March/April 2013, Vol 6, No 2

The Peer-Reviewed Forum for Evidence in Benefit Design ™ March/April 2013

Volume 6, Number 2

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

Analyzing the Medtech Industry: A Predictive Tool in Healthcare David B. Nash, MD, MBA BUSINESS

The Economic Burden of Fragile X Syndrome: Healthcare Resource Utilization in the United States ™

Patricia Sacco, MPH, RPh; Gorana Capkun-Niggli, PhD; Xin Zhang, MS; Rosemary Jose, PhD Stakeholder Perspective by Michael F. Murphy, MD, PhD

A Value-Based Analysis of Hemodynamic Support Strategies for High-Risk Heart Failure Patients Undergoing a Percutaneous Coronary Intervention David Gregory, MPA; Dennis J. Scotti, PhD, MBA; Gregory de Lissovoy, PhD, MPH; Igor Palacios, MD; Simon Dixon, MD; Brijeshwar Maini, MD; William O’Neill, MD Stakeholder Perspective by Raymond L. Singer, MD, MMM, CPE CLINICAL

Effectiveness and Costs of TNF-Alpha Blocker Use for Patients with Rheumatoid Arthritis Kavita Nair, PhD; Vahram Ghushchyan, PhD; Ahmad Naim, MD Stakeholder Perspective by Michael S. Jacobs, RPh Industry Trends

The Value of Actionable Content in a Clinical Setting: Access to Better Information Facilitates Enhanced Cancer Care Investing in Information Technology Pays Off: Meaningful Use Stage 1 Met by Majority of US Hospitals Opinion

The Doctor Won’t See You Now: He’s Clocked Out

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Low levels of platelet inhibition can raise some * questions 1-6

Factors that may impact platelet inhibition* for patients taking an oral antiplatelet include: • Genetic variation7-9 • Concomitant medications10-12 • Preexisting conditions that may impact antiplatelet response (eg, diabetes, obesity)13-15 • Patient noncompliance16-18 • Side effects that impact adherence19 *The relationship between inhibition of platelet aggregation and clinical activity has not been established.

Have you considered these factors when selecting an oral antiplatelet?

References: 1. Buonamici P, Marcucci R, Migliorini A, et al. J Am Coll Cardiol. 2007;49:2312-2317. 2. Matetzky S, Shenkman B, Guetta V, et al. Circulation.

2004;109:3171-3175. 3. Cuisset T, Frere C, Quilici J, et al. J Thromb Haemost. 2006;4:542-549. 4. Hochholzer W, Trenk D, Bestehorn H-P, et al. J Am Coll Cardiol.

2006;48:1742-1750. 5. Marcucci R, Gori AM, Paniccia R, et al. Circulation. 2009;119:237-242. 6. Bonello L, Tantry US, Marcucci R, et al; for the Working Group on High On-Treatment Platelet Reactivity. J Am Coll Cardiol. 2010;56:919-933. 7. Brandt JT, Close SL, Iturria SJ, et al. J Thromb Haemost. 2007;5:2429-2436.

8. Varenhorst C, James S, Erlinge D, et al. Eur Heart J. 2009;30:1744-1752. 9. Frere C, Cuisset T, Morange P-E, et al. Am J Cardiol. 2008;101:1088-1093. 10. Gilard M, Arnaud B, Cornily J-C, et al. J Am Coll Cardiol. 2008;51:256-260. 11. Farid NA, Payne CD, Small DS, et al. Clin Pharmacol Ther. 2007;81:735-741. 12. Yun KH, Rhee SJ, Park H-Y, et al. Int Heart J. 2010;51:13-16. 13. Angiolillo DJ, Fernandez-Ortiz A, Bernando E, et al. Diabetes. 2005;54:2430-2435. 14. Angiolillo DJ, Bernardo E, Ramírez C, et al. J Am Coll Cardiol. 2006;48:298-304. 15. Angiolillo DJ, Fernández-Ortiz A, Bernardo E, et al. J Invasive Cardiol. 2004;16:169-174. 16. Baran KW, Lasala JM, Cox DA, et al; for ARRIVE Investigators. Am J Cardiol. 2008;102:541-545. 17. Ergelen M, Uyarel H, Osmonov D, et al. Clin Appl Thromb Hemost.

2010;16:33-41. 18. Iakovou I, Schmidt T, Bonizzoni E, et al. JAMA. 2005;293:2126-2130. 19. Ho PM, Bryson CL, Rumsfeld JS. Circulation. 2009;119:3028-3035.

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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 and Bentteligence, Sharon, MA 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 GOVERNMENT

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

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA 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

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 Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX

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Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PA 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, Philadelphia School of Pharmacy, University of the Sciences Philadelphia, PA Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD 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 National Medical Director HumanaOne, Waukesha, WI MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Medical Lead, Payer and Specialty Channel Strategy, Medical Affairs Pfizer Specialty Care Business Unit, PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy Washington State University, Spokane, WA Mike Pucci Sr VP Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine

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 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

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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 Vice President, National Accounts Truveris, Inc., New York, NY Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBA Executive Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

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, Practice and Administration 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 Executive Director Drug Information Association, Horsham, PA 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

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

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 Collegeville, PA

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Volume 6, number 2

The Peer-Reviewed Forum for Evidence in Benefit Design ™

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Table of Contents

Publishing Staff

EDITORIAL

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Analyzing the Medtech Industry: A Predictive Tool in Healthcare David B. Nash, MD, MBA

business

73 The Economic Burden of Fragile X Syndrome: Healthcare Resource Utilization in the United States Patricia Sacco, MPH, RPh; Gorana Capkun-Niggli, PhD; Xin Zhang, MS; Rosemary Jose, PhD 82 Stakeholder Perspective: Rarity, Disease Heterogeneity, and a Pathway for Estimating Economic Burden

Michael F. Murphy, MD, PhD 88 A Value-Based Analysis of Hemodynamic Support Strategies for High-Risk Heart Failure Patients Undergoing a Percutaneous Coronary Intervention David Gregory, MPA; Dennis J. Scotti, PhD, MBA; Gregory de Lissovoy, PhD, MPH; Igor Palacios, MD; Simon Dixon, MD; Brijeshwar Maini, MD; William O’Neill, MD 98 Stakeholder Perspective: Careful Selection of Candidates for Percutaneous Ventricular Assist Device Is Crucial

Raymond L. Singer, MD, MMM, CPE Continued on page 67

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This publication further provides benefit design de­cision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

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(Continued)

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512.

Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for 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.

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CLINICAL

126 Effectiveness and Costs of TNF-Alpha Blocker Use for Patients with Rheumatoid Arthritis

Kavita Nair, PhD; Vahram Ghushchyan, PhD; Ahmad Naim, MD 136 Stakeholder Perspective: Assessing the Value of TNF-Alpha Blockers for Patients with Rheumatoid Arthritis

Michael S. Jacobs, RPh DEPARTMENTs

INDUSTRY TRENDS 104 The Value of Actionable Content in a Clinical Setting: Access to Better Information Facilitates Enhanced Cancer Care

A. Jacqueline Mitus, MD, and Laura Coughlin, RN

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

116 Investing in Information Technology Pays Off: Meaningful Use Stage 1 Met by Majority of US Hospitals

Caroline Helwick

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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.

Opinion 119 The Doctor Won’t See You Now: He’s Clocked Out

Scott Gottlieb, MD

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EDITORIAL

Analyzing the Medtech Industry:

A Predictive Tool in Healthcare David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits Jefferson School of Population Health, Philadelphia, PA

R

egular readers of American Health & Drug Benefits know that I like to peruse the literature from consulting companies and industry-related think tanks. A recent report from PricewaterhouseCoopers (PwC)—Operating Performance in the Medtech Industry: Trends and Imperatives1—really caught my eye.

We would likely all agree that the medical technology industry faces challenges on multiple fronts. We are still digging out of a recession, which has only increased the emphasis on cost containment as it relates to healthcare spending. According to PwC’s report, “high growth and profitability [in the Medtech industry] have given way to slower growth and flat profits, and total shareholder returns for Medtech companies have been declining over the last few years.”

In an effort to objectively evaluate different types of Medtech companies and to assess their strategies moving forward, PwC created a tool called Operating Performance Index (OPI). According to the report from PwC, the OPI “incorporates key operational drivers that can be analyzed using publicly reported data.”1 The OPI metric takes into account certain primary measures, such as revenue growth rate, operating profit, and invested capital productivity. Secondary measures include, among other things, labor productivity, growth margin, and inventory management. A more detailed discussion of the OPI is included in the full PwC report.1 The objective of the OPI is to enable astute observers to better understand the entire Medtech industry and all of its segments. PwC defines the following topics as the core areas within the industry—in vitro diagnostics, medical consumables, medical equipment, implantable devices, and diversified life sciences companies.

Using the OPI, PwC researchers examined operating performance across the entire Medtech industry from 2005 to 2011. Several key trends have emerged from this analysis: 1. The highest performing segments in the industry are in vitro diagnostics, implantable devices, and diversified life sciences companies. In fact, in vitro diagnostics have steadily improved to become the leading segment within the Medtech industry

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2. Although there was wide variation in growth rates among the various segments before the 2008 recession, all 5 segments have since converged around single-digit growth rates 3. The implantable devices segment has shown maturation of the cardiology and orthopedic implant markets. In addition, significant changes have been taking place in purchasing dynamics and buyer behavior 4. Operating performance in medical consumables has consistently lagged behind the rest of the industry.

According to the PwC analysis, “the segment also ranks among the lowest in several dimensions of overall efficiency, exhibiting, for example, the lowest gross margins, poor inventory management, low asset productivity, and labor productivity that is significantly lower than that for other segments”1 5. The diversified life sciences segment has been relatively stable over the years compared with other segments, likely because of its diverse product portfolio.

Assuming that the OPI is an effective tool to analyze the Medtech industry across these 5 segments, what advice does PwC have for this entire sector moving forward? The following discussion outlines what I consider to be the 4 take-home messages from the report.

Take-Home Messages from PwC’s Report A Clarion Call for Broadening Innovation PwC says that “in the future, Medtech companies will need to take a broader view of innovation. With the growing emphasis of healthcare costs and quality, new product innovation may become less important than, for example, clinical effectiveness, improved patient outcomes, and/or improved healthcare efficiency.”1 I surely would agree with this assessment. Innovative companies, such as Endo Health Solutions and others that have been mentioned in my previous columns, are attempting this integrative strategy with an emphasis on quality.

Move Up the Productivity Curve PwC notes that with “increasing pricing pressures, slowing growth, and threats to profitability such as the impending medical device excise tax in the United

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EDITORIAL

States, it is imperative for Medtech companies to keep taking cost out of [its] operations.”1

Medtech segment company, astute observers could better predict a firm’s short- and long-term performances.

Transform the So-Called Go-To Market Model This means that the ecosystem is changing. Medical device buyers are consolidating and the influence of physician preference is waning. As a result, these factors create new decision makers and new types of buying criteria. I interpret this transformed “go-to market model” as meaning recognition of the growth of integrated delivery systems, accountable care organizations, patient-centered medical homes, and the like. As the healthcare market evolves, strategies in going to market must also change.

It would be an interesting exercise to use the OPI tool to assess your organization. Are you willing to compare yourself to the best in breed in each of the 5 Medtech industry segments to see how you stack up?

It would be an interesting exercise to use the OPI tool to assess your organization. Are you willing to compare yourself to the best in breed in each of the 5 Medtech industry segments to see how you stack up? Obviously, there are many wonderful companies in each of these segments already. The OPI tool is very impressive: I believe that PwC has hit on another clever way to help us better understand rapidly evolving markets, such as the Medtech industry.

As always, I am very interested in your views. You can reach me at david.nash@jefferson.edu, or via my blog at http://nashhealthpolicy.blogspot.com.

Revitalize Growth Strategies for the Future PwC notes that Medtech companies must explore new avenues for growth, including emerging markets.

Companies should also consider what they call “inorganic” growth strategies. Although traditional acquisition and integration strategies are common, more creative strategies may include codevelopment through partnerships and alliances, and a variety of out-licensing approaches.

Returning to the primary OPI metrics of revenue growth, operating profit and invested capital productivity, if one assesses these core characteristics in any new

Reference

1. PricewaterhouseCoopers. Operating Performance in the Medtech Industry: Trends and Imperatives. www.pwc.com/us/en/health-industries/publications/medtech- operating-performance-growth-profitability.jhtml. October 2012. Accessed March 12, 2013.

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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.

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 At 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 $1,540 per 3.5-mg vial as of January 2013 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.

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.

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original research

The Economic Burden of Fragile X Syndrome: Healthcare Resource Utilization

in the United States

Patricia Sacco, MPH, RPh; Gorana Capkun-Niggli, PhD; Xin Zhang, MS; Rosemary Jose, PhD Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability with cognitive and behavioral impairments, and is associated with a lifetime of caretaking challenges. There is a paucity of data on the economic burden of FXS. Objective: To analyze the direct costs associated with healthcare and medication utilization for patients with FXS by using commercial and Medicare/Medicaid administrative claims data.

Methods: All-cause direct healthcare and prescription drug utilization were analyzed from the Thomson Reuters Healthcare MarketScan Commercial, the Medicare Supplemental, and the MarketScan Medicaid databases between 2004 and 2009. Inclusion criteria were â&#x2030;Ľ1 diagnosis of FXS (International Classification of Diseases, Ninth Revision, 759.83) and â&#x2030;Ľ12 months of continuous enrollment in the current health plan. Emergency department, hospitalization, outpatient visit, nonspecified procedures, and prescription drug data were analyzed for a 12month follow-up period. Because the number of Medicare patients was <50, commercial and Medicare databases were combined into a single cohort. Descriptive statistics were used to summarize the results.

Results: A total of 1505 patients were included in the study; of these, 784 patients had commercial/Medicare insurance and 721 patients had Medicaid. The mean age was 18 years. In all age-groups, the median all-cause healthcare cost per patient was significantly lower in the commercial/Medicare cohort (range, $2222-$2955) than in the Medicaid cohort (range, $4548-$9702). The annual median costs per patient for those who had any medical procedures were $1614 and $3064 for commercial or Medicare and for Medicaid, respectively. The annual median costs per patient for those with at least 1 hospitalization was $7740 in the commercial/Medicare cohort (9.4% of patients) and $4468 in the Medicaid cohort (12.5% of patients).

Conclusion: This first descriptive US claims analysis supports the overall results from surveys on the economic burden related to FXS. The cost drivers in this population included medical procedures, hospitalizations in a subset of patients, and medications to a lesser extent. This information may be relevant to payers for benefit design and allocation of resources.

A more targeted assessment of resource utilization is needed to estimate the value of interventions that reduce costs and improve the outcomes of patients with FXS.

F

ragile X syndrome (FXS) is the most common form of inherited intellectual disability, with cognitive and behavioral impairments of varying degrees that are associated with distinct physical features.1 This neurodevelopmental disorder is caused by the silencing of a single X-linked gene, the fragile X mental retardation 1 gene, and hence manifests primarily in males. The disorder has

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a prevalence of 1 in 3717 to 1 in 8918 for Caucasian males, and 1 in 8000 to 1 in 9000 females in the general population.2 In a 2003 literature review, Song and colleagues reported that FXS affected an estimated 1 in 4000 males and 1 in 8000 females.3 Higher prevalence rates have been observed among certain ethnic groups, such as African American males (1 in 2500) and Tunisian Jews.2,4

Ms Sacco is Director of Global Health Economics and Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Dr Capkun-Niggli is Director of Global Health Economics and Outcomes Research, Novartis Pharma AG, Basel, Switzerland; Ms Zhang is Statistical Analyst, Beijing Novartis Pharma Co, Ltd, Shanghai, China; and Dr Jose is Evidence Analyst, Global Health Economics and Outcomes Research, Novartis Healthcare Private Limited, Hyderabad, India.

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Key Points Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, including impaired visual and working memory, sustained attention, and executive function; it also involves behavioral impairments and an increased rate of comorbidities. ➤ Many patients with FXS have difficulty with basic functional skills and need specialized therapy, such as speech and language therapy, occupational therapy, and physical therapy. ➤ This is the first analysis of the direct costs associated with healthcare and medication utilization in patients with FXS, using claims data from commercial/Medicare and Medicaid databases. ➤ The median all-cause healthcare cost per patient with FXS was significantly lower in the commercial/ Medicare cohort ($2222-$2955) than in the Medicaid cohort ($4548-$9702). ➤ Tranquilizers, antipsychotics, antidepressants, and amphetamine-type stimulants were often prescribed for management of behavioral symptoms. ➤ The cost drivers for this patient population include medical procedures, hospitalization, and to a lesser extent, medications. ➤ These data suggest that FXS is a costly condition with considerable economic and psychosocial burden on patients and on the healthcare system as a whole. ➤

No recent studies are available that provide direct estimates for the prevalence of the full mutation allele together with clinical symptoms in the general population. However, estimates of the prevalence of FXS based on screening studies in newborn boys are in agreement with extrapolations from populations with learning difficulties. Song and colleagues conducted a systematic review to compare population screening strategies in FXS and to estimate the costs associated with these strategies; prevalence data were reported, but they are now considered outdated.3 Cognitive and developmental deficits are often evident as early as age 3 years and are usually the manifestations that lead to a diagnosis of FXS. Males usually display mild-to-moderate intellectual disability, with an average intelligence quotient (IQ) of 40 to 50 in adults; females with FXS have an average IQ of approximately 80; only 25% of females with FXS are considered to have intellectual disability. Cognitive difficulties include impairments in visual memory, working memory, sustained attention, and executive function.

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Typical behavioral symptoms of FXS include aggression, irritability, social avoidance, and autistic features.

Approximately 30% of individuals with FXS also meet the criteria for autistic disorder.5 Moreover, a number of secondary conditions are more frequent in individuals with FXS than in the general population, including anxiety, hyperactivity, self-injurious behavior, and seizures.6 Although individuals with FXS face a lifetime of challenges, there is a paucity of data on the economic burden associated with FXS for caregivers and for society. One of the earliest reports, from a survey conducted in 1992 in the state of Colorado, estimated the average lifetime cost up to age 72 years for the care and support of an individual with FXS to be nearly $2 million in 1992 dollars.7 This translates to an annual out-of-pocket (OOP) medical cost to families—including hospitalization, therapy, medications, and physician visit costs—of $17,016 annually per child in 2002 dollars.7 Surveys offer a relatively rapid and cost-effective way to collect useful data in a standardized manner across a large population of interest. Based on a 2007-2008 national survey conducted in the United States, individuals with FXS are prescribed atypical antipsychotics, antidepressants, stimulants, and other miscellaneous centrally acting agents to manage maladaptive behaviors.8 Speech and hearing therapy, as well as occupational therapy are interventions that may also be used to improve communication and daily functioning skills in this patient population.9 However, surveys cannot replace large population studies because of methodologic limitations. Data in surveys are self-reported, and survey samples may not be representative of the general population of individuals with FXS. Analyzing data from a variety of sources deepens our understanding of the unmet needs in a target population.

There are no US Food and Drug Administration–approved medications indicated for the treatment of patients with FXS or the specific behavioral symptoms associated with this syndrome; therefore, new therapies will be challenged to demonstrate clinical and economic value to key healthcare stakeholders. The use of claims data to describe direct costs can therefore help to facilitate decisions on benefit design and on allocation of resources for services and treatments by health plan administrators and policymakers.

To update the information on the economic burden of FXS in the United States, we analyzed administrative claims data from a commercially insured population, with the goal of descriptively characterizing direct costs for healthcare resource utilization and medication utilization in patients diagnosed with FXS.

Methods This study analyzed data from the Truven Health Analytics (formerly Thomson Reuters Healthcare at the

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time the data were licensed) MarketScan Commercial Claims and Encounters Database, the Medicare Supplemental and Coordination of Benefits Database, and the MarketScan Medicaid Database from January 1, 2004, through December 31, 2009. These 3 databases represented the inpatient and outpatient prescription drug claims of more than 33 million persons in the United States and provided detailed enrollment, cost, utilization, and dates of utilization for healthcare services. The inclusion of commercial, Medicare, and Medicaid databases were used to obtain an understanding of the utilization of healthcare resources and of prescription medication according to provider benefit plans.

The MarketScan Commercial Claims and Encounters Database provided data on healthcare services for individuals aged <65 years with coverage under a variety of fee-for-service (FFS), fully capitated, and partially capitated health plans. The Medicare Supplemental Database provided data on healthcare services for individuals with Medicare supplemental insurance paid for by employers. Both the Medicare-covered portion of payment and the employer-paid portion were included in this database, which contained predominantly FFS plan data.

The Medicaid database contained the healthcare services for Medicaid enrollees from 10 states covered under a variety of FFS and managed care plans.

Because of the number of patients with FXS in the Medicare Supplemental Database was <50, the commercial and Medicare supplemental databases were combined, and hereafter referred to as commercial/Medicare.

This approach was possible because deidentified patients were coded the same across the 2 databases, thereby avoiding double entries.

The study population included patients from inpatient and outpatient tables in commercial/Medicare and Medicaid databases who had at least 1 diagnosis of FXS (International Classification of Diseases, Ninth Revision [ICD-9] code 759.83) at any diagnosis position within the study period from January 1, 2004, through December 31, 2009. The first date within the study period, after which a patient had 12 months of continuous enrollment in the current health plan, was considered the index date for that patient. The follow-up period for each patient was 12 months after the index date. Patients who had coverage of HMOs or point of service (POS) insurance were excluded. The patient selection scheme for this analysis is described in Figure 1.

Because the objective of this study was to characterize direct costs for healthcare resource utilization and medication utilization, patients for whom information on medication prescriptions was not available were excluded from the study. The commercial/Medicare database contained an indicator variable characterizing availabil-

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Figure 1 Patient Selection Scheme Patients who had at least 1 ICD-9 code for FXS (759.83) in the database from January 1, 2004, through December 31, 2009 Commercial/Medicare: N = 1324 Medicaid: N = 1097 Total: N = 2421 Patients who had <12 months of continuous enrollment after index date Commercial/Medicare: N = 112 Medicaid: N = 52 Total: N = 164 Patients who had no medication coverage information Commercial/Medicare: N = 243 Medicaid: N = 0 Total: N = 243 Patients who had at least 1 ICD-9 code for FXS (759.83) had medication coverage information and at least 12 months of continuous enrollment during the postindex period Commercial and commercial/Medicare: N = 969 Medicaid: N = 1045 Total: N = 2014 Patients with HMO or POS insurance types with capitation at index date Commercial/Medicare: N = 185 Medicaid: N = 324 Total: N = 509 Patients in the study cohort Commercial/Medicare: N = 784 Medicaid: N = 721 Total: N = 1505

FXS indicates fragile X syndrome; ICD-9, International Classification of Diseases, Ninth Revision; POS, point of service.

ity of information on medication use; commercial/Medicare patients were only included if information on medication use was indicated as available. The Medicaid database, however, does not contain this variable, so we assumed that all patients in the Medicaid database had information on medication use.

All-cause healthcare resource utilization was evaluat-

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emographic Characteristics of Patients with Table 1 D Fragile X Syndrome Commercial/ Variable Medicare Medicaid Patients, N (%)

784 (100)

721 (100)

17.5 (± 15.7)

18.5 (± 15.7)

Children, 0-11, N (%)

354 (45.2)

302 (41.9)

Adolescents, 12-17, N (%)

150 (19.1)

120 (16.6)

Adults, ≥18, N (%)

280 (35.7)

299 (41.5)

Male, N (%)

558 (71.2)

582 (80.7)

Female, N (%)

226 (28.8)

139 (19.3)

Mean age, yrs (± SD) Age-group stratification, yrs

Sex

SD indicates standard deviation.

