicare/Medicaid Patient Outcomes/Advocacy Pharmacoeconomics

• Pharmacogenomics • Policy Issues • Prevention Initiatives • Real-World Evidence • Reimbursement Strategies • Social Media in Healthcare • Survey Results • Value-Based Healthcare

Manuscripts should follow the Manuscript Instructions for Authors available at www.AHDBonline.com.

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1st oral kinase inhibitor for previously treated CLL

NOW APPROVED NEW

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

1 daily dose

FOR PREVIOUSLY TREATED CLL INDICATION - IMBRUVICA™ is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily. The mechanism for the bleeding events is not well understood. IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly. Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 02/14 PRC-00286

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas. Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA™. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. ADVERSE REACTIONS – MCL: The most commonly occurring adverse reactions (≥20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). *Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions. The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%). *Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA™ dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIAL POPULATIONS - Hepatic Impairment Avoid use in patients with baseline hepatic impairment.


Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly. Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration. Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas. Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

IMBRUVICATM (ibrutinib) capsules The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Infections and Upper respiratory tract infestations infection Urinary tract infection Pneumonia Skin infections Sinusitis General disorders and Fatigue Peripheral edema administrative site Pyrexia conditions Asthenia Bruising Skin and subcutaneous tissue Rash Petechiae disorders Musculoskeletal and Musculoskeletal pain Muscle spasms connective tissue Arthralgia disorders Respiratory, thoracic Dyspnea Cough and mediastinal Epistaxis disorders Metabolism and Decreased appetite nutrition disorders Dehydration Nervous system Dizziness disorders Headache

Gastrointestinal disorders

All Grades Grade 3 or 4 (%) (%) 5 51 0 31 0 25 5 24 0 23 1 17 0 11 0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

57

17

Neutrophils Decreased

47

29

Hemoglobin Decreased

41

9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.


IMBRUVICATM (ibrutinib) capsules

IMBRUVICATM (ibrutinib) capsules

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain. Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48) All Grades Grade 3 or 4 (%) (%)

System Organ Class

Preferred Term

Gastrointestinal disorders

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia

63 23 21 21 19 15 13

4 2 2 0 2 0 0

Infections and infestations

Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection

48 21 17 10 10

2 6 6 8 0

General disorders and administrative site conditions

Fatigue Pyrexia Peripheral edema Asthenia Chills

31 25 23 13 13

4 2 0 4 0

Skin and subcutaneous tissue disorders

Bruising Rash Petechiae

54 27 17

2 0 0

Respiratory, thoracic Cough Oropharyngeal pain and mediastinal Dyspnea disorders

19 15 10

0 0 0

Musculoskeletal and Musculoskeletal pain Arthralgia connective tissue Muscle spasms disorders

27 23 19

6 0 2

Nervous system disorders

Dizziness Headache Peripheral neuropathy

21 19 10

0 2 0

Metabolism and nutrition disorders

Decreased appetite

17

2

Neoplasms benign, malignant, unspecified

Second malignancies*

10*

0

Injury, poisoning and procedural complications

Laceration

10

2

10 10

0 0

17

8

Psychiatric disorders Anxiety Insomnia Vascular disorders

Hypertension

*One patient death due to histiocytic sarcoma. Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) Percent of Patients (N=48) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

71

10

Neutrophils Decreased

54

27

Hemoglobin Decreased

44

0

* Based on laboratory measurements per IWCLL criteria and adverse reactions

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients). Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].


IMBRUVICATM (ibrutinib) capsules Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 PRC-00320

Issued: February 2014


Clinical

Original Research

Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study Kirk J. Wojno, MD; Frank J. Costa, MD; Robert J. Cornell, MD; Jeffrey D. Small, MD; Erik Pasin, MD; Wim Van Criekinge, PhD; Joseph W. Bigley, MSc; Leander Van Neste, PhD Background: The diagnosis of prostate cancer is dependent on histologic confirmation in biopsy core tissues. The biopsy procedure is invasive, puts the patient at risk for complications, and is subject to significant sampling errors. An epigenetic test that uses methylation-specific polymerase chain reaction to determine the epigenetic status of the prostate cancerâ&#x20AC;&#x201C;associated genes GSTP1, APC, and RASSF1 has been clinically validated and is used in clinical practice to increase the negative predictive value in men with no history of prostate cancer compared with standard histopathology. Such information can help to avoid unnecessary repeat biopsies. The repeat biopsy rate may provide preliminary clinical utility evidence in relation to this assayâ&#x20AC;&#x2122;s potential impact on the number of unnecessary repeat prostate biopsies performed in US urology practices. Objective: The purpose of this preliminary study was to quantify the number of repeat prostate biopsy procedures to demonstrate a low repeat biopsy rate for men with a history of negative histopathology who received a negative epigenetic assay result on testing of the residual prostate tissue. Methods: In this recently completed field observation study, practicing urologists used the epigenetic test called ConfirmMDx for Prostate Cancer (MDxHealth, Inc, Irvine, CA) to evaluate cancer-negative men considered at risk for prostate cancer. This test has been previously validated in 2 blinded multicenter studies that showed the superior negative predictive value of the epigenetic test over standard histopathology for cancer detection in prostate biopsies. A total of 5 clinical urology practices that had ordered a minimum of 40 commercial epigenetic test requisitions for patients with previous, cancer-negative biopsies over the course of the previous 18 months were contacted to assess their interest to participate in the study. Select demographic and prostate-screening parameter information, as well as the incidence of repeat biopsy, specifically for patients with a negative test result, was collected and merged into 1 collective database. All men from each of the 5 sites who had negative assay results were included in the analysis. Results: A total of 138 patients were identified in these urology practices and were included in the analysis. The median age of the men was 63 years, and the current median serum prostate-specific antigen level was 4.7 ng/mL. Repeat biopsies had been performed in 6 of the 138 (4.3%) men with a negative epigenetic assay result, in whom no evidence of cancer was found on histopathology. Conclusion: In this study, a low rate of repeat prostatic biopsies was observed in the group of men with previous histopathologically negative biopsies who were considered to be at risk for harboring cancer. The data suggest that patients managed using the ConfirmMDx for Prostate Cancer negative results had a low rate of repeat prostate biopsies. These results warrant a large, controlled, prospective study to further evaluate the clinical utility of the epigenetic test to lower the unnecessary repeat biopsy rate.

P

rostate cancer is the most frequently detected cancer in men, and approximately 16% of men are diagnosed with prostate cancer during their lifetime.1

Stakeholder Perspective, page 134 Am Health Drug Benefits. 2014;7(3):129-134 www.AHDBonline.com Disclosures are at end of text

Although the overall value of routine screening, resulting in approximately 1 million annual prostate biopsy procedures, has been recently questioned, the mortality

Dr Wojno is Director of Pathology at Comprehensive Urology, Royal Oak, MI; Dr Costa is Director at the Urology Institute of Pittsburgh, Monroeville, PA; Dr Cornell is Urologist, General Adult and Prosthetic Urology, Houston, TX; Dr Small is Urologist, Adult and Pediatric Urology, Yale, New Haven Health System, Bridgeport Hospital, CT; Dr Pasin is Urologist at Skyline Urology, Laguna Hills, CA; Dr Van Criekinge is CSO at MDxHealth Inc, Irvine, CA, and Professor at the University of Ghent, Belgium; Mr Bigley is Senior Vice President of Clinical Affairs at MDxHealth Inc, Irvine, CA; and Dr Van Neste is Director of Scientific Affairs and Research at MDxHealth Inc, Irvine, CA, and Assistant Professor at the University of Maastricht, The Netherlands.

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Clinical

Key Points Prostate cancer is the most often diagnosed cancer in men; its diagnosis is dependent on histologic confirmation with a core-tissue biopsy. ➤ As a result of the well-reported sampling errors using transrectal ultrasound–guided biopsies, many cancers are unsampled and hence undetected by histopathologic review. ➤ In the presence of persistent risk factors (eg, elevated PSA), repeat prostate biopsies are frequently used to detect occult cancer in men with previous negative findings, leading to unnecessary morbidity and increased healthcare costs. ➤ Previous studies on repeated biopsy procedures have shown that initial prostate biopsy histopathology has a 20% to 30% false-negative rate. ➤ Based on real-world data from 5 US urology practices, the use of the ConfirmMDx for Prostate Cancer test can help patients avoid unnecessary repeat biopsies and reduce healthcare waste and costs. ➤ Men who were managed based on the ConfirmMDx for Prostate Cancer test negative results had a <5% rate of repeat prostate biopsies, indicating a potential 10-fold reduction from previous rates. ➤ The ConfirmMDx for Prostate Cancer assay has been clinically validated to significantly improve the negative predictive value over histopathology to approximately 90%. ➤

rate of the disease remains significant, accounting for 10% of all cancer-related deaths.1-3 The clinical course of prostate cancer can range from indolent and self-contained to metastatic and lethal.4 Disease prognosis at the time of diagnosis is typically assessed by the tumor volume, serum prostate-specific antigen (PSA) level, clinical stage, and the use of the Gleason scoring system.5 An accurate diagnosis followed by acute treatment or active surveillance techniques for patients with disease localized within the gland can be vital for good clinical outcomes.4 Sampling errors inherent with the random tissue collection of the biopsy procedure result in a false-negative rate of approximately 25% for standard-of-care histopathology.5 Repeat biopsies are common in men with previous histopathologically negative findings, in an attempt to detect occult cancer that leads to considerable morbidity and adds costs to the healthcare system.5

Clinical Background The US Preventive Services Task Force recently published its conclusion discouraging routine PSA testing in

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the general population of US men as a result of the potential overtreatment of indolent disease.6 Such screening, along with an annual digital rectal examination (DRE), however, has led to a significant reduction in the presentation of advanced cancer.1,3,7 Urologists who treat patients with prostate cancer fear a resurgence of advanced cancer and higher mortality rates with the reduction of screening, resulting in an increase in healthcare costs to effectively treat patients with prostate cancer.8 Many at-risk men continue to be screened and evaluated for prostate cancer. When cancer is suspected, urologists typically perform a prostate biopsy, obtaining approximately 10 to 12 needle core tissue samples, per the current standard of care.4,9 As a result of the well-reported sampling errors using transrectal ultrasound methods, many cancers are undetected by histopathologic review.10 Studies on repeated biopsy procedures indicate that initial prostate biopsy histopathology has a 20% to 30% false-negative rate.11,12 This imprecision poses a diagnostic dilemma, often resulting in multiple repeat biopsies from the fear of missed cancer in men with persistent risk factors.13,14 Although diminishing rates of cancers are detected during these invasive repeat procedures, a high rate of clinically significant (ie, a Gleason score ≥7) cancer found with a repeat biopsy (65%, 53%, and 52% in second, third, and fourth or more biopsies, respectively) has been reported.15 As a result, many men are exposed to the discomfort and risk of complications from a biopsy, such as infections, prostatitis, and anxiety.16 Increasing rates of antibiotic resistance has also been reported, adding to the disease-associated risks and to morbidity.2

Description of ConfirmMDx for Prostate Cancer Molecular testing at both the DNA and RNA levels is improving cancer detection over standard techniques used in oncology. Although genetic screening predicts the lifelong risk of disease development in inherited germline cells requiring genetic counseling, epigenetic profiling of target organ tissue has been shown to be an important predictor of cancer presence.17 The result of the epigenetic assay, used in this study, of the initial biopsies has been reported to enhance the negative predictive value over histopathologic review.18,19 In 2 multicenter, blinded studies, the high negative predictive value of this epigenetic test (ConfirmMDx for Prostate Cancer; MDxHealth, Inc, Irvine, CA) was clinically validated.18,19 The assay is commercially available and uses multiplex methylation-specific polymerase chain reaction to measure the epigenetic status of prostate cancer–­ associated gene biomarkers GSTP1, APC, and RASSF1 in residual cancer-negative prostate biopsy core tissue samples.18,19 By detecting epigenetic abnormalities in a halo

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Table 1 Patient Demographics and Prostate-Related Findings Site 1 2

3

4

5

All

Patients, N

18

26

46

138

Age, yrs

PSA at biopsy, ng/mL Current PSA, ng/mL DRE Histopathology

29

19

Mean (SD)

60.38 (9.41)

65.87 (8.3)

Median (range)

59 (40-75)

67 (52-82)

60 (43-70)

61 (44-78)

65 (44-77)

63 (40-82)

â&#x2030;Ľ65 (%)

11 (38)

9 (60)

5 (31)

10 (38)

22 (55)

57 (45)

Mean (SD)

5.82 (6.81)

6.69 (6.29)

4.53 (2.23)

8.16 (15.31)

5.02 (3.25)

5.95 (7.95)

Median (range)

4.85 (0.2-37.5)

5.52 (0.78-30.4)

4.47 (0.5-11.8)

4.7 (0.4-81)

4.37 (0.33-16.6)

4.7 (0.2-81)

Mean (SD)

4.25 (5.14)

6.4 (6.02)

3.7 (2.08)

8.6 (14.37)

6.02 (6.82)

6.03 (8.45)

Median (range)

3.1 (0.2-24.5)

4.43 (2.17-25.5)

3.7 (0.5-7.3)

5.1 (0.59-75.2)

4.6 (0.33-42.91)

4.43 (0.2-75.2)

Normal, N (%)

17 (63)

19 (100)

13 (72)

19 (73)

34 (74)

102 (75)

Abnormal, N (%)

10 (37)

0 (0)

5 (28)

7 (27)

12 (26)

34 (25)

Normal, N

28

15

18

26

46

133

Abnormal, N (%)

1 (3.5)

4 (21)

0 (0)

0 (0)

0 (0)

5 (3.7)

No

27

19

17

24

45

132

Yes, N (%)

2 (6.9)

0 (0)

1 (5.6)

2 (7.7)

1 (2.2)

6 (4.3)

Negative, N

2

0

1

1

1

6

Positive, N

0

0

0

0

0

0

Repeated biopsy?

59.94 (7.77) 59.12 (10.14) 63.48 (7.73)

61.7 (8.9)

DRE indicates digital rectal examination; PSA, prostate-specific antigen; SD, standard deviation.

around the tumor, which is shown to be associated with oncogenesis, these biomarkers aid in finding evidence of occult prostate cancer unseen by histopathology.18-20 This field effect, which is measured in adjacent benign-appearing biopsy core tissues is a strong independent predictor to diagnose prostate cancer in a subsequent biopsy, with a negative epigenetic result providing a higher negative predictive value (approximately 90%) than standard histopathology alone.12,18,19 The test results from this epigenetic assay help guide urologists on decisions regarding the need for repeat biopsy for patients with a previous negative biopsy but who are still considered to be at risk for prostate cancer. The goal of this study was to determine the prevalence of repeat prostate biopsies in patients managed by urologists ordering the test for patients with a previous histopathologically negative prostate biopsy who received a negative epigenetic test result. This study was conducted in urology practices that had ordered the test for a minimum of 40 patients as a preliminary examination of the clinical utility of the molecular diagnostic to reduce unnecessary repeat biopsy procedures.

Methods Study Design This study was conducted at 5 urology centers that

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had ordered the ConfirmMDx assay to help manage their patients with previous histopathologically negative prostate biopsies. Each center reported whether patients who had a negative assay result had undergone a repeat biopsy at the time of the analysis. The median patient follow-up time after the receipt of the assay results was 9 months, compared with a median of 7.3 months between repeat biopsies in a previous retrospective study.18 Physicians from urology practices ordering a minimum of 40 ConfirmMDx tests were asked to participate. An electronic spreadsheet was used to collect demographic and medical data from clinic records related to the initial biopsy and to any repeat biopsy. No protected health information or Health Insurance Portability and Accountability Act identifiers were collected in this study. The study design was reviewed and granted a notice of exemption by the Quorum Review Institutional Review Board for all sites participating in this trial.

Collected Data Elements Men at each site were assigned a unique, confidential, study-specific identifier. The following demographic, prostate health, and biopsy outcome information was collected on electronic data collection forms for all patients who received an epigenetic assayâ&#x20AC;&#x201C;negative result: â&#x20AC;˘ Age at the time of the initial negative biopsy

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Table 2 Repeated Biopsy Rates Stratified by Available Risk Factorsa Risk factor PSA at biopsy PSA, current DRE

Biopsy result

Age

ConfirmMDx

Low risk, %

4.1 (2 of 49)

0 (0 of 49)

5.9 (6 of 102)

4.5 (6 of 133)

4.3 (5 of 117)

4.3 (6 of 138)

High risk, %

4.5 (4 of 88)

8.6 (6 of 70)

0 (0 of 34)

0 (0 of 5)

0 (0 of 9)

NOTE: High risk is defined as serum PSA concentrations exceeding 4 ng/mL, abnormal DRE results, nonbenign histopathology of the initial biopsy, and age ≥75 years. a Where data are available for patients in the study. DRE indicates digital rectal examination; PSA, prostate-specific antigen.

• Race • PSA level: preceding the negative biopsy and the most current value • DRE: suspicious or nonsuspicious • Date the negative epigenetic assay results were received by the treating physician • Initial biopsy histopathology findings: benign or nonbenign histology • Repeat biopsy: yes or no; if yes, histopathology findings of the repeat biopsy.

Patient Selection Geographically dispersed urologists who had ordered MDxHealth’s ConfirmMDx testing for a minimum of 40 men with previous negative prostate biopsies over the 18 months preceding this analysis (which was conducted in January 2014), were contacted for their interest to participate in this study. The clinical staff at the individual urology practices recorded the desired data elements from hard copy and/or from electronic medical records onto an electronic spreadsheet of all patients who had received a negative assay result report. The completed electronic forms were forwarded to MDxHealth, where the forms were merged into an accumulated database for data summaries and analyses. Results The 5 study sites reported findings for 18 patients to 46 patients per site, for a combined total of 138 patients with negative assay results. These 138 patients represent an unfiltered group of men with negative biopsy results from multiple urology clinics whose primary care urologists sent their biopsy tissue for testing with the commercial assay. By focusing on multiple centers with a sufficiently large volume, a representative sample was obtained, so that the encouraging results from this cohort can lead to the launch of a larger, controlled prospective trial to definitively answer the test’s clinical utility in standard urology practice. Table 1 lists the patient demographics and prostate-specific and repeat biopsy findings for the 138 study participants. Patients had a mean age of approximately 63

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years, covering a wide range (40-82 years), and 45% of them were aged ≥65 years. The mean PSA value across the men in the study at the time of the initial biopsy was 5.95 ng/mL, and the mean of the most recent PSA levels was 6.03 ng/mL. Of these men, 25% were reported to have had abnormal DRE findings and 5 had nonbenign, but not suspicious for cancer, histopathology reports. Table 1 also shows the repeat biopsies performed. Of the 138 patients, 6 (4.3%) underwent the repeat procedure by the time of data collection. Of the 6 repeat biopsies, 1 patient had high-grade prostatic intraepithelial neoplasia detected on histopathologic review, and all of the men were cancer-free. Table 2 illustrates the repeat biopsy rates, which are stratified according to the different risk factors available to the urologist. PSA appears to be the only clear driving factor in the decision-making process. For 11 patients, the serum PSA concentrations were >10 ng/mL when measured after the initial biopsy, which appears to be the most important trigger for a repeat biopsy (2 of the 11 patients, 18%).

Discussion Prostate cancer differs in its clinical presentation and behavior. It can be an isolated lesion that can remain subclinical during a man’s life, or it can develop into a heterogeneous, metastatic disease causing death. The advent of prostate cancer screening with factors such as annual serum PSA measurement and DRE could lead to a modest increase in overall survival in this patient population; however, it is currently part of a debate regarding what the extent of the improvement is.3,7 Recent medical guidelines (eg, by the National Comprehensive Cancer Network or American Urological Association) propose adjusted screening conventions to select men most likely to benefit because of the fear of overdiagnosis.13,21 Although radical treatment (ie, prostatectomy or radiotherapy) of low-risk cancer (often defined as a Gleason score of 6) is not the best treatment option and is progressively being replaced by active surveillance programs, highly aggressive disease is still discovered at the time of diagnosis, leading to poor clinical patient outcomes.

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Repeated Prostate Biopsies and ConfirmMDx Results

The practicing urologist must remain vigilant to detect cancers at an earlier stage, when cure is most achievable.21 On informed consultation with their physicians, many men elect to continue screening for prostate cancer, especially those who are considered to be at elevated risk as a result of their race, family history, or urinary symptoms.21 Prostate biopsy is a common procedure and is the standard of care for diagnosis. Under the current standard of care, high false-negative rates resulting from sampling errors lead to repeat biopsies in more than 40% of men who had initial negative findings, for fear of missed disease.22 These repeated procedures most often again reveal a lack of detectable cancer, while incurring considerable costs and risks to the patient. This suggests that an improved method to better stratify risk in men with histopathologically negative prostate biopsies is needed. The ConfirmMDx for Prostate Cancer assay has been clinically validated to significantly improve negative predictive value over histopathologic examination to approximately 90%.18,19 The analytical cutoffs used for each of the assay’s 3 cancer-associated biomarkers were established to maximize negative predictive value in that a negative test result can be used as an important contributing factor to improve the identification of men with sufficiently low risk for harboring occult prostate cancer, despite other clinical risk factors, who may avoid a repeat biopsy. The current study was conducted to obtain a preliminary, real-world indication of the clinical utility of negative test results of the epigenetic assay in urologic practice. The patient cohort (N = 138) included a wide range of ages, with 45% of patients in the study aged ≥65 years. The results show that the repeat biopsy rate in this cohort was <5%, demonstrating a potential 10-fold reduction with the assay from the reported rate of repeat prostate biopsy, which provides justification for a prospective, randomized multicenter clinical utility trial.22 During such a trial, the proposed substantial cost-savings, as determined by a budget impact model for the use of the assay for this indication, can also be further validated.23

Limitations Because the number of patients in this study is relatively small compared with the number of repeat biopsies performed annually, the results are only indicative of the potential that the epigenetic assay may have on patient management. This observational study was conducted by physicians using a commercial assay to manage patients with histopathologically negative prostate biopsies. It was intended to assess preliminary evidence of its primary indication (ie, generating the hypothesis that negative epigenetic test findings reported to urologists impact patient man-

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agement and are thus associated with a lower incidence of repeat procedures). Although generalizations on the clinical utility outcomes of the assay based on a small, retrospective cohort should be made with caution, this study provides a strong indication that the assay may indeed have an impact to reduce the rate of unnecessary repeat biopsies. An additional, large, prospective clinical utility trial is under development to further demonstrate the test’s impact on clinical practice.

Conclusions The use of new molecular diagnostic technologies, such as this epigenetic test, can lead to better patient management than the current standard guidelines, and can reduce the overall healthcare costs by reducing unnecessary repeat prostate biopsies. The preliminary evidence of the clinical utility from this current study strongly supports this premise and warrants a larger, prospective trial. n Funding Source This research study was funded by MDxHealth, Inc. Author Disclosure Statement Dr Wojno, Dr Costa, and Dr Cornell have received research support from MDxHealth, Inc; Dr Small has received research support from and is a paid consultant to MDxHealth, Inc; Dr Pasin has received research support from and is a speaker for MDxHealth, Inc; Dr Van Criekinge is a consultant to and owns stock in MDxHealth, Inc; Mr Bigley and Dr Van Neste are employees of and own stock in MDxHealth, Inc.

References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012; 62:10-29. 2. Loeb S, Carter HB, Berndt SI, et al. Complications after prostate biopsy: data from SEER-Medicare. J Urol. 2011;186:1830-1834. 3. Andriole GL, Crawford ED, Grubb RL, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Nat Cancer Inst. 2012;104:125-132. 4. Bostwick DG, Crawford ED, Higano CS, Roach M, eds. American Cancer Society’s Complete Guide to Prostate Cancer. Atlanta, GA: American Cancer Society; 2005. 5. Djavan B, Ravery V, Zlotta A, et al. Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol. 2001;166:1679-1683. 6. US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-191. 7. Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-990. 8. Crawford ED, Quershi Z, Mittmann N, et al. Don’t ask/don’t tell: implications of following proposed United States Public Health Services (USPHSTF) Recommendations against discussing prostate cancer (PCA) screening. Presented at: American Urological Association Annual Meeting; May 19-23, 2012; Atlanta, GA. Abstract LBA4. 9. Taneja SS, Bjurlin MA, Carter HB, et al. AUA/optimal techniques of prostate biopsy and specimen handling. 2013. www.auanet.org/common/pdf/education/clinicalguidance/Prostate-Biopsy-WhitePaper.pdf. Accessed May 5, 2014. 10. La Rosa FG, Jones C, Arangua P, et al. Finding occult prostatic cancer: the value of transperineal mapping biopsies and epigenetic assays. J OncoPathology. 2014;2:27-32. 11. Naughton CK, Miller DC, Mager DE, et al. A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol. 2000; 164:388-392.

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12. Trock BJ, Brotzman MJ, Mangold LA, et al. Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies. BJU Int. 2012;110:56-62. 13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): prostate cancer early detection. Version 1.2014. March 10, 2014. www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. Accessed May 5, 2014. 14. Shen F, Shinohara K, Kumar D, et al. Three-dimensional sonography with needle tracking: role in diagnosis and treatment of prostate cancer. J Ultrasound Med. 2008;27:895-905. 15. Resnick MJ, Lee DJ, Magerfleisch L, et al. Repeat prostate biopsy and the incremental risk of clinically insignificant prostate cancer. Urology. 2011;77:548-552. 16. Wade J, Rosario DJ, Macefield RC, et al. Psychological impact of prostate biopsy: physical symptoms, anxiety, and depression. J Clin Oncol. 2013;31:4235-4241. 17. Van Neste L, Herman JG, Otto G, et al. The epigenetic promise for prostate cancer diagnosis. Prostate. 2012;72:1248-1261.

18. Stewart GD, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol. 2013;189:1110-1116. 19. Partin AW, Van Neste L, Klein EA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol. 2014 Apr 16. Epub ahead of print. 20. Mehrotra J, Varde S, Wang H, et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate. 2008;68:152-160. 21. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. 2013. www.auanet.org/common/pdf/education/clinical-guidance/ProstateCancer-Detection.pdf. Accessed May 5, 2014. 22. Pinsky PF, Crawford ED, Kramer BS, et al. Repeat prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening trial. BJU Int. 2007;99:775-779. 23. Aubry W, Lieberthal R, Willis A, et al. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. Am Health Drug Benefits. 2013;6(1):15-24.

Stakeholder Perspective Molecular Tests Can Help to Reduce Repeated Prostate Biopsies By Kelly Huang, PhD Senior Vice President, Intrexon Corporation, Austin, TX

PAYERS: In their article in this issue, Wojno and colleagues conclude that the results of their small-scale study, with only 138 patients, warrant a prospective, larger-scale trial to confirm these results. Indeed, health plans and other payers should support the authors’ conclusion to provide more definitive evidence on the ability of ConfirmMDx to reduce the number of repeated prostate biopsies to test for prostate cancer. Molecular tests, such as ConfirmMDx, may enable the advent of personalized medicine in prostate cancer, which could reduce the cost of care through evidence-based, tailored approaches for individual care management. A robust, large-scale study with the conclusion that ConfirmMDx reduces the rate of repeated prostate biopsies would be a significant accomplishment in the efforts to reduce healthcare costs, as well as reduce potential patient complications related to unnecessary biopsies. Furthermore, health plans may consider guideline development to use a negative predictive value test when the clinical path forward is unclear, such as in the case of a biopsy with a Gleason score of 5 or 6. It may not be necessary to run such a test for a patient with a Gleason score of ≤4 and a normal digital rectal examination (DRE) or a patient with a Gleason score of ≥7 and a suspicious DRE result. A guideline-based utiliza-

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tion with demonstrated change in clinician behavior would be of special interest. Payers should consider both the economic benefits and the benefits of improvement in quality of life for patients who avoid the need for repeated biopsies. PATIENTS/PROVIDERS: As in other disease states, patients and providers should discuss the available data and experience (eg, details of the biopsy results, prostate-specific antigen history, family history, DRE results, and age) to determine the clinical course of action in the individual case. The US Preventive Services Task Force has recommended against routine testing for prostate cancer of otherwise healthy men.1 The driving force behind this recommendation relates to the potential for unnecessary overtreatment of indolent disease, as well as to the complications related to biopsy, including infection and prostatitis. Therefore, patients and providers should welcome the promise of a molecular epigenetic test, such as ConfirmMDx, that has the potential to provide true confirmation of negative biopsy results; a confirmation that, in many cases, could preclude the need for repeated biopsies and potential complications, as well as relieve the patient’s anxiety surrounding the question, “Do I have cancer?” 1. US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-191.

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APPROVED FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD) IN ADULTS The efficacy and safety of BRINTELLIX in the treatment of MDD was established in1:  6 short-term (6- to 8-week) randomized, double-blind, placebo-controlled, fixed-dose studies (including a dedicated study in the elderly) based on mean change from baseline to endpoint in MADRS or HAM-D24 total scores  1 long-term (24- to 64-week) maintenance study in adults based on time to recurrence of depressive episodes*  In clinical studies, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo in 6- to 8-week studies) were nausea, constipation, and vomiting  In pooled 6- to 8-week placebo-controlled studies, the incidence of patients who received BRINTELLIX and discontinued because of adverse reactions ranged from 5% to 8% over the 5- to 20-mg/day doses compared to 4% for placebo; nausea was the most common adverse reaction reported as a reason for discontinuation Recurrence of a depressive episode is defined as MADRS total score ≥22 or lack of efficacy as judged by the investigators.

*

INDICATION

BRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults.

IMPORTANT SAFETY INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. BRINTELLIX has not been evaluated for use in pediatric patients. CONTRAINDICATIONS Hypersensitivity: Hypersensitivity to vortioxetine or any components of the BRINTELLIX formulation. Angioedema has been reported in patients treated with BRINTELLIX. Monoamine Oxidase Inhibitors (MAOIs): Due to an increased risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX. Do not use BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. Do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue. WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality (anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania), especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients daily. Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants (SNRIs, SSRIs, and others), including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If such symptoms occur, discontinue BRINTELLIX and any concomitant serotonergic agents, and initiate supportive symptomatic treatment. If concomitant use of BRINTELLIX is clinically warranted, patients should be made aware of and monitored for potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Abnormal Bleeding: Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation. Activation of Mania/Hypomania: Activation of mania/hypomania can occur with antidepressant treatment. Prior to initiating treatment with an antidepressant, screen patients for bipolar disorder. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Hyponatremia: Hyponatremia has occurred as a result of serotonergic drugs and in many cases, appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients and patients taking diuretics or who are otherwise volume-depleted can be at greater risk. More severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Discontinue BRINTELLIX in patients with symptomatic hyponatremia and initiate appropriate medical intervention. Adverse Reactions: The most commonly observed adverse reactions for BRINTELLIX in 6- to 8-week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were by dose (5 mg, 10 mg, 15 mg, 20 mg) vs placebo: nausea (21%, 26%, 32%, 32% vs 9%), constipation (3%, 5%, 6%, 6% vs 3%), and vomiting (3%, 5%, 6%, 6% vs 1%). Drug Interactions: Concomitant administration of BRINTELLIX and strong CYP2D6 inhibitors or strong CYP inducers may require a dose adjustment of BRINTELLIX.

BRINTELLIX is a trademark of H. Lundbeck A/S registered with U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. ©2014 Takeda Pharmaceuticals U.S.A., Inc. 93507 4/2014

Please see adjacent pages for Brief Summary of Prescribing Information and visit BRINTELLIXHCP.com for full Prescribing Information and Medication Guide. Reference: 1. Brintellix (vortioxetine) prescribing information. Takeda Pharmaceuticals.


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION BRINTELLIX (vortioxetine) tablets, for oral use WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions]. BRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations]. INDICATIONS AND USAGE Major Depressive Disorder BRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults. CONTRAINDICATIONS • Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX. • The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Warnings and Precautions]. Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. The risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the BRINTELLIX Full Prescribing Information, which states: 14 additional cases in patients under the age of 18, 5 additional cases in patients between 18 and 24 years of age. There was 1 fewer case in patients between 25 and 64 years of age and 6 fewer cases in patients 65 years of age and over. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebocontrolled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications]. If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Abnormal Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.


Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions]. Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/ hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. • Hypersensitivity [see Contraindications] • Clinical Worsening and Suicide Risk [see Warnings and Precautions] • Serotonin Syndrome [see Warnings and Precautions] • Abnormal Bleeding [see Warnings and Precautions] • Activation of Mania/Hypomania [see Warnings and Precautions] • Hyponatremia [see Warnings and Precautions] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient Exposure BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebocontrolled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebocontrolled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12-month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year. Adverse Reactions Reported as Reasons for Discontinuation of Treatment In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation. Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation and vomiting. Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebocontrolled studies. Table 2 of the BRINTELLIX Full Prescribing Information shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebotreated patients in the 6- to 8-week placebo-controlled studies. The following values from Table 2 show the percentage of patients exhibiting the adverse reaction while receiving BRINTELLIX 5 mg (N=1013), 10 mg (N=699), 15 mg (N=449), 20 mg (N=455), and placebo (N=1621) respectively. Gastrointestinal Disorders: Nausea (21%, 26%, 32%, 32%, vs. 9%); Diarrhea (7%, 7%, 10%, 7%, vs. 6%); Dry Mouth (7%, 7%, 6%, 8%, vs. 6%); Constipation (3%, 5%, 6%, 6%, vs. 3%); Vomiting (3%, 5%, 6%, 6%, vs. 1%); Flatulence (1%, 3%, 2%, 1%, vs. 1%); Nervous System Disorders: Dizziness (6%, 6%, 8%, 9%, vs. 6%); Psychiatric Disorders: Abnormal Dreams (<1%, <1%, 2%, 3%, vs. 1%); Skin and Subcutaneous Tissue Disorders: Pruritus (including pruritus generalized) (1%, 2%, 3%, 3%, vs. 1%). Nausea Nausea was the most common adverse reaction and its frequency was doserelated (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than

males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies. Sexual Dysfunction Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment. In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo. Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), the following values from Table 3 of the BRINTELLIX Full Prescribing Information show the ASEX incidence of patients who developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed-dose group. The incidence in female patients treated with BRINTELLIX 5 mg (N=65), 10 mg (N=94), 15 mg (N=57), 20 mg (N=67) or placebo (N=135), respectively was 22%, 23%, 33%, 34% vs. 20%. For male patients, the incidence of treatment-emergent sexual dysfunction when treated with BRINTELLIX 5 mg (N=67), 10 mg (N=86), 15 mg (N=67), 20 mg (N=59) or placebo (N=162), respectively was 16%, 20%, 19%, 29% vs. 14%. Incidence was based on the number of subjects with sexual dysfunction during the study / number of subjects without sexual dysfunction at baseline. Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score ≥19; 2) any single item ≥5; 3) three or more items each with a score ≥4. The sample size for each dose group was the number of patients without sexual dysfunction at baseline. Physicians should routinely inquire about possible sexual side effects. Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day. Laboratory Tests BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of BRINTELLIX [see Warnings and Precautions]. In the 6-month, double-blind, placebocontrolled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients. Weight BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients. Vital Signs BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.


Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Ear and labyrinth disorders — vertigo Gastrointestinal disorders — dyspepsia Nervous system disorders — dysgeusia Vascular disorders — flushing DRUG INTERACTIONS CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Contraindications and Warnings and Precautions]. Serotonergic Drugs Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions]. Other CNS Active Agents No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3, Potential for Other Drugs to Affect BRINTELLIX. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions]. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to Affect BRINTELLIX Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1). Figure 1. Impact of Other Drugs on Vortioxetine PK

Potential for BRINTELLIX to Affect Other Drugs No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinid), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary. Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2). Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed [see Drug Interactions]. Figure 2. Impact of Vortioxetine on PK of Other Drugs

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. When treating a pregnant woman with


BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association. A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant. Animal Data In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD). Nursing Mothers It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established. Geriatric Use No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. Use in Other Patient Populations No dose adjustment of BRINTELLIX on the basis of race, gender, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. In addition, the same dose can be administered in patients with mild to moderate hepatic impairment (Figure 3). BRINTELLIX has not been studied in patients with severe hepatic impairment. Therefore, BRINTELLIX is not recommended in patients with severe hepatic impairment.

Figure 3. Impact of Intrinsic Factors on Vortioxetine PK

DRUG ABUSE AND DEPENDENCE BRINTELLIX is not a controlled substance. OVERDOSAGE Human Experience There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. Management of Overdose No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations. Distributed and marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck Deerfield, IL 60015 BRINTELLIX is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals America, Inc. Š2013 Takeda Pharmaceuticals America, Inc. LUN205P R1_Brf. September 2013 90243 L-LUN-0913-2


CLINICAL

Original Research

Treatment Patterns, Survival, and Healthcare Costs of Patients with Malignant Gliomas in a Large US Commercially Insured Population Saurabh Ray, PhD; Machaon M. Bonafede, PhD, MPH; Nimish A. Mohile, MD

Stakeholder Perspective, page 149 Am Health Drug Benefits. 2014;7(3):140-149 www.AHDBonline.com Disclosures are at end of text

Background: Glioblastoma multiforme is the most common malignant primary brain tumor in adults and is associated with poor survival rates. Symptoms often include headaches; nausea and vomiting; and progressive memory, personality, or neurologic deficits. The treatment remains a challenge, and despite the approval of multiple new therapies in the past decade, survival has not improved. Objective: To describe treatment patterns, survival, and healthcare costs of patients with incident glioblastoma in a large US population. Methods: For this population-based study, adult patients (aged â&#x2030;Ľ18 years) with incident malignant brain neoplasm who had undergone brain surgery between January 1, 2006, and December 31, 2010, were identified in the Truven Health Analytics MarketScan Research Databases. The patients were stratified into 4 cohorts based on the use of temozolomide and/or external beam radiation therapy within 90 days after brain surgery (ie, the index event). Treatment patterns, survival, and healthcare costs were assessed until patient death, disenrollment, or the end-of-study period. Results: A total of 2272 patients met the inclusion criteria; of these, 37% received temozolomide and radiation therapy, 13.8% received radiation alone, 3.9% received temozolomide alone, and 45.3% of patients received neither. The average patient age ranged from 55.3 years to 59.8 years across the study cohorts; between 29.8% and 44% of patients in each cohort were female. The duration of temozolomide use was similar between the temozolomide-only cohort and patients receiving temozolomide with external beam radiation; approximately 76% of patients received temozolomide at least 60 days, dropping to 48.1% and 23% at 180 days and 360 days of follow-up, respectively. The median survival was 456 days, ranging from 331 days in the temozolomide-only cohort to 529 days in the cohort that received neither temozolomide nor external beam radiation. The average total costs in the 6 months postindex were $106,896, from $79,099 for patients who received neither temozolomide nor radiation to $138,767 for those who received both therapies. Conclusion: The survival patterns of patients with glioblastoma seen in this real-world study of current treatments in a clinical setting is similar to the survival rate reported in clinical trials. However, further cost-effectiveness and quality-of-life analyses will be critical to better understand the role of temozolomide therapy in this patient population, considering its considerable cost burden and potential negative impact on survival seen in this study.

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lioblastoma multiforme is the most common malignant primary brain tumor in adults, with an estimated incidence of 4.43 per 100,000 person-years in the United States and a median age at presentation of 64 years.1 Glioblastoma multiforme is characterized by seizures; nausea; vomiting; headaches; and progressive memory, personality, or neurologic deficits, Dr Ray is Director, Oncology, AbbVie (formerly Abbott Laboratories), Abbott Park, IL; Dr Bonafede is Director, Outcomes Research, Truven Health Analytics, Cambridge, MA; Dr Mohile is Assistant Professor of Oncology, Neuro-Oncology, University of Rochester Medical Center, Cambridge, Rochester, NY.

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as well as treatment resistance.2 The treatment of glioblastoma multiforme is a challenge, and despite the approval of multiple new therapies in the past decade, survival remains poor. Based on a national report on the status of cancer published in 2011 in the Journal of the National Cancer Institute, the 5-year relative survival rates for glioblastoma multiforme among adults between 2000 and 2006 was only 21.3% for patients aged 20 to 39 years, 5.3% for those aged 40 to 64 years, and only 1.1% for patients aged â&#x2030;Ľ65 years in the United States.1 These national 5-year relative survival rates were slightly better when considering all tumors of the neuroepithelial tissue (65.1%, 26.6%, and 4.6% for the same 3 age-groups, respectively).1

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The current standard of care for newly diagnosed glioblastoma is derived from a randomized clinical trial published in 2005 and consists of maximal feasible surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide.3 This treatment regimen, known as the Stupp regimen, has resulted in a median survival of 14.6 months in patients receiving temozolomide therapy alone compared with 12.1 months in patients receiving external beam radiation alone.3 The adoption of the Stupp regimen has been credited for improvement in the survival of patients with glioblastoma multiforme from 2005 to 2008 compared with the survival from 2000 to 2003, particularly among younger patients.4,5 The US Food and Drug Administration (FDA) approved the use of temozolomide for the treatment of glioblastoma multiforme in March 2005. The FDA also approved carmustine wafers (initially in 1997) and bevacizumab (in 2009, for glioblastoma multiforme that has progressed after initial treatment) for the treatment of glioblastoma multiforme, but neither of these treatments has demonstrated a significant role in the upfront treatment of this disease.6 The financial costs associated with the addition of temozolomide are significant and have been well documented, particularly in European and Canadian health systems.7 In the United States, several analyses have underscored the overall costs and burden of out-ofpocket (OOP) costs incurred by patients with glioblastoma multiforme for hospital visits, ancillary care, and drug costs.8,9 The total expenditures in this patient population have also been described in 2007 by Kutikova and colleagues for 653 patients with primary malignant brain tumors and were estimated at $6364 per month compared with $277 for controls.9 These costs were mostly associated with inpatient care and likely reflect patient care before the widespread use of temozolomide.9 To our knowledge, no study has comprehensively described the total healthcare costs associated with the treatment of glioblastoma and malignant gliomas in the temozolomide era in the United States. We sought to understand the treatment patterns, survival, and economic burden incurred by patients with glioblastoma in clinical practice in the United States. In this study, we used a large commercial claims database and specifically sought to identify a cohort of patients based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) 191.xx codes that most likely represent newly diagnosed glioblastoma to describe patient survival, comorbidities, treatment duration, and healthcare expenditures in the time period after the FDA’s approval of temozolomide.

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Key Points Glioblastoma multiforme is the most common malignant primary brain tumor in adults, and its survival rates remain poor. ➤ The current standard of care consists of surgical resection followed by radiotherapy, with concurrent and adjuvant temozolomide therapy. ➤ This is the first study to analyze real-world data related to treatment patterns, costs, and survival trends associated with temozolomide therapy in patients with glioblastoma. ➤ Total healthcare costs 6 months postindex were highest ($138,767) per patient receiving temozolomide plus radiation and lowest ($79,099) for those receiving neither. ➤ The median survival time was highest (529 days) in patients who received neither temozolomide nor radiation and lowest (331 days) with temozolomide therapy alone. ➤ As can be expected, the addition of temozolomide significantly increases the cost of care, and evidence regarding its exact efficacy is limited in this patient population. ➤ Future cost-effectiveness and quality-of-life analyses are critical to better understand the role of temozolomide in this patient population. ➤

Methods Data Source and Study Design Data for this study were gathered and linked from 2 sources: (1) healthcare claims from the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Databases, and (2) the Social Security Administration (SSA) master death files. The Truven Health databases include fully integrated real-­world patient-level data, including pharmacy and medical claims and associated diagnosis and procedure codes, and enrollment data from approximately 25 million lives covered annually by self-insured employers and private health insurance plans, geographically diversified across the United States. For patients with glioma who receive supplemental Medicare benefits through employer-­sponsored health plans, information on the employer-­paid portion of Medicare-paid benefits and patients’ OOP expenses for their medical and pharmacy services were also available. The SSA death files were linked to patient enrollment data to identify patients with glioma who died, and the date of death. The combined data set was used to study the treatment patterns, survival, and healthcare costs of patients with an incident glioma who initiated treatment with

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brain surgery. A retrospective cohort study design was used with the patients stratified into 1 of 4 treatment cohorts based on the receipt of temozolomide and/or external beam radiation after their initial brain surgery.