Table 2 P revalence of the Most Common Comorbidities in Patients with Fragile X Syndrome Commercial/ Medicaid, Medicare, N (%) N (%) Comorbiditiesa Suppurative and unspecified otitis media

151 (19.3)

119 (16.5)

Specific delays in development

98 (12.5)

201 (27.9)

Hyperkinetic syndrome of childhood

96 (12.2)

151 (20.9)

Symptoms concerning nutrition, metabolism, and development

88 (11.2)

130 (18.0)

Nonsuppurative otitis media and eustachian tube disorders

86 (11.0)

72 (10.0)

Pervasive developmental disorders

86 (11.0)

97 (13.5)

As identified by ICD-9 codes.

ICD-9 indicates International Classification of Diseases, Ninth Revision.

a

ed during the 1-year postindex date and included costs resulting from emergency department visits, hospitalizations, outpatient visits, and medical procedures. The rate and proportion of patients with at least 1 hospitalization or outpatient visit during the 12 months of follow-up were presented for analysis.

Nonspecified procedures were assessed to determine what types of procedures patients with FXS were most often receiving. Procedures were identified with Current Procedural Terminology codes. The top 20 procedures in-

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curred after the index date during the 1-year follow-up period were presented for analysis.

Statistical Analysis This study was descriptive in nature, and data are presented for commercial/Medicare and Medicaid databases separately. For continuous or count variables, the mean, median, standard deviation, minimum, maximum, and 95% confidence interval (CI) limits are reported. For categorical or binary variables, the frequency distribution was estimated together with 95% CIs for proportions. To test for an association between categorical variables, the chi-squared or Fisher’s exact test (in case of expected cell counts <5) were performed. The Kruskal-Wallis test was used to evaluate whether costs have the same distribution for each group defined by a categorical variable.

Results Demographics A total of 1505 patients with FXS were included in the study population. Of these patients, 784 received care covered by commercial/Medicare insurance and 721 had Medicaid insurance coverage.

Table 1 lists patient demographic characteristics at the index date. The mean age in the commercial/Medicare and the Medicaid cohorts was 18 years. In both benefit plans, approximately 15% to 20% of patients were adolescents. The percentages of adults were similar in the commercial/Medicare and Medicaid cohorts (35.7% and 41.5%, respectively). In the commercial/ Medicare cohort, 71.2% of patients were male compared with 80.7% in the Medicaid cohort.

Comorbidities The 6 most prevalent comorbid conditions in our study sample cohorts are listed in Table 2. In general, developmental disorders, otitis media, and symptoms concerning nutrition were among the most prevalent comorbid conditions in patients with FXS. Of the 6 conditions listed in Table 2, most were more common in the Medicaid cohort. Specific delays in development were reported twice as prevalent in the Medicaid population (27.9%) than in the commercial/Medicare population (12.5%), and pervasive developmental disorders were reported more frequently in Medicaid patients (13.5%) than in commercial/Medicare patients (11.0%).

Healthcare Utilization and Costs Table 3 shows all-cause healthcare utilization and costs per patient with FXS. All-cause healthcare utilization and the mean costs per patient for each age-group in the commercial/Medicare and the Medicaid cohorts

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Table 3 Healthcare Utilization and Costs Per Patient Commercial/Medicare (N = 784) N (%)

Mean, $

Median, $ 95% CI

Children, 0-11

354 (45.2)

7851.6

2955.0

5415.810,287.4

Adolescents, 12-17

150 (19.1)

5667.9

2222.1

Adults, ≥18

280 (35.7)

8752.2

Male

558 (71.2)

Female

Medicaid (N = 721)

P value

N (%)

Mean, $

<.049a

302 (41.9)

15,016.9

4547.8

9418.220,615.6

3015.28320.7

120 (16.6)

10,490.6

4580.6

7974.413,006.8

2384.3

5649.011,855.4

299 (41.5)

22,538.8

9701.7

19,158.025,919.5

7153.17

2619.2

5419.18887.2

582 (80.7)

16,662.2

5973.3

14,142.019,182.5

226 (28.8)

9242.54

2356.1

5492.912,992.2

139 (19.3)

20,400.3

5153.6

10,521.630,279.1

No treatment intervention

24 (3.1)

95.5

0.0

0-255.2

13 (1.8)

0.0

0.0

–

Drug therapy only

18 (2.3)

664.9

246.2

175.81154.0

7 (1.0)

1418.1

1577.9

115.82720.5

Procedure only

186 (23.7)

4466.2

1614.2

3415.75516.7

85 (11.8)

7068.1

3063.9

5118.09018.2

Drug therapy and procedure

556 (70.9)

9416.0

3453.2

7148.011,684.1

616 (85.4)

19,354.5

6641.7

16,143.022,566.0

21,676.7

7740.3

10,902.932,450.5

90 (12.5)

25,847.3

4467.7

11,363.040,331.6

4642.8

1751.4

3717.35568.3

702 (97.4)

12,608.3

3355.2

10,957.914,258.8

Parameter

Median, $ 95% CI

P value

Age, yrs <.001a

Sex .584a

.135a

Care received NA

NA

Inpatient and outpatient costs Patients with hospitalizationa

74 (9.4)

747 Patients with outpatient visita (95.3)

NA

NA

Kruskal-Wallis test.

CI indicates confidence interval; NA, not available.

a

were substantially higher than the corresponding median costs. Outliers were identified in the data, so median costs may be more representative of the findings; therefore, we report median costs for the results.

The median costs in the commercial/Medicare cohort were consistently lower than for the Medicaid cohort. In the overall study population, costs per patient were 1.5 to 2 times lower in the commercial/Medicare cohort than in the Medicaid cohort; among adults, costs were almost 4-fold lower ($2384) in the commercial/Medicare cohort than in the Medicaid cohort ($9702).

The median healthcare cost for males with FXS receiving commercial/Medicare benefits was $2619 com-

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pared with $5973 for males with Medicaid benefit coverage for the same 12-month period. Only a small proportion of patients received no treatment—3.1% in the commercial/Medicare group and 1.8% in the Medi­ caid group—during the 12 months of follow-up. “No treatment” was defined as not receiving any medication or a procedure during the study period; no differentiation was made for procedures that were used for diagnostic purposes or for those potentially used for treatment. The majority of patients in both cohorts received a combination of medications and procedures—70.9% in commercial/Medicare and 85.4% in Medicaid.

The majority of patients with FXS received care in an outpatient environment. In the commercial/Medi-

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Table 4 The 20 Most Frequently Utilized Procedures in Each Cohort, Identified with CPT Code CPT Code/Commercial/Medicare Cohort (N = 784)

Patients, N (%)

104-Office visits, established patient

681 (86.9)

104-Office visits, established patient

545 (75.6)

115-Preventive care visits

270 (34.4)

190-Case management services

342 (47.4)

120-Outpatient consults

269 (34.3)

499-Unmapped codes

251 (34.8)

130-Injections: immunizations

235 (30.0)

331-Blood count, automated

220 (30.5)

101-Office visits, new patient

223 (28.4)

303-Laboratory tests, organ/disease panel

208 (28.8)

319-Other chemistry tests

199 (25.4)

111-Emergency department visits

201 (27.9)

031-Venipuncture (draw blood)

194 (24.7)

101-Office visits, new patient

200 (27.7)

369-Other microbiology tests

178 (22.7)

186-Physical medicine: other procedures

196 (27.2)

331-Blood count, automated

177 (22.6)

149-Speech/hearing therapy

193 (26.8)

306-Routine urinalysis

158 (20.2)

120-Outpatient consults

190 (26.4)

303-Laboratory tests, organ/disease panel

157 (20.0)

031-Venipuncture (draw blood)

187 (25.9)

111-Emergency department visits

145 (18.5)

319-Other chemistry tests

171 (23.7)

186-Physical medicine: other procedures

116 (14.8)

139-Therapeutic psychiatric services

164 (22.7)

372-Surgical pathology

111 (14.2)

306-Routine urinalysis

137 (19.0)

131-Injections: therapeutic/IV

109 (13.9)

130-Injections: immunizations

132 (18.3)

349-Immunology tests

107 (13.6)

198-Medical supplies and devices

125 (17.3)

470-Anesthesia services

103 (13.1)

115-Preventive care visits

125 (17.3)

198-Medical supplies and devices

101 (12.9)

131-Injections: therapeutic/IV

122 (16.9)

149-Speech/hearing therapy

95 (12.1)

369-Other microbiology tests

111 (15.4)

133-Other preventive medical services

91 (11.6)

150-Other ENT services (nonsurgical)

109 (15.1)

Patients, N (%)

CPT Code/Medicaid Cohort (N = 721)

CPT indicates Current Procedural Terminology; ENT, ear, nose, throat; IV, intravenous.

care cohort, 95.3% of patients had at least 1 outpatient visit during the 12-month follow-up period compared with 97.4% in the Medicaid cohort. In the commercial/ Medicare cohort, 9.4% of patients had at least 1 hospitalization annually compared with 12.5% of patients in the Medicaid cohort. The mean all-cause healthcare utilization costs for a patient with at least 1 hospitalization was $21,677 (median, $7740) in the commercial/ Medicare cohort and $25,847 (median, $4468) in the Medicaid cohort.

During the 12-month follow-up period, we reported the percentage of patients who only received a procedure as part of their care, without concomitant drug therapy. Almost 24% of commercial/Medicare patients received a procedure aloneâ&#x20AC;&#x201D;with a median cost of $1614 per patientâ&#x20AC;&#x201D;compared with approximately 12% of Medicaid patients, with a median cost of $3064 per patient. The 20 most frequently utilized procedures are shown in Table 4.

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Drug Utilization In both cohorts, the most frequently prescribed therapeutic drug classes were similar. Tranquilizers, antidepressants, amphetamine-type stimulants, and anticonvulsants were often prescribed, but, in general, were more frequent in the Medicaid population, as shown in Figure 2.

A detailed analysis of psychotropic medications prescribed to manage behavioral symptoms is shown in Table 5. In general, the utilization of specific medications is similar between the commercial/Medicare and Medicaid cohorts; however, the overall percentage of patients receiving risperidone in the commercial/Medicare population was 4.9% versus 14.0% in the Medicaid cohort.

Within each cohort, adolescents had the highest percentage of utilization of risperidone. Similarly, clonidine was used in only 3.3% of the commercial/Medicare patients versus in 10.4% of Medicaid patients, with the highest utilization being found in adolescents. There were also

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Figure 2 Most Frequently Prescribed Therapeutic Drug Classes for Patients with Fragile X Syndrome 45 40

27.5

12.5

Opiate analgesics

Anticonvulsants

6.8

Antidepressants

17.2 12.4

10.2

8.3 6.7

7.9

Tranquilizers

Amphetamine-type stimulants

Medicaid

Commercial/Medicare

4.7

Medicaid

Medicaid

4.5

10.4

8.9

Commercial/Medicare

8.3

Medicaid

6.2 5.3

13.8

12.3 9.3

8.9

Commercial/Medicare

10.3 10.0

19.5

19.3

17.5

Commercial/Medicare

Medicaid

Sympathomimetic

agents

16.0

Commercial/Medicare

7.9

Commercial/Medicare

6.0

10.8 8.7

Commercial/Medicare

11.3

18.4

Medicaid

18.6

15

0

33.4

35.3

22.2

20

Medicaid

Patients, %

28.1

25

5

34.2

31.1

30

10

38.3

35.8

34.0

35

Children Adolescents Adults

Adrenals and combinations

Therapeutic drug class

substantially higher percentages of adolescents receiving sertraline, aripiprazole, and methylphenidate in both cohorts compared with the child and adult age-groups.

Discussion To our knowledge, this is the first study in the United States to use administrative claims data to report direct healthcare costs and medication utilization in patients who are diagnosed with FXS. This is also the first study to report findings for healthcare costs for patients with FXS based on longitudinal data. Although FXS is an orphan disease, and the budget impact is presumably modest compared with many other diseases, the findings are relevant to payers who are tasked with allocating resources and with the redesigning of private health benefit plans and Medicaid programs to implement cost-saving initiatives.

A notable observation was the higher overall costs in Medicaid patients versus commercial/Medicare patients.

Medicaid-insured patients received more prescribed drugs and incurred higher outpatient costs than patients in the commercial/Medicare cohort. These differences between benefit plans appear to be contrary to what has been reported from the national survey of parents, which found that the type of insurance (private or public) was not associated with reported financial burden on families.10 However, the survey did not look at actual health-

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care costs, and the majority of the population was in the high-income bracket.

In a recent study by Bailey and colleagues, caregivers reported 9.2 hours daily of family caregiving for males with FXS and an additional 5.5 hours daily of paid help.11 Most families reported that FXS had at least some financial impact on the family, and caregivers had to take an average of 19.4 hours from work monthly to care for their childâ&#x20AC;&#x2122;s needs.11 With these new emerging data on the indirect costs associated with caring for a child with FXS, it is likely that the overall economic burden is underestimated, independent of the socioeconomic status of the patient. Teasing out factors that drive economic disparities and differences between the Medicaid and commercial/Medicare cohorts will require further investigation.

The outliers that we observed in the data set reflect the fact that high expenditures tend to concentrate among a minority of families that have a member with FXS, a finding that was also reported by Ouyang and colleagues.10 Although the mean costs per patient in our analysis were similar to those reported in the 1992 survey,7,12 the median costs per patient in both cohorts were â&#x2030;¤50% of the corresponding mean costs in the study cohorts. The main cost drivers we identified were medical procedures and hospitalizations, which were distributed differentlyâ&#x20AC;&#x201D;procedures (nonspecified) drove costs in the majority of patients, whereas hospitalizations (all-cause)

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3.7 2.0 1.1 1.4 0.6 0.6 0.0 0.0

Fluoxetine hydrochloride

Escitalopram oxalate

Citalopram hydrobromide

Paroxetine hydrochloride

Bupropion hydrochloride

Venlafaxine hydrochloride

Trazodone hydrochloride

www.AHDBonline.com 0.9

Quetiapine fumarate

1.1

Lisdexamfetamine dimesylate 2.6 2.6 0.0 0.0

Clonidine

Guanfacine

Minocycline

Lithium carbonate

Miscellaneous

3.7

Dexmethyl-phenidate hydrochloride

Methylphenidate hydrochloride 7.9

4.0

Aripiprazole

Stimulants

4.0

Risperidone

Antipsychotic agents

Medicaid

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0.0

2.7

6.7

8.0

2.7

2.0

19.3

4.0

8.7

8.0

2.0

1.3

0.0

4.0

5.3

4.0

6.7

10.0

0.7

2.9

1.4

1.8

0.0

1.1

5.4

2.9

2.9

4.3

2.5

4.3

4.6

2.9

2.1

5.4

3.6

6.8

0.3

1.5

2.9

3.3

1.0

2.4

9.2

2.2

4.5

4.9

1.3

1.8

1.9

2.0

2.4

3.2

3.4

6.0

0.0

0.7

3.0

9.6

0.0

3.3

9.9

0.7

1.7

10.3

0.3

0.0

0.0

2.0

1.7

0.7

2.3

2.0

0.8

0.0

1.7

19.2

1.7

1.7

15.0

6.7

8.3

20.8

4.2

1.7

3.3

2.5

0.0

3.3

5.9

10.0

1.7

1.0

1.0

7.7

0.0

0.3

6.7

7.7

5.4

15.1

3.3

2.7

2.3

6.0

4.7

3.7

5.0

9.0

0.8

0.7

1.9

10.4

0.3

1.8

9.4

4.6

4.3

14.0

2.2

1.4

1.5

3.7

2.6

2.4

4.0

6.2

Children, % Adolescents, % Adults, % Total, % Children, % Adolescents, % Adults, % Total, % (n = 354) (n = 150) (n = 280) (N = 784) (n = 302) (n = 120) (n = 299) (N = 721)

Sertraline hydrochloride

Antidepressants

Drug

Commercial/Medicare

Table 5 Percentage of Patients with Fragile X Syndrome Prescribed Psychotropic Medications

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clustered in a subset of patients with FXS. In addition, overall we found that medications were a much weaker cost driver than procedures or hospitalizations.

One or more comorbidities were present in 10% to 30% of the patients, with higher percentages in the Medicaid cohort. We note that developmental disorders, otitis media, and nutrition-related symptoms were more prevalent in the Medicaid cohort than in the commercial/Medicare cohort.

Whether insurer selection leads to a bias toward healthier populations in the commercial/Medicare cohort cannot be determined from our data; there is limited scope for such selection, because eligibility for Medicaid is determined by economic circumstances and not primarily by insurers. Less favorable socioeconomic circumstances in patients who qualify for Medicaid benefits may adversely impact general health status; all explanations, however, remain speculative based on the current evidence.

Delays in development, otitis media, pervasive developmental disorders, and autism-like psychiatric presentation, particularly in males with FXS, are important causes of healthcare utilization.13 Autistic disorder is a strong predictor of outcomes for individuals with FXS, and the combination of pervasive developmental disorders and autistic disorders leads to more limited independence in adults, greater need for daily assistance, and less possibility to coreside with family.14,15 In the US national parent survey, problems with inattention-hyperactivity and affect were reported in a large majority of men (84.7% and 71.7%, respectively), and in >50% of women (65.5% and 58.8%, respectively).16 More than 33% of men had also been diagnosed with or treated for aggression (43.0%), self-injury (47.3%), and autism spectrum disorder (37.3%).16 In our FXS study sample, 11% to 13% of patients also had a diagnosis of pervasive developmental disorders, which suggests that there is substantial potential economic burden in this subpopulation. Furthermore, our sample showed a trend toward higher median costs in the men in both cohorts, but we did not conduct a comparison of costs between men and women. We did find that individuals with FXS were frequently prescribed psychotropic drugs, such as antidepressants, stimulants, tranquilizers, and antipsychotics, that are often used to treat disorders such as hyperactivity, anxiety, and inattention, similar to findings reported elsewhere.17 Many patients with FXS have difficulty achieving basic functional skills and need specialized therapy, such as speech and language therapy, occupational therapy, and physical therapy to address developmental challenges. Such expenditures may account for approximately 30% of the total employment impact and financial burden on families of children with FXS.10 A recent survey

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of families in the United States who had at least 1 child who was a carrier of FXS or who had the full mutation reported that 72% of males and 47% of females were receiving at least 1 type of therapy, most frequently speech and language therapy and occupational therapy, in males and females.9 In our study, 12.1% and 26.7% of commercial/Medicare and Medicaid patients, respectively, were receiving speech and language therapy during the 12month follow-up period (data not shown). Although the numbers are not directly comparable between studies, the similarities highlight the relevance of speech and language therapy and occupational therapy in the medical care of individuals with FXS. The strengths of this analysis are derived from the use of claims databases, which reduce responder bias, compared with surveys, and ensure a diagnosis of FXS for all included patients. We were able to confirm comorbidities and prescription drug utilization, which deepens our understanding of the potential unmet medical needs in individuals with FXS. Finally, the database captures patients who received inpatient services at a hospital and patients who received outpatient medical care, thus reflecting real-world healthcare resource utilization.

Limitations Several limitations can be noted when interpreting our study results. Patients were included based on the specific ICD-9 code for FXS; therefore, the size of the population of interest may have been underestimated.

For Medicaid patients, the long-term care database that potentially covers older patients with FXS was not included. However, we do not believe that excluding patients who are aged >65 years substantially biases the results, because the diagnostic test for FXS was only commercially available in 1999, and newborn screening is not mandated in the United States. There is no published epidemiologic study reporting the prevalence of patients with FXS who are aged >65 years that would further inform this assumption.

Also, patients with HMO or POS insurance coverage were excluded from the study, because FFS equivalents for HMO and POS insurance types are not reported in the database and could have biased the results.

Furthermore, it was assumed that all patients in the Medicaid database have information on prescriptions, which may result in an underestimation of results related to prescription drug use in these patients. In this initial assessment of medication utilization, we did not analyze the treatment patterns of medications used, because the objective was to take a global view of all of the medications used rather than preselecting treatment patterns.

We may have underestimated the overall economic burden, because only medical services and prescription

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drug costs reimbursed by the health plan were captured in the claims database; medical services that patients received, but that were not covered by the benefit plan in this database, may have been paid for privately, thereby incurring OOP expenses for families.

We did not assess indirect costs (eg, loss in work productivity) for caregivers or other paid assistance required by the family. Costs described in this study resulted from all causes and were not specifically related to FXS. The data were not analyzed in relation to total patient expenditures or to costs in patients without FXS, which would be relevant for a payer to consider.

Given the sometimes large variations in costs, it will be useful for future analyses to include a more detailed view of the patients who may be considered outliers, both with very low and very high costs of care.

Finally, because these data are from a population with FXS in the United States alone, these results may not be generalizable to healthcare systems outside of the United States.

Conclusion These results from administrative claims support and complement results from surveys on the economic burden related to the care of individuals who are diagnosed with FXS. In our study, we identified the procedures and hospitalizations clustered in a subset of patients as the main drivers of direct healthcare costs. Prescription drug utilization appeared to be less of a contributor to overall cost. It is the opinion of the authors that a more targeted assessment of resource utilization is needed to identify FXS-specific cost drivers to characterize the incremental direct and indirect costs associated with this intellectual disability. Such data will be critical to capturing the true value of future treatment interventions that reduce healthcare and social care resource utilization and improve patient outcomes. n

Author Disclosure Statement Ms Sacco is an Employee and Stockholder of Novartis Pharmaceuticals Corp; Dr Capkun-Niggli is an Employee of Novartis Pharma AG; Ms Zhang is an Employee of Beijing Novartis Pharma Co, Ltd; and Dr Jose is an Employee of Novartis Healthcare Private Limited. No additional financial compensation was provided to the authors for this study.

References

1. Hersh JH, Saul RA; Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127:994-1006.

2. Crawford DC, Acu単a JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001;3:359-371.

3. Song FJ, Barton P, Sleightholme V, et al. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess. 2003;7:1-106.

4. Falik-Zaccai TC, Shachak E, Yalon M, et al. Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to the absence of AGG interruptions on a rare Mediterranean haplotype. Am J Hum Genet. 1997;60:103-112.

5. Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. Advances in the treatment of fragile X syndrome. Pediatrics. 2009;123:378-390.

6. Bailey DB Jr, Skinner D, Sparkman KL. Discovering fragile X syndrome: family experiences and perceptions. Pediatrics. 2003;111:407-416.

7. Lauria DP, Webb MJ, McKenzie P. The economic impact of the fragile X syndrome on the state of Colorado. International Fragile X Conference Proceedings.

1992:393-405.

8. Bailey DB Jr, Raspa M, Bishop E, et al. Medication utilization for targeted symptoms in children and adults with fragile X syndrome: US survey. J Dev Behav Pediatr.

2012;33:62-69.

9. Martin GE, Ausderau KK, Raspa M, et al. Therapy service use among individuals with fragile X syndrome: findings from a US parent survey. J Intellect Disabil Res. 2012 Sep 14. [Epub ahead of print].

10. Ouyang L, Grosse S, Raspa M, Bailey D. Employment impact and financial burden for families of children with fragile X syndrome: findings from the National Fragile X Survey. J Intellect Disabil Res. 2010;54:918-928.

11. Bailey DB Jr, Raspa M, Bishop E, et al. Health and economic consequences of fragile X syndrome for caregivers. J Dev Behav Pediatr. 2012;33:705-712.

12. Beckett L, Yu Q, Long AN. The impact of Fragile X: prevalence, numbers affected, and economic impact. A white paper prepared for the National Fragile X Foundation. September 2005.

13. Tranfaglia MR. Fragile X syndrome: a psychiatric perspective. Results Probl Cell Differ. 2012;54:281-295.

14. Bailey DB, Raspa M, Olmsted MG. Using a parent survey to advance knowledge about the nature and consequences of fragile X syndrome. Am J Intellect Dev Disabil.

2010;115:447-460.