Patient Selection and Cohorts Patients were included if they (1) were diagnosed with malignant cancer of the brain (ICD-9-CM, 191.xx) on or between January 1, 2006, and December 31, 2010; (2) had undergone brain-related surgery (set as the index event) within 90 days (before or after) of the first diagnosis of 191.xx; (3) were aged ≥18 years at the index date; and (4) were continuously enrolled with medical and pharmacy benefits for 6 months before the index date. Patients were excluded if they (1) had a diagnosis of another primary cancer (ICD-9-CM, 140.xx-195.xx and 200.xx-208.xx) in the 6 months before the index date; (2) had a diagnosis of secondary brain metastases (ICD9-CM, 198.3) before the index date; (3) received chemotherapy or temozolomide, or had index-eligible brain surgery during the preindex period; or (4) used an off-­ label or nonstandard-of-care therapy as part of their first line of therapy (ie, in the 90 days after their index brain surgery), including carmustine wafer, bevacizumab, or other chemotherapy, or stereotactic radiosurgery. The follow-up period varied for each patient and ran from the index date until a patient’s date of death, disenrollment from an eligible health plan, or until March 31, 2011, whichever occurred first. Although there was no minimal postindex continuous enrollment requirement, fully adjudicated data were available through March 31, 2011, providing at least 3 months of potential data availability for all patients. To evaluate mortality as a study outcome, the analysis was limited to the subset of patients in the commercial and Medicare databases that could be linked to the SSA death data, to determine if a patient died during the study period. Patient survival was censored at the end of the follow-up. Patients were divided into the following 4 mutually exclusive cohorts based on whether they received temozolomide and/or external beam radiation in the 90 days after the index brain surgery. The 4 cohorts included those who (1) received temozolomide only, (2) received external beam radiation only, (3) received both temozolomide plus external beam radiation, and (4) received neither temozolomide nor external beam radiation. Study Outcomes This study is focused on 3 types of outcomes—patterns of treatment, survival, and healthcare costs. Treatment patterns. Among patients in 1 of the 2 temozolomide cohorts, the total duration and medication possession ratio of the first temozolomide episode is

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described. The end of the initial episode of temozolomide is defined as either patient death or disenrollment, or the start of a 60-day gap in temozolomide therapy. The proportion of patients restarting temozolomide therapy after a 60-day gap was also calculated. Survival. The survival time was calculated using the date of death as obtained from the SSA; patients without a date of death were censored at the end of follow-up. Healthcare costs. Total insurance-covered healthcare costs are reported, including both patient and plan portions of each claim for all services utilized during the study period (including those not specifically listed below). The data source includes only fully adjudicated and paid claims. The costs are reported in 3 categories of expenditures based on the location and type of healthcare resource used: inpatient, outpatient, and pharmacy. The outpatient expenditures are separated into emergency, outpatient hospital, and office visits. The pharmacy costs are classified by antiemetics, cancer therapies, neutropenia-related drugs, and pain-related drugs. The expenditures were evaluated in 3 time periods relative to the index brain surgery—6 months before the index brain surgery, 6 months after the index brain surgery, and 12 months after the index brain surgery.

Analysis Descriptive statistics were used for all 3 outcomes. In addition, the baseline patient clinical and demographic characteristics are described, including age, sex, health plan type, and urbanicity, as well as relevant concomitant medications and comorbid conditions. Results We identified 69,495 patients with an ICD-9-CM code of 191.xx in the MarketScan Research databases, of which 17,137 (24.7%) had brain surgery within 90 days of the 191.xx diagnosis. Of those patients, 12,143 (70.9%) were adults at the time of the index brain surgery and had 6 months of continuous medical and pharmacy coverage before the index brain surgery. An additional 4773 patients were excluded for either having another primary cancer, evidence of brain metastases, having had brain surgery, chemotherapy administration, or the use of a carmustine wafer in the 6 months of having the index brain surgery, leaving 7370 evaluable patients with a malignant brain tumor. Data regarding patient survival were available for 2484 of these patients. An additional 212 patients used a nonstandard-of-care therapy as a first-line treatment, resulting in a final study sample of 2272 patients. The overall incidence of maligant brain tumors was 0.0056% between the years 2006 and 2010, with a range in individual years from 0.0053% to 0.0060% among

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Table 1 Demographic and Clinical Characteristics Patients who received temozolomide All patients only Patient characteristicsa (N = 2272) (N = 89) Age, yrs, mean (SD)

Patients who Patients who received received radiation therapy temozolomide and only radiation therapy (N = 313) (N = 841)

Patients who did not receive temozolomide or radiation therapy (N = 1029)

56.9 (14.5)

55.3 (15.1)

59.8 (14.1)

56.7 (12.1)

56.3 (16.2)

18-34 yrs, N (%)

181 (8)

9 (10.1)

20 (6.4)

38 (4.5)

114 (11.1)

35-44 yrs, N (%)

260 (11.4)

13 (14.6)

30 (9.6)

79 (9.4)

138 (13.4)

45-54 yrs, N (%)

503 (22.1)

18 (20.2)

54 (17.3)

228 (27.1)

203 (19.7)

55-64 yrs, N (%)

648 (28.5)

23 (25.8)

73 (23.3)

303 (36)

249 (24.2)

â&#x2030;Ľ65 yrs, N (%)

680 (29.9)

26 (29.2)

136 (43.5)

193 (22.9)

325 (31.6)

Female sex, N (%)

838 (36.9)

32 (36)

102 (32.6)

251 (29.8)

453 (44)

Urban residence, N (%)

1936 (85.2)

72 (80.9)

263 (84)

704 (83.7)

897 (87.2)

Indemnity, N (%)

482 (21.2)

15 (16.9)

82 (26.2)

145 (17.2)

240 (23.3)

PPO, N (%)

1142 (50.3)

43 (48.3)

147 (47)

453 (53.9)

499 (48.5)

HMO, N (%)

312 (13.7)

21 (23.6)

42 (13.4)

103 (12.2)

146 (14.2)

POS, N (%)

238 (10.5)

6 (6.7)

32 (10.2)

94 (11.2)

106 (10.3)

98 (4.3)

4 (4.5)

10 (3.2)

46 (5.5)

38 (3.7)

Anemia, N (%)

93 (4.1)

1 (1.1)

13 (4.2)

23 (2.7)

56 (5.4)

Anxiety, N (%)

120 (5.3)

6 (6.7)

13 (4.2)

45 (5.4)

56 (5.4)

Aphasia, N (%)

69 (3)

6 (6.7)

14 (4.5)

27 (3.2)

22 (2.1)

Cerebrovascular disease/ stroke, N (%)

458 (20.2)

11 (12.4)

74 (23.6)

179 (21.3)

194 (18.9)

Cognitive deficiency, changes, or memory loss, N (%)

127 (5.6)

2 (2.2)

15 (4.8)

49 (5.8)

61 (5.9)

Depression, N (%)

123 (5.4)

6 (6.7)

16 (5.1)

36 (4.3)

65 (6.3)

Fatigue, N (%)

235 (10.3)

7 (7.9)

31 (9.9)

92 (10.9)

105 (10.2)

Headache, N (%)

502 (22.1)

12 (13.5)

54 (17.3)

212 (25.2)

224 (21.8)

Hemiparesis/hemiplegia, N (%)

50 (2.2)

1 (1.1)

5 (1.6)

21 (2.5)

23 (2.2)

Insomnia, N (%)

34 (1.5)

1 (1.1)

3 (1)

11 (1.3)

19 (1.8)

430 (18.9)

29 (32.6)

61 (19.5)

159 (18.9)

181 (17.6)

Antianxiety, N (%)

414 (18.2)

12 (13.5)

52 (16.6)

141 (16.8)

209 (20.3)

Anticonvulsants, N (%)

783 (34.5)

38 (42.7)

109 (34.8)

314 (37.3)

322 (31.3)

Antidepressants, N (%)

406 (17.9)

20 (22.5)

47 (15)

130 (15.5)

209 (20.3)

Age-group

Health plan type

Other/unknown, N (%) Comorbid conditions

Seizures/epilepsy, N (%) Medication use

Antiemetics, N (%)

151 (6.6)

6 (6.7)

20 (6.4)

54 (6.4)

71 (6.9)

Corticosteroids/ glucocorticosteroids, N (%)

913 (40.2)

35 (39.3)

138 (44.1)

366 (43.5)

374 (36.3)

Pain medications (ie, NSAIDs/ COX-2 inhibitors), N (%)

304 (13.4)

12 (13.5)

46 (14.7)

112 (13.3)

134 (13)

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Table 1 Demographic and Clinical Characteristics (Continued) Patients who received temozolomide All patients only Patient characteristicsa (N = 2272) (N = 89)

Patients who Patients who received received radiation therapy temozolomide and only radiation therapy (N = 313) (N = 841)

Patients who did not receive temozolomide or radiation therapy (N = 1029)

Pain medications (ie, narcotic analgesics), N (%)

593 (26.1)

16 (18)

85 (27.2)

212 (25.2)

280 (27.2)

Sedatives/hypnotics, N (%)

218 (9.6)

8 (9)

32 (10.2)

77 (9.2)

101 (9.8)

Survival time/death estimates

b

Mean survival, days (SD)

592.6

499.1

Median survival, days

456

Patients alive at end of follow-up, N (%)

1177 (51.8)

Mean survival, days (SD)

809.1 668

1095 (48.2)

Median survival, days

654

551.2

447

272

307.2

492.1

128 (40.9) 891.6

275.7

524.3

228.5

259

361.7

269 (32) 682

331.5

373.5

581.3

737 (71.6)

437.9

850.2

555.5

748

572 (68) 427

674 529

556

185 (59.1) 371.9

508.6 426

865.5

46 (51.7)

327.9

584.4 415

43 (48.3)

532.7

Observed deaths, N (%)

359.9

462.9

331

Median survival, days Mean survival, days (SD)

474.8

292 (28.4)

285.6

229.2

369.4

72

Patient demographic characteristics are presented as of the index date. Clinical characteristics are related to the 6 months before the index. All survival time estimates measure survival time from index date. Patients who did not die during the available follow-up were included in the analysis and were censored as of the end of their enrollment. COX indicates cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; POS, point of service; PPO, preferred provider organization; SD, standard deviation. a

b

patients in the MarketScan Research databases. The remaining 2272 patients were divided into 4 treatment cohorts based on their receipt of temozolomide and/or external beam radiation in the 90 days after their index brain surgery. The reason for this was to uncover real-world treatment patterns and to further identify a specific cohort that most likely represents a group of patients with malignant glioma receiving standard-ofcare therapy. The largest group included 1029 patients (45.3%) who did not receive temozolomide or external beam radiation in the 90 days after their index brain surgery. The second group of 841 (37%) patients received both temozolomide and radiation therapy, and is the cohort that most clearly represents the current standard-of-care therapy for patients with malignant gliomas in the United States. Smaller percentages of patients received radiation alone (13.8%) and temozolomide alone (3.9%).

Patient Characteristics Demographic and clinical characteristics are displayed in Table 1. These groups were generally well balanced in terms of age, sex, geographic region, type of health plan, and the length of follow-up. The median age of the final study sample was 58 years (mean, 56.9;

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standard deviation, 14.5); a total of 63.1% of the patients were male, and 29.9% were aged >65 years. Corticosteroids (40.2%), anticonvulsants (34.5%), narcotic analgesics (26.1%), and anxiety medications (18.2%) were frequently used in the 6 months before the index brain surgery. Similarly, during the 6 months before the index, nearly 22.1% of patients had a claim with a diagnosis of headache, 20.2% had a diagnosis of cerebrovascular disease or stroke, and 18.9% had a diagnosis of seizures.

Survival The median survival time was 456 days across all 2272 patients, ranging from a median of 331 days among patients who received only temozolomide to 529 days among patients who received neither temozolomide nor radiation therapy. In the cohort of patients receiving both radiation and temozolomide, the median survival was 426 days (14.2 months). Death was observed in nearly half (48.2%) of the patients, ranging from 28.4% among those who received neither temozolomide nor radiation therapy to 68% among patients who received both temozolomide and radiation. Temozolomide Use As shown in Table 2, 39.6% of patients used temozolo-

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Table 2 Oral Temozolomide Use Characteristics

Characteristic Patients using oral TMZ in first 90 days postindex, N (%)a Total duration of initial TMZ therapy, days, mean (SD) TMZ prescription fills, N, mean (SD)

All patients (N = 2272)

Patients who received temozolomide only (N = 89)

Patients who received temozolomide and radiation therapy (N = 841)

899 (39.6)

88 (98.9)

811 (96.4)

177.9 (152.9)

155.4 (180.9)

180.3 (149.5)

6.1 (5.2)

5.5 (6)

6.1 (5.1)

72.7 (25.4)

73.4 (31.1)

72.6 (24.8)

672 (76.5)

55 (70.5)

617 (77)

486 (59.9)

37 (53.6)

449 (60.4)

351 (48.1)

26 (44.1)

325 (48.4)

192 (30.9)

19 (38)

173 (30.2)

116 (23)

10 (25)

106 (22.8)

25 (8.2)

3 (12)

22 (7.9)

Patients with a 60-day gap in TMZ use, N (%)

658 (29)

51 (58)

607 (74.8)

Patients using TMZ after a 60-day gap, N (%)

144 (6.3)

15 (29.4)

129 (21.3)

177 (178.52)

221 (244.98)

172 (169.65)

TMZ MPR during initial TMZ therapy, N, mean (SD) Total duration of initial TMZ therapyb Patients with ≥60 days, N (%) ≥120 days, N (%) ≥180 days, N (%) ≥270 days, N (%) ≥360 days, N (%) ≥540 days, N (%) 60-day gap in TMZ therapy

Days from start of 60-day gap to restart of TMZ, mean (SD)

The end of therapy with temozolomide was defined as either patient death, patient disenrollment, or the start of a 60-day gap in therapy with temozolomide. MPR is only calculated while a patient is receiving therapy. b The total duration of temozolomide therapy in each time interval is only calculated for patients who are still alive and are enrolled over that same time period. MPR indicates medication possession ratio; SD, standard deviation; TMZ, temozolomide. a

mide in the 90 days after their index surgery. The duration of this therapy was, on average, 180 days for patients who received both temozolomide and radiation therapy and 155 days for patients who did not receive radiation therapy. Medication possession ratios were similar for patients who did and did not receive radiation therapy (72.6% and 73.4%, respectively). The majority of patients received temozolomide for at least 120 days (59.9%), and nearly half (48.1%) of the patients received temozolomide for at least 180 days. A total of 30.9% of the patients received temozolomide for at least 270 days.

Healthcare Costs Table 3 lists the healthcare costs incurred by patients before and after their index brain surgery. The mean total cost over the 6 months before the index brain surgery was $11,949, ranging from $11,564 in the radiation-only cohort to $12,850 in the temozolomide-only cohort. The average total cost in the 6 months after the index surgery was markedly higher, averaging $106,896, ranging from $79,099 among patients who did not receive temozolomide or radiation to $138,767 among pa-

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tients who received both temozolomide and radiation. The total costs in the 12 months after the index surgery were higher than the costs after only 6 months, with an average cost of $131,815, and ranging from $88,827 among patients who did not receive temozolomide or radiation to $184,107 among patients who received both temozolomide and radiation. All 3 components of the total cost (ie, inpatient, oupatient, and pharmacy) showed a pattern similar to the total costs in the periods before and after the surgery.

Discussion Although the Stupp regimen—which consists of radiotherapy and temozolomide being administered concomitantly, and then temozolomide is used after radiotherapy—has become the standard of care for newly diagnosed patients with glioblastoma, there are limited data on this patient population since the introduction of this regimen in a clinical practice setting. Using administrative claims and mortality data, this study provides data that are useful for understanding treatment patterns, survival, and the healthcare costs associated with glio-

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Table 3 Healthcare Expenditures, by Index Cohort

All patients (N = 2272) Total healthcare expenditures

Patients who received temozolomide only (N = 89)

Patients who Patients who Patients who received received did not receive radiation therapy temozolomide and temozolomide or only radiation therapy radiation therapy (N = 313) (N = 841) (N = 1029)

Mean, $ SD, $ Mean, $ SD, $ Mean, $ SD, $ Mean, $ SD, $ Mean, $ SD, $

Expenditures in the 6 months preindex surgery Total healthcare expenditures

11,949

17,609

12,850

15,636

11,564

17,550

12,320

19,873

11,686

15,735

Total inpatient

5368

14,133

6108

11,833

5265

13,835

6403

16,225

4490

12,424

Total outpatient

5548

7288

5873

8122

5207

6660

5005

7857

6067

6874

Emergency department

346

1299

283

579

237

649

361

1394

373

1407

Outpatient, hospital

2748

5231

2838

6020

2414

3859

2533

5799

3019

5021

Outpatient, office visits

547

463

417

471

539

444

451

396

639

499

Other outpatient

1906

3726

2335

4586

2016

4111

1661

3828

2036

3418

1034

1578

869

1177

1093

1528

912

1242

1129

1840

Antiemetics

4

52

1

4

10

87

4

43

4

46

Cancer therapies

0

0

0

0

0

0

0

0

0

0

Neutropenia-related

3

146

0

0

0

0

0

0

7

217

Painkillers

35

253

24

76

32

141

27

231

43

302

Total retail/mail-order pharmacy expenditures (all drugs)

Expenditures in the 6 months postindex surgery Total healthcare expenditures

106,896

97,678

111,066

108,664

111,456

84,701

138,767

76,627

79,099

107,140

Total inpatient

61,423

81,688

72,041

101,250

56,634

67,477

59,121

57,768

63,843

98,632

Total outpatient

36,109

38,660

22,895

25,786

52,063

39,975

58,860

37,701

13,804

24,174

525

1643

523

915

507

1239

680

1668

403

1767

21,602

32,426

13,488

21,868

30,963

36,302

38,047

38,144

6016

14,008

Emergency department Outpatient, hospital Outpatient, office visits

831

1039

1052

1937

901

1309

1211

1084

479

578

13,151

22,518

7832

12,280

19,691

25,540

18,923

25,266

6905

17,490

9364

11,323

16,130

9479

2759

3840

20,786

9590

1452

3046

Antiemetics

431

1110

549

862

400

1266

905

1453

44

335

Cancer therapies

7057

9757

13,555

7710

586

2100

17,204

8116

170

1396

Neutropenia-related

38

532

19

179

31

411

71

747

16

337

Painkillers

43

161

36

145

52

168

42

125

40

185

Other outpatient Total retail/mail-order pharmacy expenditures (all drugs)

Expenditures in the 12 months postindex surgery Total healthcare expenditures

131,815

121,379

134,512

115,938

131,869

101,065

184,107

112,929

88,827

117,423

Total inpatient

68,645

90,003

74,465

102,251

63,385

73,947

71,487

73,371

67,419

104,511

Total outpatient

49,212

58,986

35,427

43,706

63,124

48,980

82,750

68,286

18,763

32,572

732

1943

815

1421

723

1583

965

2032

538

1988

29,128

48,770

18,110

28,083

38,082

45,189

52,060

64,125

8615

17,910

1306

1567

1547

2564

1363

1724

1883

1782

796

911

18,046

30,249

14,955

29,688

22,956

27,190

27,841

36,118

8814

21,993

Emergency department Outpatient, hospital Outpatient, office visits Other outpatient

Continued

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Table 3 Healthcare Expenditures, by Index Cohort (Continued) Patients who Patients who Patients who received received received temozolomide radiation therapy temozolomide and All patients only only radiation therapy (N = 2272) (N = 89) (N = 313) (N = 841) Total healthcare expenditures Mean, $ SD, $ Mean, $ SD, $ Mean, $ SD, $ Mean, $ SD, $ Total retail/mail-order pharmacy expenditures (all drugs)

Patients who did not receive temozolomide or radiation therapy (N = 1029) Mean, $ SD, $

13,957

17,723

24,621

19,657

5360

8504

29,870

17,173

2645

5502

575

1495

715

1158

578

1892

1190

1911

59

421

10,059

14,915

20,349

14,691

1529

5482

23,962

14,533

402

2905

Neutropenia-related

96

1296

249

1694

84

1312

181

1856

16

337

Painkillers

78

380

49

212

87

316

89

424

68

371

Antiemetics Cancer therapies

SD indicates standard deviation.

blastoma as observed in a large, representative commercially insured US population. The current ICD-9-CM classification system does not clearly discriminate patients by histopathology, and patients with a diagnosis code of 191.xx can represent a heterogeneous group of tumor types. Although this is a limitation of this current analysis, malignant gliomas make up the overwhelming majority of malignant brain tumors in adults, and the contribution of other rare tumors is likely inconsequential.10 One group that may be coded as 191.xx may include lower-grade gliomas, which eventually progress into higher-grade tumors. To purify our sample, we determined the treatments that patients received to better understand their potential tumor makeup. We created 4 mutually exclusive categories based on the patients’ exposure to radiation and/or temozolomide therapy. Remarkably, more than 40% of patients received neither of these therapies. The relatively high median survival in this group suggests that many of these patients might have had lower-grade histologies, for whom upfront radiation and/or temozolomide are not clearly standard-of-care therapies.11 It is possible that this cohort includes elderly or poorly performing patients in whom a decision was made not to pursue active treatment; however, these patients did not appear substantively different from the other treatment cohorts, particularly in terms of the distribution of age-groups. Therefore, it is more likely that, in this analysis, less-aggressive treatment is an indicator of lower-­ grade gliomas, where such less-aggressive treatment is clinically reasonable. The preindex healthcare utilization was similar across the 4 cohorts; therefore, the difference in treatment cohort costs does not appear to be a result of the background comorbid burden, or the patient’s clinical profile. Furthermore, we sought to characterize a cohort of patients that

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most likely represent patients with newly diagnosed glioblastoma based on the type of treatments that they received. For that purpose, we defined the standard of care based on the Stupp regimen,3 and after applying exhaustive inclusion and exclusion criteria, we were able to identify 841 patients who received radiation plus temozolomide therapy. Although a small portion of these patients could have anaplastic gliomas, given the emerging treatment patterns in tertiary care centers,12 we believe that our cohort of 841 patients receiving temozolomide plus radiation are patients with glioblastoma. This is because anaplastic gliomas are rare compared with glioblastoma, and the median survival in this cohort (of 426 days, or 14.2 months) fits closely with the findings reported with the Stupp regimen for glioblastoma (14.6 months).3 The role of temozolomide for anaplastic gliomas in the upfront setting, however, remains controversial. Anaplastic gliomas, which are World Health Organization grade 3 tumors, make up less than 50% of all malignant gliomas; they are a heterogenous group of tumors in terms of their histology, molecular markers, treatment, and survival.13 Because of the rarity of these tumors, few large phase 3 clinical trials have been conducted to inform optimal therapies. In the United States, the treatment of these tumors is increasingly extrapolated from studies done on patients with glioblastoma. A recently published large phase 3 trial has confirmed a role of chemotherapy for 1p/19q codeleted anaplastic oligodendrogliomas, but because this study was conceived more than 20 years ago, it investigated procarbazine, lomustine, and vincristine therapy rather than temozolomide therapy.14 An ongoing large phase 3 trial from the Radiation Therapy Oncology Group (RTOG) is addressing the role of temozolomide in anaplastic gliomas (clinicaltrials.gov identifiers NCT01847235 and NCT00033280); but as of now, there

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CLINICAL

are no prospective data that demonstrate efficacy of temozolomide in this population. Given the costs and the lack of evidence, one may consider enrolling such patients in active RTOG trials that are aiming to properly and systematically address the question of temozolomide’s efficacy in anaplastic gliomas. Not surprising, our study shows that healthcare utilization and costs increase after patients with malignant glioma have surgery. In our analysis, in the 1 year after surgery in the 841 patients with presumed glioblastoma who received radiation and temozolomide therapy, the total healthcare expenditure was $184,107. This cost is substantially higher than in the study by Kutikova and colleagues, which did not report any inclusion of temozolomide data, but that estimated the 1-year healthcare costs to be less than $80,000.9 In this current analysis, the total costs for patients who received both temozolomide and external beam radiation were 1.8 times greater over 6 months than for patients who received neither, and 2.1 times greater over 12 months. After 6 months, the cost for patients who did not receive temozolomide or external beam radiation returned to their presurgery levels; the average 6-month preindex cost was $11,868; the average cost for months 7 to 12 postindex were $9728. Our descriptive analysis did not identify predictors of healthcare costs, treatment patterns, or patient survival. There are several known predictors of improved survival, such as age, performance status, and tumor O6-methylguanine-DNA methyltransferase (MGMT) methylation.15 Patients managed with methylation of the MGMT promoter have shown improved survival, but broad implementation of testing remains impractical,16 warranting further research and potential promise for treatment prognosis, at least among some subgroups of patients.17 As the US population ages, we expect a rise in the incidence of glioblastoma, and the burden on third-party payers may change substantially over the next few decades.18 The Stupp regimen excluded patients aged >70 years, and there is controversy regarding the role of adjuvant chemotherapy in older patients. A recent phase 3 study showed that temozolomide therapy alone in highly functioning elderly patients is tolerable and is noninferior to radiation therapy alone.19 Another study comparing radiation with temozolomide to radiation alone demonstrated a marginal improvement in survival with chemotherapy,20 and even poorly functioning elderly patients seem to derive some benefit from temozolomide therapy.21

Limitations This study had several limitations. In addition to the previously noted limitation regarding the specificity of ICD-9-CM coding, there are additional limitations inher-

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ent in the data source used in this analysis. Administrative claims data lack information on disease severity or staging. Similarly, there is limited information on patient or provider characteristics that may influence medical decision-making. This also limits our ability to differentiate the treatment cohorts or to potentially predict or explain the reasons for administering temozolomide and/or external beam radiation therapy. Although it is necessary to describe the baseline characteristics and to establish the incident event, the preindex continuous enrollment requirement may bias the study sample toward patients with stable health insurance who may be healthier than patients with intermittent health insurance, or the uninsured. The 4 cohorts were defined based on treatments received in the 90 days after the index surgery event, because this corresponded with a clinically reasonable time period to initiate either temozolomide or external beam radiation therapy. Patients in any of these cohorts could potentially receive (or initiate) temozolomide therapy outside of this 90-day time period.

Conclusion Based on our analysis, the addition of temozolomide to the treatment regimens for glioblastoma increases the cost of care, and the use of temozolomide potentially indicates greater disease severity. Although survival in this clinical practice setting–based analysis is similar to the survival reported in clinical trials, further cost-effectiveness and quality-of-life analyses will be critical to better understanding the value of temozolomide therapy in treating this patient population, particularly because of the availability of generic temozolomide. n Funding Source This study was funded by Abbott Laboratories. Author Disclosure Statement Dr Ray is an employee of and has stocks in AbbVie; Dr Bonafede reported no conflicts of interest; Dr Mohile is a consultant to Truven Health Analytics and to Abbott Laboratories, and is on the speaker’s bureau of NovoTTF.

References

1. Kohler BA, Ward E, McCarthy BJ, et al. Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103:714-736. 2. Central Brain Tumor Registry of the United States. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004-2007. February 2011. www.cbtrus.org/2011-NPCR-SEER/WEB-0407-Report-3-­3-­ 2011.pdf. Accessed March 15, 2014. 3. Stupp R, Mason WP, van den Bent MJ, et al; for the European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996. 4. Koshy M, Vilano JL, Dolecek TA, et al. Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neurooncol. 2012;107:207-212. 5. Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol. 2012;107:359-364.

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6. Stupp R, Tonn JC, Brada M, Pentheroudakis G; for the ESMO Guidelines Working Group. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(suppl 5):v190-v193. 7. Lamers LM, Stupp R, van den Bent MJ, et al; for the EORTC 26981/22981 NCI-C CE3 Intergroup Study. Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study. Cancer. 2008;112:1337-1344. 8. Raborn ML, Pelletier EM, Smith DB, Reyes CM. Patient out-of-pocket payments for oral oncolytics: results from a 2009 US claims data analysis. J Oncol Pract. 2012;8 (3 suppl):9s-15s. 9. Kutikova L, Bowman L, Chang S, et al. Utilization and cost of health care services associated with primary malignant brain tumors in the United States. J Neurooncol. 2007;81:61-65. 10. Porter KR, McCarthy BJ, Freels S, et al. Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro Oncol. 2010;12:520-527. 11. Papagikos MA, Shaw EG, Stieber VW. Lessons learned from randomised clinical trials in adult low grade glioma. Lancet Oncol. 2005;6:240-244. 12. Abrey LE, Louis DN, Paleologos N, et al; for the Oligodendroglioma Study Group. Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol. 2007;9:314-318. 13. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492-507. Erratum in: N Engl J Med. 2008;359:877. 14. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lo-

mustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344-350. 15. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003. 16. DeAngelis LM. Chemotherapy for brain tumors—a new beginning. N Engl J Med. 2005;352:1036-1038. 17. Fietkau R, Putz F, Lahmer G, et al. Can MGMT promoter methylation status be used as a prognostic and predictive marker for glioblastoma multiforme at the present time? A word of caution. Strahlenther Onkol. 2013;189:993-995. 18. Werner MH, Phuphanich S, Lyman GH. The increasing incidence of malignant gliomas and primary central nervous system lymphoma in the elderly. Cancer. 1995; 76:1634-1642. 19. Wick W, Platten M, Meisner C, et al; for the NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707-715. 20. Malmström A, Grønberg BH, Marosi C, et al; for the Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13:916-926. 21. Gállego Pérez-Larraya J, Ducray F, Chinot O, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol. 2011;29:3050-3055.

Stakeholder Perspective Treatment Decisions in the Management of Malignant Gliomas By Jeffrey A. Bourret, PharmD, MS, BS, RPh, BCPS, FASHP Senior Director, North America Medical Affairs, Pfizer Inc, Collegeville, PA

PAYERS: Glioblastoma multiforme (GBM) is an extremely aggressive malignant brain tumor, accounting for more than 50% of all functional brain tumor cases in humans.1 Before 2005, the standard of care for treatment was surgery, radiation therapy, and chemotherapy. The standard of care changed after the study by Stupp and colleagues that demonstrated an improvement in median survival of 14.6 months for patients treated with radiotherapy plus temozolomide compared with 12.1 months with radiotherapy alone.2 In the current article by Ray and colleagues, the authors used large databases to describe the treatment patterns, survival, and healthcare costs associated with the new standard of care for patients with GBM. They conclude, as may be expected, that the costs are higher in patients receiving temozolomide, and their analysis from real-world data on survival closely mirrors that seen in clinical trials. What should be of interest to payers to build on this study are additional analyses to determine which subgroups may respond better to treatment based on a patient’s baseline health status and age. In particular, the

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O6-methylguanine-DNA methyltransferase gene in patients with GBM has been shown to be of potential use for its prognostic and predictive values in targeting specific patients who may respond better to treatment.3 Although the medical community believes that this test is still not ready for routine use in clinical practice, watching its development and application in actual practice may help with treatment decisions.4 PATIENTS/PROVIDERS: As with any therapy for cancer, quality of life will continue to play a critical role in treatment decisions related to patients with GBM, by patients, providers, as well as payers. n 1. Kohler BA, Ward E, McCarthy BJ, et al. Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103:714-736. 2. Stupp R, Mason WP, van den Bent MJ, et al; for the European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996. 3. Costa BM, Caeiro C, Guimarães I, et al. Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation: a Portuguese multicentre study. Oncol Rep. 2010;23:1655-1662. 4. D’Alessandris QG, Montano N, Larocca LM, et al. Prognostic impact of MGMT promoter methylation in glioblastoma—a systemic review. J Cancer Sci Ther. 2014;6: 136-141.

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The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.


In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on the next page of this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.


Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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Review Article

Current Challenges in Health Economic Modeling of Cancer Therapies: A Research Inquiry

Jeffrey D. Miller, MS; Kathleen A. Foley, PhD; Mason W. Russell, MAPE Background: The demand for economic models that evaluate cancer treatments is increasing, as healthcare decision makers struggle for ways to manage their budgets while providing the best care possible to patients with cancer. Yet, after nearly 2 decades of cultivating and refining techniques for modeling the cost-effectiveness and budget impact of cancer therapies, serious methodologic and policy challenges have emerged that question the adequacy of economic modeling as a sound decision-making tool in oncology. Objectives: We sought to explore some of the contentious issues associated with the development and use of oncology economic models as informative tools in current healthcare decision-making. Our objective was to draw attention to these complex pharmacoeconomic concerns and to promote discussion within the oncology and health economics research communities. Methods: Using our combined expertise in health economics research and economic modeling, we structured our inquiry around the following 4 questions: (1) Are economic models adequately addressing questions relevant to oncology decision makers; (2) What are the methodologic limitations of oncology economic models; (3) What guidelines are followed for developing oncology economic models; and (4) Is the evolution of oncology economic modeling keeping pace with treatment innovation? Within the context of each of these questions, we discuss issues related to the technical limitations of oncology modeling, the availability of adequate data for developing models, and the problems with how modeling analyses and results are presented and interpreted. Discussion: There is general acceptance that economic models are good, essential tools for decision-­ making, but the practice of oncology and its rapidly evolving technologies present unique challenges that make assessing and demonstrating value especially complex. There is wide latitude for improvement in oncology modeling methodologies and how model results are presented and interpreted. Conclusion: Complex technical and data availability issues with oncology economic modeling pose serious concerns that need to be addressed. It is our hope that this article will provide a framework to guide future discourse on this important topic.

C

ancer is the second most common cause of death in the United States, currently accounting for nearly 1 of every 4 deaths annually.1 Not surprising, the development of innovative cancer treatments is an important focus of pharmaceutical drug development. The payoff has been meaningful, with new treatments helping to significantly increase cancer survival among men and women and in nearly all racial and ethnic groups.2,3 This improvement, however, has come at a considerable expense; the total direct medical spending on can-

Mr Miller is Director, Economic Modeling, Strategic Consulting, Truven Health Analytics; Dr Foley is Senior Director, Strategic Consulting, Truven Health Analytics; Mr Russell is Vice President, Strategic Consulting, Truven Health Analytics, Cambridge, MA.

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cer care in the United States is estimated to have cost as much as $124.5 billion in 2010, with estimated expenditures of almost $160 billion by 2020.4 The cost of new cancer therapies has garnered the attention of a diverse constituency of patients, clinicians, healthcare payers, and public policymakers.5 As decision makers struggle for ways to better manage their budgets while providing the best care possible to patients with cancer, there is a pressing need to assess the value of cancer treatments in a rigorous and robust manner. Of course, the question about what constitutes “value” in cancer care is a topic of ongoing discussion at all levels. Fundamentally, value is defined as the health outcomes achieved per dollar spent, but there is no universally accepted definition of what good value—or even acceptable value—means in cancer care.6,7 Value means

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Key Points As innovative, high-cost cancer therapies continue to come to market, economic modeling is needed to provide better insight into the meaning of value. ➤ Despite the refining of modeling the costeffectiveness and budget impact of cancer therapies, serious methodologic and policy challenges remain concerning the adequacy of modeling as a sound decision-making tool in oncology. ➤ This article is a call to action, addressing 4 key concerns related to economic modeling in oncology. ➤ Some oncology model outcomes lack practical meaning, and model developers need to focus on informing practical decision-making. ➤ Cost analyses should emphasize clinically meaningful rather than statistically significant outcomes. ➤ Appropriate and robust biologic, epidemiologic, and economic data from larger trials are needed to provide meaningful parameters for oncology economic modeling. ➤ Oncology economic models must keep pace with changing treatment paradigms, and must reflect real-world value. ➤ Models should also address the off-label use of cancer treatments vis-à-vis personalized medicine. ➤ As personalized medicine in oncology changes, models will need to connect economic outcomes more directly with patient outcomes. ➤

something different to each stakeholder, whether a patient with cancer or a caregiver, a physician treating patients with cancer, a healthcare payer, or another medical decision maker. As innovative new cancer therapies come to market bearing high price tags, the need for economic modeling to help provide better insight into what constitutes “value” is of paramount importance. Yet, after nearly 2 decades of cultivating and refining techniques for the modeling of cost-effectiveness and budget impact of cancer therapies— the 2 main economic models used for evaluating cancer therapies (Table 1)—serious methodologic and policy challenges have emerged that bring into question the adequacy of economic modeling, as it currently stands, as a sound decision-making tool in oncology. As an ongoing research endeavor, in this article we are exploring some of the contentious issues in the development and use of oncology economic models as informative tools in current healthcare decision-making. Our goal is to draw attention to these complex pharmacoeconomic

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concerns and to promote discussion among the various stakeholders regarding the need for improvements in, and the best practices for, oncology economic modeling.

Method The focus of our research is on the processes and the means by which economic models are used to evaluate healthcare technologies in oncology. We have structured our inquiry around 4 questions: 1.  Are economic models adequately addressing questions relevant to oncology decision makers? 2. What are the methodologic limitations of oncology economic models? 3. What guidelines are followed for developing oncology economic models? 4.  Is the evolution of oncology economic modeling keeping pace with treatment innovation? Within the context of each of these questions, we are investigating issues related to the technical limitations of oncology modeling, the availability of adequate data for developing models, and the problems regarding how oncology modeling analyses and results are presented and interpreted. Our investigation is largely based on our years of professional experience with developing oncology economic models on behalf of the industry (ie, pharmaceutical and biotechnology corporations), insurers and other healthcare payers, and government healthcare technology assessment agencies. Moreover, as part of our professional duties, we continuously monitor venues of published literature and activities of professional and scientific organizations to keep abreast of the latest changes and advances in pharmacoeconomics and health economic evaluation. In addition to developing numerous oncology economic models, we conduct several literature reviews annually on the economic aspects of cancer treatment, and this has afforded us the luxury of broad and deep exposure in the field of oncology economic modeling. Discussion 1. Are economic models adequately addressing questions relevant to oncology decision makers? Economic models typically involve the evaluation of clinical, economic, and humanistic (ie, quality of life) outcomes in 1 or more hypothetical patient cohorts defined by demographics, disease history, clinical characteristics or presentation, and other factors. Oncology-­ related economic models are used by pharmaceutical companies, health plans, Pharmacy & Therapeutics Committees, hospitals, clinicians, and the government (eg, Medicare, Medicaid), among many others (Table 2). Clinicians and formulary managers in oncology practice often seek a realistic understanding of the potential im-

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Table 1 The 2 Health Economic Models Primarily Used in the Evaluation of Cancer Therapies Cost-Effectiveness Models

• Cost-effectiveness models assess the overall clinical and economic value of a new cancer therapy in relation to existing

therapies or in relation to other healthcare interventions

• Estimates of clinical-economic value are generated using a variety of clinical outcomes, combined with the costs incurred

by patients in achieving those outcomes

• Many cost-effectiveness models calculate the additional cost per an additional unit gain of benefit from a therapy, with

the results being presented as incremental cost-effectiveness ratios, such as cost per life-year gained or cost per clinical event avoided

• Common approaches for constructing cost-effectiveness models may include decision tree and Markov (cohort) models

Budget Impact Models • Budget impact models help to determine the financial impact of introducing a new cancer therapy within a particular

healthcare setting

• These models are typically used for estimating systemwide (ie, pharmacy and medical) budget impact and are frequently

used by managed care payers and by other healthcare reimbursement authorities (eg, a budget impact model may be used by a hospital formulary manager to determine the impact a new cancer drug would have on the hospital’s overall budget for oncology treatments)

• Aside from drug costs, budget impact models typically utilize clinical data, combined with associated healthcare costs and

cost offsets, all in context of the expected utilization in the healthcare system

• Results are often expressed as projections of cost per member per month

pacts of treatment on funding decisions about cancer therapies. Yet, given the current state of oncology economic modeling, are these healthcare decision makers receiving the proper information they need? Our experience and observation over the years is that model developers tend to target everything and everyone possible, with the idea that analyses and results can be sorted out later by the end user (ie, healthcare decision makers). This lack of focus can lead to considerable uncertainty about what is meaningful and actionable about results and findings from modeling studies. The issue is further compounded by the divergent perspectives of payers and providers: our experience is that the former often care mainly about direct clinical and economic outcomes (eg, cure rates, survival, costs of care), whereas the latter may care as much (or more) about other outcomes, such as the impact of treatment on patient functioning and on quality of life. Whether the current oncology economic models meet decision maker needs remains an open question, but what little has been reported in the literature suggests that, in general, economic models (not only oncology models) consistently fall short of being able to support informed decision-making.8-12 One of the reasons that oncology models may fall short of decision maker needs is that the outcomes of the models lack practical meaning. Although a variety of outcomes metrics can be generated by oncology economic models, these usually entail combinations of incre-

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Table 2 Who Uses Oncology Economic Models? • Pharmaceutical companies (for internal decision-making) • Health economics researchers working for the healthcare industry

or in academia

• Health plans and integrated health networks • Physician group practices • Pharmacy & Therapeutics Committees • Healthcare guideline committees • Hospitals and other healthcare institutions • Medical directors • Clinicians • Health technology assessment agencies • Government (ie, Medicare, Medicaid, Department of Veterans

Affairs, Department of Defense)

mental costs and benefits of treatment to create incremental cost-effectiveness ratios (ICERs). Typical ICERs in oncology economic models are the weekly, monthly, or annual costs of survival; the quality-adjusted or progression-free survival; the cost per responder; and the cost per adverse event avoided.13,14 Based on our professional experience and what we have observed in real-world healthcare settings, there is considerable uncertainty among decision makers on what to make of these metrics—particularly the more

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familiar (and controversial) cost per quality-adjusted lifeyear (QALY). The rationale behind this metric is that it explicitly includes a common denominator that facilitates comparisons across different treatments, at various stages, and even across diseases. From a theoretical perspective, the QALY is meant to reflect benefit or utility arising from a particular treatment. In the case of a cancer therapy, improved utility may arise from improved survival or improved quality of life. From our real-world observations and professional experience, few decision makers, however, understand how the QALY is derived or how to interpret it. The cost per QALY metric has long been an integral component of cost-effectiveness (or cost-utility) modeling of cancer therapies, and it has been regarded in some circles as the “convenient yardstick” for measuring and comparing health effects of interventions across various diseases and conditions.15,16 This metric, however, has been politically demonized in deliberation about US healthcare reform.17 Cancer therapies with high cost and small incremental improvement in survival or quality of life may find it difficult to meet societal thresholds for what is considered acceptable value for the money.18,19 Therefore, the denominator of the cost per QALY metric has been a focus of debate, with the general misgivings for the QALY being well-illustrated in oncology. A patient’s health state and its associated weight may change, depending on, for example, the patient with cancer’s initial health state, or the state to which the patient’s health is raised, all of which are confounded by the rapid fluctuations in health status experienced by most patients with cancer.20-22 In addition, the practice of developing QALY weights based on valuations from members of the general population can be problematic, because such individuals may misunderstand what it is really like to have cancer.22 Most people have strong emotional reactions to the idea of having cancer—cancer is dreaded more than other life-threatening conditions, such as Alzheimer’s disease, heart disease, and stroke.23,24 There are inherent difficulties collecting valid judgments on cancer health states and QALY weights by people who do not have cancer—a priori fear of cancer is not commensurate with actual experience.25 For these reasons, and for many others, the QALY metric shows limitations in its ability to accurately capture the value of the health gains deemed important by patients with cancer.22 There is good evidence that the cost per QALY metric is not sufficiently accurate or reliable enough to be used by decision makers as a basis for the comparison of the costs of different cancer therapies. But what are the alternatives? One simple and transparent option is for costs to be related to primary health outcomes relevant to the disease

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in question, with emphasis on clinically meaningful findings rather than on statistically significant results.8,21 Decisions about what defines “clinically meaningful” will require coordination between various stakeholders, including physicians providing care, managed care organizations, the government, and drug manufacturers designing and conducting clinical trials. Inroads in this area have already been made by the American Society of Clinical Oncology Cancer Research Committee.26 Thus, from the perspective of oncology economic modeling, greater consideration could be given to disease-specific outcomes, such as cancer progression, intensity of cancer pain, or loss of function as a result of cancer.26 Although Neumann and Weinstein assert that “these outcomes do not permit comparisons among diseases and conditions or between treatment and prevention,”15 these metrics may provide more meaningful results for clinicians and patients. Another option is to create models that could accommodate variations in survival outcomes beyond median survival. Recent research indicates that patients place greater value on the probability—even a small probability—of a substantial improvement in survival than they do on the greater probability of smaller gain in survival.27 Incorporating the value of these “hopeful gambles” into models may better reflect the value to patients than current modeling strategies.27 This implies that there should be an increased role for behavioral economics in economic modeling of cancer therapies, at least to complement the traditional grounding of health economic models in standard economic theory.28-31 Finally, we must also ask, is cost-effectiveness even the right metric to model? Given the life-threatening nature of cancer, neither payers nor clinicians seem particularly compelled to worry about whether a given treatment is below a threshold value for cost-effectiveness. What is likely of greater interest is the balance of comparative benefits and costs among competing treatments. Therefore, an ideal health economic model would help decision makers assess which treatments work best for which patients under which scenarios. This question is very different from whether a given treatment meets an arbitrary threshold for cost-effectiveness.