15. Bailey DB Jr, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008;146A:2060-2069.

16. Hartley SL, Seltzer MM, Raspa M, et al. Exploring the adult life of men and women with fragile X syndrome: results from a national survey. Am J Intellect Dev Disabil. 2011;116:16-35.

17. McKinney C, Renk K. Atypical antipsychotic medications in the management of disruptive behaviors in children: safety guidelines and recommendations. Clin Psychol Rev. 2011;31:465-471.

Stakeholder Perspective Rarity, Disease Heterogeneity, and a Pathway for Estimating Economic Burden

By Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer, Worldwide Clinical Trials, King of Prussia, PA

This article presents a landmark descriptive characterization of healthcare resource and medication utilization based on administrative claims data for fragile X syndrome in the United States. The implications transcend fragile X

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syndrome, because the methods and results provide direction for researchers, healthcare providers, and policymakers who are invested in developing or coordinating therapy for rare illnesses, which may afflict many patients. In an

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Stakeholder Perspective Continued environment in which access to therapy is dictated by economic parameters as much as by unmet clinical need, Sacco and colleagues provide a pathway for evaluating the economic impact of rare diseases with diverse clinical presentations on a healthcare system.

RESEARCHERS: Methodological rigor is reflected in the description of prevalence and of disease phenotypes, the strengths and limitations of the databases accessed, patient eligibility criteria, and in the spectrum of measures evaluated related to comorbidities and services.

These are key attributes capturing healthcare resource utilization for a disease with a complex phenotype. Utilization differences between Medicaid and commercial/ Medicare patients stress the importance of identifying patient subgroups (and outliers) and either adjusting the design or the analysis of studies in rare disorders to facilitate more precise estimates of economic burden.

By their nature, pharmacoeconomic evaluations for rare diseases present unique challenges. The number of patients available for research is small, the disease presentation is heterogeneous even within one indication, and reevaluations at time points during a product’s life cycle are required if there are concerns regarding immuno­ genicity (ie, biosimilars) or rare adverse events.1,2 Challenges are accentuated by development programs based on few studies (including studies using only surrogate markers) rather than on clinical outcomes to estimate utilization and cost.3 Accessing data in the structured tertiary care centers characteristic of orphan disease research hampers generalizability. Finally, significant international differences exist in the type of pharmacoeconomic information used for coverage decisions, with notable inconsistencies for rare diseases.4 Country- and disease-specific healthcare utilization data from claims analyses offer a technique to inform this process.

PAYERS: The 1983 US Orphan Drug Act and subsequent acts in the United States and internationally provided an impetus for orphan drug development, emphasizing an important unmet need and creating an economically viable strategy for pharmaceutical research.5 With more than 7000 rare diseases recognized, advances in genetics may further subdivide illnesses into genetically distinct rare disorders. Characterized by premium pricing, compounds developed for one orphan indication can expand into other clinical areas, or can benefit from off-label use. Blockbuster status within a 7-year market exclusivity period has been achieved by a number of brand-name drugs with orphan designations.6 Estimating resources for delivery of care by any one funding entity is also difficult, because patients

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with genetic disorders transition from pediatric to adult service providers.

Previously featured in American Health & Drug Benefits, a “tipping point” has been reached for orphan drug pricing, prompting increased scrutiny, a focus on appropriate use, and a rising burden on patients through various cost-sharing mechanisms.7 Policies by Medicare, Medicaid, and US commercial plans can present a labyrinth of coverage decisions, levels of reimbursement, coding mechanisms to ensure payment, and settings through which a service or a product may or must be provided. Capturing medical procedures, hospitalizations, medications, and related services in appropriately complementary observational and interventional research will facilitate benefit design, given the implication of this research.

PATIENTS: The development of innovative therapy for rare, devastating, and lifelong conditions represents a laudable achievement. However, given the chronicity of indications, the cost of acquisition by the patient becomes a determining factor in adherence.

The increasing availability of therapy may paradoxically be associated with less accessibility, and unintended consequences from well-intentioned acts prompt concern regarding policy.8,9 However, analyses of US claims data of patients with fragile X syndrome create a set of hypotheses suggesting that the economic sequelae of interventions for rare diseases are measurable, that maximal benefits may be discerned in a subset of patients, and that medical procedures and hospitalizations, more than prescription drug utilization, are key to estimating overall cost. The impact of innovative therapy on caregiver burden offers an important dimension for additional inquiry. n 1. Simoens S, Verbeken G, Huys I. Biosimilars and market access: a question of comparability and costs? Target Oncol. 2012;7:227-231.

2. Simoens S. Biosimilar medicines and cost-effectiveness. Clinicoecon Outcomes Res. 2011;3:29-36.

3. Kesselheim AS, Myers JA, Avorn J. Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA. 2011;305:2320-2326.

4. Vegter S, Rozenbaum MH, Postema R, et al. Review of regulatory recommendations for orphan drug submissions in the Netherlands and Scotland: focus on the underlying pharmacoeconomic evaluations. Clin Ther. 2010;32:1651-1661.

5. Meekings KN, Williams CS, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today. 2012;17:660-664.

6. Wellman-Labadie O, Zhou Y. The US Orphan Drug Act: rare disease research stimulator or commercial opportunity? Health Policy. 2010;95:216-228.

7. Hyde R, Dobrovolny D. Orphan drug pricing and payer management in the United States: are we approaching the tipping point? Am Health Drug Benefits. 2010;3:15-23.

8. Murphy SM, Puwanant A, Griggs RC; for the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and Inherited Neuropathies Consortium (INC) Consortia of the Rare Disease Clinical Research Network. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol.

2012;72:481-490.

9. Côté A, Keating B. What is wrong with orphan drug policies? Value Health. 2012; 15:1185-1191.

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In patients with acute coronary syndrome (ACS)

BRILINTA: Proven superior to clopidogrel across a broad range of ACS patients at reducing thrombotic cardiovascular (CV) events, including CV death The difference between treatments was driven by CV death and MI with no difference in stroke BRILINTA and clopidogrel were studied with aspirin and other standard therapies

INDICATIONS BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina, nonñST-elevation myocardial infarction, or ST-elevation myocardial infarction).

BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily.

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA WARNING: BLEEDING RISK ï BRILINTA, like other antiplatelet agents, can cause signiˇcant, sometimes fatal, bleeding ï Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage ï Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG).

When possible, discontinue BRILINTA at least 5 days prior to any surgery ï Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA ï If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS ï Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided.

After any initial dose, use with aspirin 75 mg - 100 mg per day

Please read additional Important Safety Information on next page and Brief Summary of Prescribing Information, including Boxed WARNINGS, on following pages.

To see results across a broad range of ACS patients, visit

BRILINTAtouchpoints.com

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA (continued) CONTRAINDICATIONS ï BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins. BRILINTA is also contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product WARNINGS AND PRECAUTIONS ï Moderate Hepatic Impairment: Consider the risks and beneˇts of treatment, noting the probable increase in exposure to ticagrelor ï Premature discontinuation increases the risk of MI, stent thrombosis, and death ï Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel.

Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes ï BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers.

Avoid simvastatin and lovastatin doses >40 mg ï Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy ADVERSE REACTIONS ï The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) ï In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias.

PLATO excluded patients at increased risk of bradycardic events. Consider the risks and beneˇts of treatment

Reference: BRILINTA Prescribing Information, AstraZeneca.

BRILINTA is a registered trademark of the AstraZeneca group of companies. ©2013 AstraZeneca.

2398004 2/13

BRILINTA® (ticagrelor) Tablets WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage [see CONTRAINDICATIONS].

• Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery [see WARNINGS AND PRECAUTIONS].

• Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA [see WARNINGS AND PRECAUTIONS].

• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see WARNINGS AND PRECAUTIONS].

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75-100 mg per day [see WARNINGS AND PRECAUTIONS and CLINICAL STUDIES (14) in full Prescribing Information].

BRIEF SUMMARY of PRESCRIBING INFORMATION: For full Prescribing Information, see package insert.

INDICATIONS AND USAGE Acute Coronary Syndromes BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis [see Clinical Studies (14) in full Prescribing Information]. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily [see Warnings and Precautions and Clinical Studies (14) in full Prescribing Information].

DOSAGE AND ADMINISTRATION Initiate BRILINTA treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. ACS patients who have received a loading dose of clopidogrel may be started on BRILINTA. BRILINTA can be administered with or without food. A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its scheduled time.

CONTRAINDICATIONS History of Intracranial Hemorrhage BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies (14) in full Prescribing Information].

Active Bleeding BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions and Adverse Reactions].

Severe Hepatic Impairment BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hypersensitivity BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product [see Adverse Reactions].

WARNINGS AND PRECAUTIONS General Risk of Bleeding Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding. BRILINTA increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding.

Fatal and life-threatening bleeding rates were not increased [see Adverse Reactions]. In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal antiinflammatory drugs [NSAIDS]). When possible, discontinue BRILINTA five days prior to surgery.

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding. If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions and Adverse Reactions].

Concomitant Aspirin Maintenance Dose In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a maintenance dose of aspirin of 75-100 mg [see Dosage and Administration and Clinical Studies (14) in full Prescribing Information].

Moderate Hepatic Impairment BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Dyspnea Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

Discontinuation of BRILINTA Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA will increase the risk of myocardial infarction, stent thrombosis, and death.

Strong Inhibitors of Cytochrome CYP3A Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

Cytochrome CYP3A Potent Inducers Avoid use with potent CYP3A inducers, such as rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS Clinical Trials Experience The following adverse reactions are also discussed elsewhere in the labeling: • Dyspnea [see Warnings and Precautions] 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 practice. BRILINTA has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.

Bleeding PLATO used the following bleeding severity categorization: • Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.

• Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.

• Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).

• Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.

Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.

Figure 1 Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event

Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days.

Table 1 Non-CABG related bleeds (KM%)

Total (Major + Minor) Major Fatal/Life-threatening Fatal Intracranial (Fatal/Life-threatening)

BRILINTA N=9235 8.7 4.5 2.1 0.2 0.3

Clopidogrel N=9186 7.0 3.8 1.9 0.2 0.2

As shown in Table 1, BRILINTA was associated with a somewhat greater risk of non-CABG bleeding than was clopidogrel. No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel. In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for BRILINTA and clopidogrel.

BRILINTA® (ticagrelor) Tablets Table 2 CABG bleeds (KM%) Patients with CABG BRILINTA Clopidogrel N=770 N=814 Total Major 85.8 86.9 Fatal/Life-threatening 48.1 47.9 Fatal 0.9 1.1 Although the platelet inhibition effect of BRILINTA has a faster offset than clopidogrel in in vitro tests and BRILINTA is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of BRILINTA compared to clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

No data exist with BRILINTA regarding a hemostatic benefit of platelet transfusions.

Drug Discontinuation In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for BRILINTA and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of BRILINTA patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients.

Common Adverse Events A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 3. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on BRILINTA or clearly related to the drug’s pharmacologic effect (dyspnea).

Table 3 Percentage of patients reporting non-hemorrhagic adverse events at least 3% or more in either group BRILINTA (%) Clopidogrel (%) N=9235 N=9186 Dyspnea1 13.8 7.8 Headache 6.5 5.8 Cough 4.9 4.6 Dizziness 4.5 3.9 Nausea 4.3 3.8 Atrial fibrillation 4.2 4.6 Hypertension 3.8 4.0 Non-cardiac chest pain 3.7 3.3 Diarrhea 3.7 3.3 Back pain 3.6 3.3 Hypotension 3.2 3.3 Fatigue 3.2 3.2 Chest pain 3.1 3.5 1 Includes: dyspnea, dyspnea exertional, dyspnea at rest, nocturnal dyspnea, dyspnea paroxysmal nocturnal

Bradycardia In clinical studies BRILINTA has been shown to increase the occurrence of Holterdetected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA and clopidogrel patients, respectively. In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.

Gynecomastia In PLATO, gynecomastia was reported by 0.23% of men on BRILINTA and 0.05% on clopidogrel. Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO. Lab abnormalities Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA and approximately 0.2 mg/dL on clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders – Hypersensitivity reactions including angioedema [see Contraindications].

DRUG INTERACTIONS Effects of other drugs Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5.

CYP3A inhibitors [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A inducers [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

2

Aspirin Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see Warnings and Precautions and Clinical Studies (14) in full Prescribing Information].

Effect of BRILINTA on other drugs Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.

Simvastatin, lovastatin BRILINTA will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3) in full Prescribing Information].

Digoxin Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in BRILINTA therapy [see Clinical Pharmacology (12.3) in full Prescribing Information].

Other Concomitant Therapy BRILINTA can be administered with unfractionated or low-molecularweight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred. In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).

Nursing Mothers It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of BRILINTA in pediatric patients have not been established.

Geriatric Use In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age.

The relative risk of bleeding was similar in both treatment and age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment BRILINTA has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, BRILINTA is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment [see Contraindications, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Renal Impairment No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not expected to be dialyzable. Treatment of overdose should follow local standard medical practice.

Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken. Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility [see section (13.1) in full Prescribing Information] PATIENT COUNSELING INFORMATION [see section (17) in full Prescribing Information]

Issued: January 24, 2013 BRILINTA® is a trademark of the AstraZeneca group of companies.

Distributed by: AstraZeneca LP, Wilmington, DE 19850 © AstraZeneca 2011, 2012 1/13 2394501 2/13

business business

Original research

A Value-Based Analysis of Hemodynamic Support Strategies for High-Risk Heart Failure Patients Undergoing a Percutaneous Coronary Intervention David Gregory, MPA; Dennis J. Scotti, PhD, MBA; Gregory de Lissovoy, PhD, MPH; Igor Palacios, MD; Simon Dixon, MD; Brijeshwar Maini, MD; William O’Neill, MD

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2013;6(2):88-99 www.AHDBonline.com Disclosures are at end of text

Background: The economic burden of heart disease is heavy and growing. As advanced technologies for treating heart disease become available, decision makers need to be able to assess the relative value of such options against existing standards of care.

Objectives: To compare the clinical and economic benefits of a percutaneous ventricular assist device (pVAD) versus an intra-aortic balloon pump (IABP) observed during the 90-day duration of the PROTECT II clinical trial, and to supplement these findings with a simulation of the longer-term value of this technology through the use of a Markov model to estimate the incremental cost-effectiveness of a pVAD relative to an IABP, in terms of quality-adjusted life-years (QALYs).

Methods: Hospital bills were collected for patients enrolled in the PROTECT II trial who received hemodynamic support for high-risk percutaneous coronary intervention (PCI) provided by a pVAD (Impella 2.5) versus a conventional IABP during a 90-day episode of care (EOC).

Length of stay, charges, and costs were analyzed for the index admissions, intensive care unit confinements, readmissions, and overall EOC. In addition, a probabilistic Markov model was used to project these parameters and their impact on a patient’s quality of life for up to 10 years in relation to a pVAD versus an IABP. Results: Hospital costs for the index admission were lower for the IABP compared with the pVAD ($33,684 vs $47,667; P <.001), whereas readmission length of stay and costs were lower for the pVAD versus the IABP (5 days vs 7 days; and $11,007 vs $21,834, respectively; P <.001). The total 90-day hospital charges were similar for the pVAD and the IABP ($172,564 vs $172,758, respectively; P = .785); however, the total 90-day EOC cost was lower for the IABP than for the pVAD ($44,032 vs $53,171, respectively; P <.001). The median hospital days for the entire EOC were 7 days for the pVAD versus 9 days for the IABP (P = .008). Critical care stays were considerably shorter for a pVAD than for an IABP on readmissions (3.88 days vs 7.00 days; P = .145). Reduction in major adverse cardiovascular and cerebrovascular events resulted in a projected gain of 0.26 QALYs over 10 years, yielding an incremental cost-effectiveness ratio of $39,389/QALY. Conclusions: For high-risk patients with advanced heart failure undergoing PCI, the new pVAD reduced major adverse events, critical care and readmission length of stay, and readmission cost over the 90-day EOC, and was determined to be cost-effective over the longterm. These findings can assist decision makers in forming value-based judgments with regard to new hemodynamic support strategies.

Mr Gregory is Executive Vice President and Partner, Presscott Associates, a Division of ParenteBeard, LLC, New York, NY; Dr Scotti is the Alfred E. Driscoll Professor of Healthcare & Life Sciences Management, Fairleigh Dickinson University, Teaneck, NJ; Dr de Lissovoy is Adjunct Associate Professor, Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Dr Palacios is Director, Cardiac Catheterization Lab, Massachusetts General Hospital, Boston, MA; Dr Dixon is Chair, Cardiovascular Medicine, Beaumont Health System, Royal Oak, MI; Dr Maini is Director, Advanced Cardiac & Endovascular Interventional Laboratory, Cardiovascular Research & Education, PinnacleHealth, Wormleysburg, PA; Dr O’Neill is Medical Director, Center for Structural Heart Disease, Henry Ford Hospital, Detroit, MI.

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ore than 1 in 3 American adults have at least one type of cardiovascular disease, which is the leading cause of death in the United States for men and women.1 The total annual burden of heart disease is estimated to be $312.6 billion in combined direct and indirect costs.1 In addition to an overall annual cost of more than $34 billion,2 heart failure is one of the main medical conditions necessitating acute hemodynamic support. Advanced heart failure is the leading source for hospital readmissions among the Medicare population and commercial populations.3-8 Symptomatic patients with multivessel coronary artery disease or unprotected left main and depressed left ventricular functions carry a high risk for morbidity and mortality while undergoing percutaneous coronary intervention (PCI), which is a common treatment for such patients.

Patients with heart failure typically have extended nonviable myocardium and a cardiac reserve that is too low to respond to temporary ischemia during percutaneous procedures. This often leads to hemodynamic instability, from severe hypotension to cardiogenic shock or even death. Temporary hemodynamic support is often used during these high-risk procedures to prevent catastrophic hemodynamic decompensation and to improve heart function and outcomes. Such an approach is frequently the only option for select patients who have been turned down for cardiac surgery because of their high clinical and coronary anatomy risks.

The traditional treatment for patients with high-risk PCI has been the intra-aortic balloon pump (IABP), although its effectiveness has been questioned 9-13 and has led patients and providers to express the need for alternative therapeutic options. The newly introduced percutaneous ventricular assist device (pVAD), Impella 2.5, is unique among the few currently available pVADs by virtue of its miniaturized size, self-contained motor, and because its placement does not require invasion of the heart muscle.

The Impella 2.5 is a minimally invasive percutaneous catheter-based device that is powered and controlled by its console and is designed to provide partial circulatory support. The Impella pump pulls 2.5 L/min of blood from the left ventricle through an inlet area near the tip and expels blood from the catheter into the ascending aorta (Figure 1). The 9F catheter/12F motor pump can be inserted via a standard catheterization procedure through the femoral artery, into the ascending aorta, across the valve, and into the left ventricle.

By contrast, the IABP, which has been in use since the late 1960s, is a volume displacement catheter that relies on the native heart function to provide continued systemic forward flow, requiring varying doses of inotropic agents to improve contractility.

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Key Points Heart failure is the main cause for hospital readmissions in patients with heart disease. ➤ Heart failure is a leading condition requiring acute hemodynamic support, especially in patients undergoing high-risk percutaneous coronary intervention. ➤ This is the first economic analysis to compare the resource utilization and costs for an intra-aortic balloon pump (IABP)—the current standard of care for this patient population—and a newly introduced percutaneous ventricular assist device (pVAD) in patients requiring acute hemodynamic support. ➤ The results show that index hospitalization costs were lower for the IABP versus the pVAD ($33,684 vs $47,667), but readmission length of stay and costs were reversed; both were lower in the pVAD cohort than in the IABP cohort (5 days vs 7 days; and $11,007 vs $21,834). ➤ The major adverse event rate was 22% lower and the major adverse cardiovascular/cerebrovascular event rate was 29% lower in the pVAD cohort versus the IABP cohort. ➤ The long-term analysis further shows the potential value of pVAD use versus IABP in terms of qualityadjusted life-years and cost-effectiveness. ➤

A key difference between this new pVAD and the IABP is the pVAD’s ability to directly unload the left ventricle, thereby augmenting coronary flow and providing better hemodynamic support compared with the traditional IABP.14-16 No studies have been published that compare the resource utilization and the treatment costs associated with the pVAD versus IABP from a US perspective.

The PROTECT II study was a multicenter, randomized trial designed to assess whether a high-risk percutaneous revascularization strategy with the support of the new pVAD technique would result in better outcomes compared with a revascularization strategy with the support of an IABP.14 Using the clinical and economic data from this clinical study, we present the first resource utilization and relative value assessment of pVAD in relation to the current standard of care, namely, the IABP. The purpose of this present study is to (1) evaluate and document the clinical and economic benefits of this pVAD during the 90-day duration of the PROTECT II trial, and (2) to supplement these findings with a simulation analysis of the longer-term value of this technology through the use of a Markov model to estimate the incremental cost-effectiveness of a pVAD versus an IABP expressed in terms of quality-adjusted life-years (QALYs).

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Figure 1 T he Impella 2.5 Percutaneous Catheter-Based Device Pigtail Inlet area

Placement marker Cannula

Outlet area Motor housing

Backloading lumen

Open pressure area

Table 1 Baseline Characteristics of the Study Population IABP (N = 211)

pVAD (N = 216)

P value

67 (± 11)

68 (± 11)

.583

Male sex, %

82.0

80.6

.704

Current NYHA class III/IV, %

54.9

58.9

.434

Left ventricular ejection fraction, %

24.0 (± 6.3)

23.3 (± 6.3)

.258

64.5

63.4

.825

6 (± 7)

6 (± 6)

.562

29.5 (± 13.7)

30.3 (± 13.2)

.595

Characteristics Age (± SD), years

Nonsurgical candidate, % STS mortality score SYNTAX score

IABP indicates intra-aortic balloon pump; NYHA, New York Heart Association; pVAD, percutaneous ventricular assist device; SD, standard deviation; STS, Society of Thoracic Surgeons; SYNTAX, Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery.

Methods Study Design and Participants The PROTECT II study design and methods have been published previously.14 In brief, PROTECT II was conducted in 112 sites in the United States, Canada, and Europe. Each site had to demonstrate previous experi-

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ence with hemodynamic support for nonemergent highrisk PCI. A predetermined need for hemodynamic support, which was assessed by the treating physician, was required to qualify the patient for enrollment. Between 2008 and 2010, 216 patients who met the eligibility requirements received a pVAD and 211 received an IABP and were enrolled at US hospitals, with 38 of these facilities agreeing to participate in this economic study.

All patients (mean age, 68 years) had a history of heart disease; 81% of them were men.

The study population was very well matched in terms of demographics, previous cardiac history, and degree of heart failure as described in Table 1, which shows no statistical differences among these and other baseline attributes. The study was approved by the institutional review board at each participating institution.

Analytic Approach The results of the PROTECT II clinical trial were analyzed for clinical and economic benefits. Major adverse events (AEs), including death, myocardial infarction, stroke, repeat revascularization, need for cardiac or vascular operations (including vascular operations for limb ischemia), acute renal dysfunction, aortic insufficiency, cardiopulmonary resuscitation or ventricular tachycardia requiring cardioversion, severe hypotension and angiographic failure,14 and, more specifically, major adverse cardiovascular and cerebrovascular events (MACCEs), were tracked from the index procedure through 90 days of follow-up and compiled for both study arms to generate clinical comparisons.

MACCEs included large acute myocardial infarctions (AMIs),17 major strokes, repeat revascularizations, and death. (AMI was defined as the development of new Q-waves or CK-MB elevation 8 times above the upper normal value within 72 hours after a PCI for periprocedural AMI, or more than twice the upper normal value beyond 72 hours of the PCI for spontaneous AMI.) When CK-MB was not available, troponin values were used instead using the same threshold. In addition, hospital charges, costs, and length of stay were measured for the 90-day episode of care (EOC), including the index admission and any related readmissions.