2. What are the methodologic limitations of oncology economic models? A variety of techniques can be used for developing health economic models, but most oncology economic models are based on decision analysis.32-34 Although oncology economic models can be enormously complex, models by definition are supposed to be simplified representations of reality.35 However, making generalizations and simplifications in economic models about the superiority or inferiority of one cancer therapy over another

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involves accounting for vast complexities and nuances of actual clinical practice and its associated costs. Using economic models to compute overall cost-effectiveness may hide important heterogeneity, leading to the overestimation or underestimation of particular subgroups of patients with cancer or of patients in diverse treatment settings or various healthcare systems.36-38 All of these factors pose numerous challenges in the design and development of oncology economic models, and in the worst case can impede clear interpretation of the results generated by the models. Unfortunately, in the end, decision makers are frequently left with noninterpretable “noise.”38 Therefore, reminders are needed that these models are merely representations of reality— some representing reality quite well, with others being fictitious at best. Oncology economic models are also inherently complex and “data hungry.” They attempt to synthesize biologic, epidemiologic, and economic data from diverse sources. The availability of appropriate and robust data to populate model parameters, however, is quite limited. Traditionally, clinical trials and observational studies of healthcare interventions have provided the crucial clinical data inputs for economic modeling. Some examples include efficacy and safety data regarding disease symptoms and progression, adverse events, and death, as well as data regarding patient drug utilization behaviors (eg, therapy discontinuation or switching), all of which are used to derive probability estimates for model parameters. Although these data may be appropriately collected, analyzed, and incorporated into an economic model, the fact still remains that they are most applicable to the intents of the original study in terms of treatment setting, patient demographics, health and disease status, and the time period over which the study was conducted. Moreover, much greater attention is paid to collecting efficacy and safety data in oncology clinical trials than to the collection of health economic data; for this reason, the quality of economic data collection may not always meet expectations or satisfy the needs of economic modeling.39 Incentives inherent in the clinical research enterprise lead to clinical trials designed for the specific purpose of regulatory approval and maximizing market penetration.5 More often than not, economic data for oncology economic models must come from alternative sources not linked in parallel to the clinical data—such as naturalistic, noninterventional studies (including both prospective and retrospective observational studies).5 This poses problems on its own, not only from potential selection bias, but also because of the conundrum that such studies can be conducted only after the US Food and Drug Administration (FDA)’s approval of the drug label, and drug utilization and expenditure have already begun.39

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Funneling disparate clinical and economic data directly into models to examine economic questions over an extended period and across different geographic units or population subgroups is complex and fraught with opportunity for bias or outright error. This is especially true when clinical trial safety and efficacy end points are collected over short periods and explicitly omit information pertaining to resource utilization, costs, or patient preferences.40 Consequently, uncertainty about the clinical-economic benefits and harms are associated with oncology therapies, which preclude decision makers from reliably assessing the value of these therapies.5 In many cases, clinical trial data available for use in oncology economic models are derived from small, early-­ phase, nonrandomized trials with only 1 study arm. According to 1 study based on data from Clinicaltrials.gov, 98% of oncology-related clinical trials registered from 2007 to 2010 have 1000 participants or fewer, and 75% have 100 or fewer participants.41 In fact, compared with cardiovascular disease and mental health clinical trials, oncology clinical trials were found to be the smallest, with a median number of 43 patients. Moreover, most (approximately 71%) of the trials were early phase (phase 0-2), and approximately 65% were single-group, nonrandomized (approximately 64%), and nonblinded (approximately 88%).41 Although these statistics reflect the reality of drug development, which appropriately designs trials for regulatory purposes, they highlight the fact that clinical trials do not reflect the experience of the majority of patients. Based on these data from Clinicaltrials.gov, small oncology trials are unlikely to be informative for establishing the effectiveness of treatments with modest effects or for comparing effective treatments to enable better decisions in practice.41 A lack of head-to-head clinical-economic data is one of the larger problems in developing economic models for cancer therapies, especially because there tends to be more routine off-label use of cancer drugs.5 Reviews of clinical practice suggest that nearly 50% to 75% of cancer care is provided off label.5,42 Thus, data from sources other than registration-oriented clinical trials (eg, medical rec­ ords and patient registries) may prove necessary to evaluate which patients do best under which treatment scenarios, and to appropriately capture the costs of treatment.5 Although some sources of real-world data, such as comprehensive databases of healthcare claims, capture aspects of cancer-related care and its associated costs, they usually do not include the cancer disease stage and may lack other important clinical details (eg, an accurate recording of line of therapy, and positive evidence of survival). Smaller electronic medical record data sets typically capture cancer-specific data elements, but may not include non–cancer-related care and may even miss

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the important aspects of resource utilization, such as cancer-related hospitalizations, altogether. Whether based on clinical trial data sets or on claims databases, even when modeling data approach the point of being adequate, it is difficult to calibrate them to the real world without real-world reference populations.9,43 Additional methodologic limitations for oncology modeling coincide with the fact that new oncology treatments are increasingly targeted at advanced (ie, metastatic) disease, and that the majority of drugs for the treatment of cancer that are coming to market have late-stage indications.22 This phenomenon results from the frequent need for an overall survival end point and the ethics of not withholding the current standard of care, which leads to trial designs that begin with patients with advanced-stage cancer who have been heavily pretreated and who have exhausted existing standard treatment options.44 Correspondingly, the majority of oncology economic models are models for late-stage disease. Therapies that may significantly improve survival and/or convey other benefits in early-stage disease often fail to differentiate themselves in late-stage, difficult-to-treat patient populations, and corresponding economic models have an intrinsic ceiling on the type and number of economic benefits that can be evaluated.44 Rarely are new economic models developed, or the old models updated, to reflect the shifts in treatment paradigms. Manufacturers struggling to justify the price of new therapies that are only applicable to a small number of patients with metastatic disease are deprived of the true real-world value, because the drugs are used in earlier lines of therapy or in larger, earlier-stage populations, where survival benefits are much greater, and the drugs are much more likely to demonstrate an acceptable effectiveness for the cost. Conceptually, it would be interesting to compare an economic model for a cancer drug at the time of its launch, and then build variations on that model as its indications and target population expand over time (eg, 10 years later), and to compare the cost-effectiveness ratios from the before and after scenarios to observe how they change.

3. What guidelines are followed for developing oncology economic models? In recent years, published guidelines have been made available for organizations developing and evaluating health economic models to encourage appropriate conduct for decision-making purposes. Notable examples have been published by the International Society for Pharmacoeconomics and Outcomes Research (most recently in collaboration with the Society for Medical Decision Making),32,45,46 the Academy of Managed Care Pharmacy,47 and WellPoint.48

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Most health economic modeling guidelines are a subset of comprehensive, country-specific guidelines for economic evaluation in healthcare technology assessments (eg, guidelines issued by the Canadian Agency for Drugs and Technologies in Health [CADTH] and the UK National Institute for Health and Care Excellence). Although published guidelines have provided an important foundation for standardizing economic models, they tend to be more dogmatic (ie, locked in the incontrovertible belief of their own truth) than practical, particularly for the unique challenges posed by oncology. Moreover, the speed at which economic modeling methodologies have progressed in the past 2 decades has been outpaced by advances in oncology treatment technologies. Historically, it is unclear how closely researchers have followed the guidelines for economic model development. For oncology modeling, guideline deviation may be a consequence of accommodating the unique aspects of new treatments for cancer and the populations in which they are being applied. Without practical guidelines for developing oncology models, researchers interested in developing economic models of cancer therapies have carte blanche choice in modeling methods, resulting in inconsistent or substandard results that prove frustrating for the end users. Although disease-specific economic modeling guidelines have been published (eg, diabetes49), only CADTH has published economic modeling guidelines that are specific to cancer, and the motivation for issuing this guidance closely resonates with the issues we discuss here.50 According to Mittmann and colleagues in a publication by the Canadian Agency for Drugs and Technologies in Health, â&#x20AC;&#x153;Current general pharmacoeconomic guidelines do not provide sufficient direction to ensure a consistent approach to the conduct of economic analyses in oncology technology assessment. The decision to develop a guidance document was based on the observed heterogeneity and quality of the analyses in oncology submissions to decision-making bodies where some of these economic analyses have been conducted in an inappropriate or misleading fashion.â&#x20AC;?50 By addressing considerations that are fundamentally important to oncology (ie, model scope, structure, and assumptions; model data choices and quality of data; as well as uncertainty, sensitivity, and validation of model results as they all uniquely pertain to cancer), the CADTH guidelines are a small but meaningful step in the right direction for improving best practices for oncology economic modeling. It is important to note that there is no clear guidance in the United States about how or by whom the information generated by economic models should be interpreted and incorporated into decision-making processes. More-

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over, because most drug formulary decision-making activities occur behind closed doors, researchers must fumble their way through the development of economic models that have a weak sense of expectations and only a vague idea about what the true goals and objectives should be. Aside from the achievement (or not) of formulary placement of a modeled cancer drug, feedback or constructive criticism of model design and presentation are rare.

4. Is the evolution of oncology economic modeling keeping pace with treatment innovation? Oncology is one of the fastest growing therapeutic areas in the pharmaceutical industry and is also one of the most innovative, especially with new products focused on the immunologic aspects of cancer and new targets for interrupting cell proliferation. The advent of targeted cancer therapies, or personalized medicine, that allow physicians to tailor treatment to individual patients is profoundly changing the management of many types of cancer and is presenting interesting challenges in economic modeling. What has been (or will be) the impact of cancer therapy innovation on the way health economic models are developed and perceived? For the most part, questions about the cost implications of personalized therapies are not easily answered by the hypothetical cohort simulations that are so often used in health economic models.9,51 The new heterogeneous focus in cancer treatment is creating difficulties for economic modeling, which historically evolved on the paradigm of homogeneous patient populations. Models need to incorporate not only the reality of heterogeneous populations, but also the reality of rapidly evolving treatment paradigms in which newer expensive therapies displace former standards of care that become available generically at significantly reduced costs. Models also need to address the off-label nature of treatments for cancer, but it remains unclear how to best incorporate off-label use when pharmaceutical manufacturers face regulatory restrictions that limit the promotion of the value of their products to what has been approved in product labels.5 One notable example is the FDA Modernization Act of 1997, which contains a provision (ie, Section 114) stipulating the conditions under which drug companies can promote health economics information to formulary decision makers.52 Finally, the growing use of companion diagnostics in oncology warrants full consideration in economic models. Both diagnostic radiology and genetic testing have their own issues regarding the costs and benefits that precede treatment selection. In some regards, the value of any given treatment is partially dependent on the accuracy of disease staging and genetic testing, which may predict treatment response, and this is remiss in most oncology economic models.

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Drug reimbursement authorities and other healthcare decision makers seldom make definitive yes or no verdicts about the adoption of new therapies for cancer; rather, they tend to make nuanced judgments about how the use of medical technologies affects particular sets or subpopulations of patients.23 In the future, this is going to be increasingly relevant with the advent of personalized medicine that uses biomarker testing and the push toward patient-centered care, where therapies are tailored to the needs of an individual or a subpopulation, all while limiting budget exposure.23,53 We observe, however, that although we are heading in this direction, economic models continue to be developed on a one-sizefits-all basis, despite the continued reluctance of US payers to use explicit cost-effectiveness considerations to determine the value of cancer therapies. It is likely that as personalized medicine in oncology rapidly evolves, payers will pay more attention to economic models that evaluate treatment access and healthcare resources that are directed at patients who are the most likely to benefit, and to models that tie economic outcomes more directly to patient outcomes.23 Although this would be a step in the right direction, genomics and other means for trying to get the right drugs to the right patients will fall flat if arbitrary or capricious thresholds of value persevere. As such, oncology economic modeling will likely be stretched from competing forces: one side pushing for generating economic evidence that will grant patients with cancer greater access to treatments, and the other side attempting to respond to fiscal pressures and the need to balance expenditures. With the drive toward obtaining system-wide efficiencies from directing resources toward patients who will gain the most benefit at the least cost, it seems clear that oncology economic models will need reorientation for predicting budgetary impact, rather than decision cost thresholds.23

Conclusions Methodologic and policy challenges in health economic modeling of cancer therapies are considerable, but perhaps not insurmountable. On one level, oncology is similar to the other areas in healthcare that are under pressure to control expenditures while maintaining or improving quality of care and patient outcomes. However, unlike many other areas in healthcare, the practice of oncology and its rapidly evolving technologies present unique challenges that make assessing and demonstrating value especially complex. There is wide latitude for improvement in oncology modeling methodologies, and the way model results are presented and interpreted. We believe that economic models are good, essential tools for helping decision makers assess complex scenarios. However, the technical and data issues associated with

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oncology economic modeling raise serious questions that now require discussion within the oncology and health economics research communities. It is our hope that this article will provide a framework to guide future discourse on this important topic. n Funding Source Funding for this study and for the preparation of this article was provided by Truven Health Analytics. An earlier, unpublished version of this study was funded by a grant from the Pharmaceutical Research and Manufacturers of America. Author Disclosure Statement Mr Miller and Dr Foley are employees of Truven Health Analytics; Mr Russell is currently an employee of Truven Health Analytics, and was an employee of inVentive Health Clinical and was working under contract with Truven Health Analytics at the time of the writing of this article.

References

1. American Cancer Society. Cancer facts and figures 2014. 2014. www.cancer.org/ acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed March 5, 2014. 2. Eheman C, Henley SJ, Ballard-Barbash R, et al. Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. 2012;118:2338-2366. 3. Jemal A, Ward E, Thun M. Declining death rates reflect progress against cancer. PLoS One. 2010;5:e9584. 4. Yabroff KR, Lund J, Kepka D, Mariotto A. Economic burden of cancer in the United States: estimates, projections, and future research. Cancer Epidemiol Biomarkers Prev. 2011;20:2006-2014. 5. Mullins CD, Montgomery R, Tunis S. Uncertainty in assessing value of oncology treatments. Oncologist. 2010;15(suppl 1):58-64. 6. Abernethy A, Abrahams E, Barker A, et al. Turning the tide against cancer through sustained medical innovation: the pathway to progress. Clin Cancer Res. 2014; 20:1081-1086. 7. Porter ME. What is value in health care? N Engl J Med. 2010;363:2477-2481. 8. Nichol MB, Knight TK, Epstein J, et al. Opinions regarding the Academy of Managed Care Pharmacy dossier submission guidelines: results of a small survey of managed care organizations and pharmaceutical manufacturers. J Manag Care Pharm. 2007;13:360-371. 9. Ferrusi IL, Leighl NB, Kulin NA, Marshall DA. Do economic evaluations of targeted therapy provide support for decision makers? J Oncol Pract. 2011;7(3 suppl):36s-45s. 10. Hulme C, Browne C, Mansfield J, et al. Determining cost-effectiveness of advanced cancer care: a systematic review of economic models. BMJ Support Palliat Care. 2011;1 (suppl 1):A21-A22. 11. Leung MY, Halpern MT, West ND. Pharmaceutical technology assessment: perspectives from payers. J Manag Care Pharm. 2012;18:256-264. 12. Avalere Health, LLC. Do decision makers really use budget impact models generated by manufacturers? Slides presented at the International Society for Pharmacoeconomics and Outcomes Research Annual International Meeting; June 2-6, 2012; Washington, DC. www.ispor.org/meetings/WashingtonDC0512/releasedpresentations/ IP7-Hughes-Only-Slides.pdf. Accessed March 5, 2014. 13. Fryback DG, Craig BM. Measuring economic outcomes of cancer. J Natl Cancer Inst Monogr. 2004:134-141. 14. Tappenden P, Chilcott J, Ward S, et al. Methodological issues in the economic analysis of cancer treatments. Eur J Cancer. 2006;42:2867-2875. 15. Neumann PJ, Weinstein MC. Legislating against use of cost-effectiveness information. N Engl J Med. 2010;363:1495-1497. 16. Neumann PJ. What next for QALYs? JAMA. 2011;305:1806-1807. 17. Johnson FR. Editorial: Moving the QALY forward or just stuck in traffic? Value Health. 2009;12(suppl 1):S38-S39. 18. Grusenmeyer PA, Wong YN. Interpreting the economic literature in oncology. J Clin Oncol. 2007;25:196-202. 19. Greenberg D, Earle C, Fang CH, et al. When is cancer care cost-effective? A systematic overview of cost-utility analyses in oncology. J Natl Cancer Inst. 2010;102:82-88. 20. Smith MD, Drummond M, Brixner D. Moving the QALY forward: rationale for change. Value Health. 2009;12(suppl 1):S1-S4.

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21. McGregor M, Caro JJ. QALYs: are they helpful to decision makers? Pharmacoeconomics. 2006;24:947-952. 22. Garau M, Shah KK, Mason AR, et al. Using QALYs in cancer: a review of the methodological limitations. Pharmacoeconomics. 2011;29:673-685. 23. Neumann PJ, Bliss SK, Chambers JD. Therapies for advanced cancers pose a special challenge for health technology assessment organizations in many countries. Health Aff (Millwood). 2012;31:700-708. 24. Zikmund-Fisher BJ, Fagerlin A, Ubel PA. Risky feelings: why a 6% risk of cancer does not always feel like 6%. Patient Educ Couns. 2010;81(suppl):S87-S93. 25. Williams R. Will the QALY survive? ISPOR Connections. 2007;13:13-14. 26. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology Perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32:1277-1280. 27. Lakdawalla DN, Romley JA, Sanchez Y, et al. How cancer patients value hope and the implications for cost-effectiveness assessments of high-cost cancer therapies. Health Aff (Millwood). 2012;31:676-682. 28. Determinants of health economic decisions in actual practice: the role of behavioral economics. Summary of the presentation given by Professor Daniel Kahneman at the ISPOR 10th Annual International Meeting First Plenary Session; May 16, 2005; Washington, DC, USA. Value Health. 2006;9:65-67. 29. Robinson LA, Hammitt JK. Behavioral economics and the conduct of benefit-cost analysis: towards principles and standards. J Benefit-Cost Anal. 2011;2. Article 5. 30. Frank RG. Behavioral economics and health economics. Working paper 10881, October 2004. www.nber.org/papers/w10881.pdf. Accessed April 12, 2014. 31. Liebman J, Zeckhauser R. Simple humans, complex insurance, subtle subsidies. Working paper 14330, September 2008. www.nber.org/papers/w14330.pdf. Accessed April 12, 2014. 32. Weinstein MC, O’Brien B, Hornberger J, et al; for the ISPOR Task Force on Good Research Practices—Modeling Studies. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices—Modeling Studies. Value Health. 2003;6:9-17. 33. Nuijten MJ, Starzewski J. Applications of modelling studies. Pharmacoeconomics. 1998;13:289-291. 34. Reeder CE, Gordon D. Managing oncology costs. Am J Manag Care. 2006;12(1 suppl):S3-S16; quiz S17-S19. 35. Roberts M, Russell LB, Paltiel AD, et al; for the ISPOR-SMDM Modeling Good Research Practices Task Force. Conceptualizing a model: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-2. Med Decis Making. 2012;32:678-689. 36. Hall PS, Rautenberg TA, McCabe C. Cost analysis for cancer subgroups. Br J Cancer. 2009;100:1513. 37. Kreif N, Grieve R, Radice R, et al. Methods for estimating subgroup effects in cost-effectiveness analyses that use observational data. Med Decis Making. 2012;32: 750-763. 38. Sculpher M. Subgroups and heterogeneity in cost-effectiveness analysis. Pharmacoeconomics. 2008;26:799-806. 39. Bodrogi J, Kaló Z. Principles of pharmacoeconomics and their impact on strategic imperatives of pharmaceutical research and development. Br J Pharmacol. 2010;159: 1367-1373. 40. Meropol NJ, Schrag D, Smith TJ, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology guidance statement: the cost of cancer care. J Clin Oncol. 2009;27:3868-3874. 41. Califf RM, Zarin DA, Kramer JM, et al. Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA. 2012;307:1838-1847. 42. “Off-label” indications for oncology drug use and drug compendia: history and current status. J Oncol Pract. 2005;1:102-105. 43. Stout NK, Knudsen AB, Kong CY, et al. Calibration methods used in cancer simulation models and suggested reporting guidelines. Pharmacoeconomics. 2009;27: 533-545. 44. Goss TF, Picard EH, Tarab A. Recognizing value in oncology innovation. White paper. June 2012. www.phrma.org/sites/default/files/flash/phrma_innovation_oncology. pdf. Accessed March 5, 2014. 45. Caro JJ, Briggs AH, Siebert U, Kuntz KM; for the ISPOR-SMDM Modeling Good Research Practices Task Force. Modeling good research practices—overview: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-1. Value Health. 2012;15:796-803. 46. Sullivan SD, Mauskopf JA, Augustovski F, et al. Budget impact analysis-principles of good practice: report of the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force. Value Health. 2014;17:5-14. 47. AMCP Format Executive Committee. The AMCP format for formulary submissions version 3.1. December 2012. http://amcp.org/WorkArea/DownloadAsset.aspx?id= 16209. Accessed March 5, 2014. 48. WellPoint. Health technology assessment guidelines: drug submission guidelines for new products, new indications, and new formulations. Updated September 2008. www.anthem.com/shared/noapplication/f0/s0/t0/pw_b155849.pdf. Accessed March 5, 2014. 49. American Diabetes Association Consensus Panel. Guidelines for computer modeling of diabetes and its complications. Diabetes Care. 2004;27:2262-2265. 50. Mittmann N, Evans WK, Rocchi A, et al. Addendum to CADTH’s guidelines for the economic evaluation of health technologies: specific guidance for oncology

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products. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health. December 2009. www.cadth.ca/media/pdf/H0405_Guidance_for_Oncology_Prodcuts_ gr_e.pdf. Accessed March 5, 2014. 51. Elkin EB, Marshall DA, Kulin NA, et al. Economic evaluation of targeted cancer interventions: critical review and recommendations. Genet Med. 2011;13:853-860. 52. US Food and Drug Administration Modernization Act of 1997, §114 (21 USC

352[a]). www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFood DrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDAMA/ FullTextofFDAMAlaw/UCM089145.pdf. Accessed March 5, 2014. 53. American Society of Clinical Oncology. Accelerating progress against cancer: ASCO’s blueprint for transforming clinical and translational cancer research. November 2011. www.asco.org/sites/default/files/blueprint.pdf. Accessed March 5, 2014.