To predict the economic value of the hemodynamic support strategies under review beyond the period for which empirical data were collected, a Markov model (described below) was developed to estimate an incremental cost-effectiveness ratio (ICER) adjusted for approximation of patient perceptions of the quality of their gains in life expectancy. This metric is offered in recognition of the recent trend toward longer retention of members by health plans. Historically, member retention was 2 to 3 years on average18; however, increased

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switching costs, uncertainty surrounding the impact of the Affordable Care Act, and payer consolidation have resulted in fewer choices for employers, leading to stabilization and extension of member retention patterns.19,20

Measures of Clinical Benefits The index and 90-day postindex major AEs and MACCEs were assessed as clinical end points during the PROTECT II clinical trial, with the MACCE incidence rates forming the basis for the economic study, both for the 90-day EOC assessment and the 10-year model. It is important to note that all readmissions within 90 days were also assessed from a timing, diagnostic, and resource consumption standpoint. In addition, changes in the New York Heart Association (NYHA) functional classification during the study period were tracked to assess the pVADs’ impact on quality of life.

Measures of Economic Benefits A retrospective economic analysis of the PROTECT II trial was undertaken to measure hospital resource utilization and the costs incurred during the 90-day EOC. Hospital charges, costs, and length of stay were tracked for medical or surgical and critical care levels of service during the index admission, as well as for hospital readmissions, including repeated revascularization procedures. Primary data sources for index admissions and readmissions were the clinical case report forms and copies of detailed hospital bills, as well as Centers for Medicare & Medicaid Services UB04 forms. Although these forms provided billed charges, such charges were converted to cost via institution-specific cost-to-charge ratios using (1) total and (2) department-level billing data to enhance accuracy.

Index admission hospital bills were obtained for 133 (63%) patients with an IABP and 130 (60%) patients with a pVAD, and they were determined to be representative of the full clinical trial population. Charges and costs for patients receiving an IABP who were missing bills were estimated by selecting similar patients treated at the same group of hospitals from the Medicare Provider Analysis and Review file for the 2009 federal fiscal year. The charges and costs of index admissions for missing pVAD bills were modeled by extrapolating from the available billing records using a bootstrapping technique.

Hospital bills were collected for approximately 36% of all-cause readmissions, and basic diagnostic and lengthof-stay data were collected on all readmissions via the clinical case report forms.

For patients with missing bills, the charges and costs were imputed from the mean values for each study group.

Hospital resource use and costs for the complete EOC were calculated as the sum of the index admissions and

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any subsequent readmissions irrespective of cause and/or primary diagnosis.

Structure and Specification of the Markov Model To further assess the value of pVADs in the treatment of patients undergoing high-risk PCIs, a Markov model was constructed using TreeAge 2011 Healthcare Pro (Williamstown, MA) to capture and to simulate the short- and long-term consequences of the lower rates of targeted MACCEs observed in the PROTECT II trial, as well as their impact on quality-adjusted life expectancy.

A diagram of the decision tree is depicted in Figure 2.

The specific measurements, assumptions, and sources underlying the input parameters used to generate the model outputs are detailed in the Appendices (available online at AHDBonline.com).

The EOC in the PROTECT II study and the last date of follow-up were 90 days after the procedure. Our model simulates the course of treatment of a hypothetical cohort based on the PROTECT II outcomes at 90 days.

Our base-case simulation used a long-term, 10-year time horizon (40 cycles of 90 days each).

The application of the 90-day trial outcomes as the basis for the long-term, 10-year time frame analysis in our study conforms to accepted guidelines for cost-effectiveness analyses, as outlined by Weinstein and colleagues in the Report of the ISPOR Task Force on Good Research Practices.21 They wrote, “Lifetime horizons are appropriate for many models and are almost always required for models in which options have different time-varying survival rates.

Shorter horizons may be justified if survival and long-term chronic sequelae do not differ among options or based on an understanding of the disease process and the effect of interventions. In any case, the lack of long-term follow-up data should not be used as a rationale for failing to extend the time horizon as long as is relevant to the decision under analysis.”21 On completion of the index procedure, the patients entered 1 of 4 “health states” reflecting the extent of heart failure (mild, moderate, or severe), scored by their NYHA functional classification or cardiac or cerebrovascular death. Subsequent Markov nodes simulated postprocedural MACCEs, including large AMI, major stroke, repeat revascularization and cardiac-related mortality, as well as cost consequences over the model’s 10-year time horizon. It should be noted that these are not mutually exclusive transitional events; a stroke or repeated revascularization could take place after an AMI, and the model permits any combination of MACCEs to occur after the index event. Clinical and cost parameters during the initial 90-day EOC—spanning from the initial high-risk PCI admission, during which a pVAD or IABP was inserted (index admission) through the 90-day

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Figure 2 S tructure of the Markov Model No MAE #

=Continue

RR

Continue #

pRR

Maximum MAE exceeded

Survive background mortality

AMI

#

pAMI

Dead if(t_strokes+t_AMI+t_RR=maxMAE; 1; 0) Continue =Continue # Maximum MAE exceeded Dead if(t_strokes+t_AMI+t_RR=maxMAE; 1;0) Continue # Maximum MAE exceeded

Stroke

Mild HF pMildInit

pStroke

2

=Continue

if(t_strokes+t_AMI+t_RR=maxMAE; 1;0) Death pDeath*rrDeathStroke*rrDeathAMI

Dead

Dead

Die from background mortality

IABP 1

Which device is most cost-effective?

=Continue

ProbToProb(tbl_Mortality[age]; 1/4) Moderate HF pModInit

Clone 2: transition

Severe HF #

Clone 2: transition

Dead 0 Impella 2.5

Clone 1: overall strategy

AMI indicates acute myocardial infarction; IABP, intra-aortic balloon pump; HF, heart failure; MAE, major adverse event; pAMI, probability of an AMI; pRR, probability of repeated revascularization.

follow-up period—were based on empirical findings from the PROTECT II trial and associated claims data.

Device costs in the model were set at $20,000 for the pVAD and $1000 for the IABP. Capital costs common with the pVAD and the IABP were excluded from the analysis. Future probabilities of MACCEs (a defined subset of the PROTECT II composite of major AE end points), quality-of-life utility adjustments, and accrual of costs were assigned according to estimates derived from the published literature. Costs and utilities were discounted at 3%.

Our analysis was limited to the direct costs of inpatient medical care, which account for 65% of IABP total costs and 70% of pVAD costs, and are the primary driver of resource consumption for the clinical condition under investigation.22 This study, therefore, adopted the perspective of the healthcare system rather than the perspective of economic consequences to society at large.

Model Assumptions (Post–90-Day Cycles) Cost parameters. A cost was estimated for nonfatal MACCE-associated treatment during the first and subsequent years based on analysis of site billing data and literature review. Long-term costs were assigned to AMI, stroke, and death. Repeat revascularizations were assumed to have incremental acute costs but no long-term

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and ongoing costs. A cost for death was assigned only if the death was associated with the patient reaching the maximum number of nonfatal MACCEs for their health state as determined by the expert opinion of independent specialists in interventional cardiology and cardiothoracic surgery. Deaths attributable to the natural course of heart failure and/or other-cause mortality were assumed to not have a resource-intensive, high-cost period immediately preceding death.

Clinical parameters. The Markov model was constructed for patients to experience 1 of the following 5 clinical consequences in each 90-day cycle: • No MACCE (resulting in no disutility, no increased costs or no increased risk of death) • AMI (resulting in a permanent disutility, increased costs, and an increased risk of death) • Stroke (resulting in a permanent disutility, increased costs, and an increased risk of death) • Repeat revascularization (resulting in a temporary disutility, a one-time incremental cost, and no increased risk of death) • Cardiac or cerebrovascular death (resulting in a final utility weight of zero and a one-time incremental cost of death).

For these post–90-day cycles, the nonfatal MACCE probabilities were estimated by tapering (using cycle tiers)

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and then leveling the incidence rates observed in the PROTECT II study at a pace that generated 10-year incidence rates generally consistent with the literature.

To be conservative, probabilities for all nonfatal MACCEs were held constant after year 5 to reflect no differential between the study groups.

Survival parameters. The Seattle Heart Failure Model and several longitudinal cardiac mortality studies were the primary sources used to project survival based on NYHA functional classification as recorded at study entrance.23-26 Health utility parameters. Because the original study design did not provide for the development of an instrument to directly measure QALYs specific to the context and patient population of the trial, all patients were assigned a baseline utility weight according to their NYHA functional classification at study onset as derived from the Tufts Medical Center’s Cost-Effectiveness Analysis Registry.27 For patients who experienced a nonfatal MACCE, a “disutility” value was applied that discounted the quality of life subsequent to the occurrence of the particular event. Disutility weights were based on QALY values included in the Tufts registry and reported in the literature for the MACCEs of interest.28-38 An incremental cost per QALY was calculated as follows: (Mean costs pVAD) – (mean costs IABP) ICER =

(Mean QALYs pVAD) – (mean QALYs IABP)

Results Clinical Benefits Key clinical findings from the PROTECT II trial are presented in Table 2, along with levels of significance associated with differences between study groups. Major AE rates at 90 days for the pVAD were 40.0% versus 51.0% for an IABP (P = .023), a 22% relative reduction, including a 52% relative reduction in repeat revascularization (6.0% for a pVAD vs 12.4% for an IABP; P = .024). A significant portion of the differential in AE rates was observed after hospital discharge, with a 56% relative reduction in major AE rates (P = .002).

More specific, overall MACCE rates for the study period were significantly reduced by 29% (P = .033). Finally, the advantage in major AE and MACCE reduction evidenced by the pVAD increased as the trial progressed over the 90-day period, a trend worth noting for extended model projections.

Economic Benefits Comparative results for the economic variables under review during the 90-day time period of the PROTECT II trial are presented in Table 3. Hemodynamic support with a pVAD demonstrated reductions in overall length

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Table 2 Key Clinical Findings from the PROTECT II Trial IABP pVAD (N = 211), (N = 216), % % P value

Adverse event

Repeat revascularization 12.4

6.0

.024

Major AE rate

51.0

40.0

.023

Major AE rate after hospital discharge

18.1

7.9

.002

MACCE

31.0

21.9

.033

AE indicates adverse event; IABP, intra-aortic balloon pump; MACCE, major adverse cardiac and cerebrovascular event; pVAD, percutaneous ventricular assist device.

of stay, with mean hospital days for the entire EOC of 9.6 days for the pVAD and 10.7 days for an IABP (P = .026), a 10% relative reduction. Moreover, the median reduction in EOC length of stay was 2 days (7 days vs 9 days, respectively, or a 22% reduction; P = .008). The primary driver of this reduction was a 2-day length-of-stay savings during readmissions for patients with a pVAD, or a 29% relative reduction (P <.001). In addition, patients with a pVAD experienced a 40% relative reduction in critical care length of stay during readmissions (3.88 days with a pVAD vs 7.00 days with an IABP; P = .145).

With regard to charge data, the mean charge for the index stay was lower for an IABP than for the pVAD ($124,778 vs $154,470, respectively; P <.001). By contrast, readmission charges were substantially lower for the pVAD than an IABP ($35,855 vs $102,260, respectively; P <.001), resulting in comparable 90-day EOC charge levels ($172,564 for a pVAD and $172,758 for an IABP; P = .785) despite the inclusion of the higher pVAD acquisition charge.

Given the variation in charge levels and accounting across facilities, we also calculated hospital cost levels using facility-specific cost-to-charge ratios to generate more stable economic results (Table 3). The mean cost of the index admission was higher for patients with a pVAD than for patients with an IABP ($47,667 vs $33,684, respectively; P <.001) largely as a result of the device acquisition cost. However, this upfront incremental cost for a pVAD was offset by its lower mean readmission costs than for the IABP ($11,007 vs $21,834, respectively; P <.001).

Lower mean readmission costs for the pVAD were attributable in part to the previously noted 40% reduction in critical care unit length of stay (ie, 3.12 fewer days on average) in patients with the pVAD for which hospital bills were secured. Of note, the projected payer cost for these readmissions was substantially similar to the reported hospital costs based on estimated diagno-

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Table 3 Mean Values for Economic Measures from the PROTECT II Trial Economic variables

Treatment

Index admissions, all cases

IABP (N = 211)

pVAD (N = 216)

Difference

P valuea

Total charge

$124,778

$154,470

$29,692

<.001

Total cost

$33,684

$47,667

$13,983

<.001

7.4

7.1

–0.30

<.331

IABP (N = 100)

pVAD (N = 108)

Difference

Total charge

$102,261

$35,856

–$66,405

<.001

Total cost

$21,834

$11,007

–$10,827

<.001

7.0

5.0

–2.0

<.001

IABP (N = 211)

pVAD (N = 216)

Difference

Total charge

$172,758

$172,564

–$194

<.785

Total cost

$44,032

$53,171

$9139

<.001

LOS, daysd

10.7

9.6

–1.10

<.026

LOS, days Readmissions, all cases

b

LOS, days EOC, all cases

c

P values derived from the nonparametric Mann-Whitney test. Statistical significance is reached when P <.050.

Readmission sample size (N) represents the total number of readmissions, not the total number of study subjects that experienced at least 1 readmission. c The pVAD case cost reflects costs derived for actual billed charges. For the incremental cost-effectiveness ratio model, pVAD’s index and EOC costs were increased by approximately $5000 to align the study data with the actual hospital acquisition cost for the pVAD as reported by the manufacturer. d The median values for EOC LOS are 9 days for IABP and 7 days for pVAD (P = .008).

EOC indicates episode of care; IABP, intra-aortic balloon pump; LOS, length of stay; pVAD, percutaneous ventricular assist device. a

b

ase-Case Results for the Markov Model Table 4 B (10-Year Time Horizon) IABP pVAD Estimated outcomes (N = 211) (N = 216) Cost Mean, $

75,655.58

85,896.66

Minimum, $

71,906.62

2090.03

Maximum, $

80,032.57

9382.27

Standard deviation, $

1467.07

1285.73

Effectiveness, QALYs Mean

2.22

2.48

Minimum

2.11

2.36

Maximum

2.34

2.59

Standard deviation

0.04

0.04

Cost-effectiveness Incremental cost, $

10,241.08

Incremental QALY

0.26

Estimated ICER, $

39,388.77

IABP indicates intra-aortic balloon pump; ICER, incremental cost-effectiveness ratio; pVAD, percutaneous ventricular assist device; QALY, quality-adjusted life-year.

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sis-related group assignments, subject to negotiated rate differences that a particular plan may experience. The overall EOC costs averaged $53,171 for patients with the pVAD and $44,032 (P <.001) for patients with an IABP, a $9139 difference.

Cost-Effectiveness Analysis Although the 90-day data are helpful for payer decision makers, a 10-year Markov simulation using the 90-day base-case parameters as an anchor for the model was used to project relative value over a longer time horizon. The estimated 10-year incremental cost for a pVAD relative to an IABP was $10,241, with an estimated incremental gain of 0.26 QALYs (Table 4). This equates to an ICER of $39,389 per QALY, which is below the widely accepted willingness-to-pay thresholds of $50,000 and $100,000 for other advanced cardiovascular technologies.39-44 Sensitivity Analyses The base-case results do not take into consideration the uncertainty inherent in point estimates assumed for base-case parameters. A Monte Carlo analysis with second-order probabilistic sensitivity analysis (2-dimensional probabilistic sensitivity analysis) was conducted applying gamma and triangular distributions, respectively, to the EOC cost (1 standard deviation) and mortality (±10%)

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Discussion Many of the newly introduced treatment regimens specifically target conditions that are common and costly, such as AMI and heart failure. As these interventions proliferate, decision makers will need to understand and balance the short-term costs of procedures versus the long-term costs for ongoing care with respect to improvement in objective clinical outcomes. In this context, medical technology will need to evolve in ways that offer outcome-based solutions that lead to increased quality and shared savings opportunities for all stakeholders.

The introduction and increased adoption of pVADs challenges the traditional paradigms that are currently used to assess medical technology. In the case of pVAD utilization, the acquisition cost is significantly greater than standard-of-care devices and must be assessed in a context of potentially decreasing the frequency of serious major AEs and lowering the rates of readmission over a reasonable time horizon. At 90 days after a procedure, patients in the PROTECT II study receiving pVAD support experienced a 29% reduction in MACCE and a 2-day median decrease in hospital days relative to IABP, in part because of a reduction associated with fewer expensive critical care days.

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Figure 3 Probabilistic Sensitivity Analysis Scatter Plot $30,000 $30,000

Costs QALY

$1 00 ,00 0p

Incremental cost

er QA LY

Costs QALY

$15,000 $15,000

er 0p

LY

QA

,00

$50

ICER $39,389 per QALY

00

Costs QALY

Costs QALY

-$15,000 -$15,000

-0.25 -0.25

0 0.1 0.2 0.3 0.4 0.5 0 0.1 0.2 0.3 0.4 0.5

Quality of life-years

ICER indicates incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Figure 4 Cost-Effectiveness Acceptability Curves for pVAD versus IABP 100 90

Iterations cost-effective, %

variables. Figure 3 shows the results of the 2-dimensional probabilistic sensitivity analysis to illustrate the robustness of the model to simultaneous variation of these input parameters randomly drawn from their respective probability distributions for 1000 replications of the Markov simulation. The position of the points in the northeast quadrant indicates that there is a high probability that pVAD is more costly, but more effective, than IABP. Further interpretation of the cost-effectiveness results is facilitated by the cost-effectiveness acceptability curves presented in Figure 4. The horizontal axis defines various levels of societal willingness to pay for an intervention that yields better outcomes at a higher cost. In the United States, a range of $50,000 to $100,000 per QALY is frequently cited as describing the upper range of “good value for the money.”39-44 The curves indicate the likelihood that a technology would be considered “cost-effective” over a broad range of willingness-to-pay thresholds.

One-way sensitivity analyses (Table 5) were also performed to test the robustness of the model relative to key assumptions. The results revealed that the model was moderately sensitive to changes in the time horizon, death probabilities, EOC cost, MACCE probabilities, and the cost of death. The impact of the level of disutility associated with the MACCEs of AMI and stroke was minimal, given that these events occurred in a minority of the patients flowing through the model.

80 70 60

IABP pVAD

50 40 30 20 10 0 0

10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000 100,000

Willingness to pay, $

IABP indicates intra-aortic balloon pump; pVAD, percutaneous ventricular assist device.

The PROTECT II clinical study demonstrated that the pVAD provided superior hemodynamic support during the index PCI compared with the IABP.14 Fewer patients were discharged from the catheterization laboratory with the pVAD in place after a procedure compared with an IABP,14 suggesting more hemodynamic stability in the pVAD group that may have also contributed to

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Table 5 One-Way Sensitivity Analyses Sensitivity range

ICER range, $ thousands

Episode of care costsa

Base case to

$39.5 to $58.5

Major AE taperb

Base case to year 2

$39.5 to $47.8

AMI disutilities

–0.24 to –0.12

$39.5 to $40.7

–0.5 to –0.3

$39.5 to $41.8

Base case to $0

$39.5 to $45.1

Death probabilities

0% to 10%

$39.5 to $59.3

Discount rate

0% to 5%

$33.5 to $43.1

Model parameter

Stroke disutilities Cost of death

c

+$5000

Base case, $58,194 for pVAD episode of care costs.

Base case, nonfatal major adverse cardiovascular and cerebrovascular event probabilities equilibrate at year 5. c Base case, $23,774 for cost of death.

AMI indicates acute myocardial infarction; ICER, incremental cost-effectiveness ratio; AE, adverse event; pVAD, percutaneous ventricular assist device. a

b

the shorter length of stay. It is also hypothesized that the enhanced circulatory support provided by the pVAD during the index PCI allowed the investigators to use, more often and more aggressively, adjunctive therapies, such as rotational atherectomy on complex calcified lesions. This potentially led to a more complete revascularization and, consequently, to fewer readmissions for target and nontarget repeat revascularizations, less in-stent thrombosis, and less spontaneous myocardial infarction after discharge in these particular patients.

Similar to other studies that suggested the long-term effect of hemodynamic support on outcomes, the Kaplan Maier curves in the PROTECT II trial continued to diverge over time, with fewer overt major AEs requiring readmission in the pVAD arm, emphasizing the potential beneficial long-term effect of a more potent circulatory device in this high-risk patient population.

The clinical findings also indicate that AE rates were further reduced in the second half of the study, suggesting that an early learning curve with respect to the pVAD technology may be mitigated over a relatively short period of time. If true, this observation presents an opportunity for improved outcomes and increased efficiency based on appropriate patient selection and well-defined treatment protocols. It is important to note that the majority of the billing records for this economic analysis were obtained for patients enrolled during the first half of the study and early in the learning curve, suggesting that treatment costs and associated cost-effectiveness metrics are conservatively reported.

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Furthermore, a recently published study of the budget impact of pVAD utilization on commercial payers demonstrated that the incremental costs of accelerated adoption are minimal based on a retrospective commercial claims analysis that identified a low incidence rate for this patient cohort in the commercial population.22 Moreover, that study confirmed the results reported in our economic analysis that postindex costs are unremarkable when compared with the index costs of care.

The use of Markov modeling provides decision makers with another lens through which to view the extended relative benefits of a particular medical technology.

Specifically, the 10-year ICER (equating to $39,389 per QALY) reported in this study reflects the long-term value of the device under study and is derived from a modest increase in quality of life for patients with a pVAD, supplemented by a modest extension of life expectancy that is driven by reduced MACCEs. It is also telling us that the acquisition cost of a pVAD begins to dissipate shortly after the initial 90 days (during which the device is purchased), and that inpatient costs begin to moderate annually based on fewer MACCEs experienced by patients treated with the new device.

The enactment of the Affordable Care Act will likely accelerate a fundamental transformation in the delivery of acute and chronic care that may ultimately lead to an increased use of value-based payment strategies. This legislation encourages the formation of accountable care organizations that integrate hospitals, physicians, and other care providers to improve the coordination of care and overall efficiency, with the prospect of shared savings as the reward.

As this transformation evolves, value-based outcome measures will be expanded to encompass extended EOC benefits, patient-reported outcomes, and quality-of-life measures.45 Providers of cardiovascular care will be particularly affected, because they will have to carefully consider the costs and benefits of multiple alternative therapies for managing a population that is increasingly older, and with a growing prevalence of complex chronic conditions. Analyses similar to those presented in this article should help decision makers adjust to the rapidly changing landscape of healthcare delivery, insurance coverage, and reimbursement policies.

Limitations The present study was performed from the perspective of the United States only, and the results may not be applicable to other healthcare systems.

Although index billing data were available for approximately 62% of the study population, modeling was necessary for the remainder of the patients, as well as for the longer time horizon.

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Nonacute services (eg, professional, rehabilitation, and other ancillary care) were not included in this analysis and should be considered for future studies that examine incremental cost-effectiveness associated with the use of pVADs. Measures of utility or health-state preference were not included in the original design of the PROTECT II trial.

Accordingly, the QALY weightings used in this economic study were based on literature-derived utility scores.

To remedy this shortcoming, future research efforts should endeavor to explicitly incorporate study-specific indicators of health-state utility as perceived by patients enrolled in clinical trials.

Conclusions This PROTECT II economic analysis demonstrated that the nonemergent use of a pVAD during high-risk PCI resulted in significant reductions in the risk of MACCE (including repeat revascularizations requiring a readmission), readmission costs, and length of stay, despite moderately higher 90-day EOC costs. Moreover, when a multiyear extended timeline is considered for judging the value of pVAD use, our study suggests that the incremental expenditure per QALY gained is cost-­ effective and well within the willingness-to-pay range that is widely accepted for other advanced cardiovascular technologies. The short-term and the longer-term findings presented in this article have implications for medical coverage decisions and underscore a value proposition that health plans and accountable care organizations should carefully consider during the technology assessment process.