Stakeholder Perspective Disruptive Innovation, Uncertain Value, and Economic Modeling in Oncology By Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer, Worldwide Clinical Trials, King of Prussia, PA

Innovations in healthcare technology frequently outpace innovations in its management.1 In an era of disruptive innovation, Miller and colleagues provide an insightful, richly annotated critique of health economic modeling of cancer therapeutics that is relevant to researchers, payers, and providers charged with enhancing access to therapy. Organized as a series of 4 questions, the attributes and limitations of current economic modeling for oncology products are systematically presented, acknowledging that clinical, economic, and humanistic outcomes may be differentially weighted contingent on the perspectives of diverse stakeholders. Advancing alternative strategies for data acquisition and analyses, the commentary is incisive, prompts review of the supporting literature, and creates a template for additional research and discussion. RESEARCHERS: Although casting a large net during data acquisition is useful for hypothesis generation, the lack of a subsequent testable hypothesis will limit the utility of modeling as a decision-making exercise. A lack of focus may result in implications with few actionable attributes, particularly if derived data based on combinations of incremental cost and benefits are nodal points for determining access to therapy. Frequently difficult to interpret, a derived variable also may inadequately capture disease-specific outcomes for competing cancer therapies, may fail to reflect the humanistic element as a modifying variable, and may obscure the heterogeneity within the patient population treated, where much of the signal resides.2 Both time and geography in a disease characterized by different standards of care further limit the utility of many models, particularly if economic data are obtained through “piggybacking” on traditional registration studies,3 which by definition include

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investigators and patients who may not be fully representative of those ultimately receiving a product. Tracking patients who are ineligible for these studies in a parallel observational cohort will enhance generalizability by permitting access to naturalistic healthcare utilization data for similar patients who are not included within the original study. Nevertheless, the off-label use of oncology therapies after market authorization will require access to medical records and patient registries to complement the clinical trial data. The concept of combining trial-based information for short-term outcomes and modeling-based economic evaluations for longer-term cost and outcomes creates an informative pathway for decision-making on a population-level development,4 requiring an iterative, collaborative interface between clinical trialists and economic modelers throughout the clinical development process. The alternative highlighted by Miller and colleagues, which captures temporal trends from product launch through long-term commercialization, offers a nuanced approach to a definition of “value,” acknowledging that changes in incidence or prevalence,5 as well as transitions in standard of care, impact the conclusions derived from basic economic modeling. PAYERS: For novel therapeutic entities, it is axio­ matic that the quality of data supporting economic analyses before marketing is inversely related to the level of management that is subsequently required. Within this mosaic, adoption and reimbursement technologies evaluating safety, efficacy, value for the money (cost-effectiveness), and budgetary impact represent critical domains addressed in the data set presented for review. Yet, Miller and colleagues provocatively question the propriety of an arbitrary threshold of value based on cost-effectiveness

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Stakeholder Perspective Continued data across diseases, when the balance of comparative benefits and costs within competing treatments for a given cancer may be more appropriate to consider. Limitations in traditional metrics include a lack of focus on subgroups, wherein both cost and benefit are most meaningful (targeted therapy); the time frame over which estimates are derived (temporal changes in healthcare); the geographic location and practice setting from which data have been derived; as well as the lack of formal incorporation of patient preferences and social values. Because difficult-to-treat patients with late-stage disease are frequently evaluated in the drug development process for oncology, attempts to express benefits in terms that are solely economic also will place undue influence on the traditional benchmarks that stand apart from the concerns of individual physicians and patients. Given the limited guidelines for economic modeling specific to cancer, Miller and colleagues emphasize the importance of transparency in processes dictating coverage as a method for remediation. As in a “Gedankenexperiment,” which evaluates the likely clinical and economic viability of a proposed therapeutic before clinical development,6 knowledge of processes driving formulary placement and reimbursement decisions before data are actually generated and analyzed economically permits the development of more meaningful and actionable conclusions. PATIENTS: The utility of health economic modeling to inform decision-making at the population level is well established. However, translating the results of that algorithm to the patient level can be perceived as a conflict in physician–patient relationships for providers,

unless the impact of allocation of healthcare resources for other patients is also considered.7 Correspondingly, although an average or a median gain in benefit is arguably the least biased estimate for therapeutic utility on a population level, patients differ in attitudes regarding risk based on the dispersion of estimates of benefit versus risk surrounding these point estimates, thereby living in the standard deviations rather than at the mean.8 Payers, providers, and patients therefore may view the same data and their implications through very different prisms. Economic modeling that can incorporate patient and provider perspectives using disease-specific outcomes in oncology that also resonate with the concerns of payers will better reflect the realities of decisions encountered in practice, redefining “value” in an era of innovation as much more than economics. 1. Herzlinger RE. Why innovation in health care is so hard. Harv Bus Rev. 2006;84: 58-66,156. 2. Ramaekers BL, Joore MA, Grutters JP. How should we deal with patient heterogeneity in economic evaluation: a systematic review of national pharmacoeconomic guidelines. Value Health. 2013;16:855-862. 3. Glick HA, Doshi JA, Sonnad SS, Polsky D. Economic Evaluation in Clinical Trials. Oxford, England: Oxford University Press; 2007. 4. Goeree R, Diaby V. Introduction to health economics and decision-making: is economics relevant for the frontline clinician? Best Pract Res Clin Gastroenterol. 2013; 27:831-844. 5. Rotily M, Roze S. What is the impact of disease prevalence upon health technology assessment? Best Pract Res Clin Gastroenterol. 2013;27:853-865. 6. Trusheim MR, Berndt ER, Douglas FL. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat Rev Drug Discov. 2007;6:287-293. 7. Lessard C, Contandriopoulos AP, Beaulieu MD. The role (or not) of economic evaluation at the micro level: can Bourdieu’s theory provide a way forward for clinical decision-making? Soc Sci Med. 2010;70:1948-1956. 8. Lakdawalla DN, Romley JA, Sanchez Y, et al. How cancer patients value hope and the implications for cost-effectiveness assessments of high-cost cancer therapies. Health Aff (Millwood). 2012;31:676-682.

Reports from ASCO MAY 30 - JUNE 3, 2014

an e-newsletter brought to you by the publishers of THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN™

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Call for Papers Neurology Theme Issue American Health & Drug Benefits is publishing a Neurology Theme Issue in September 2014 Take part in the conversation on the human brain and the focus on brain research. The aging of the US population and the growing clinical and economic burden associated with neurologic disorders have placed the field of neurology at the forefront of medical research and drug development. American Health & Drug Benefits is a peer-reviewed journal reaching providers, payers, and policy decision makers in the United States. All articles submitted for publication in this journal undergo the journal’s rigorous peer-review process and acceptance is dependent on that review. Readers are invited to submit original research, case reports, or systematic reviews on any topic related to the field of neurology. Topics of particular interest include: ORIGINAL RESEARCH

REVIEW ARTICLES

• Case studies/case series

• Alzheimer’s disease: diagnosis, treatment

• Comparative effectiveness analyses

• Dementia update

• Cost-effective analyses

• Developments in neurology

• Drug therapy for a neurologic disorder

• Economic burden of neurologic disorders

• Health economics research outcomes

• Emerging therapies

• New therapies for multiple sclerosis,

• Epilepsy: new developments

seizures, migraine

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For your members with COPD (chronic obstructive pulmonary disease)

The only once-daily ICS/LABA (inhaled corticosteroid/long-acting beta2-agonist) for the maintenance treatment of COPD. Contact your GlaxoSmithKline Account Manager to schedule a presentation. Indications • BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 -adrenergic agonist (ICS/LABA) indicated for the longterm, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. • BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for BREO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including vilanterol. • The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. CONTRAINDICATIONS • BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients. WARNINGS AND PRECAUTIONS • BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2 -agonist. • BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. • Oropharyngeal candidiasis has occurred in patients treated with BREO ELLIPTA. Advise patients to rinse the mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. • An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. – In replicate 12-month studies of 3255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving BREO ELLIPTA 100/25 mcg (6% [51 of 806 subjects]), fluticasone furoate (FF)/vilanterol (VI) 50/25 mcg (6% [48 of 820 subjects]), and FF/VI 200/25 mcg (7% [55 of 811 subjects]) than in subjects receiving VI 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving VI or FF/VI 50/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA at the approved strength (100/25 mcg) and in 7 subjects receiving FF/VI 200/25 mcg (<1% for each treatment group). • Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations. • Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. • Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.


Important Safety Information for BREO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur. • If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. • Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. BREO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. • Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. • Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines. • Be alert to hypokalemia and hyperglycemia. ADVERSE REACTIONS • The most common adverse reactions (≥3% and more common than placebo) reported in two 6-month clinical trials with BREO ELLIPTA (and placebo) were nasopharyngitis, 9% (8%); upper respiratory tract infection, 7% (3%); headache, 7% (5%); and oral candidiasis, 5% (2%). • In addition to the events reported in the 6-month studies, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA in two 1-year studies included COPD, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia. DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur. • BREO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents. • Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with reversible obstructive airways disease. • Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. USE IN SPECIFIC POPULATIONS • Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Fluticasone furoate exposure may increase in these patients. Monitor for systemic corticosteroid effects. Please see Brief Summary of Prescribing Information, including Boxed Warning, for BREO ELLIPTA on the following pages. BREO ELLIPTA was developed in collaboration with


BRIEF SUMMARY BREOTM ELLIPTATM (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in BREO ELLIPTA [see Warnings and Precautions (5.1)]. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. 1 INDICATIONS AND USAGE BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Important Limitations of Use: BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. 4 CONTRAINDICATIONS The use of BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11) of full prescribing information]. 5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthmarelated death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. 5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD. The initiation of BREO ELLIPTA in this setting is not appropriate. BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA no longer controls symptoms of bronchoconstriction; the patientâ&#x20AC;&#x2122;s inhaled, shortacting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of BREO ELLIPTA beyond the recommended dose is not appropriate in this situation. 5.3 Excessive Use of BREO ELLIPTA and Use With Other Long-Acting Beta2Agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including BREO ELLIPTA 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences

these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects]; 100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group). 5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)]. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered. 5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full prescribing information]. 5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA


can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of BREO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take BREO ELLIPTA [see Contraindications (4)]. 5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]). 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]). 5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium. 6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).] Systemic and local corticosteroid use may result in the following: Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]; Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were Caucasian. They had a mean age of 62 years and an average smoking

history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/ vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease

Adverse Event

a

BREO ELLIPTA 100 mcg/25 mcg (n = 410) %

Vilanterol 25 mcg (n = 408) %

Fluticasone Furoate 100 mcg (n = 410) %

Placebo (n = 412) %

9

10

8

8

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasisa

7

5

4

3

5

2

3

2

Nervous system disorders Headache

7

9

7

5

Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.

12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia. 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of BREO ELLIPTA, are both substrates of CYP3A4. Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with longterm ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) of full prescribing information]. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. 7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/ or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while


taking BREO ELLIPTA. Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day). Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/ m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/ day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. 8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk. 8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman. 8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing information]. 10 OVERDOSAGE No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. 10.1 Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)]. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days. 10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/ min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol. Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below. Fluticasone Furoate: Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (approximately equal to the MRHDID in adults on a mcg/m2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed

in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/ day, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis). Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/ day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,000 times, respectively, the MRHDID in adults on a mcg/m2 basis). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Asthma-Related Death Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthmarelated death. BREO ELLIPTA is not indicated for the treatment of asthma. 17.2 Not for Acute Symptoms BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used. Patients should be instructed to notify their physicians immediately if they experience any of the following: Symptoms get worse; Need for more inhalations than usual of their rescue inhaler; Significant decrease in lung function as outlined by the physician. Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation. 17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used. 17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush. Pneumonia: Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems). Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Hypercorticism and Adrenal Suppression: Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk. Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered. 17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. BREO and ELLIPTA are trademarks of GlaxoSmithKline. BREO ELLIPTA was developed in collaboration with

Š2013, GlaxoSmithKline. All rights reserved. Revised 05/2013 Š2013 GlaxoSmithKline group of companies. All rights reserved. Printed in USA. MH3770R0 October 2013

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Better informed teams provide better care.” Matthew P. Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Murray, UT

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RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues. Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

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Review Article

The Impact of 5-HT3RA Use on Cost and Utilization in Patients with ChemotherapyInduced Nausea and Vomiting: Systematic

Review of the Literature

Michael S. Broder, MD, MSHS; Claudio Faria, PharmD, MPH; Annette Powers, PharmD, MBA; Jehangeer Sunderji, MD; Dasha Cherepanov, PhD Background: Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists. Objective: To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT3RAs. Methods: PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of “ondansetron,” “granisetron,” “palonosetron,” “dolasetron mesylate,” “costs,” “cost analysis,” and “economics.” We included records published (fulllength articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT3RAs for the treatment or prevention of CINV. Results: Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT3RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT3RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT3RAs. Fewer patients receiving palonosetron versus with ondansetron or other 5-HT3RAs required rescue medication or used outpatient or inpatient care. In Europe and in Canada, the total pharmacy costs and use of rescue medications reported are lower for patients receiving prophylaxis with palonosetron. Conclusions: This analysis shows that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT3RAs in the United States. Therefore, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.

C

hemotherapy-induced nausea and vomiting (CINV) is an adverse effect of cancer treatment. It may occur within a few minutes of or up to 24 hours after the administration of chemotherapy (ie, acute CINV), or it may occur more than 24 hours after treatment (ie, delayed CINV). CINV may last up to 7 days.1-7

Stakeholder Perspective, page 181 Am Health Drug Benefits. 2014;7(3):171-182 www.AHDBonline.com Disclosures are at end of text

Although there are several patient-specific factors that place patients at an increased risk for developing CINV (eg, female sex, low consumption of alcohol, history of motion or morning sickness, age under 50 years, previous CINV), the most contributory risk factor is the emetogenic potential of the chemotherapy regimen itself.8

Dr Broder is President, Partnership for Health Analytic Research, LLC, Beverly Hills, CA; Dr Faria is Director, Health Economics and Outcomes Research, Eisai Inc, Woodcliff Lake, NJ; Dr Powers is Senior Director, Health Economics and Outcomes Research (HEOR) and Reimbursement Services, Eisai Inc, Woodcliff Lake, NJ; Dr Sunderji is Associate Medical Director, Partnership for Health Analytic Research, LLC, Beverly Hills, CA; Dr Cherepanov is Associate Director, Outcomes Research, Partnership for Health Analytic Research, LLC, Beverly Hills, CA.

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Key Points Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy. ➤ Previous studies have examined the impact of CINV prophylaxis with palonosetron and other 5-HT3RAs on cost and utilization, but this is the first systematic review of the published literature on this topic. ➤ A total of 32 studies were included in this systematic literature review, of which 14 studies report costs and 25 reported utilization. ➤ This review indicates that palonosetron is associated with higher treatment costs but also with lower rescue medication use and outpatient and inpatient services use compared with other 5-HT3RAs. ➤ Based on this analysis, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV. ➤

More than 90% of patients undergoing highly emetogenic chemotherapy (HEC) will experience emesis without antiemetic prophylaxis, and 30% to 90% of those undergoing moderately emetogenic chemotherapy (MEC) will vomit without the prophylactic administration of antiemetics.8 From 10% to 30% of the patients receiving low emetogenic risk chemotherapy (LEC), and <10% of patients receiving minimal emetogenic risk chemotherapy (MinEC), will experience emesis without the administration of antiemetics.3,6,7,9 The dose, frequency, and length of administration, as well as the combination of agents may impact the emetogenicity of the chemotherapy.7 Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy.1-4,6,7,9 The use of prophylactic antiemetic medications in patients undergoing HEC may reduce the incidence of CINV to as low as 30%.7 A multidrug regimen containing a 5-hydroxytryptamine receptor antagonist (5HT3RA) is the standard approach for CINV prophylaxis.7 Drugs in this category include dolasetron mesylate, granisetron, ondansetron, palonosetron, and tropisetron, with palonosetron recommended as the preferred 5-HT3RA for CINV prophylaxis with MEC by the guidelines of the National Comprehensive Cancer Network (NCCN), the Multinational Association of Supportive Care in Cancer/Economic Society for Medical Oncology (MASCC/ESMO), and the American Society of Clinical Oncology (ASCO).5,7,10

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Secondary rescue medications are used to treat breakthrough CINV among patients who have received prophylaxis.7 These medications may include metoclopramide, lorazepam, diphenhydramine, olanzapine, prochlorperazine, or dexamethasone. CINV increases direct costs (eg, medication, office visits, or hospitalizations) and indirect costs (eg, missed work).3,4,9 The effective prevention of CINV may reduce these costs. The clinical and economic impact of CINV underscore the importance of achieving CINV prophylaxis.3,4,9 Palonosetron—which has greater binding affinity and a longer half-life than the other 5-HT3RAs, binds allosterically, stimulates receptor internalization, demonstrates positive cooperativity, and cross talks with the neurokinin (NK)-1 signaling pathway—prevents both acute and delayed CINV more effectively than the other 5-HT3RAs.7,11-14 The extent to which the clinical benefit of 5-HT3RAs translates into reduced costs or utilization of healthcare services among patients with CINV has been shown in individual studies for subsets of outcomes,3,15 but no summary of the literature exists. We conducted a systematic literature review of published research on the healthcare costs and utilization associated with the use of 5-HT3RAs for the prevention of CINV in patients receiving chemotherapy, with the goal of comparing palonosetron with the other 5-HT3RAs.

Methods This systematic review of the literature was conducted according to the Cochrane Collaboration model.16,17 The searches were done in PubMed and in 3 additional databases of the National Institute for Health Research Centre for Reviews and Dissemination (NIHRCRD), including the Database of Abstracts of Reviews of Effects, the National Health Service Economic Evaluation Database, and the Health Technology Assessment Database. We also searched conference abstracts that were presented at meetings of the Academy of Managed Care Pharmacy, ASCO, International Society for Pharmacoeconomics and Outcomes Research, and MASCC. Searches for articles were conducted on July 12, 2012 (PubMed) and July 5, 2012 (NIHRCRD). The searches of conferences covered the years 2010, 2011, and 2012. The searched terms included the medical subject headings, subheadings, and key words “5-HT3RAs,” “dolasetron mesylate,” “granisetron,” “ondansetron,” “palonosetron,” “tropisetron,” “Anzemet,” “Kytril,” “Zofran,” “Aloxi,” “Navoban,” “cost,” “cost analysis,” “economics,” “utilization,” “CINV,” “emesis,” “nausea,” and “vomiting.” We excluded full-length articles that were published before 1997 and were not in the English language, or those that did not report data on human subjects,

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Figure Flow Chart of Review Process Identification (N = 434) Records identified through database search (N = 194)

Records identified through conference abstract search AMCP: 3; ASCO: 3; ISPOR: 6; MASCC: 8 (N = 20)

Records identified through expert recommendation (N = 133)

Records identified through references (N = 87)

Screening Records after duplicates (29) removed (N = 405)

• • • • •

Records screened (N = 405)

Eligibility Total records evaluated for eligibility (N = 193)

Records excluded at title and abstract screening (N = 212) Not CINV No cost/utilization data No drug of interest Not drug therapy Time frame outside of range (1997 and earlier) Not in English or did not include human subjects

Records excluded at full-text review (N = 161) • Not CINV • No cost/utilization data • No drug of interest • Not drug therapy

Included Records included in systematic review (N = 32)

AMCP indicates Academy of Managed Care Pharmacy; ASCO, American Society of Clinical Oncology; CINV, chemotherapy-induced nausea and vomiting; ISPOR, International Society for Pharmacoeconomics and Outcomes Research; MASCC, Multinational Association of Supportive Care in Cancer.

CINV, 5-HT3RAs, pharmacologic treatment, or cost and utilization. If a study was duplicated as a full-length article and a conference abstract, only the article was retained for review. Data abstracted from accepted articles included study metadata, design, patients, treatments, and healthcare cost and utilization. The cost data included pharmacy costs (eg, acquisition/administration of 5-HT3RAs, acquisition/administration of rescue medication), medical costs (eg, outpatient, inpatient), total healthcare costs (eg, total pharmacy, total medical). The utilization data included the rates of rescue medication use, outpatient service use, inpatient service use, and any healthcare resource use (eg, medication, outpatient, or inpatient use). A single reviewer abstracted the articles. As part of the quality assurance process, all data were independently reabstracted, all inconsistencies were discussed, and final determinations were recorded in the review. The Oxford Centre for Evidence-Based Medicine’s (OCEBM) level of evidence scale was used to assess quality of evi-

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dence and to assign a grade of 1 to 5 to each of the included studies, where 1 indicated a study with the strongest scientific basis for support of conclusions and 5 the weakest (eg, expert opinion).18 Randomized controlled trials (RCTs) were assigned a quality score using the Jadad scale, which assigns points on a scale of 0 to 5 based on a study’s use of randomization, and blinding and on its description of withdrawals and dropouts from participation.19 The costs were directly abstracted from studies, and no currency conversions or inflation adjustments were applied in this review.

Results The initial search identified 434 studies, including 414 journal articles and 20 conference abstracts (Figure). Of these, 29 were duplicates, 212 were ineligible after screening titles and abstracts, and 161 were ineligible after screening the full articles. A total of 32 studies were included in this review, of which 21 were fulllength articles and 11 were conference abstracts.

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The 32 studies were published between 1998 and 2012 and reported data from 1995 to 2011 (Appendix A, available at www.AHDBonline.com).1,3,4,6,9,15,20-45 Of the 32 studies, 19 were conducted in the United States. A total of 7 studies were RCTs; 8 were nonrandomized, prospective studies; 14 were retrospective cohort analyses; and 3 were cost-efficacy analyses. Sample sizes ranged from 36 patients43 to 11,974 patients.30 The OCEBM levels of evidence ranged from 1b to 3b for all reviewed studies, and Jadad scores ranged from 2 to 5 for the 7 RCTs.

Description of Included Studies A variety of indications for chemotherapy were represented in the studies, including breast, lung, head, neck, ovarian, gastrointestinal, colorectal, urogenital cancers, lymphoma, leukemia, and bone marrow transplant (Appendix A). Two studies included only patients with breast cancer,21,37 and in 7 other studies, the majority (â&#x2030;Ľ50%) of patients had breast cancer.1,6,22,28,31,32,38 Chemotherapy treatment protocols (single or multiday) ranged from 1 to 5 days. A total of 9 studies included solely HEC regimens, 9 included only MEC regimens, and 13 included some combination of chemotherapy (eg, HEC, MEC, LEC, and MinEC). The studies examined single and multiple 5-HT3RAs, alone and in combination with other medications. Of the 32 studies, 25 included palonosetron. Dosing schedules ranged from a single intravenous (IV) administration of a 5-HT3RA to courses of IV and oral formulations given over several days. CINV prophylaxis was administered with and without adjunctive aprepitant and dexamethasone. Rescue medications included metoclopramide, lorazepam, diphenhydramine, prochlorperazine, and dexamethasone. A total of 14 studies reported cost data, and 25 reported data on utilization (Appendix A). Costs were reported in US dollars (7 studies), Euros (5 studies), and Canadian dollars (2 studies), based on a variety of sources and in several ways. The medication acquisition costs were from government schedules, prices paid by other payers, or from average wholesale prices. Medical costs were reported by treatment setting (outpatient, inpatient, or in aggregate) and in a variety of ways, such as mean cost per office visit and cost per cycle. The inpatient costs, either hospital admissions or emergency department visits, were stated per event (eg, per admission), per chemotherapy cycle, and per patient. Healthcare Costs Associated with 5-HT3RA Use in the United States A total of 7 US studies reported costs associated with the use of 5-HT3RAs for CINV, although only 4 studies compared the costs associated with the use of palonose-

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tron and other drugs of this class (Table 1). Two studies reported the cost of 5-HT3RA prophylaxis acquisition and rescue medication, 3 studies reported the cost of outpatient or inpatient medical services, and 6 studies reported the total pharmacy or total treatment costs. Avritscher and colleagues reported the 5-HT3RA prophylaxis acquisition costs of $49.74 per cycle for ondansetron alone, $207.20 for palonosetron alone, $324.51 for ondansetron when administered with aprepitant, and $482.46 for palonosetron when administered with aprepitant.21 Another study reported the cost of acquisition for ondansetron, which was $1651 for the IV formulation and $539 for the oral formulation compared with $684 for oral granisetron.25 Avritscher and colleagues reported the cost of rescue medications as $35.25, regardless of the specific 5-HT3RA used.21 The previous study also reported a rescue medication cost of $102 among patients receiving oral ondansetron, $96 for IV ondansetron, and $86 for patients receiving oral granisetron.25 A retrospective study of patients receiving HEC reported daily outpatient costs for CINV events of $1216 per cycle in patients receiving palonosetron compared with $1356 for patients taking other 5-HT3RAs.15 A more recent retrospective study reported daily outpatient costs for CINV events for patients receiving palonosetron prophylaxis were approximately $1048 compared with $1339 when taking other 5-HT3RAs.24 Balu and colleagues also reported mean emergency department service costs for CINV events of $1664 for patients receiving palonosetron compared with $1890 for patients receiving other 5-HT3RAs, and mean inpatient costs of $2581 for the palonosetron cohort compared with $2671 for other 5-HT3RAs.15 For patients receiving any 5-HT3RA, Avritscher and colleagues reported a mean cost of $60.30 per clinic office visit for a CINV event and $5237 per hospitalization.21 Fox-Geiman and colleagues reported the total pharmacy cost, including prophylaxis, rescue medication, and drug administration, to be $641 per cycle for patients receiving oral prophylaxis with ondansetron, $1747 for IV ondansetron, and $770 for oral granisetron.25 A recent study reported a mean total pharmacy cost of $2129 in patients with CINV taking one of several 5-HT3RAs.31 The total treatment costs, including all healthcare charges for prophylaxis and the treatment of CINV events, were reported in 5 studies.15,21,31,33,34 Two studies reported that palonosetron when used alone was less costly than any other 5-HT3RAs.15,33 Avritscher and colleagues modeled the direct medical costs of ondansetron-based multiple drug therapies and palonosetron-based multiple drug therapies over 4 cycles of chemotherapy and reported that treatment costs with palonosetron-based regimens were higher compared with ondansetron-based

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Table 1 Cost of CINV Treatment in the United States, by 5-HT3RAa Ondansetron, Palonosetron, Granisetron, Multiple $ $ $ 5-HT3RAsb, $

Study

Notes

Acquisition cost of 5-HT3RA prophylaxisc Avritscher, 201021

49.74d

207.20d

IV and oral formulations

Avritscher, 201021

324.51d

482.46d

IV and oral formulations with aprepitant

Fox-Geiman, 2001

25

Fox-Geiman, 200125

539.00

684.00

Oral formulation

1651.00

IV formulation

Acquisition cost of rescue medicationc Avritscher, 201021

35.25d

Fox-Geiman, 200125

102.00

Fox-Geiman, 2001

96.00

25

86.00

Cost related to oral prophylaxis Cost related to IV prophylaxis

Outpatient medical costs for CINV treatment with 5-HT3RA 60.30d

Avritscher, 201021 Balu, 2010

15

Craver, 201124

Cost per office visit

1216.00

1356.00

Mean daily cost of outpatient services for CINV-related events in patients with HEC

1048.00

1339.00

Mean daily hospital outpatient costs

5237.00d

Mean cost per hospitalization

Inpatient medical costs for CINV treatment with 5-HT3RA Avritscher, 201021 15

2581.00

2671.00

Mean daily cost of inpatient services for CINV-related events in patients with HEC

Balu, 201015

1664.00

1890.00

Mean daily cost of emergency department services for CINV-related events in patients with HEC

Balu, 2010

Total pharmacy costc Fox-Geiman, 200125

641.00

Fox-Geiman, 200125

1747.00

770.00

Mean cost of treatment with oral medication, including scheduled 5-HT3RA and rescue medication cost Mean cost of treatment with IV medication, including scheduled 5-HT3RA and rescue medication cost 2129.00

Knoth, 201131

Among patients with CINV

Total treatment cost Avritscher, 201021

269.00

858.00

Mean cost for 4 cycles (84 days) of 5-HT3RA and dexamethasone (prophylaxis)

Avritscher, 201021

635.00

1177.00

Mean cost for 4 cycles (84 days) of 5-HT3RA, dexa足 methasone (prophylaxis), and aprepitant (after emesis)

Avritscher, 201021

1336.00

1939.00

Mean cost for 4 cycles (84 days) of 5-HT3RA, dexamethasone, and aprepitant (prophylaxis)

Balu, 201015

2004.00

2039.00

Mean daily total medical cost associated with CINV events including inpatient, outpatient, and emergency department visits

Balu, 201015

2056.00

2268.00

Mean daily total medical cost associated with CINV events, including inpatient, outpatient, and emergency department visits for patients with HEC treatment

4816.00

Total costs are the sum of medical and pharmaceutical claims in patients with CINV

1223.00

Adjusted mean costs for CINV-related events (medical and pharmaceutical claims) in patients receiving MEC

1604.00

Mean total cost per cycle per patient experiencing a CINV event (5-HT3RA infusion or medical claims with CINV diagnosis); group primarily treated with palonosetron (72%) for CINV

Knoth, 201131 Knoth, 201133 Knoth, 201134

1127.00

Cost per cycle unless indicated otherwise; currency is US dollars. Data included some combination of the indicated 5-HT3RAs (specific breakdown was not provided by given article), unless otherwise noted. Medication cost assumption: IV regimens administered with dexamethasone unless noted. d Number represents a model input used by author. 5-HT3RA indicates 5-hydroxytryptamine receptor antagonist; CINV, chemotherapy-induced nausea and vomiting; HEC, highly emetogenic chemotherapy; IV, intravenous; MEC, moderately emetogenic chemotherapy. a

b c

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Table 2 Utilization Associated with CINV Treatment in the United States, by 5-HT3RAa Ondansetron, Palonosetron, Granisetron, Dolasetron, Multiple % % % % 5-HT3RAsb, %

Study

Notes

Rescue medication Avritscher, 201021

61c

56c

IVb and oral regimens (patients with emesis)

3

Feinberg, 2009

67

24

Prescribed as follow-up therapy on days 2-5

Feinberg, 2012

4

83

28

From day 2 to 7 days after last round of chemotherapy

Fox-Geiman, 200125

91

Fox-Geiman, 2001

79

Gralla, 199827

25

25

85

Oral regimen IV regimen

31

IV and oral regimens (day 1)

Grote, 2006

7

IV regimen (day 1); at least 1 dose of aprepitant and dexamethasone

Grote, 200629

21

Days 1-5; at least 1 dose of aprepitant and dexamethasone

Knoth, 201132

7

29

Knoth, 2011

12

16

33

Knoth, 201235 Knoth, 201236 Mattiuzzi, 2010

41

30

Within first cycle of chemotherapy Within first cycle of chemotherapy

11

8

20

20

Prescribed as follow-up therapy on days 2-5

24

14

27

31

Within 1 cycle of chemotherapy

11

6

Mattiuzzi, 2010

10

Schwartzberg, 20116

35

41

Day 1: 5-HT3RA on days 1-5 Day 1: palonosetron on days 1, 3, 5 35

Prescribed as follow-up therapy on days 2-5

Outpatient Avritscher, 201021

10c

5c

Office visit (patients with emesis)

Yeh, 2011

10

8

Outpatient, related to CINV

0.4c

0.2c

1

1

45

Inpatient Avritscher, 201021 Feinberg, 2012

4

Hospitalization (patients with emesis) Hospital readmission related to CINV from day 1 to 7 days after last round of chemotherapy

Hatoum, 201230

4

6

Hospitalization (breast cancer group)

Hatoum, 201230

10

14

Hospitalization (lung cancer: carboplatin group)

Hatoum, 201230

16

23

Hospitalization (lung cancer: cisplatin group)

Knoth, 2012

35

6

Hospitalization among patients with CINV

Knoth, 2012

35

1

Emergency department visit related to CINV for patients with CINV

10

Emergency department/hospital admission events

7

Lin, 201139 Yeh, 201145

5

0

Hospital readmission related to CINV from day 1 to 7 days after last round of chemotherapy

Yeh, 201145

0

0

Emergency department visit related to CINV for patients with CINV

Rate per cycle for all patients unless indicated otherwise. Data included some combination of the indicated 5-HT3RAs (specific breakdown was not provided by given article), unless otherwise noted. c Represents a model input used by author. 5-HT3RA indicates 5-hydroxytryptamine receptor antagonist; CINV, chemotherapy-induced nausea and vomiting; IV, intravenous. a

b

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regimens.21 A recent study of patients undergoing HEC or MEC and using 5-HT3RAs reported total CINV-related treatment costs (ie, medical and pharmaceutical claims) of $4816, although the costs for palonosetron alone were not reported.31 A study of commercially insured patients who were primarily treated with palonosetron (72%) reported a treatment cost of $1604 per cycle for a patient experiencing a CINV event (ie, 5-HT3RA infusion or medical claims with CINV diagnosis), but the study did not report costs for palonosetron alone.34

Healthcare Utilization Associated with 5-HT3RA Use in the United States In all, 16 studies reported data on healthcare utilization related to the use of 5-HT3RAs for CINV in the United States, of these 12 reported rescue medication use, 2 reported outpatient medical service use, and 6 reported inpatient service use (Table 2). Of the 12 studies, 10 that reported the frequency of rescue medication use in the United States specifically presented comparative results between patients receiving palonosetron and patients receiving other 5-HT3RAs. Of these 10 studies, 8 found lower rescue medication use among patients receiving palonosetron. One RCT reported lower rescue medication use in patients receiving palonosetron compared with patients receiving ondansetron (6% vs 11%, respectively).41 Four retrospective studies also reported lower rescue medication utilization rates in those treated with palonosetron compared with ondansetron (24% vs 67%, respectively3; 28% vs 83%, respectively4; 8% vs 11%, respectively35; and 14% vs 24%, respectively36). Knoth and colleagues also reported higher rescue antiemetic rates in Medicaid patients with cancer who received granisetron (20%) and dolasetron (20%) compared with palonosetron (8%).35 Another retrospective study of commercially insured patients also reported higher rescue medication needs in patients given granisetron (27%) and dolasetron (31%) compared with palonosetron (14%).36 Three other retrospective studies reported rescue medication needs in patients treated with palonosetron versus with multiple 5-HT3RAs (7% vs 12%, respectively,32 16% vs 30%, respectively,33 and 35% vs 35%, respectively6). The rates of rescue medication use were 61% in patients receiving ondansetron and 56% in patients receiving palonosetron in one cost-efficacy analysis study.21 Of 10 outpatient or inpatient utilization rate comparisons reported in 6 studies, 8 comparisons were lower among patients receiving palonosetron prophylaxis than in patients receiving other 5-HT3RAs, and 2 comparisons had equivalent rates between the palonosetron and other 5-HT3RA cohorts (Table 2). Two studies reported lower rates of physician office visits (5% vs 10%, respectively)

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and outpatient service use (8% vs 10%, respectively) related to CINV among patients receiving palonosetron compared with patients receiving ondansetron.21,45 Patients receiving palonosetron had lower or equivalent rates of outpatient service use compared with patients treated with ondansetron: the rates of hospitalization were approximately 0.2% versus approximately 0.4%, respectively,21 whereas the rates of hospital readmission (which are related to CINV from days 1-7 after the last round of chemotherapy) were 1% versus 1%, respectively,4 and 0% versus 5%, respectively.45 Yeh and colleagues reported the same rate (0%) of emergency department visits related to CINV in patients receiving palonosetron and in patients receiving ondansetron.45 In comparing patients treated with palonosetron with patients treated with any other 5-HT3RA, fewer patients in the palonosetron group had hospitalizations (4% vs 6%, respectively; 10% vs 14%, respectively; and 16% vs 23%, respectively30) and emergency department or hospital admission events (7% vs 10%, respectively39).

Healthcare Cost Associated with 5-HT3RA Use in Europe and Canada A total of 7 studies reported the costs associated with the use of 5-HT3RAs for CINV in Europe and Canada. Of these studies, 6 reported the cost of 5-HT3RA acquisition, 5-HT3RA administration, or rescue medication; 3 studies reported the cost of outpatient or inpatient medical services; and 5 studies reported the total pharmacy or total treatment costs (Appendix B, available at www. AHDBonline.com). Only 1 study reported costs for the use of palonosetron.26 The acquisition costs of 5-HT3RAs and rescue medication costs varied by study. For example, 1 study reported the acquisition cost of ondansetron ranged from €17.90 to €57.75, tropisetron from €14.80 to €23.59, and granisetron from €26.16 to €41.60,22 whereas another study reported the costs for rescue medication ranged from €7.22 for all cycles to €11.20 for cycles with CINV per treatment cycle per patient.9 The outpatient and inpatient medical costs varied across the studies. For example, the outpatient medical costs for CINV treatment ranged from €0.23 for medical consultation in patients treated with tropisetron22 to €9.28 for outpatient care in patients treated with ondansetron.40 The inpatient medical costs varied from €0.43 for emergency department admission per cycle22 to €151.86 per patient for hospitalization.40 Of the 5 studies that reported the total costs, only 1 study reported the costs associated with the use of palonosetron.26 There were substantially lower total pharmacy costs related to prophylaxis with palonosetron compared with tropisetron: €107.25 versus €410.50, respectively.26

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Table 3 Utilization Rates Associated with CINV Treatment in Europe and Canada, by 5-HT3RAa Rescue medication Ondansetron, Palonosetron, Tropisetron, Granisetron, Multiple % % % % 5-HT3RAsb, %

Study Aapro, 2006

23

20

Aapro, 2006

20

Day 1 IV palonosetron 0.25 mg

17

20

Barrajon, 200022c

Notes Day 1 with IV palonosetron 0.75 mg

5

5

3

Celio, 201123

9

Day 1 with palonosetron and 1-day Dexa

Celio, 201123

27

Days 2-5 with palonosetron and 1-day Dexa

Celio, 201123

29

Days 1-5 with palonosetron and 1-day Dexa

Celio, 201123

11

Day 1 with palonosetron and 3-day Dexa

Celio, 201123

17

Days 2-5 with palonosetron and 3-day Dexa

Celio, 201123

20

Days 1-5 with palonosetron and 3-day Dexa

Giordano, 201126

9

Gralla, 200328

24

Gralla, 200328 Gralla, 2003

27

28

Gralla, 200328

12

All cycles

16

Days 2-5 with palonosetron 0.25 mg

23

Days 2-5 with palonosetron 0.75 mg

19

Days 1-5 with palonosetron 0.25 mg

24

Days 1-5 with palonosetron 0.75 mg

Ihbe-Heffinger, 2004

6

IV regimen

Ihbe-Heffinger, 20049

10

Oral or rectal regimens

9

Musso, 200942

40

20

Days 1-5 after the end of treatment

Rigacci, 2012

8

Day 1, after first chemotherapy administration on day 1

Rigacci, 201243

39

Days 1-5, after first chemotherapy administration on day 1

Rigacci, 201243

4

Day 1, after second chemotherapy administration on day 15

Rigacci, 201243

11

Days 1-5, after second chemotherapy administration on day 15

43

Schroeder, 201144

9

Day 1

Schroeder, 201144

34

Days 2-3

Outpatient Barrajon, 200022c

4

2

5

Medical consultation

Ihbe-Heffinger, 2004

11

Medical consultation

Ihbe-Heffinger, 20049

3

Outpatient hospital visit

9

Inpatient Barrajon, 200022c

0

1

0

Barrajon, 2000

1

1

1

22c

Ihbe-Heffinger, 20049

Emergency department visit Hospitalization 1

Hospitalization

33

Any medication, outpatient or inpatient use

Any healthcare resource Ihbe-Heffinger, 20049

Rate per cycle for all patients unless indicated otherwise. Data included some combination of the indicated 5-HT3RAs (specific breakdown was not provided by given article), unless otherwise noted. c This was calculated by dividing the number of events for each 5-HT3RA by 120 (ie, the number of chemotherapy cycles). 5-HT3RA indicates 5-hydroxytryptamine receptor antagonist; CINV, chemotherapy-induced nausea and vomiting; Dexa, dexamethasone; IV, intravenous. a

b

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Healthcare Utilization Associated with 5-HT3RA Use in Europe and Canada A total of 9 studies reported data on healthcare utilization related to the use of 5-HT3RAs for CINV in Europe or in Canada, and, of these, 8 studies reported utilization associated with the use of palonosetron (Table 3). The use of rescue medication varied widely (3%-40% of patients), considering which 5-HT3RA was used, treatment time relative to chemotherapy, and treatment duration, dosage, and administration route. Similar to US studies, the rates of rescue medication use were lower for palonosetron versus for other 5-HT3RAs: 20% vs 23%, respectively20; 9% vs 12%, respectively26; 16% vs 24% or 19% vs 27%, respectively28; and 20% vs 40%, respectively.42 The use of outpatient services, including medical consultations and hospital visits, ranged from 2% (tropisetron) to 11% (multiple 5-HT3RAs) and the use of inpatient services, including emergency department visits and hospitalizations, ranged from 0% (ondansetron or granisetron) to 1% (ondansetron, tropisetron, granisetron, or multiple 5-HT3RAs), but no rates were reported for palonosetron in these studies.9,22 Discussion Our literature review shows that CINV prophylaxis with palonosetron compared with ondansetron is generally associated with higher acquisition costs, a finding supported by the ASCO guidelines that reported a higher total cost per treatment cycle for palonosetron than for granisetron, ondansetron, and dolasetron.10 However, palonosetron is generally associated with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT3RAs. In Europe and in Canada, the total pharmacy costs and rescue medication use are lower for patients treated with palonosetron. Overall, the healthcare utilization results from Europe and Canada are consistent with results from the United States. This study highlights the use of palonosetron as a standard treatment, which may lead to the reduced utilization of rescue medications and healthcare services for CINV, and possibly result in subsequent cost-savings related to medical outpatient and inpatient services. A recent comprehensive review of efficacy data suggests that patients who receive palonosetron experience less nausea, both acute (relative risk [RR], 0.86; 95% confidence interval [CI], 0.76-0.96; P = .007) and delayed (RR, 0.82; 95% CI, 0.75-0.89; P <.001), and less acute vomiting (RR, 0.76; 95% CI, 0.66-0.88; P = .002) and delayed vomiting (RR, 0.76; 95% CI, 0.68-0.85; P <.001).11 The NCCN recommends palonosetron as the preferred 5-HT3RA for patients undergoing HEC.7 Palonosetron is also recommended by the NCCN, MASCC/