It is our hope that this study encourages researchers and health plans to consider developing new metrics that offer a more practical guidance with regard to judging new technology. Toward this end, it may be useful to construct a quality-adjusted per-member per-month metric that acknowledges the incremental per-member per-month cost of a technology for a defined period of time and adjusts it to account for measurable indicators of quality, such as increased patient satisfaction (ie, patient-reported outcomes), reduced short-term AEs, and/ or better management of comorbidities. n Source of Funding The research was funded by Abiomed, Inc, the manufacturer of the Impella 2.5.

Author Disclosure Statement Mr Gregory is advisor and consultant to Abiomed and Dr Scotti and Dr de Lissovoy are consultants to Abiomed; Dr Maini is on the Speakers’ Bureau of and receives honoraria from Abiomed. Dr Dixon and Dr O’Neill have reported no conflicts of interest.

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20. The Henry J. Kaiser Family Foundation. Employer Health Benefits 2012 Annual Survey. http://ehbs.kff.org/pdf/2012/8345.pdf. Accessed March 20, 2013.

21. Weinstein MC, O’Brien B, Hornberger J, et al. 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.

22. Gregory DA, Scotti DJ. A budget impact model to estimate the cost dynamics of treating high-risk heart failure patients with advanced percutaneous cardiac assist devices: the payer perspective. J Manag Care Med. 2013;16:61-69.

23. Levy WC, Mozaffarian D, Linker DT, et al. Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113:1424-1433.

24. Ahn SA, Jong P, Yusuf S, et al. Early versus delayed enalapril in patients with left ventricular systolic dysfunction: impact on morbidity and mortality 15 years after the SOLVD trial. J Am Coll Cardiol. 2006;47:1904-1905.

25. Solomon SD, Anavekar N, Skali H, et al. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation. 2005; 112:3738-3744.

26. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.

27. Center for the Evaluation of Value and Risk in Health. Cost Effectiveness Analysis Registry. https://research.tufts-nemc.org/cear4/. Accessed January 24, 2013.

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28. Mahoney EM, Greenberg D, Lavelle TA, et al. Cost and cost-effectiveness of carotid stenting versus endarterectomy for patients at increased surgical risk: results from the SAPPHIRE trial. Catheter Cardiovasc Interv. 2011;77:463-472.

29. Tsevat J, Goldman L, Soukup JR, et al. Stability of time-tradeoff utilities in survivors of myocardial infarction. Med Decis Making. 1993;13:161-165.

30. Goeree R, Blackhouse G, Petrovic R, et al. Cost of stroke in Canada: a 1-year prospective study. J Med Econ. 2005;8:147-167.

31. Chaplin S, Scuffham PA, Alon M, et al. Secondary prevention after PCI: the cost-effectiveness of statin therapy in the Netherlands. Neth Heart J. 2004;12:331-336.

32. Greving JP, Visseren FL, de Wit GA, Algra A. Statin treatment for primary prevention of vascular disease: whom to treat? Cost-effectiveness analysis. BMJ. 2011;342:d1672.

33. Regier DA, Sunderji R, Lynd LD, et al. Cost-effectiveness of self-managed versus physician-managed oral anticoagulation therapy. CMAJ. 2006;174:1847-1852.

34. Alehagen U, Rahmqvist M, Paulsson T, Levin LA. Quality-adjusted life year weights among elderly patients with heart failure. Eur J Heart Fail. 2008;10:1033-1039.

35. Bakhai A, Stone GW, Mahoney E, et al. Cost effectiveness of paclitaxel-eluting stents for patients undergoing percutaneous coronary revascularization: results from the TAXUS-IV trial. J Am Coll Cardiol. 2006;48:253-261.

36. Bakhai A, Stone GW, Grines CL, et al. Cost-effectiveness of coronary stenting and abciximab for patients with acute myocardial infarction: results from the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial. Circulation. 2003;108:2857-2863.

37. Cohen DJ, Taira DA, Berezin R, et al. Cost-effectiveness of coronary stenting in acute myocardial infarction: results from the Stent Primary Angioplasty in Myocar-

dial Infarction (Stent-PAMI) trial. Circulation. 2001;104:3039-3045.

38. Post PN, Stiggelbout AM, Wakker PP. The utility of health states after stroke: a systemic review of the literature. Stroke. 2001;32:1425-1429.

39. Cutler DM, Rosen AB, Vijan S. The value of medical spending in the United States, 1960-2000. N Engl J Med. 2006;355:920-927.

40. Doan QV, Chiou CF, Dubois RW. Review of eight pharmacoeconomic studies of the value of biologic DMARDs (adalimumab, etanercept, and infliximab) in the management of rheumatoid arthritis. J Manag Care Pharm. 2006;12:555-569.

41. Ohsfeldt RL, Gandhi SK, Smolen LJ, et al. Cost effectiveness of rosuvastatin in patients at risk of cardiovascular disease based on findings from the JUPITER trial.

J Med Econ. 2010;13:428-437.

42. Reynolds MR, Magnuson EA, Wang K, et al. Cost-effectiveness of transcatheter aortic valve replacement compared with standard care among inoperable patients with severe aortic stenosis: results from the placement of aortic transcatheter valves (PARTNER) trial (cohort B). Circulation. 2012;125:1102-1109.

43. Cohen DJ, Lavelle TA, Van Hout B, et al. Economic outcomes of percutaneous coronary intervention with drug-eluting stents versus bypass surgery for patients with left main or three-vessel coronary artery disease: one-year results from the SYNTAX trial. Catheter Cardiovasc Interv. 2012;79:198-209.

44. Bischof M, Briel M, Bucher HC, et al. Cost-effectiveness of drug-eluting stents in a US Medicare setting: a cost-utility analysis with 3-year clinical follow-up data.

Value Health. 2009;12:649-656.

45. US Department of Health and Human Services. National Strategy for Quality Improvement in Health Care. March 2011. www.healthcare.gov/news/reports/national qualitystrategy032011.pdf. Accessed March 20, 2013.

Stakeholder Perspective Careful Selection of Candidates for Percutaneous Ventricular Assist Device Is Crucial

By Raymond L. Singer, MD, MMM, CPE Chief, Division of Cardiothoracic Surgery, Vice Chair, Quality and Patient Safety, Department of Surgery, Lehigh Valley Health Network, Allentown, PA

PAYERS: Approximately 6 million people in the United States have heart failure (HF), and nearly 700,000 new cases are diagnosed annually. The incidence of HF approaches 10 per 1000 population after age 65 years. It is estimated that by 2030, an additional 3 million people will have HF, a 25% increase in prevalence.

The most common cause of HF in patients aged >65 years is advanced coronary artery disease (CAD). These compromised patients are likely to have comorbidities that may preclude them from being candidates for coronary artery bypass graft (CABG) surgery. As an alternative, the less-invasive but high-risk option of a percutaneous coronary intervention (PCI) can serve this population well, improving quality of life (QOL), reducing major adverse events (AEs), as well as reducing hospital admissions.

For patients with ventricular dysfunction and complex coronary anatomy, the use of an adjunct mechanical device for vascular support during high-risk PCI improves outcomes. The intra-aortic balloon pump (IABP) provides ischemic protection by increasing the diastolic pressure and improves cardiac output by providing af-

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ter-load reduction. The Impella 2.5 is a percutaneous ventricular assist device (pVAD) that reduces the workload of the left ventricle. Although this device lacks the ischemic protection of an IABP, it is much more effective in reducing the left ventricle workload.

The PROTECT II study by Gregory and colleagues is a prospective, multicenter, randomized trial comparing the Impella 2.5 pVAD to the use of an IABP in patients who require high-risk PCI. Historically, the IABP has been the most widely used mechanical support device for the failing left ventricle; however, it only modestly improves hemodynamic parameters. Therefore, the hypothesis of the PROTECT II trial is that the Impella 2.5 system is superior to the IABP in preventing intra- and postprocedural major AEs dur足 ing high-risk PCI. The Impella 2.5 arm of PROTECT II indeed had a 22% relative reduction in major AEs, as well as 56% fewer major AEs after hospital discharge. Repeat revascularizations were also lower by 52% at 90 days. Repeat revascularization impacts readmission rates and patient QOL. Costs were higher in the Impella 2.5 arm during

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Hemodynamic Support Strategies for Patients Undergoing PCI

Stakeholder Perspective Continued the hospital index stay; however, the results showed lower costs for the Impella 2.5 arm over the IABP arm during readmissions through 90 days.

From a payer perspective, this study provides strong evidence to support the use of Impella 2.5–assisted PCI in patients with ventricular dysfunction and complex coronary anatomy who require high-risk, mechanically assisted PCI. The use of this device significantly reduces major AEs, improves quality-adjusted life-years, and is cost-effective. Reductions in repeated revascularizations, readmission costs, and length of stay are particularly important in this era of healthcare reform, in which readmission rates will impact reimbursement. It is equally important to recognize that case selection is critical. The Impella 2.5 pVAD remains an expensive technology, and, like all invasive devices, its use is not without risk.

Furthermore, payers should be wary about overuse.

Using this device in patients who would have had successful PCI outcomes without it is unproductive and wasteful of precious healthcare dollars. Therefore, the patient’s clinical condition and coronary anatomy should clearly support the indication for a pVAD-assisted PCI. Clinical judgment based on defined protocols and best practice observations are paramount. Like all new and expensive technologies, the appropriateness of case selection should be reviewed, and the annual use of each provider and/or institution should be monitored to ensure best practice standards.

PATIENTS: Patients with advanced CAD, impaired ventricular function, and congestive HF are faced with a poor QOL and compromised survival. Despite advances in medical therapy, myocardial revascularization remains the best option for this population of patients. But the pathway to achieve myocardial revascularization remains controversial. As a cardiovascular surgeon, I am particularly aware of the debates regarding best treatment options for patients with 3-vessel CAD and impaired ventricular function, particularly in patients with diabetes.

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For example, the Bypass Angioplasty Revascularization Investigation trial concluded that CABG had better rates of survival than PCI in patients with diabetes.1 More recently, the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial reached a similar conclusion.2 Even beyond diabetes, there are many trials that advocate surgical myocardial revascularization rather than PCI in patients with 3-vessel CAD and impaired ventricular function.

Therefore, the first issue facing this growing population of patients with advanced CAD, ventricular dysfunction, and HF is informed consent. As Dr Mark Hlatky stated recently, “Many PCIs today are ad hoc procedures, performed at the time of diagnostic coronary angiography, with the same physician making the diagnosis, recommending the treatment, and performing the procedure.”3 Therefore, it is important for patients to learn about all available treatment options, including medical therapy and CABG, along with a complete discussion of the benefits and risks of each treatment.

In the select population of patients who have failed medical therapy and who have been identified by an experienced cardiovascular surgeon not to be candidates for CABG, high-risk PCI using an adjunct mechanical device, such as an IABP or the Impella 2.5, is appropriate. The PROTECT II trial supports the conclusion that Impella 2.5–assisted PCI significantly reduces major AEs and is more cost-effective than IABP-assisted PCI. The reductions in repeated revascularizations, readmission costs, and length of stay all impact QOL and provide greater clinical benefit for this high-risk patient population. n 1. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:1761-1769.

2. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367:2375-2384.

3. Hlatky MA. Compelling evidence for coronary-bypass surgery in patients with diabetes. N Engl J Med. 2012;367:2437-2438.

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LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET TAKEN TWICE DAILY FOR ADULT PATIENTS WITH TYPE 2 DIABETES

Improving glycemic control for adult patients with type 2 diabetes

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WARNINGS AND PRECAUTIONS Lactic Acidosis Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

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The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

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Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

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WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

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History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

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Important safety InformatIon

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Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

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JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.

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JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).

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IndIcatIon and Important LImItatIons of Use

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JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

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JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects

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Results are adjusted for a 0.1% mean A1C increase for placebo (n=65).

(n=140)

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Superiority of both free-combination therapies, consisting of the twice-daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24.

Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001).

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Metformin 1000 mg twice daily Baseline A1C 8.5%

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Metformin 500 mg twice daily Baseline A1C 8.7%

JENTADUETO Linagliptin 2.5 mg Metformin 1000 mg twice daily§ Baseline A1C 8.7%

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Linagliptin 5 mg once daily Baseline A1C 8.7%

JENTADUETO Linagliptin 2.5 mg Metformin 500 mg twice daily§ Baseline A1C 8.7%

*A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. Results adjusted for 0.1% mean A1C increase for placebo. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study.

1

significant a1c reductions (placebo-adjusted) at 24 weeks1*†‡

The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

Monitoring of Renal Function Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal.

In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

B:11.25” T:10.5” S:9.75”

Impaired Hepatic Function Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.

Hypoglycemia Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Vitamin B12 Levels Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels.

Monitor hematologic parameters annually.

Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. Hypoxic States Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.

ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.

In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).

Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator).

DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended.

The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase.

USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known.

JENTADUETO should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk.

Metformin is excreted in human milk in low concentrations.

Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established.

JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

JD PROF ISI MAR152012 Reference: 1. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.

Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.

find out more about JentadUeto and the savings card program at www.jentadueto.com Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

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JD384500PROFA

Jentadueto™ (linagliptin and metformin hydrochloride) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as

an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions] • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions] • A history of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]

WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin.

Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a

patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery [see Boxed Warning].

Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin.

Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug.

ADVERSE REACTIONS: 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. Linagliptin/ Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1

Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study Placebo Linagliptin Metformin Combination of n=72 Monotherapy Monotherapy Linagliptin with n=142 n=291 Metformin n=286 n (%) n (%) n (%) n (%)

Nasopharyngitis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.

Linagliptin Monotherapy: Nasopharyngitis was reported in ≥5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglycemia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and ≥1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.

DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations.

Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,

based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Metformin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, 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: Safety and effectiveness of JENTADUETO in pediatric patients have not been established.

Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].

OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.

Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions].

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED January 2012

JD/BS/01-12

JD148400PROF

Industry Trends

The Value of Actionable Content in a Clinical Setting: Access to Better Information

Facilitates Enhanced Cancer Care A. Jacqueline Mitus, MD, and Laura Coughlin, RN

A

ing sophistication of diagnostic tools and chemotherapy regimens requires that providers take into account increasingly more patient-specific information when making clinical decisions.

To provide the best care, health professionals need “actionable content,” namely, information that can automatically prompt the best decisions about care at the point in time when clinical decisions need to be made.

Implicit in this definition is integration of the information into a comprehensive workflow, as well as the ability to utilize information from many different sources by various stakeholders.

Dr Mitus is Senior Vice President, Clinical Content Development and Strategy, and Ms Coughlin is Vice President, InterQual Development and Clinical Strategy at McKesson Health Solutions, Newton, MA.

Actionable Content in Practice What might actionable content look like in practice, and what benefits does it yield in terms of clinical decision-making and administrative efficiency? For example, an oncologist is meeting a 44-year-old premenopausal woman who has been diagnosed in the early stage of triple-negative breast cancer. She has a family history of breast cancer, but she has not undergone genetic testing for a BRCA1 or BRCA2 mutation that would confirm (or reject) a familial predisposition to breast or to ovarian cancer.

A solution-based electronic system that includes clinical and payer guidelines is designed to provide actionable content in this particular set of circumstances would offer clinical guidance regarding the appropriateness of molecular diagnostic testing, as well as a recommendation about which commercially available test is indicated and covered by payers. In addition, the treating physician may be presented with options for chemotherapy regimens that take these factors into account, while considering the latest outcome studies and research available. This solution also could inform the oncologist which treatments the patient’s health insurance plan will cover, and at which facility. It could even alert the oncologist to specific clinical trials from which this patient may benefit.

All of this information would be made available while the oncologist is sitting in the examination room with the patient. This system could also queue up relevant

ll available patient and medical information drives clinical decisions. However, the inability to provide evidence-based medical information when and where it is most useful can compromise efforts to deliver the best care. Payers and providers alike understand the importance of actionable content—namely, information designed to prompt or to suggest an action—but they struggle with how to deploy such information directly into the context of day-to-day patient care.

In the world of oncology specifically, we have more information today than ever before. We have information about various types of cancer at the molecular level, the evolution of many tumors at several stages in different people, diagnostic tests, chemotherapy regimens, and more. In fact, the volume of cancer-related information available today makes it a challenge for anyone to keep up with it. The number of randomized clinical trials (RCTs), for example, is expanding exponentially. “You would have to read 500 RCTs per week in 2008 to cover the published RCTs in PubMed,” noted cancer expert Carl Heneghan in 2010.1 And, according to his research, this problem is only going to grow more acute. “At current rates we can expect to see 50,000 RCTs per year published by 2018-9.”1 In oncology, the American Association for Cancer Research publishes more than 26,000 pages of original research annually in only 6 journals.2 The sheer volume of external information is not the only barrier that providers face in determining a patient’s needs at a given moment in the course of care. The grow-

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information for the treatment facility, register the patient in the oncology care center, schedule visits, and send referrals to the patient’s insurance provider (complete with the appropriate diagnostic and clinical codes), all of which are performed transparently in the background. As soon as the oncologist and the patient discuss the treatment options and agree on the course of action, the oncologist would click “okay” in the electronic system and the workflow system that is supporting the actionable content system would automatically set those procedural wheels in motion.

A Framework for Linking Clinical Concepts to Business Processes Healthcare stakeholders must be able to ingest, synthesize, and use information that is fact-based, comprehensive, and current to make the best decisions and to enact them in a timely manner. This content comes from a variety of sources, including: • Current evidence-based guidelines, published outcome studies, emerging data about new diagnostic and therapeutic interventions (eg, molecular tests and drugs), clinical code sets, and more • Patient-specific data, such as laboratory and other test results that are available in electronic medical records (EMRs) and insurance information • Practice- and facility-specific data, including information about hospitals and research facilities in the area and reimbursement contracts with insurers.

Once the relevant and validated content is identified, the next step is to ensure its availability at the right points in the care continuum, as well as to seamlessly deliver this information into workflows in a way that does not require users to access other systems. These points of care include: • The practitioner at the various points where well-­ informed decisions must be made • The patient when appropriate • Additional care providers as needed • The facilities where procedures will be performed, prescriptions will be filled, and more • The insurance companies that will be covering the cost of procedures and treatments • The internal departments that handle billing and scheduling.

Rules must be applied to information for it to become actionable in medicine. These can be quite simple, such as an automated reminder to the patient and the physician about the need to schedule an annual mammogram, or very complex, such as when clinical specificity is combined with artificial intelligence, or a computational system that can learn and improve on its decision-making over time, to identify oncologic risk factors and rec-

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ommend proactive preventive treatments.

As structured or codified data gradually replace text within EMRs and other healthcare information systems, the power of this information to positively influence decision-making becomes more readily apparent. This advancement makes it possible to efficiently feed multiple, complex data streams from multiple systems to automatically initiate a rule that can then serve up a recommended course of action. Even when structured data are not available, technologies, such as natural language processing, can apply structure to narrative text, thereby minimizing human intervention through the use of rules.3

As payer and provider organizations alike experiment with new care delivery and payment models, the ability to tie clinical concepts to business processes (eg, to use quality metrics as a basis for reimbursement) has become essential.

As payer and provider organizations alike experiment with new care delivery and payment models, the ability to tie clinical concepts to business processes (eg, to use quality metrics as a basis for reimbursement) has become essential. For example, concepts such as “worsening,” “severe,” and “over time” are common parameters that need a specific definition to become actionable, measurable, and to be used as part of a reimbursement model.

Information must appear directly in workflows at various points of care or in “transactions” (eg, authorization, benefit design, and network selection) on demand, with an understanding of the context into which it is being delivered, to become truly actionable.

“Content as a service” is a term we use to refer to the delivery method for providing actionable, rules-based information at any point of care.4 A centralized repository electronic system houses the rules, which are then deployed seamlessly into diverse healthcare workflows via web service calls. This provides multistakeholder alignment around a common set of information, which can result in better decisions, increased efficiency, and shared accountability between payers, providers, and patients, ultimately leading to better patient care.

One such example is the patient care plan. At its most basic, a care plan is a living document designed to guide and to focus the patient and his or her care providers on the ongoing assessment and management of clinical issues. The plan is typically generated using evidence-based assessments to identify a list of problems, goals, and interventions. The consistent delivery of the assessment at the point of care, and the sharing of the results of that

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assessment across multiple settings of care using content as a service, can help to ensure the consistent delivery of high-quality care.

Benefits Across the Healthcare Continuum In terms of its ability to support optimal decision-making among all stakeholders in an oncology setting—from the provider to the patient to the insurer—the value of actionable content cannot be underestimated.

For healthcare providers, high-value, actionable content advances the art and science of care delivery by ensuring that they have access to the best, most current, and most relevant clinical knowledge at the point of patient interaction. Where possible, offloading operational tasks can free clinicians to focus on the delivery of care rather than on the administrative processes that support it.

For insurers (or payers), actionable content can connect all the stakeholders in a way that would be nearly impossible without a significant investment in other resources. Playing a central role in supplying the content, rules, and increasingly automated and intelligent solutions, payers can continue to transform their role from processors of claims to enablers of high-quality, clear, consistent, and transparent care, all while removing the administrative inefficiencies that exist in delivering and in paying for appropriate care.

For patients, actionable content can transform a complicated, disjointed and impersonal healthcare system into one that “knows” their individual clinical needs in context and provides a personalized “healthcare global positioning system” to help patients manage their own care.

When stakeholders are aligned around the same actionable content, healthcare has a powerful tool for optimizing quality, efficiency, and care coordination.

The end result is better clinical and financial outcomes.

Actionable content offers healthcare a powerful tool for driving quality, efficiency, and care coordination. n Author disclosure statement Dr Mitus and Ms Coughlin are employees of McKesson Corporation.

References

1. Heneghan C. How many randomized trials are published each year? March 17, 2010. http://blogs.trusttheevidence.net/carl-heneghan/how-many-randomized-trialsare-published-each-year. Accessed March 25, 2013.

2. http://cancerres.aacrjournals.org/site/misc/InfoforLibrarians.xhtml. Accessed March 25, 2013.

3. Demner-Fushman D, Chapman WW, McDonald CJ. What can natural language processing do for clinical decision support? J Biomed Inform. 2009;42:760-772.

4. Mitus AJ, Silverstein S, Zubiller M, for McKesson Health Solutions. Actionable content: a framework for better decision-making. 2012. http://betterhealth.mckesson. com/2012/07/actionable-content-a-framework-for-better-decision-making/. Accessed March 25, 2013.

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American Health & Drug Benefits® Topics include:

• Interviews with payers and dermatologists • American Academy of Dermatology highlights • Unmet needs in rosacea • Review of currently approved and future therapies AHDB_PPD40513

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. 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 • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. 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 • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

WARNINGS WARNINGS ANDAND PRECAUTIONS PRECAUTIONS (continued) (continued) Dizziness Dizziness and and Confusional Confusional State: State: 18%18% of patients of patients experienced experienced dizziness dizziness and 12% and 12% of patients of patients experienced experienced a confusional a confusional state; state;

1% of1%patients of patients experienced experienced gradegrade 3/4 dizziness, 3/4 dizziness, and 3% andof3%patients of patients experienced experienced gradegrade 3/4 confusional 3/4 confusional state. state.

Instruct Instruct patients patients to avoid to avoid situations situations where where dizziness dizziness or confusion or confusion may may be a be problem a problem and not andto nottake to take otherother medications medications that that may may causecause dizziness dizziness or confusion or confusion without without adequate adequate medical medical advice. advice.

Neuropathy: Neuropathy: 18%18% of patients of patients experienced experienced neuropathy neuropathy (approximately (approximately 9% peripheral 9% peripheral neuropathy). neuropathy).