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ESMO, and ASCO guidelines as the preferred 5-HT3RA for CINV prophylaxis with MEC,5,7,10 and is the preferred 5-HT3RA according to the MASCC/ESMO guidelines for anthracycline combined with cyclophosphamide chemotherapy when an NK1 receptor antagonist is not available.5 The utilization data evaluated in the reviewed studies support the hypothesis that patients managed with palonosetron use fewer outpatient, emergency department, and inpatient care services than patients who receive other 5-HT3RA agents. The utilization of medical services related to CINV may have a role as an important metric for plans, providers, and patients in identifying the appropriate therapy for CINV prophylaxis. This review focused on 2 specific outcomes—medical costs and utilization—but the evidence we report has implications for patients in terms of quality of life, indirect costs, and treatment discontinuation resulting from CINV. Studies have shown that CINV adversely impacts quality of life of patients with cancer.46 Patients with cancer have rated being free from CINV as one of the most favorable health states after perfect health and complete remission.47 Less quantifiable but still impor­ tant, indirect costs associated with CINV may include lost productivity and patient and family anxiety. Studies have previously documented the impact of CINV on indirect costs in terms of reduced productivity or workdays lost.9,48,49 A Canadian study found that indirect costs accounted for up to 66% of the total cost of CINV among 72 patients,49 whereas a US study reported that 23% of their patients were not able to work as a result of emesis.48 CINV prophylaxis may also be important in avoiding chemotherapy discontinuation as a result of CINV complications. The NCCN antiemesis guidelines cite research that suggests that compliance with therapy—in particular, infusion therapy appointments—is decreased in patients who experience nausea and vomiting.7,50 Several independent studies have demonstrated the benefits of compliance to antiemetic guidelines for CINV prophylaxis before single-day HEC or MEC.51-53 A recent prospective observational study of oncology practices in the United States reported the incidence of no CINV was significantly higher in the guideline-consistent CINV prophylaxis (GCCP) cohort compared with the guideline-inconsistent CINV prophylaxis (GICP) cohort over 5 days postchemotherapy (53.4% vs 43.8%, respectively; P <.001).52 The adjusted odds of no CINV in the GCCP group were 1.31 (95% CI, 1.07-1.69).52 An earlier prospective observational study, which was conducted in 8 European countries, reported a higher complete response (no emesis and no use of rescue therapy) rate in a GCCP cohort (59.9%) compared with in

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a GICP cohort (50.7%; P = .008).51 After controlling for a variety of confounding factors, patients in the GCCP cohort had 1.43 times the odds of complete response (95% CI, 1.04-1.97; P = .027) compared with patients in the GICP cohort.51 Despite the wide availability of guidelines on the prevention of CINV and the worldwide evidence of favorable outcomes with higher guideline compliance, adherence to and implementation of treatment recommendations in antiemetic guidelines on CINV are often suboptimal.51-53 Studies indicate that more effective clinical uptake of guidelines, developed by consensus opinions of international experts published by the MASCC, ASCO, and the NCCN, for the prevention of CINV improve patient outcomes, including the reduced incidence of CINV and healthcare visits to manage CINV and improved quality of care and cost-savings.51-53

sociated with higher total acquisition costs, as well as with lower use of rescue medications and outpatient and inpatient services, compared with ondansetron or other 5-HT3RAs in the United States. In Europe and in Canada, the total pharmacy costs and rescue medication use are lower for patients who receive palonosetron. This study supports the use of palonosetron as the preferred 5-HT3RA, because it may lead to reduced service utilization for CINV. n

Strengths and Limitations The strength of this research lies in its comprehensive review and in its synthesis of global literature that is published in peer-reviewed journals and is presented at professional congresses. This study also has limitations. To conduct a comprehensive review, we did not exclude studies that used relevant outcomes of interest (eg, costs, utilization) as model inputs.21,38,40 The studies included in this review varied in designs, patients, 5-HT3RA regimens, and definition of outcomes, and the data presented in this study, particularly regarding costs, were derived from a variety of sources, and were reported in several ways across the reviewed studies. Thus, the heterogeneity of these data prevented us from conducting a meta-analysis. This literature review includes studies published between 1998 and 2012, many of which would not have reflected the dramatically lower cost of generic ondansetron, which became available in 2006. This may be a significant limitation in our assessment of drug costs, but it would not be expected to impact nondrug costs. We were unable to examine the costs of managing CINV when the current prevention and treatment guidelines are being followed, because the guidelines are not organized in a way that would make it clear how to assess the costs associated with implementing various recommendations. Future studies should develop models to compare the cost of care associated with compliant versus noncompliant treatment guideline recommendations in relation to CINV prophylaxis.

References

Conclusion The use of palonosetron for CINV prophylaxis is as-

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Funding Source Funding for this study was provided by Eisai Inc. Author Disclosure Statement Dr Broder, Dr Sunderji, and Dr Cherepanov are employees of the Partnership for Health Analytic Research, LLC, a health services research company paid by Eisai Inc, to conduct this research; Dr Faria and Dr Powers are employees of Eisai Inc. 1. Abali H, Çelik I. Tropisetron, ondansetron, and granisetron for control of chemotherapy-induced emesis in Turkish cancer patients: a comparison of efficacy, side-­ effect profile, and cost. Cancer Invest. 2007;25:135-139. 2. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database Syst Rev. Jan 2010:CD006272. Update in: Cochrane Database Syst Rev. 2013;12:CD006272. 3. Feinberg BA, Gilmore J, Haislip S, et al. Data-driven medical decision-making in managing chemotherapy-induced nausea and vomiting. Community Oncol. 2009;6:62-67. 4. Feinberg B, Gilmore J, Haislip S, et al. Impact of initiating antiemetic prophylaxis with palonosetron versus ondansetron on risk of uncontrolled chemotherapy-induced nausea and vomiting in patients with lung cancer receiving multi-day chemotherapy. Support Care Cancer. 2012;20:615-623. 5. Roila F, Herrstedt J, Aapro M, et al; for the ESMO/MASCC Guidelines Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243. 6. Schwartzberg L, Jackson J, Jain G, et al. Impact of 5-HT3 RA selection within triple antiemetic regimens on uncontrolled highly emetogenic chemotherapy-induced nausea/vomiting. Expert Rev Pharmacoecon Outcomes Res. 2011;11:481-488. 7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): antiemesis. Version 2.2014. www.nccn.org/ professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 6, 2014. 8. Wickham R. Best practice management of CINV in oncology patients: II. Antiemetic guidelines and rationale for use. J Support Oncol. 2010;8(2 suppl 1):10-15. 9. Ihbe-Heffinger A, Ehlken B, Bernard R, et al. The impact of delayed chemotherapy-induced nausea and vomiting on patients, health resource utilization and costs in German cancer centers. Ann Oncol. 2004;15:526-536. 10. Basch E, Prestrud AA, Hesketh PJ, et al; for the American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198. 11. Botrel TE, Clark OA, Clark L, et al. Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis. Support Care Cancer. 2011;19:823-832. 12. De Leon A. Palonosetron (Aloxi): a second-generation 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting. Proc (Bayl Univ Med Cent). 2006;19:413-416. 13. Smith HS, Cox LR, Smith EJ. 5-HT3 receptor antagonists for the treatment of nausea/vomiting. Ann Palliat Med. 2012;1:115-120. 14. Rojas C, Li Y, Zhang J, et al. The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ther. 2010;335:362-368. 15. Balu S, Craver C, Gayle J, Buchner D. Cost consequences of initiating palonosetron versus other 5-hydroxytryptamine 3 receptor antagonists for prevention of chemotherapy-induced nausea and vomiting among patients with cancer treated with highly emetogenic chemotherapy in a hospital outpatient setting. J Support Oncol. 2010;8. Abstract PA-2. Poster presented at the 6th Annual Chicago Supportive Oncology Conference; Chicago, IL; October 7-9, 2010. Poster PA-2. 16. Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Cochrane Collaboration; 2011. Updated March 2011. www. cochrane-handbook.org. Accessed August 7, 2012. 17. Yoshii A, Plaut DA, McGraw KA, et al. Analysis of the reporting of search strategies in Cochrane systematic reviews. J Med Libr Assoc. 2009;97:21-29. 18. OCEBM Levels of Evidence Working Group. The Oxford 2011 levels of evidence. www.cebm.net/index.aspx?o=5653. Accessed May 6, 2014.

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19. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12. 20. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449. 21. Avritscher EB, Shih YC, Sun CC, et al. Cost-utility analysis of palonosetron-based therapy in preventing emesis among breast cancer patients. J Support Oncol. 2010;8:242-251. 22. Barrajon E, de las Peñas R. Randomised double blind crossover study comparing ondansetron, granisetron and tropisetron. A cost-benefit analysis. Support Care Cancer. 2000;8:323-333. 23. Celio L, Frustaci S, Denaro A, et al; for the Italian Trials in Medical Oncology Group. Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial. Support Care Cancer. 2011;19:1217-1225. 24. Craver C, Gayle J, Balu S, Buchner D. Impact on hospital outpatient visit costs by initiating palonosetron versus other 5-hydroxytryptamine3 receptor antagonists for prevention of chemotherapy induced nausea and vomiting (CINV) among patients with cancer. Value Health. 2011;14. Abstract PCN48. 25. Fox-Geiman MP, Fisher SG, Kiley K, et al. Double-blind comparative trial of oral ondansetron versus oral granisetron versus IV ondansetron in the prevention of nausea and vomiting associated with highly emetogenic preparative regimens prior to stem cell transplantation. Biol Blood Marrow Transplant. 2001;7:596-603. 26. Giordano G, Tambaro R, Mondello P, et al. Chlorpromazine plus methoclopramide and prednisone is effective in late hemesis control of patients pretreated with palonosetron than with tropisetron. Support Care Cancer. 2011;19(suppl 2). Abstract 145. 27. Gralla RJ, Navari RM, Hesketh PJ, et al. Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Clin Oncol. 1998;16:1568-1573. 28. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 29. Grote T, Hajdenberg J, Cartmell A, et al. Combination therapy for chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: palonosetron, dexamethasone, and aprepitant. J Support Oncol. 2006;4:403-408. 30. Hatoum HT, Lin SJ, Buchner D, Cox D. Comparative clinical effectiveness of various 5-HT3 RA antiemetic regimens on chemotherapy-induced nausea and vomiting associated with hospital and emergency department visits in real world practice. Support Care Cancer. 2012;20:941-949. 31. Knoth RL, Chang E, Broder M, Powers A. Examining health care costs in chemotherapy-induced nausea and vomiting: a retrospective analysis. J Manag Care Pharm. 2011;17:250. Poster presented at the Academy of Managed Care Pharmacy’s 23rd Annual Meeting and Showcase; Minneapolis, MN; April 27-29, 2011. Poster PRR-36. 32. Knoth RL, Chang E, Broder M, Powers A. Chemotherapy induced nausea and vomiting following prophylactic 5-HT3-RA antiemetic treatment in highly emetogenic chemotherapy. Support Care Cancer. 2011;19(suppl 2). Abstract 471. Poster presented at the 2011 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium; Athens, Greece; July 23-25, 2011. 33. Knoth RL, Chang E, Broder M, Powers A. Chemotherapy induced nausea and vomiting following prophylactic 5-HT3-RA antiemetic treatment in moderately emetogenic chemotherapy. Support Care Cancer. 2011;19(suppl 2). Abstract 468. Poster presented at the 2011 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium; Athens, Greece; July 23-25, 2011. 34. Knoth RL, Chang E, Broder M, Powers A. Health care costs in chemotherapy induced nausea and vomiting: a retrospective analysis of a commercially insured U.S. patient population. Support Care Cancer. 2011;19(suppl 2). Abstract 458. Healthcare costs related to chemotherapy-induced nausea and vomiting: a retrospective analysis in a U.S. commercially insured population. Poster presented at the 2011 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium; Athens, Greece; July 23-25, 2011. 35. Knoth RL, Faria C, Li X, Powers A. Examining the use of rescue antiemetic

medication for chemotherapy-induced nausea and vomiting in a Medicaid population. Support Care Cancer. 2012;20(suppl 1). Abstract 722. Poster presented at the 2012 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium; New York, NY; June 28-30, 2012. 36. Knoth RL, Faria C, Chang E, Broder M. Examining the use of rescue antiemetic medication for chemotherapy induced nausea and vomiting in a commercial population. Value Health. 2012;15:Abstract PCN10. Poster presented at the International Society for Pharmacoeconomics and Outcomes Research 15th Annual European Congress; November 3-7, 2012; Berlin, Germany. 37. Lachaine J, Laurier C, Langleben A, Vaillant L. Cost-effectiveness and quality of life evaluation of ondansetron and metoclopramide for moderately emetogenic chemotherapy regimens in breast cancer. Crit Rev Oncol Hematol. 1999;32:105-112. 38. Lachaine J, Laurier C. Cost-efficacy analysis of ondansetron regimens for control of emesis induced by noncisplatin, moderately emetogenic chemotherapy. Am J Health Syst Pharm. 2002;59:1837-1846. 39. Lin S, Hatoum HT, Balu S. Effect of antiemetic prophylaxis against chemotherapy-induced nausea and vomiting with 5-HT3 receptor antagonists in patients with lymphoma. Value Health. 2011;14: Abstract PCN4. Poster presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 14th Annual European Congress; November 5-8, 2011; Madrid, Spain (poster title modified to: Effect of 5-HT3 RA prophylaxis for chemotherapy induced nausea & vomiting in patients with lymphoma). 40. Lordick F, Ehlken B, Ihbe-Heffinger A, et al. Health outcomes and cost-effectiveness of aprepitant in outpatients receiving antiemetic prophylaxis for highly emetogenic chemotherapy in Germany. Eur J Cancer. 2007;43:299-307. 41. Mattiuzzi GN, Cortes JE, Blamble DA, et al. Daily palonosetron is superior to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting in patients with acute myelogenous leukemia. Cancer. 2010;116:5659-5666. 42. Musso M, Scalone R, Bonanno V, et al. Palonosetron (Aloxi) and dexamethasone for the prevention of acute and delayed nausea and vomiting in patients receiving multiple-day chemotherapy. Support Care Cancer. 2009;17:205-209. 43. Rigacci L, Landi C, Caruso JP, et al. Single dose palonosetron and dexamethasone in preventing nausea and vomiting induced by high emetogenic ABVD regimen in Hodgkin lymphoma patients. Leuk Res. 2012;36:182-185. 44. Schroeder H, Nadaraja S, Rosthoej S, et al. Palonosetron in the prevention of chemotherapy-induced nausea and vomiting in children with acute lymphoblastic leukemia treated with high-dose methotrexate. J Clin Oncol. 2011;29(15 suppl). Abstract 9535. 45. Yeh YC, McDonnell A, Klinger E, et al. Comparison of healthcare resource use between patients receiving ondansetron or palonosetron as prophylaxis for chemotherapy-induced nausea and vomiting. J Oncol Pharm Pract. 2011;17:179-185. 46. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol. 2006;24:4472-4478. 47. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13:219-227. 48. Lindley CM, Hirsch JD, O’Neill CV, et al. Quality of life consequences of chemotherapy-induced emesis. Qual Life Res. 1992;1:331-340. 49. O’Brien BJ, Rusthoven J, Rocchi A, et al. Impact of chemotherapy-associated nausea and vomiting on patients’ functional status and on costs: survey of five Canadian centres. CMAJ. 1993;149:296-302. 50. Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol. 1988;6:1746-1752. 51. Aapro M, Molassiotis A, Dicato M, et al; for the PEER investigators. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol. 2012;23: 1986-1992. 52. Gilmore JW, Peacock NW, Gu A, et al. Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE study. J Oncol Pract. 2014;10:68-74. 53. Jordan K, Gralla R, Jahn F, Molassiotis A. International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): content and implementation in daily routine practice. Eur J Pharmacol. 2014;722:197-202.

Stakeholder Perspective The Value of Pharmaceuticals in the Prevention and Treatment of CINV By Atheer A. Kaddis, PharmD Senior Vice President, Sales and Development, Diplomat Specialty Pharmacy, Flint, MI

PATIENTS: Chemotherapy-induced nausea and vomiting (CINV) is one of the most common adverse effects of cancer treatment.1 Symptoms may range from slight nausea to persistent vomiting with dehydration,

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which can severely impact quality of life.2 A better understanding of the etiology and pathophysiology of CINV has led to the approval of several effective targeted agents, including the serotonin receptor antagonists Continued

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Stakeholder Perspective Continued and neurokinin-1 (NK1) receptor antagonists. Even with these advances, challenges remain regarding the prevention and management of CINV. Depending on the severity of their symptoms, patients may be hesitant to continue with potentially lifesaving therapy. Although most CINV is observed with infused chemotherapy agents, it is also seen with some oral oncolytic therapies and can lead to lower adherence rates, even for the currently available oral oncolytic therapies. PAYERS/PROVIDERS: The direct and indirect costs of CINV are also significant. These include costs related to the acquisition of antiemetic drugs, as well as expenses associated with unscheduled office or emergency department visits, hospitalization admissions, and loss of productivity for patients and their caregivers.3 Broder and colleagues conducted an extensive, systematic review of the published literature on the prevention and treatment of CINV between 1997 and 2010, and found that the patients receiving palonosetron had lower rescue medication use and less inpatient and outpatient services despite higher acquisition treatment costs. On the surface, a skeptic may think that the conclusions are biased toward a higher-cost therapy and may note that a study funded by the pharmaceutical manufacturer would also introduce bias. This could not be further from the truth. The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) antiemesis guidelines were updated in 2011.4,5 Both organizations recommend the use of a 5-hydroxytryptamine receptor antagonist (5-HT3RA; preferably administered before the first dose of chemotherapy), dexamethasone, and an NK1 receptor antagonist for the prevention of CINV in highly emetogenic chemotherapy (HEC). Aprepitant (oral) and fosaprepitant (intravenous [IV]), both NK1 receptor antagonists, are considered equivalent. For moderately emetogenic chemotherapy, a 5-HT3RA with dexamethasone is recommended. Both guidelines list palonosetron, a second-generation IV 5-HT3RA, as preferred on day 1, because of its efficacy for the prevention of acute and delayed CINV.4,5 Simple enough? Not quite. The complicating factors, as always, are in gaining broad acceptance of clinical guidelines, and the cost of new preferred therapies compared with previously accepted therapies. It is widely known that general acceptance of clinical practice guidelines is difficult because of a variety of documented reasons.6 Although some barriers to physician acceptance of clinical practice guidelines are very

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difficult to change, such as a perceived lack of self-efficacy and a lack of physician agreement, one of the barriers can effectively be overcome: the lack of awareness. It is the responsibility of the healthcare community to ensure that we are all aware of the updated antiemetic guidelines that were published 3 years ago.5,6 Once awareness of the updated guidelines is achieved, additional questions must be addressed. Most of the questions arise as a result of the cost differences between brand and generic drugs, in addition to the route of administration of the antiemetic therapies. Should IV or oral therapies be used, especially when choosing 5-HT3RAs? Yes, palonosetron is preferred for the prevention of HEC, because of its efficacy in acute and delayed CINV. However, can acute and delayed CINV also effectively be treated with a lower-cost 5-HT3RA with an effective regimen to prevent delayed CINV? When choosing between 5-HT3RAs other than palonosetron, should oral drugs be given preference over IV therapies because of cost? Finally, one of the most concerning issues regarding the use of antiemetics for payers is how long the medications should be used. The administration of CINV prophylaxis should only occur over a 3-day period, pref­ erably beginning 1 day before the administration of chemotherapy, according to the NCCN and the ASCO guidelines.4,5 Breakthrough treatment should occur over a longer period of time, and is highly dependent on the emetogenic potential of the chemotherapy regimen and the cycles of therapy. Payers have historically been challenged with these issues regarding the cost-effective use of antiemetics for CINV. The use of the recently published guidelines, and a keen focus on the issues raised here, should help with achieving the goals of providing patients with value-based cancer care as it relates to the management of CINV. n 1. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13:219-227. 2. Bliss JM, Robertson B, Selby PF. The effect of nausea and vomiting upon quality of life measures. Br J Cancer. 1992;66(suppl 19):14S-23S. 3. Haiderali A, Menditto L, Good M, et al. Impact on daily functioning and indirect/ direct costs associated with chemotherapy-induced nausea and vomiting (CINV) in a US population. Support Care Cancer. 2011;19:843-851. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis. Version 2.2014. www.nccn.org/ professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 15, 2014. 5. Basch E, Prestrud AA, Hesketh PJ, et al; for the American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. April 13, 2011. www.asco.org/sites/www.asco.org/files/antiemetics_ full_guideline_update_92211.pdf. Accessed May 15, 2014. 6. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282:1458-1465.

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Vol 7, No 3


BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.


Take a bite out of G-CSF acquisition costs* GRANIX ™ is another option in short-acting G-CSF therapy GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40134 February 2014.

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AHDB May 2014, Vol 7, No 3  

American Health and Drug Benefits May 2014, Vol 7, No 3

AHDB May 2014, Vol 7, No 3  

American Health and Drug Benefits May 2014, Vol 7, No 3

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