ThereThere werewere no cases no cases of grade of grade 3 or higher 3 or higher neuropathy neuropathy adverse adverse reactions reactions reported. reported.

RiskRisk of Second of Second Primary Primary Malignancies: Malignancies: CasesCases of acute of acute myelogenous myelogenous leukemia leukemia havehave beenbeen reported reported in patients in patients receiving receiving POMALYST POMALYST as anasinvestigational an investigational therapy therapy outside outside of multiple of multiple myeloma. myeloma.

ADVERSE ADVERSE REACTIONS REACTIONS In the Inclinical the clinical trial trial of 219 of patients 219 patients who who received received POMALYST POMALYST alonealone (n=107) (n=107) or POMALYST or POMALYST + low-dose + low-dose dexamethasone dexamethasone (low-dose (low-dose dex)dex) (n=112), (n=112), all patients all patients had at hadleast at least one treatment-emergent one treatment-emergent adverse adverse reaction. reaction.

• In •the InPOMALYST the POMALYST alonealone versus versus POMALYST POMALYST + low+ dose low dose dexamethasone dexamethasone arms,arms, respectively, respectively, mostmost common common adverse adverse reactions reactions (≥30%) (≥30%) included included fatigue fatigue and asthenia and asthenia (55%, (55%, 63%), 63%), neutropenia neutropenia (52%, (52%, 47%),47%), anemia anemia (38%, (38%, 39%), 39%), constipation constipation (36%, (36%, 35%),35%), nausea nausea (36%, (36%, 22%), 22%), diarrhea diarrhea (34%, (34%, 33%), 33%), dyspnea dyspnea (34%, (34%, 45%),45%), upperupper respiratory respiratory tracttract infection infection (32%, (32%, 25%), 25%), backback painpain (32%, (32%, 30%), 30%), and pyrexia and pyrexia (19%, (19%, 30%)30%) • 90% • 90% of patients of patients treated treated withwith POMALYST POMALYST alonealone and 88% and 88% of patients of patients treated treated withwith POMALYST POMALYST + low-dose + low-dose dex had dex at hadleast at least one one treatment-emergent treatment-emergent NCI CTC NCI Grade CTC Grade 3 or 43 adverse or 4 adverse reaction reaction • In •the InPOMALYST the POMALYST alonealone versus versus POMALYST POMALYST + low+ dose low dose dexamethasone dexamethasone arms,arms, respectively, respectively, mostmost common common GradeGrade 3/4 adverse 3/4 adverse reactions reactions (≥15%) (≥15%) included included neutropenia neutropenia (47%, (47%, 38%), 38%), anemia anemia (22%, (22%, 21%),21%), thrombocytopenia thrombocytopenia (22%, (22%, 19%), 19%), and pneumonia and pneumonia (16%,(16%, 23%).23%).

For other For other GradeGrade 3 or 43 toxicities or 4 toxicities besides besides neutropenia neutropenia and thrombocytopenia, and thrombocytopenia, holdhold treatment treatment and restart and restart treatment treatment at at 1 mg1less mg than less than the previous the previous dosedose whenwhen toxicity toxicity has resolved has resolved to less to than less than or equal or equal to Grade to Grade 2 at the 2 atphysician’s the physician’s discretion discretion • 67% • 67% of patients of patients treated treated withwith POMALYST POMALYST and 62% and 62% of patients of patients treated treated withwith POMALYST POMALYST + low-dose + low-dose dex had dex at hadleast at least one one treatment-emergent treatment-emergent serious serious adverse adverse reaction reaction • In •the InPOMALYST the POMALYST alonealone versus versus POMALYST POMALYST + low+ dose low dose dexamethasone dexamethasone arms,arms, respectively, respectively, mostmost common common serious serious adverse adverse reactions reactions (≥5%) (≥5%) werewere pneumonia pneumonia (14%, (14%, 19%), 19%), renalrenal failure failure (8%,(8%, 6%),6%), dyspnea dyspnea (5%,(5%, 6%),6%), sepsis sepsis (6%,(6%, 3%),3%), pyrexia pyrexia (3%,(3%, 5%) 5%) dehydration dehydration (5%,(5%, 3%),3%), hypercalcemia hypercalcemia (5%,(5%, 2%),2%), urinary urinary tracttract infection infection (0%,(0%, 5%),5%), and febrile and febrile neutropenia neutropenia (5%,(5%, 1%) 1%)

DRUG DRUG INTERACTIONS INTERACTIONS No formal No formal drugdrug interaction interaction studies studies havehave beenbeen conducted conducted withwith POMALYST. POMALYST. Pomalidomide Pomalidomide is primarily is primarily metabolized metabolized

by CYP1A2

by CYP1A2 and and CYP3A. CYP3A. Pomalidomide Pomalidomide is also is also a substrate a substrate for P-glycoprotein for P-glycoprotein (P-gp).

(P-gp).

Coadministration Coadministration of POMALYST of POMALYST withwith drugsdrugs that that are strong are strong inhibitors inhibitors or inducers or inducers of CYP1A2, of CYP1A2, CYP3A, CYP3A, or P-gp or P-gp should should be avoided. be avoided.

Cigarette Cigarette smoking smoking may may reduce reduce pomalidomide pomalidomide exposure exposure due due to CYP1A2 to CYP1A2 induction. induction.

Patients Patients should should be advised be advised that that smoking smoking may may reduce reduce the effi thecacy efficacy of pomalidomide. of pomalidomide.

USEUSE IN SPECIFIC IN SPECIFIC POPULATIONS POPULATIONS Pregnancy: Pregnancy: If pregnancy If pregnancy doesdoes occuroccur during during treatment, treatment, immediately immediately discontinue discontinue the drug the drug and refer and refer patient patient to antoobstetrician/ an obstetrician/

gynecologist gynecologist experienced experienced in reproductive in reproductive toxicity toxicity for further for further evaluation evaluation and counseling. and counseling.

Report Report any suspected any suspected fetalfetal exposure exposure to POMALYST to POMALYST to the toFDA the via FDAthe viaMedWatch the MedWatch program program at 1-800-332-1088 at 1-800-332-1088 and also and also to Celgene to Celgene Corporation Corporation at 1-888-423-5436. at 1-888-423-5436.

Nursing Nursing Mothers: Mothers: It is not It isknown not known if pomalidomide if pomalidomide is excreted is excreted in human in human milk.milk.

Pomalidomide Pomalidomide was excreted was excreted in the inmilk the milk of of lactating lactating rats.rats.

Because Because manymany drugsdrugs are excreted are excreted in human in human milk milk and because and because of the ofpotential the potential for adverse for adverse reactions reactions in nursing in nursing infants infants fromfrom POMALYST, POMALYST, a decision a decision should should be made be made whether whether to discontinue to discontinue nursing nursing or toordiscontinue to discontinue the drug, the drug, taking taking into into account account the importance the importance of the ofdrug the drug to the tomother. the mother.

Pediatric Pediatric Use:Use: Safety Safety and effectiveness and effectiveness of POMALYST of POMALYST in patients in patients under under the age the of age18ofhave 18 have not been not been established. established.

Geriatric Geriatric Use:Use: No dosage No dosage adjustment adjustment is required is required for POMALYST for POMALYST based based on age. on age.

Patients Patients greater greater thanthan or equal or equal to 65toyears 65 years of age of age werewere moremore likelylikely thanthan patients patients less than less than or equal or equal to 65toyears 65 years of age of to ageexperience to experience pneumonia. pneumonia.

Renal Renal and and Hepatic Hepatic Impairment: Impairment: Pomalidomide Pomalidomide is metabolized is metabolized in the inliver. the liver.

Pomalidomide Pomalidomide and its andmetabolites its metabolites are primarily are primarily excreted excreted by the bykidneys. the kidneys.

The infl Theuence influence of renal of renal and hepatic and hepatic impairment impairment on the onsafety, the safety, efficacy, efficacy, and pharmacokinetics and pharmacokinetics of of pomalidomide pomalidomide has not hasbeen not been evaluated. evaluated.

AvoidAvoid POMALYST POMALYST in patients in patients withwith a serum a serum creatinine creatinine >3.0>3.0 mg/dL. mg/dL. AvoidAvoid POMALYST POMALYST in in patients patients withwith serum serum bilirubin bilirubin >2.0>2.0 mg/dL mg/dL and AST/ALT and AST/ALT >3.0>3.0 x ULN. x ULN. Please Please see full see Prescribing full Prescribing Information, Information, including including Boxed Boxed WARNINGS, WARNINGS, CONTRAINDICATIONS, CONTRAINDICATIONS, WARNINGS WARNINGS ANDAND PRECAUTIONS, PRECAUTIONS, and and ADVERSE ADVERSE REACTIONS. REACTIONS. POMALYST® POMALYST® is a registered is a registered trademark trademark of Celgene of Celgene Corporation.

Corporation.

POMALYST POMALYST REMS™ REMS™ is a trademark is a trademark of Celgene of Celgene Corporation.

Corporation. ©2013 ©2013 Celgene Celgene Corporation Corporation 02/1302/13 US-POM120044 US-POM120044

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This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily.

500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements.

Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported.

5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

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2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis.

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.

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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 practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

(continued)

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

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Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea

n (%)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders

General disorders and administration site conditions

Cardiac Disorders

(continued)

Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).

7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided.

Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and Cosmos Communications

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diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy.

Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)].

The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over.

No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

Call for Papers Cancer Care Theme Issue American Health & Drug Benefits will be publishing a theme issue on cancer care in July 2013

The growing focus on targeted therapies and diagnostics, and the ever-increasing cost of cancer care, require a thorough examination of current and emerging trends in oncology, focusing on benefit design, utilization, and health outcomes.

Readers are invited to submit manuscripts for this issue, including original research, cost-effective analyses, evidence-based comprehensive reviews, case studies, and industry surveys/trends.

All articles will undergo the journal’s rigorous peer-review process. Manuscripts must follow the format described in the Information for Authors (available at www.AHDBonline.com).

Areas of particular interest include: ➤ Benefit ➤ Best

care and health disparities

considerations in cancer care

➤ Emerging

trends in hematology/oncology

➤ End-of-life ➤ Health

➤ Managing ➤ Patient

practices in oncology

➤ Cancer ➤ Cost

design for cancer therapies

navigation initiatives

➤ Pathways

plan initiatives in oncology

and practice guidelines

➤ Personalized ➤ Survivorship ➤ Targeted

issues

toxicities of cancer therapies

medicine in oncology programs

cancer therapies

➤ Value-based

cancer care

Submission deadline extended to May 20, 2013 Articles should follow the Manuscript Instructions for Authors at www.AHDBonline.com.

Submit articles to editorial@engagehc.com. For more information, call 732-992-1889.

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JOIN AHDBâ&#x20AC;&#x2C6;Peer Review American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other healthcare experts who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal.

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewersâ&#x20AC;&#x2122; names will be published online at the end of the year.

Please indicate at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted to AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to) those listed below.

Please mark the categories that apply to your expertise: Administration/management Benefit design Disease management/state (eg, asthma, diabetes, heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@engagehc.com Your Information _______________________________________________________________________________________ First Name

Last Name

Credentials

_______________________________________________________________________________________ Title Company _______________________________________________________________________________________ Address _______________________________________________________________________________________ E-mail Phone Vol 6, No 2

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Industry Trends

Investing in Information Technology Pays Off: Meaningful Use Stage 1 Met by

Majority of US Hospitals

By Caroline Helwick

A

ccording to a new Health Information and Management Systems Society (HIMSS) Leadership Survey (http://himss.files.cms-plus.com/HIMSS org/Content/files/leadership_FINAL_REPORT_ 022813.pdf), which was released at the 2013 HIMSS annual conference, the government’s efforts to impact provider investments in information technology (IT) to qualify for Meaningful Use and International Classification of Diseases, Tenth Revision (ICD-10) conversions are paying off.

“We found this year that healthcare organizations are making strong progress towards federal mandates,” said Jennifer Horowitz, CPHIMS, FHIMSS, Senior Director of Research for HIMSS Analytics. “It seems we have reached a tipping point.”

This annual survey covers a range of topics crucial to health IT. The survey included 298 respondents, primarily senior IT executives, who represented almost 600 hospitals in the United States. Data were collected via a web-based survey from December 2012 to February 2013.

The survey results showed that 66% of those leading health organizations, mostly hospitals, have already qualified for Meaningful Use Stage 1, and 75% expect to qualify for Stage 2 in 2014. ICD-10 conversion is expected to be completed on time by 87% of respondents.

Other key results from the survey included: • 51% of respondents reported that their organization participates in at least 1 health information exchange in their area • 47% indicated that implementing Current Procedural Terminology-10/ICD-10 continues to be the top focus for their financial IT systems • Most respondents noted that IT can impact patient care by improving clinical and quality outcomes, reducing medical errors, or helping to standardize care by the use of evidence-based medicine • 22% noted that a focus on security systems was their current key infrastructure priority • 19% reported a security breach in the past year; the current concerns largely pertain to ensuring that information delivered on mobile devices is secure.

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Level of Investment Only 5% of organizations made no investment in Meaningful Use Stage 1 last year; 17% invested between $1 million and $2 million, 11% invested $3 million to $4 million, 6% invested between $5 million and $9 million, and 5% invested ≥$20 million.

The expected return on this investment was less than $2 million for 30% of respondents, whereas 23% expected a return of $2 million to $3 million and 16% expected to see a return of $4 million to $5 million.

Of note, 7% of respondents expected a return on investment of at least $10 million. For Meaningful Use Stage 2, the majority (38%) of the respondents in the survey expected to see less than a $2-million return on investment.

Almost 50% of the respondents said that the primary financial IT focus is on implementing ICD-10, which is due by October 2014. Of the respondents, 20% planned to invest less than $250,000 for this purpose, but 33% did not know how much this effort would cost. In addition, 15% of the respondents planned to devote funds to upgrading their financial analytics systems.

A definite increase in IT budgets was predicted by 47% of respondents, and a probable increase by 29%, primarily owing to the overall growth in IT systems and the need for additional staff.

Lingering Cost Concerns Survey respondents continue to express concerns about IT staffing shortages, vis-à-vis the growing role of IT in healthcare. Approximately 50% of the respondents plan to increase their IT staff over the next year, but 21% were concerned that their IT objectives could not be sufficiently met because of a lack of staff. The greatest staffing need was in the area of clinical application support, which was indicated by 33% of respondents.

A lack of adequate financial support was a potential barrier for 15% of respondents, and 13% worried that the vendor would be unable to deliver the product. Difficulty in end-user acceptance, however, was rarely a concern, as was difficulty proving return on investment as this concept matures, which were expressed by only 7% and 4% of users, respectively. n

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Vol 6, No 2

Sometimes one simple idea changes everything Introducing

BD Simplist

TM

A LINE OF READY-TO-ADMINISTER PREFILLED INJECTABLES FROM ONE TRUSTED SOURCE

Prefilled injectables designed with high safety standards in mind: Yours

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路 Reduce potential for medication error with up to 8 fewer steps than injections with a vial and syringe 路 Individually packaged, clearly labeled and barcoded for easy identification 路 High demand pharmaceuticals supplied from our new, state-of-the-art pharmaceutical plant

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For more information on the BD Simplist product line, visit www.bdsimplist.com NOW AVAILABLE in Diphenhydramine Hydrochloride Injection, USP 50 mg/mL (NDC 76045-102-10) Order from your drug wholesaler today.

INDICATIONS Diphenhydramine Hydrochloride Injection, USP is effective in adults and pediatric patients, other than premature infants and neonates, when diphenhydramine hydrochloride in the oral form is impractical.

For amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated. For active treatment of motion sickness and for use in parkinsonism, when oral therapy is impossible or contraindicated in the elderly who are unable to tolerate more potent agents, mild cases of parkinsonism in other age groups and in other cases of parkinsonism in combination with centrally acting anticholinergic agents.

IMPORTANT SAFETY INFORMATION Diphenhydramine hydrochloride is contraindicated in neonates, premature infants and as antihistamine therapy in nursing mothers and as a local anesthetic and when a patient is hypersensitive to other antihistamines of similar chemical structure.

Considerable caution should be used in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction.

Local necrosis has been associated with the use of subcutaneous or intradermal use of the drug. It has an atropine-like action and, therefore should be used with caution in patients with a history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease or hypertension and in patients with lower respiratory disease including asthma.

It has additive effects with alcohol and other CNS depressants. MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines.

The most frequent adverse reactions are: Nervous System: sedation, sleepiness, dizziness, disturbed coordination; GI System: epigastric distress; and Respiratory System: thickening of bronchial secretions.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see Brief Summary for additional Important Safety Information on following page.

1. Data on File, BD Rx. 2. Potter P, Perry A, Stockert P, Hall A. Vial & Syringe Injection Steps. Basic Nursing. 7th ed. (St. Louis, MO: Mosby, 2010), 442-447.

3. Diphenhydramine Hydrochloride Injection, USP Prescribing Information. Franklin Lakes, NJ: BD Rx Inc.; 12/2012.

BD, BD Rx Logo and BD Simplist are trademarks of Becton, Dickinson and Company. 漏2013 BD. BDRx0057b

BD Rx Inc. 1 Becton Drive Franklin Lakes, NJ 07417 www.bdrxinc.com

DIPHENHYDRAMINE HYDROCHLORIDE INJECTION, USP Rx Only This is a Brief Summary of the full prescribing information about Diphenhydramine Hydrochloride Injection, USP. INDICATIONS AND USAGE Diphenhydramine hydrochloride in the injectable form is effective in adults and pediatric patients, other than premature infants and neonates, for the following conditions when diphenhydramine hydrochloride in the oral form is impractical.

Antihistaminic: For amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated.

Motion Sickness: For active treatment of motion sickness.

Antiparkinsonism: For use in parkinsonism, when oral therapy is impossible or contraindicated as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups and in other cases of parkinsonism in combination with centrally acting anticholinergic agents.

CONTRAINDICATIONS Use in Neonates or Premature Infants: This drug should not be used in neonates or premature infants.

Use in Nursing Mothers: Because of the higher risk of antihistamines for infants generally, and for neonates and prematures in particular, antihistamine therapy is contraindicated in nursing mothers.

Use as a Local Anesthetic: Because of the risk of local necrosis, this drug should not be used as a local anesthetic.

Antihistamines are also contraindicated in the following conditions: Hypersensitivity to diphenhydramine hydrochloride and other antihistamines of similar chemical structure.

WARNINGS Antihistamines should be used with considerable caution in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction.

Local necrosis has been associated with the use of subcutaneous or intradermal use of intravenous diphenhydramine.

Use in Pediatric Patients: In pediatric patients, especially, antihistamines in overdosage may cause hallucinations, convulsions or death.

As in adults, antihistamines may diminish mental alertness in pediatric patients. In the young pediatric patient, particularly, they may produce excitation.

Use in the Elderly (approximately 60 years or older): Antihistamines are more likely to cause dizziness, sedation and hypotension in elderly patients.

PRECAUTIONS General: Diphenhydramine hydrochloride has an atropine-like action and, therefore should be used with caution in patients with a history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease or hypertension. Use with caution in patients with lower respiratory disease including asthma.

Information for Patients: Patients taking diphenhydramine hydrochloride should be advised that this drug may cause drowsiness and has an additive effect with alcohol.

Patients should be warned about engaging in activities requiring mental alertness such as driving a car or operating appliances, machinery, etc.

Drug Interactions: Diphenhydramine hydrochloride has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc).

MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to determine mutagenic and carcinogenic potential have not been performed.

Pregnancy: Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 5 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to diphenhydramine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatric Use: Diphenhydramine should not be used in neonates and premature infants (see CONTRAINDICATIONS).

Diphenhydramine may diminish mental alertness, or in the young pediatric patient, cause excitation. Overdosage may cause hallucinations, convulsions or death (see WARNINGS and OVERDOSAGE).

See also DOSAGE AND ADMINISTRATION section.

ADVERSE REACTIONS The most frequent adverse reactions are underscored: 1. General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of mouth, nose and throat.

2. Cardiovascular System: Hypotension, headache, palpitations, tachycardia, extrasystoles.

3. Hematologic System: Hemolytic anemia, thrombocytopenia, agranulocytosis.

4. Nervous System: Sedation, sleepiness, dizziness, disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, neuritis, convulsions.

5. GI System: Epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation.

6. GU System: Urinary frequency, difficult urination, urinary retention, early menses.

7. Respiratory System: Thickening of bronchial secretions, tightness of chest or throat and wheezing, nasal stuffiness.

OVERDOSAGE Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in pediatric patients. Atropine-like signs and symptoms; dry mouth; fixed, dilated pupils; flushing and gastrointestinal symptoms may also occur.

Stimulants should not be used.

Vasopressors may be used to treat hypotension.

For more information concerning this drug or to report an adverse event please call BD Rx Inc., at 1-866-943-8534.

For the full prescribing information, visit www.BDRxInc.com Rev 12/12

BD Simplist

â&#x201E;˘

BD, BD Rx Logo and BD Simplist are trademarks of Becton, Dickinson and Company. Š 2013 BD BDRx0054

BD Rx Inc. Franklin Lakes, NJ 07417

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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—Distributors, Employers, Manufacturers, Patients, Payers, 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, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Health Information Exchange • Health Plan Initiatives • Health Outcomes • Innovations in Healthcare • Literature Reviews • Managed Care • Medicare/Medicaid • Patient Outcomes

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

• Pharmacoeconomics • Pharmacogenomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Social Media and Health • Survey Results • Value-Based Healthcare

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

Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

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S E I G R E L L A D FOO * IN CHILDREN HAVE

INCREASED BY

18% 1

Take a closer look at who should carry an EpiPen® (epinephrine) Auto-Injector As food allergies rise, the risk of anaphylaxis may also increase.1-3 Which is why it’s important to identify patients at risk for anaphylaxis and help them create an action plan: avoid the allergen first, and always carry an EpiPen 2-Pak®.3 For more than 20 years, EpiPen has been the #1 prescribed epinephrine auto-injector,4† with over 41 million units dispensed.5‡ There is no FDA-approved therapeutic equivalent.6 Indications EpiPen® (epinephrine) 0.3 mg and EpiPen Jr® (epinephrine) 0.15 mg Auto-Injectors are indicated in the emergency treatment of type 1 allergic reactions, including anaphylaxis, to allergens, idiopathic and exercise-induced anaphylaxis, and in patients with a history or increased risk of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to body weight.

Important Safety Information EpiPen Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK, OR INTRAVENOUSLY.

underlying cardiac disease or taking cardiac glycosides or diuretics. Patients with certain medical conditions or who take certain medications for allergies, depression, thyroid disorders, diabetes, and hypertension, may be at greater risk for adverse reactions. Other adverse reactions include transient moderate anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties.

EpiPen and EpiPen Jr Auto-Injectors are intended for immediate self-administration as emergency supportive Epinephrine should be used with caution in patients with therapy only and are not intended as a substitute for certain heart diseases, and in patients who are on drugs immediate medical or hospital care. that may sensitize the heart to arrhythmias, because it You are encouraged to report negative side effects may precipitate or aggravate angina pectoris and produce of prescription drugs to the FDA. Visit www.fda.gov/ ventricular arrhythmias. Arrhythmias, including fatal medwatch, or call 1-800-FDA-1088. ventricular fibrillation, have been reported in patients with Please see Brief Summary of the full Prescribing Information on the adjacent page. * Reported prevalence from 1997 through 2007. † As of December 2011. ‡ Since 1990.

References: 1. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549-1555. 2. Simons FER. Anaphylaxis. J Allergy Clin Immunol.

2010;125(suppl 2):S161-S181. 3. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel. J Allergy Clin Immunol. 2010;126(6):S1-S58. 4. Data on file. Mylan Specialty L.P. 5. Data on file. Mylan Specialty L.P. IMS data as of June 2012. 6. U.S. Department of Health and Human Services Food and Drug Administration. Approved Drug Products With Therapeutic Equivalence Evaluations. 32nd ed. Washington, DC: U.S. Department of Health and Human Services; 2012.

epipen.com

EpiPen®, EpiPen Jr®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned subsidiary, Mylan Specialty L.P. © 2012 Mylan Specialty L.P. All rights reserved. 9/12 EPI12-1046/EPI500320-01

EpiPen® 0.3 mg EPINEPHRINE AUTO-INJECTOR EpiPen Jr® 0.15 mg EPINEPHRINE AUTO-INJECTOR BRIEF SUMMARY. See package insert for full Prescribing Information.

DO NOT REMOVE ACTIVATION CAP UNTIL READY FOR USE. THIS UNIT CONTAINS NO LATEX. INDICATIONS AND USAGE: EpiPen and EpiPen Jr Auto-Injectors are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate administration in patients, who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (See DOSAGE AND ADMINISTRATION section of the full Prescribing Information).

Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema.

EpiPen and EpiPen Jr Auto-Injectors are intended for immediate selfadministration as emergency supportive therapy only and are not a substitute for immediate medical care.

CONTRAINDICATIONS: There are no absolute contraindications to the use of epinephrine in a life-threatening situation.

WARNINGS: EpiPen and EpiPen Jr Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK. Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis.

Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis. (see ADVERSE REACTIONS). Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection.

DO NOT INJECT INTRAVENOUSLY. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration.

Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergictype reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive.

Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in

patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias.

It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, lifethreatening situation.

Epinephrine is light sensitive and should be stored in the carrier tube provided. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (See USP Controlled Room Temperature). Do not refrigerate. Protect from light. Before using, check to make sure the solution in the auto-injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate.

PRECAUTIONS: (1) General EpiPen and EpiPen Jr Auto-Injectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision.

Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens as well as idiopathic and exercise-induced anaphylaxis should be carefully instructed about the circumstances under which epinephrine should be used.

It must be clearly determined that the patient is at risk of future anaphylaxis, since the following risks may be associated with epinephrine administration (see DOSAGE and ADMINISTRATION section of the full Prescribing Information).

Epinephrine should be used with caution in patients who have cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, quinidine, or other anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias.

The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors.

Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include: hyperthyroid individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using EpiPen Auto-Injector, and pediatric patients under 15 kg (33 lbs.) body weight using EpiPen Jr Auto-Injector.

Despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen or EpiPen Jr Auto-Injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used.

(2) Information for Patients Complete patient information, including dosage, direction for proper administration and precautions can be found inside each EpiPen/ EpiPen Jr Auto-Injector carton.

Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms.

In case of accidental injection, the patient should be advised to immediately go to the emergency room for treatment. Since the epinephrine in the EpiPen Auto-Injector is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an inadvertent administration to these areas. (see ADVERSE REACTIONS).

(3) Drug Interactions The carrier tube is not waterproof.

The blue safety release helps prevent accidental injection and should be kept on until it will be used.

Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias.

The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine and diphenhydramine.

The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as propranolol.

The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentoloamine. Ergot alkaloids may also reverse the pressor effects of epinephrine.

(4) Carcinogenesis, Mutagenesis, Impairment of Fertility Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay. Epinephrine had a moderate degree of mutagenicity, and was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay.

Studies of epinephrine after repeated exposure in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE. (5) Usage in Pregnancy Pregnancy Category C: There is no study on the acute effect of epinephrine on pregnancy. Epinephrine has been shown to have developmental effects when administered subcutaneously in rabbits at a dose of 1.2 mg/kg daily for two to three days (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg daily for 10 days (approximately 7 times the maximum daily subcutaneous or intramuscular dose on a mg/m2 basis) and in hamsters at a subcutaneous dose of 0.5 mg/kg daily for 4 days (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg daily for 10 days (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although, there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known if epinephrine passes into breast milk.

ADVERSE REACTIONS: Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs [see PRECAUTIONS, Drug Interactions]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life-threatening allergic reaction.

Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury.

OVERDOSAGE: Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive.

If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measure, it may be necessary to administer another pressor drug.

Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients.

(Epinephrine) Auto-Injectors

Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support.

Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-blocking drug such as propranolol.

(Epinephrine) Auto-Injectors

Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Suitable corrective measures must be taken in such situations.

Rx only.

MANUFACTURED FOR Mylan Specialty L.P., Basking Ridge, NJ 07920, USA by Meridian Medical Technologies, Inc., Columbia, MD 21046, USA, a Pfizer company.

EpiPen®, EpiPen Jr ®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L.P. of Basking Ridge, NJ 07920, USA. © 2012 Mylan Specialty L.P. All rights reserved.

03-500-04C August 2012

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Ted Okon; John D. Sprandio, MD

TARGET AUDIENCE

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

LEARNING OBJECTIVES

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

SATURDAY, MAY 4, 2013 7:00 am - 8:00 am

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

Simultaneous Symposia/Product Theaters

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

www.regonline.com/avbcc2013

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

*Agenda is subject to change.

AVBCCAsize20413

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer CareTM, is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care. Each supplement will explore a specific topic to be considered when developing value-based strategies.

IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013

Â&#x2122;

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation.

Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies.

Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care , is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-ef

topic to be considered when developing value-based

newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5

By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6

By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

www.valuebasedcancer.com/myeloma AVBCC100Asize21213

CLINICAL CLINICAL

Original Research

Effectiveness and Costs of TNF-Alpha Blocker Use for Patients with Rheumatoid Arthritis Kavita Nair, PhD; Vahram Ghushchyan, PhD; Ahmad Naim, MD

Kavita Nair

Stakeholder Perspective, page 136

Am Health Drug Benefits.

2013;6(2):126-136 www.AHDBonline.com Disclosures are at end of text

Background: Rheumatoid arthritis (RA) is ranked among the highest of all chronic diseases in terms of its adverse impact on health-related quality of life, limitations in physical function, increased pain and fatigue, and diminished work performance and attendance compared with other debilitating chronic conditions.

Objective: To compare healthcare expenditures, utilization, and productivity-related outcomes for patients with RA using tumor necrosis factor (TNF)-alpha blockers compared with patients with mild, moderate, or severe RA who are not using these medications.

Design and Methods: Patients with RA were identified from the 1998-2007 Medical Expen足 d足iture Panel Survey database, using International Classification of Diseases, Ninth Revision, Clinical Modification codes (714.xx); the patients were classified as (1) TNF-alpha blocker users, identified on the basis of pharmacy or intravenous therapy utilization, or (2) TNF-alpha blocker nonusers (but could be using other RA-related medications). Patients who were not using TNF-alpha blockers were subclassified as having mild, moderate, or severe RA; nonusers were not subclassified by disease severity. An algorithm was created for this study that combined and ranked 5 patient-reported health-related outcomes used to classify RA severity in the TNF-alpha blocker nonusers group. The main outcome measures included healthcare expenditures, medical service utilization, and work-related productivity for patients with RA. Results: A total of 1152 patients were included in this study. TNF-alpha blocker users (N = 65) were found to have lower odds of being unemployed compared with nonusers who had moderate (N = 159) or severe (N = 208) RA, using patients with mild RA as the reference group (N = 720; P <.01 for both comparisons). Only significant results were included in this study. There were no differences between patients with mild RA who were TNF-alpha blocker users versus nonusers with regard to all-cause emergency department visits, hospitalizations, and average length of hospital stay. The medical, prescription, and total healthcare costs were higher for TNF-alpha blocker users than for patients with mild RA who did not use these agents. Patients with moderate or severe RA who did not use TNF-alpha blockers also had higher incremental annual medical expenditures ($1088 and $1640, respectively) than nonusers with mild RA; these incremental cost differences were lower than the difference in users of TNF-alpha blockers ($2096).

Conclusions: Based on this study, the use of TNF-alpha blocker treatment had a positive impact on employment status and was associated with fewer hospitalizations compared with other RA medications and compared with patients who did not use TNF-alpha blockers in patients with moderate or severe RA. The determination of RA severity may be biased, because it was based on patient self-reports and not on provider assessments; however, self-reporting is a common, validated method of assessing RA severity.

Dr Nair is Associate Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Pharmaceutical Outcomes Research, University of Colorado Anschutz Medical Campus; Dr Ghushchyan is Assistant Research Professor, Center for Pharmaceutical Outcomes Research, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus; Dr Naim is Associate Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, Johnson & Johnson, Horsham, PA, and Adjunct Assistant Professor of Quality Assurance/Regulatory Affairs, School of Pharmacy, Temple University, Philadelphia, PA.

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March/April 2013

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Effectiveness and Costs of TNF-Alpha Blockers

R

heumatoid arthritis (RA) is a chronic autoimmune disease that causes pain, stiffness, swelling, and loss of function in the joints; it occurs when the patient’s immune system attacks healthy tissue. RA is ranked among the highest of all chronic diseases for its adverse impact on health-related quality of life (QOL), limitations in physical function, increased pain and fatigue, and diminished work performance and attendance.1 Roughly 1.3 million adults in the United States have RA, representing approximately 1% of the population.2,3 Worldwide, approximately 0.5% of the adult population is affected by RA.3 Without optimal treatment, approximately 30% of patients with RA become permanently work disabled within 2 to 3 years of diagnosis.4 Predictors of poor outcomes in the initial stages of RA include a relatively low functional score early in the disease progression, lower socioeconomic status, lower education level, strong family history of the disease, and early involvement of multiple joints.4 The 2008 American College of Rheumatology (ACR) recommendation for first-line pharmacologic treatment of RA is the use of nonbiologic disease-modifying antirheumatic drugs (DMARDs), which have been found to slow the progression of joint destruction when used over the long-term.5 If patients fail to respond to nonbiologic DMARDs, the ACR’s current recommendation is to administer biologic DMARDs, or tumor necrosis factor (TNF)-alpha blockers, to patients with moderate disease activity and poor prognosis, as well as to patients with high disease activity and to patients with RA of intermediate or long duration.5 TNF-alpha blockers target specific components of the immune system, instead of broadly affecting many areas of the immune system, and they intercept TNF in the joints, potentially eliciting rapid improvement of symptoms. These medications are frequently used along with other medications for the treatment of RA. Adalimumab, etanercept, and infliximab are the primary biologic drugs (and TNF-alpha blockers) recommended in the 2008 ACR guidelines.

Aggressive RA treatment with TNF-alpha blockers has been shown to help prevent long-term disability from RA, to improve QOL, and to decrease fatigue, even among patients with mild RA.6-8 The safety and effectiveness of TNF-alpha blockers for the treatment of RA are monitored through the examination of various observational cohorts and registries that have been created to complement information obtained from randomized controlled trials.9 Drug resistance and high cost are major concerns associated with the use of TNF-alpha blocker medications.10 The severity of RA can vary; it is therefore important to classify disease severity (which is assessed in several ways) to help monitor the progression of the disease and

Vol 6, No 2

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Key Points Rheumatoid arthritis (RA) is among the highest of chronic diseases in adverse impact on a patient’s quality of life, physical function, and work performance/attendance. ➤ This study compared patients with RA who used TNF-alpha blockers and those who did not use these agents to evaluate the impact on physical functioning and healthcare utilization to consider the impact of these agents on disease activity. ➤ This is the first study to link the use of TNF-alpha blockers to patient-reported outcomes. ➤ TNF-alpha blocker users had lower odds of being unemployed compared with nonusers who had moderate or severe RA. This difference was not found among patients with mild RA who did not use these medications. ➤ The total healthcare costs were higher for TNFalpha blocker users than for patients with mild RA who did not use these agents. However, patients with severe RA who did not use these medications had more emergency department visits and hospitalizations and longer hospital stays than users of these high-cost drugs. ➤

to assess the effectiveness of medications and interventions that are designed to treat the disease.11 Accepted methods for determining RA severity are based on the 2010 ACR standards and involve clinical assessment (ie, history, physical examination), laboratory tests (eg, erythrocyte sedimentation rate), and imaging procedures (eg, x-rays, magnetic resonance imaging).12 Because the presentation of RA affects many components of a patient’s functioning, such as physical, functional, and emotional burdens, no single measure can reliably capture disease activity in all patients. One approach used to address this limitation has been the “pooling” of individual measures of disease activity into composite scores.13 Examples of composite disease activity indices that have been used in clinical trials involving RA-based treatments include the Simplified Disease Activity Index, Clinical Disease Activity Index, and Disease Activity Score.14-16 These scales involve measures that are scored using a single number on a continuous scale.

Patient self-reports of RA severity have also been widely used through various validated instruments.17,18 Many factors play a role in how much benefit patients can derive from medications for RA. Measuring a patient’s symptom experience is an important way of am-

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plifying the patient’s voice, and can be clinically impor­ tant to aid healthcare professionals in tailoring the use of oral and biologic DMARDs. RA instruments that assess patient-reported outcomes include the Health Assessment Questionnaire (HAQ), the modified HAQ, and the multidimensional HAQ, with questions ranging from 8 to 20 items and assessing various aspects of patient functionality and overall mental health status.19 In these instruments, patients are asked about various aspects of their functionality (eg, dressing themselves, getting out of bed without difficulty, bending), and the degree to which it is difficult to perform these functions on a regular basis. Therefore, patient self-reports of their functional limitations are a widely accepted method of assessing RA severity.17,18 The cost of untreated RA represents a significant financial burden on the US healthcare system and the economy, predominantly because of lost productivity.20,21 Patients, employers, family members or caregivers, payers, and society as a whole share this significant economic burden. A US claims-based analysis of excess payer- and beneficiary-paid costs per patient with RA (compared with matched controls) reported annual excess healthcare costs of $8.4 billion, indirect costs of $10.9 billion, and total annual societal costs of $19.3 billion (including direct, indirect, and intangible costs, such as QOL deterioration).22 According to this analysis, patients incurred an estimated 28% of that burden, employers incurred 33% of that burden, the government spent 20% of the cost, and caregivers incurred an estimated 19% of the total cost. Adding intangible costs of QOL deterioration ($10.3 billion) and premature mortality ($9.6 billion), the total annual societal costs of RA (direct, indirect, and intangible) increased to $39.2 billion.22 Benefits in terms of enhanced productivity and quality-adjusted life-years conferred by the use of TNF-alpha blockers have been demonstrated in several cost-effectiveness analyses.23-25 These evaluations have been based on the concept that, if treated, patients with RA will not progress to a greater disease severity—or will not progress as quickly—and thereby will avoid or defer the high costs and low utilization associated with more severe and progressed disease.26 Previous studies have looked at patterns of TNF-alpha blocker treatment but have not linked these patterns to productivity-based, financial expenditures–based, and utilization-based outcomes.6-8,10 In addition, population-­ based studies of patients with RA using nationally representative data sources have not been successful in identifying differences in severity for patients with RA, because the information required to determine RA severity is often not available in these data sources. The Medical Expenditure Panel Survey (MEPS) database,

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cosponsored by the Agency for Healthcare Research and Quality and the National Center for Health Statistics, is a nationally representative survey of the US civilian noninstitutionalized population.

The uniqueness of the MEPS database lies in its abundance of information, which includes patient self-reported outcomes of functioning and mental health, along with information on sociodemographics, medical utilization, cost of healthcare services, employment, missed workdays, and Short Form (SF)-12 scores. The ability to link these many domains within the MEPS data source allowed the authors of this study to develop different severity categories for RA based on a unique algorithm created by the authors for this study.

This RA severity–ranking algorithm was based on 5 health-related outcomes (ie, SF-12 physical and mental summary scores, patient’s perceived physical and mental health status, and the number of comorbid conditions), which were used to group TNF-alpha blocker nonusers into the 3 mutually exclusive RA severity cohorts— mild, moderate, and severe RA. Patients with RA using TNF-alpha blockers were not grouped using this algorithm and were not ranked. In addition, the MEPS data provide self-reports of work loss because of illness.

The objective of the present study was to use data from the MEPS for the following outcomes—healthcare expenditures, utilization, and self-reported productivity— and to compare these outcomes between patients with RA who are TNF-alpha blocker users and TNF-alpha blocker nonusers with mild, moderate, or severe RA.

Methods We used 1998-2007 MEPS data that are available for public use. The MEPS is used to collect detailed information on (1) sociodemographic characteristics, such as age, sex, race, ethnicity, and education; (2) economic characteristics, such as employment status, annual wage(s), and missed workdays because of illness and injury; and (3) health characteristics, such as perceived physical and mental health status, SF-12 physical and mental summary scores, health conditions, comorbidities, smoking status, and physical function variables.

Outcome Measures The main outcomes of interest in the current analysis were healthcare expenditures, medical service utilization, and work-related productivity of patients with RA. Total annual healthcare expenditures were defined as the sum of all-cause medical and pharmacy expenditures; in addition, medical and pharmacy expenditures were described separately, and were inflation adjusted to 2010 costs.

Medical service utilization and pharmacy components

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included the all-cause annual number of office-based visits, outpatient visits, hospitalizations, average length of stay for hospitalizations, as well as the annual number of prescribed medications.

Productivity was estimated using multiple measures.

First, we studied 1 full year of employment status, which we obtained from respondents’ answers to the annual MEPS. Respondents who were employed during all 3 rounds of the survey within a calendar year were assumed to be employed for a full year. Then, for those who were employed, we studied days (a half day or more) of work missed as a result of illness or injury; and finally, we explored the annual wage differences. Each person in the MEPS database has a record of his/her total annual wages.

The MEPS medical conditions file in the MEPS database contains 3-digit International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes based on medical and pharmacy utilization and self-reporting. We identified patients with RA by the presence of the ICD-9 diagnosis code 714, and stratified them into 1 of 2 major groups: TNF-alpha blocker users and TNF-alpha blocker nonusers. Users of TNF-alpha blockers were identified on the basis of pharmacy utilization and/or relevant intravenous therapy at office-based or outpatient visits with the ICD-9-CM diagnosis code 714.

TNF-alpha blocker nonusers were classified into 1 of 3 groups according to RA severity ranking (mild, moderate, or severe) as determined by the algorithm developed for this study (as described below). Users of TNF-alpha blockers were not included in the severity-ranking analysis, because of the assumption that patients with the most severe form of RA were taking these medications, which is typically normative practice for this patient population.

RA Severity Algorithm The RA severity–ranking algorithm was based on 5 health-related outcomes, which were used to group TNF-alpha blocker nonusers into the 3 mutually exclusive RA severity cohorts. The 5 health-related outcomes included in the algorithm were: • SF-12 physical summary score • SF-12 mental summary score • Patients’ perceived physical status • Patients’ perceived mental status • Number of comorbid chronic conditions.

The RA severity–ranking algorithm assigned equal weight to each of these 5 variables, with a total severity score ranging from 0 to 5. Patients with a severity score of 0 to 2 were assigned to the “mild RA” cohort, patients with a severity score of 3 were classified as having “mod-

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erate RA,” and patients with a severity score of 4 or 5 were classified as the “severe RA” group. The RA severity–ranking algorithm for each patient was based on the following formula: Severity score = RSF12-P + RSF12-M + RPH-P + RPH-M + RNCC where: • RSF12-P = 1 if a patient’s SF-12 physical summary score was in the bottom quartile (lower SF-12 scores) among all adult patients with RA in the MEPS database, and 0 otherwise • RSF12-M = 1 if a patient’s SF-12 mental summary score was in the bottom quartile (lower SF-12 scores) among all adult patients with RA in the MEPS, and 0 otherwise • RPH-P = 1 if a patient’s perceived physical score was in the bottom quartile (worse health status) among all adult patients with RA in the MEPS, and 0 otherwise • RPH-M = 1 if a patient’s perceived mental score was in the bottom quartile (worse health status) among all adult patients with RA in the MEPS, and 0 otherwise • RNCC = 1 if a patient’s number of chronic conditions was in the top quartile (higher number of chronic conditions) among all adult patients with RA in the MEPS, and 0 otherwise.

Therefore, a higher severity score indicates a worse physical and/or mental state and a higher number of chronic comorbidities. Based on this algorithm and on TNF-alpha blocker use, patients in the MEPS-based sample with RA were assigned to 1 of the following 4 mutually exclusive groups—TNF-alpha blocker users, TNF-alpha blocker nonusers with mild RA, TNF-alpha blocker nonusers with moderate RA, and TNF-alpha blocker nonusers with severe RA. To control for confounding factors in the statistical analyses, several sociodemographic and clinical (comorbidity) characteristics were identified. The number of chronic conditions was calculated by summing the total number of ICD-9-CM codes for chronic conditions reported for each individual, excluding RA, to create a measure of comorbidity burden. The following variables were measured categorically—age (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, ≥80 years); education (no degree, high school degree or equivalent, other degree, bachelor’s degree, master’s degree, PhD); race (white, black, American Indian, other race); ethnicity (Hispanic or non-Hispanic); and insurance coverage (private, public, or uninsured).

Data Analysis Negative binomial regression was used to estimate the impact of the type of RA group (ie, TNF-alpha blocker user or TNF-alpha blocker nonuser with mild, moderate,

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Table 1 Sociodemographic Characteristics TNF-alpha blocker nonusers Mild RA Moderate RA Severe RA

Variable 720 (62.50) 159 (13.81) 208 (18.05) Sample size, N (%) 59.0 (0.83) 60.5 (1.65) 58.6 (0.95) Age (mean SE) 205 (29.11) 41 (27.23) 45 (24.20) Sex, N (% male) Race 578 (85.05) 126 (86.55) 160 (81.58) White, N (%) 106 (10.22) 27 (11.06) 30 (9.61) Black, N (%) 86 (7.16) 31 (9.88) 27 (6.52) Hispanic, N (%) 10 (1.06) 3 (0.73) 4 (1.11) American Indian, N (%) 26 (3.67) 3 (1.66) 14 (7.70) Other, N (%) Region 286 (37.12) 67 (35.72) 90 (38.43) South, N (%) 159 (24.03) 33 (22.39) 52 (28.72) Midwest, N (%) 167 (21.79) 42 (31.31) 48 (21.42) West, N (%) 108 (16.99) 17 (10.58) 18 (11.44) Northeast, N (%) Education 134 (13.97) 63 (33.42) 71 (28.60) No degree, N (%) 430 (64.19) 76 (53.83) 110 (57.71) Completed high school, N (%) 83 (12.62) 13 (8.70) 8 (3.73) Bachelor’s degree, N (%) 23 (3.28) 1 (0.45) 3 (1.30) MA/PhD, N (%) 48 (5.94) 6 (3.60) 16 (8.70) Other degree, N (%) Income 95 (10.73) 55 (28.09) 70 (27.01) Poor, N (%) 45 (4.68) 17 (12.76) 24 (10.75) Near poor, N (%) 117 (14.77) 31 (21.30) 35 (15.10) Low income, N (%) 236 (35.20) 43 (27.32) 54 (30.80) Medium income, N (%) 227 (34.62) 13 (10.52) 25 (16.32) High income, N (%) Insurance status 461 (68.44) 61 (47.36) 66 (37.32) Private insurance, N (%) 203 (25.21) 82 (44.15) 125 (54.98) Public insurance, N (%) 56 (6.34) 16 (8.48) 17 (7.69) Uninsured, N (%) RA indicates rheumatoid arthritis; SE, standard error; TNF, tumor necrosis factor. or severe RA) on healthcare utilization outcomes and missed workdays. A generalized linear model with log link and gamma distribution was used to estimate the impact of the type of RA group on healthcare expenditures. The Heckman selection model, which is a 2-stage model that is used to estimate the costs for populations that may include individuals with zero costs as well, was used to estimate the impact of the type of RA group on

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TNF-alpha blocker users 65 (5.6) 55.9 (2.14) 17 (28.03) 55 (90.85) 8 (5.87) 7 (5.30) 0 (0.00) 2 (3.28) 20 (20.55) 18 (30.19) 17 (31.48) 10 (17.79) 10 (12.86) 35 (56.93) 15 (22.81) 2 (4.22) 3 (3.17) 11 (13.96) 3 (2.15) 7 (13.12) 19 (28.50) 25 (42.27) 45 (71.29) 19 (27.95) 1 (0.75)

the annual wage. These outcome variables were regressed using the type of RA group (ie, “mild RA” as the reference group), controlling for age, sex, race, ethnicity, region of residence, education, income, type of insurance coverage, and comorbidity. To estimate wages and employment, income was excluded from the models. All analyses were conducted with STATA version 11 (Stata Corporation, College Station, TX).

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Table 2 Differences in Unemployment Rates between the Study Groups Unadjusted mean, %

Incidence rate ratio

TNF-alpha blocker nonusers, with mild RA

53

Reference group

TNF-alpha blocker nonusers, with moderate RA

75

3.19

1.78-5.71

.000

TNF-alpha blocker nonusers, with severe RA

84

5.64

2.79-11.40

.000

TNF-alpha blocker users

60

1.92

0.95-3.86

.069

Study cohort

95% confidence interval P value

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; TNF, tumor necrosis factor.

Table 3 Differences in Missed Workdays between the Study Groups Study cohort

Unadjusted mean (SE)

Incidence rate ratio

95% confidence interval

P value

Missed workdays TNF-alpha blocker nonusers with mild RA

7.07

Reference group

TNF-alpha blocker nonusers with moderate RA 23.79

1.92

0.97-3.79

.060

TNF-alpha blocker nonusers with severe RA

22.67

1.99

0.35-11.37

.440

TNF-alpha blocker users

2.61

0.61

0.23-1.58

.303

3.12

Reference group

Missed workdays staying in bed TNF-alpha blocker nonusers with mild RA

TNF-alpha blocker nonusers with moderate RA 12.07

2.22

1.14-4.30

.019

TNF-alpha blocker nonusers with severe RA

4.61

1.20

0.35-4.11

.769

TNF-alpha blocker users

2.24

1.18

0.48-2.86

.719

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; SE, standard error; TNF, tumor necrosis factor.

Results A total of 1152 patients were included in the study.

Approximately 5.6% of the patients (N = 65) were using TNF-alpha blockers. Of the patients with RA who were not using these drugs, 720 patients (62.50% of the study sample) had mild RA, 159 (13.81%) had moderate RA, and 208 (18.05%) had severe RA. The sociodemographic characteristics of all study groups are depicted in Table 1.

Approximately 70% to 75% of the patients in all groups were female. The mean age ranged from 55 to 60 years across the various study cohorts. Between 80% and 90% of all patients were white, and one third of all members resided in the Midwest or the South. The majority of patients (55%-65%) had completed a high school education.

Outcomes Productivity (unemployment, missed workdays, and annual wages). As shown in Table 2, TNF-alpha block-

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er nonusers with severe RA were approximately 5 times more likely to be unemployed (incidence rate ratio [IRR], 5.64; P <.000) compared with TNF-alpha blocker nonusers with mild RA. TNF-alpha blocker nonusers with moderate RA showed a similar trend; they were approximately 3 times more likely to be unemployed (IRR, 3.19; P <.000) compared with TNF-alpha blocker nonusers with mild RA. There was no significant difference between TNF-alpha blocker users and nonusers with mild RA regarding the likelihood of being employed.

With regard to overall missed workdays and workdays that resulted in individuals staying in bed, few differences were seen among the 3 groups when adjusting for various covariates (Table 3). One noticeable difference was that TNF-alpha blocker nonusers with moderate RA were twice as likely to miss workdays by staying in bed compared with TNF-alpha blocker nonusers with mild RA. However, there was no significant difference be-

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Table 4 Differences in Healthcare Expenditures between the Study Groups (2009 US $) P value (for Mean marginal mean marginal difference, $ difference)

Unadjusted mean, $

Standard error, $

5972

651

Reference group

TNF-alpha blocker nonusers with moderate RA

13,148

3597

1088

.195

TNF-alpha blocker nonusers with severe RA

17,630

2349

1640

.035

TNF-alpha blocker users

13,072

2731

2096

.027

TNF-alpha blocker nonusers with mild RA

2301

147

Reference group

TNF-alpha blocker nonusers with moderate RA

4912

991

611

.001

TNF-alpha blocker nonusers with severe RA

5645

436

698

.000

10,207

1516

2454

.000

8273

706

Reference group

TNF-alpha blocker nonusers with moderate RA

18,060

4384

1864

.037

TNF-alpha blocker nonusers with severe RA

23,275

2436

2484

.002

TNF-alpha blocker users

23,280

3449

4880

.000

Annual medical expenditures, excluding prescriptions TNF-alpha blocker nonusers with mild RA

Annual prescribed medication expenditures

TNF-alpha blocker users Total annual healthcare expenditures TNF-alpha blocker nonusers with mild RA

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; TNF, tumor necrosis factor.

tween TNF-alpha blocker users and nonusers with mild RA, or between TNF-alpha blocker nonusers with severe RA and those with mild RA with regard to the likelihood of missing workdays.

The unadjusted mean number of missed workdays was lowest for TNF-alpha blocker users, ranging from approximately 20 days (moderate and severe RA) to 11 days (mild RA), compared with all other groups. Of note, we were not able to estimate the costs associated with the lost workdays.

With regard to significant differences in wages, TNF-alpha blocker nonusers with moderate RA constituted the only group whose mean wage was significantly lower than that of TNF-alpha blocker nonusers with mild RA ($7175; P <.001).

Healthcare expenditures. The incremental impact on annual medical expenditures, prescribed medication expenditures, and total healthcare expenditures is shown in Table 4. All 3 categories of expenditures were higher for TNF-alpha blocker users compared with nonusers with mild RA. For example, on average, TNF-alpha blocker users spent $2096 more in annual medical expenditures compared with TNF-alpha blocker nonusers

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with mild RA (the reference group). Similarly, on average, TNF-alpha blocker users spent $2454 more in annual prescribed expenditures and $4880 more in total healthcare expenditures compared with TNF-alpha blocker nonusers with mild RA. The total healthcare expenditures, on average, were $1864 higher for TNF-alpha blocker nonusers with moderate RA and $2484 higher for TNF-alpha blocker nonusers with severe RA compared with TNF-alpha blocker nonusers with mild RA. Annual prescription expenditures were $611 higher for TNF-alpha blocker nonusers with moderate RA and $698 higher for TNF-alpha blocker nonusers with severe RA compared with patients with mild RA, and annual medical expenditures were $1088 higher for TNF-alpha blocker nonusers with moderate RA and $1640 higher for TNF-alpha blocker nonusers with severe RA compared with TNF-alpha blocker nonusers with mild RA. Healthcare resource utilization. The notable differences in medical service utilization between the various study groups were with regard to all-cause emergency department visits, the number of hospitalizations, the average length of stay for a hospitalization, and the

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Table 5 Differences in Healthcare Utilization between the Study Groups Unadjusted mean

Standard error

Incidence rate ratio

95% confidence interval P value

Office visits, N TNF-alpha blocker nonusers with mild RA TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users Outpatient visits, N

12.09

0.71

Reference group

12.83

1.13

0.88

0.71-1.10

.274

19.55

3.57

0.88

0.71-1.09

.243

19.63

3.18

1.16

0.96-1.40

.131

TNF-alpha blocker nonusers with mild RA TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users Emergency department visits, N TNF-alpha blocker nonusers with mild RA TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users Hospitalizations, N

1.26

0.14

Reference group

2.54

1.35

0.77

0.45-1.33

.353

2.28

0.46

0.68

0.44-1.04

.077

1.62

0.47

0.98

0.52-1.86

.962

0.23

0.03

Reference group

0.58

0.10

1.59

1.10-2.31

.014

0.89

0.11

1.76

1.24-2.52

.002

0.42

0.20

1.35

0.54-3.39

.525

TNF-alpha blocker nonusers with mild RA TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users Average length of stay, days

0.76

0.14

Reference group

2.40

0.54

1.40

0.85-2.29

.188

4.15

0.99

2.24

1.24-4.04

.008

1.48

0.73

1.64

0.71-3.79

.248

TNF-alpha blocker nonusers with mild RA TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users Prescription medications, refills included, N

0.16

0.03

Reference group

0.44

0.09

1.56

0.99-2.45

.053

0.59

0.08

1.65

1.07-2.53

.022

0.40

0.15

1.91

0.86-4.23

.112

TNF-alpha blocker nonusers with mild RA TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users

28.98

1.35

Reference group

53.36

5.00

1.22

1.04-1.43

.012

69.77

4.90

1.25

1.07-1.46

.006

52.24

5.35

1.49

1.22-1.82

.000

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; TNF, tumor necrosis factor.

number of prescribed medications (Table 5). Significant differences with regard to emergency department visits and hospitalizations were observed between TNF-alpha blocker nonusers with severe RA and TNF-alpha blocker nonusers with mild RA. The differences in the number of prescribed medications were significant between TNF-alpha blocker users and nonusers with mild RA, as

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well as between TNF-alpha blocker users with severe RA and nonusers with mild RA. With regard to emergency department visits and hospitalizations, TNF-alpha blocker nonusers with severe RA were almost twice as likely to incur an emergency department visit (IRR, 1.76; P = .002) and a hospitalization (IRR, 2.24; P = .008) compared with nonusers with mild

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RA. This group was almost 1.5 times more likely to have a greater length of stay (IRR, 1.65; P = .022) compared with nonusers with mild RA as well. TNF-alpha blocker users had a greater likelihood of having more prescription medications (IRR, 1.49; P <.001) as were nonusers with severe RA (IRR, 1.25; P = .006) and nonusers with moderate RA (IRR, 1.22; P = .012) compared with nonusers of TNF-alpha blockers with mild RA.

Discussion This study is unique in comparing how TNF-alpha blocker treatment affects patient-reported outcomes versus TNF-alpha blocker nonuse among patients with varying degrees of RA severity. The outcomes examined in this study are more detailed than those observed from claims data alone and emphasize the importance of patient-reported measures in examining how drug treatment can influence key outcomes in the management of RA. To our knowledge, this is the first study to link patterns of TNF-alpha blocker treatment to patient-reported outcomes. Our results reveal that TNF-alpha blocker treatment confers increased benefit with regard to employment status and is associated with lower rates of hospitalizations and emergency department visits compared with other RA medications and compared with nonuse of TNF-alpha blockers in patients with moderate or severe RA. As anticipated, one of our key findings was that patients with RA who were using TNF-alpha blockers incurred the highest total healthcare, medical, and prescription expenditures compared with the other RA groups. However, despite these increased costs, we found that patients with severe RA who were not using TNF-alpha blockers had more emergency department visits and hospitalizations and longer hospital stays compared with the other groups.

Another key finding was that TNF-alpha blocker users had a greater likelihood of being employed compared with TNF-alpha blocker nonusers with moderate or severe RA. Unadjusted means also show that TNF-­ alpha blocker users were less likely to have missed workdays compared with the other RA groups (ie, users and nonusers), although these differences were not significant. The demonstrated positive impact of TNF-alpha blocker use on employment status may be of importance to employers and to payers alike.

Our study results, although unique, can be corroborated by previously reported findings on TNF-alpha blocker use and the association with productivity. Breedveld showed that early intervention with TNF-inhibitors improves patients’ functional status and health-related QOL, reduces fatigue, decreases job loss, and reduces the amount of work time missed.27 He concluded that al-

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though the drug costs are high, TNF-alpha blocker use is cost-effective as a result of the compensation in increased employment and productivity.27 Augustsson and colleagues estimated the effect of TNF-antagonist treatment on workforce participation in a population-based registry of patients with RA, showing that in unadjusted analyses, significant improvements in hours worked weekly were observed in patients at 6 months (mean, +2.4 hours weekly; 95% confidence interval [CI], 1.3-3.5), with further increases compared with baseline at 1-year follow-up (mean, +4.0 hours weekly; 95% CI, 2.4-5.6) and at 2-year follow-up (mean, +6.3 hours weekly; 95% CI, 4.2-8.4), resulting in significant indirect cost benefits.28 In a prospective, single-arm intervention study, Hoving and colleagues evaluated the outcomes and costs associated with a 6-month course of TNF inhibitors by examining their effect on perceived work ability, QOL, and fatigue in patients with RA.7 They reported that all 3 of these outcomes showed a significant improvement in mean scores from baseline at 6 months. There was a 2-fold increase per patient per week (PPPW) in average total direct and indirect costs. Direct costs included costs for TNF inhibitors, other medications, specialist visits, and hospital admissions, as well as costs related to comorbidities and side effects.7 Indirect costs included the costs of productivity losses (absenteeism from paid work because of RA, rests taken at work, and employees’ departures from their jobs). The overall total costs (PPPW) at 6 months were nearly double the costs observed at baseline.7 Our present study confirms the benefits of TNF-alpha blockers with regard to enhancing patients’ productivity, and illustrates the associated direct healthcare expenditures of treating this group of patients with RA, thereby providing a balanced picture of the overall costs and benefits for TNF-alpha blocker users. Employers and other payers can use this information to assess all cost components of managing this RA subgroup of TNF users to make better-informed decisions about coverage and access issues related to TNF-alpha blockers for their members. Such medication data that can demonstrate a tradeoff of savings on other healthcare costs provides additional value for payers. Such tradeoffs can include a return on investments related to workplace productivity, QOL, or activities of daily living.29 Further research is needed to inform clinical decisions such as what point in the RA disease process is the optimal time to initiate TNF-alpha blockers to derive the greatest cost-effectiveness and the most benefit to patients.

Limitations Certain limitations should be considered when inter-

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preting the results of this study. First, the measure of RA severity was based on patient self-reports of their functioning and level of disability and not on provider assessments. Therefore, the determination of RA severity may be biased, although, as discussed before, patient self-reporting is a validated and common method of assessing RA severity.17,18 In addition, the RA severity–ranking algorithm that was developed for this study has not been previously validated. The small (N = 65) sample of TNF-alpha blocker users may further limit the generalizability of our findings.

We also did not determine how many patients in each of the TNF-alpha blocker nonuser groups were taking any other RA medications. Therefore, we do not know how other RA drug treatment influenced the outcomes we examined. Our goal, however, was to compare the impact of TNF-alpha blocker use and nonuse on patient outcomes.

Furthermore, we examined all-cause and not RA-specific healthcare and pharmacy expenditures and utilization, which may have been influenced by non–RA-related factors. We also did not examine differences between the employed and unemployed patients with RA to determine the incremental impact of employment on the outcomes we measured. Finally, we were unable to measure presenteeism, an important productivity measure that was not available in the MEPS database.

Conclusions RA is ranked among the highest of all chronic diseases for its adverse impact on health-related QOL, limitations in physical function, increased pain and fatigue, and dim­ inished work performance and attendance.

TNF-alpha blockers are used for the treatment of patients with RA, but their use is often limited by payers, because of the drugs’ high costs. Our findings highlight that TNF-alpha blockers are able to reduce some of the negative effects of RA and to prevent or minimize the occurrence of high-cost drivers of healthcare utilization (ie, emergency department visits), and potentially keep workers employed longer, a very meaningful goal in these days of lean internal corporate resources. This finding should be of interest to payers when trying to justify the high cost of TNF-alpha blockers, by realizing the potential of these medications to prevent or minimize high-cost drivers of healthcare utilization. However, we would like to use caution in our interpretation of these findings, because only some of these differences were statistically significant. n Acknowledgments The authors thank Victoria Porter, medical writer, for her assistance with the preparation of this manuscript.

Study Funding Funding for this study was provided by Janssen Health Services.

Author Disclosure Statement Dr Nair is a consultant to Janssen and receives grants from Daiichi Sankyo, Janssen, and Takeda. Dr Naim is an employee of Janssen Scientific Affairs and owns stocks of Johnson & Johnson. Dr Ghushchyan has nothing to disclose.

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2. Helmick CG, Felson DT, Lawrence RC, et al, for National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15-25.

3. Carmona L, Cross M, Williams B, et al. Rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2010;24:733-745.

4. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005;72:1037-1047.

5. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784.

6. Lindén C, Björklund A. Living with rheumatoid arthritis and experiencing everyday life with TNF-α blockers. Scand J Occup Ther. 2010;17:326-334.

7. Hoving JL, Bartelds GM, Sluiter JK, et al. Perceived work ability, quality of life, and fatigue in patients with rheumatoid arthritis after a 6-month course of TNF inhibitors: prospective intervention study and partial economic evaluation. Scand J Rheumatol. 2009;38:246-250.

8. Bejarano V, Quinn M, Conaghan PG, et al, for Yorkshire Early Arthritis Register Consortium. Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis. Arthritis Rheum.

2008;59:1467-1474.

9. Curtis JR, Jain A, Askling J, et al. A comparison of patient characteristics and outcomes in selected European and US rheumatoid arthritis registries. Semin Arthritis Rheum. 2010;40:2.e1-14.e1.

10. Delavallée L, Semerano L, Assier E, et al. Active immunization to tumor necrosis factor-alpha is effective in treating chronic established inflammatory disease: a long-term study in a transgenic model of arthritis. Arthritis Res Ther. 2009;11:R195.

11. Bardwell WA, Nicassio PM, Weisman MH, et al. Rheumatoid Arthritis Severity Scale: a brief, physician-completed scale not confounded by patient self-report of psychological functioning. Rheumatology (Oxford). 2002;41:38-45.

12. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569-2581.

13. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol. 2005;23(5 suppl 39):S100-S108.

14. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 2003;42: 244-257.

15. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther. 2005;7:R796-R806.

16. van der Heijde DM, van ’t Hof MA, van Riel PL, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990;49:916-920.

17. Alten R, Pohl C, Choy EH, et al; OMERACT RA Flare Definition Working Group. Developing a construct to evaluate flares in rheumatoid arthritis: a conceptual report of the OMERACT RA Flare Definition Working Group. J Rheumatol. 2011; 38:1745-1750.

18. Mason JH, Anderson JJ, Meenan RF, et al. The rapid assessment of disease activity in rheumatology (radar) questionnaire. Validity and sensitivity to change of a patient self-report measure of joint count and clinical status. Arthritis Rheum. 1992;35: 156-162.

19. Zatarain E, Strand V. Monitoring disease activity of rheumatoid arthritis in clinical practice: contributions from clinical trials. Nat Clin Pract Rheumatol. 2006;2:611-618.

20. Filipovic I, Walker D, Forster F, Curry AS. Quantifying the economic burden of productivity loss in rheumatoid arthritis. Rheumatology (Oxford). 2011;50:1083-1090.

21. Franke LC, Ament AJ, van de Laar MA, et al. Cost-of-illness of rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol. 2009;27(4 suppl 55):S118-S123.

22. Birnbaum H, Pike C, Kaufman R, et al. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26:77-90.

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CLINICAL

23. Davies A, Cifaldi MA, Segurado OG, Weisman MH. Cost-effectiveness of sequential therapy with tumor necrosis factor antagonists in early rheumatoid arthritis.

J Rheumatol. 2009;36:16-26.

24. Kobelt G, Lindgren P, Geborek P. Costs and outcomes for patients with rheumatoid arthritis treated with biological drugs in Sweden: a model based on registry data.

Scand J Rheumatol. 2009;38:409-418.

25. Brennan A, Bansback N, Nixon R, et al. Modelling the cost effectiveness of TNF-alpha antagonists in the management of rheumatoid arthritis: results from the British Society for Rheumatology Biologics Registry. Rheumatology (Oxford). 2007; 46:1345-1354.

26. Benucci M, Li Gobbi F, Sabadini L, et al. The economic burden of biological

therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNFalpha treatment in Italian patients. Int J Immunopathol Pharmacol. 2009;22:1147-1152.

27. Breedveld F. The value of early intervention in RA—a window of opportunity.

Clin Rheumatol. 2011;30(suppl 1):S33-S39.

28. Augustsson J, Neovius M, Cullinane-Carli C, et al. Patients with rheumatoid arthritis treated with tumour necrosis factor antagonists increase their participation in the workforce: potential for significant long-term indirect cost gains (data from a population-based registry). Ann Rheum Dis. 2010;69:126-131.

29. Solomon DH. The comparative safety and effectiveness of TNF-alpha antagonists [corrected]. J Manag Care Pharm. 2007;13(1 suppl):S7-S18.

Stakeholder Perspective Assessing the Value of TNF-Alpha Blockers for Patients with Rheumatoid Arthritis

By Michael S. Jacobs, RPh Vice President, National Accounts, Truveris, Inc, New York, NY

Modern pharmaceutical therapies, such as tumor necrosis factor (TNF)-alpha blockers for patients with rheumatoid arthritis, have approached being perceived as “magic” for many patients with this condition and their physicians.

PAYERS: These therapies, however, often exceed tens of thousands of dollars annually in cost on a per-­ patient basis and are therefore a difficult “sale” to payers of all types (with the possible exception of the government), who are concerned with the value of the investment itself, or at least with the alternative value that can be purchased for this substantial financial investment in an individual’s healthcare. When health plan sponsors examine the impact that TNF-alpha blockers have in the more global context of payer thought and decision-making processes, such as budgeting, the coverage rules and coverage decisions become even murkier for payers.

When the relatively improved clinical efficacy associated with these therapies is compared with the efficacy of substantially less expensive alternate therapies, and with the “value” that is being purchased, appropriate cost-sharing burden levels become a true concern for all stakeholders—payers, patients, and family members. And when all of these dimensions of therapy and coverage components are combined, these questions not only concern the patients themselves but also the impact these issues have on family members, coworkers, and, of course, plan sponsors. All of this “noise,” regretfully, can obscure the identified and promised clinical value of the therapy with TNF-alpha blockers.

PATIENTS/PHYSICIANS: According to the study

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presented by Nair and colleagues, patients with rheumatoid arthritis who were receiving TNF-alpha blocker therapy were found to have lower odds of being unemployed compared with nonusers of this therapy who had moderate or severe disease. From a patient (and most likely a physician) perspective, this therapy is a significant advancement in the treatment of rheumatoid arthritis. From a cost perspective, the payer will need to address a number of questions, such as, “Would this patient be employed even with this therapy?” or “Is the economic value of the employment reasonable when the cost of the employment, including therapy, combined with the other costs of employment, such as wages and taxes, is calculated?”

EMPLOYERS: Employers, who are often the health plan sponsors themselves, pay wages based on a number of considerations and variables, including the value received for the work effort performed and the financial compensation paid. According to the Bureau of Business and Economic Research at the University of New Mexico, the average annual wage in the United States in 2011 (preliminary estimate) was $48,301.1 If we add to this amount the cost of expensive therapies, such as those identified in the present study, the question now becomes, “Is this employee worth the total cost of employment?” This is one question that should be addressed in the near future, as these expensive therapies become more common within the healthcare system. n 1. Bureau of Business and Economic Research. Annual average wage/salary disbursements per job, U.S. and States 2000-2011. Revised October 12, 2012. http://bber. unm.edu/econ/us-wage.htm. Accessed April 9, 2013.

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Vol 6, No 2

ANNUAL CONFERENCE

"! !

!

!

Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

*

3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

*Agenda is subject to change.

PMPMERSONALIZED EDICINE IN ONCOLOGY O

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION • For Autologous Use Only.

• The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.

• Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine.

• Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag.

• Do Not Initiate Infusion of Expired Product.

• Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not Use a Cell Filter.

• Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use.

• Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

I n controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

• Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

• Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONS 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 practice.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, Randomized to PROVENGE controlled clinical trials. The control was non-activated autologous peripheral blood PROVENGE (N = 601) Control* (N = 303) mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer.

The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011.

2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

©2013 Dendreon Corporation.

All rights reserved. January 2013.

Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-01.13-002.00

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com