AHDB July 2013

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ July 2013

Volume 6, Number 5

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Hematology/Oncology Theme Issue EDITORIAL

Increasing Importance of Oncology Drug Management for Payers James T. Kenney, Jr, RPh, MBA

The Changing Face of Cancer Care: Evolution to a Collaborative Model Michael Kolodziej, MD, FACP PERSPECTIVES ™

Defining Value in Cancer Care: AVBCC 2013 Steering Committee Report Linda Bosserman, MD, FACP; Douglas Burgoyne, PharmD; Craig K. Deligdish, MD; John E. Hennessy, CMPE; James T. Kenney, Jr, RPh, MBA; Kevin B. Knopf, MD, MPH; James Lang, PharmD; Grant D. Lawless, MD, RPh, FACP; Douglas M. Long; Jennifer Malin, MD, PhD; Thomas A. Marsland, MD; Patrick McKercher, RPh, PhD; Leonard Natelson; Gary M. Owens, MD; Matthew C. Palmgren, PharmD; Lillie D. Shockney, RN, BS, MAS; Jayson Slotnik, JD, MPH; F. Randy Vogenberg, RPh, PhD; Burt Zweigenhaft, BS CLINICAL

Patient-Reported Outcomes Are Changing the Landscape in Oncology Care: Challenges and Opportunities for Payers Erin Zagadailov, PharmD, MS; Michael Fine, MD; Alan Shields, PhD Stakeholder Perspective by Matthew Mitchell, PharmD, MBA BUSINESS

Rapid Expansion of New Oncology Care Delivery Payment Models: Results from a Payer Survey Rhonda Greenapple, MSPH Stakeholder Perspective by Gary M. Owens, MD

Review of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy

6

EST. 2008

YEAR ANNIVERSARY

Michael K. Wong, MD, PhD; Xufang Wang, MD, MBA; Maruit J. Chulikavit, MPH; Zhimei Liu, PhD Stakeholder Perspective by Nicholas J. Vogelzang, MD

www.AHDBonline.com ©2013 Engage Healthcare Communications, LLC

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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July 2013

Volume 6, number 5 The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

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Table of Contents

Publishing Staff

Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Director, Client Services Joseph Beck Ron Gordon Projects Manager John Welz Senior Production Manager Lynn Hamilton

INTRODUCTION

224 Progress in Cancer Care: Challenges and Opportunities

Dalia Buffery, MA, ABD EDITORIAL

225 Increasing Importance of Oncology Drug Management for Payers

James T. Kenney, Jr, RPh, MBA 227 The Changing Face of Cancer Care: Evolution to a Collaborative Model

Michael Kolodziej, MD, FACP PERSPECTIVES

The Lynx Group

236 Defining Value in Cancer Care: AVBCC 2013 Steering Committee Report

Linda Bosserman, MD, FACP; Douglas Burgoyne, PharmD; Craig K. Deligdish, MD; John E. Hennessy, CMPE; James T. Kenney, Jr, RPh, MBA; Kevin B. Knopf, MD, MPH; James Lang, PharmD; Grant D. Lawless, MD, RPh, FACP; Douglas M. Long; Jennifer Malin, MD, PhD; Thomas A. Marsland, MD; Patrick McKercher, RPh, PhD; Leonard Natelson; Gary M. Owens, MD; Matthew C. Palmgren, PharmD; Lillie D. Shockney, RN, BS, MAS; Jayson Slotnik, JD, MPH; F. Randy Vogenberg, RPh, PhD; Burt Zweigenhaft, BS BUSINESS

249 R apid Expansion of New Oncology Care Delivery Payment Models: Results from a Payer Survey

Rhonda Greenapple, MSPH 256 S takeholder Perspective: New Oncology Care Delivery Payment Models to Enhance Care Efficiency Gary M. Owens, MD

Continued on page 222

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econo­metric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the im­provement of healthcare.

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.

Contact Information: For subscription information and edi­torial queries, please contact: editorial@engagehc.com; tel: 732-992-1892; fax: 732-992-1881.

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

July 2013

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(Continued)

CLINICAL

264 P atient-Reported Outcomes Are Changing the Landscape in Oncology Care: Challenges and Opportunities for Payers

Erin Zagadailov, PharmD, MS; Michael Fine, MD; Alan Shields, PhD

274 Stakeholder Perspective: Assessing the Value of Patient-Reported Outcomes

Matthew Mitchell, PharmD, MBA BUSINESS

275 R eview of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy Michael K. Wong, MD, PhD; Xufang Wang, MD, MBA; Maruit J. Chulikavit, MPH;

Zhimei Liu, PhD

286 S takeholder Perspective: Cost and Effectiveness of Therapies for Advanced Kidney Cancer: The Need for Economic and Clinical Analyses

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Nicholas J. Vogelzang, MD

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Vol 6, No 5

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, Greenville, SC ENDOCRINOLOGY

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

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA 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, 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 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

EPIDEMIOLOGY Research

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

PATIENT ADVOCACY

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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POLICY & PUBLIC HEALTH

health & value promotion

Jeffrey A. Bourret, RPh, MS, FASHP Medical Lead, Specialty & Payer Strategy Medical Affairs, Pfizer, Inc., PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

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

Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, 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

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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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 CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

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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Progress in Cancer Care: Challenges and Opportunities

By Dalia Buffery, MA, ABD Editorial Director, American Health & Drug Benefits

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esearchers have made great strides in unlocking the biology of cancer, especially on the molecular and immunologic levels, and this is rapidly being translated into new therapies. With more than 900 oncology compounds currently in development,1 advancements in molecular sequencing, and new diagnostic modalities, cancer care has become a major focus for investment and research, and with it come challenges and opportunities.

New therapies and novel diagnostics for cancer are coming to the market at a greater rate than for other clinical categories, and this trend is reflected in increased rates of survival and lower cancer-related US mortality since the 1990s.2 Cancer care is changing, as evident in new payer–provider collaboration efforts and new approaches to cancer drug management that are described by James T. Kenney, Jr, RPh, MBA, and by Michael Kolodziej, MD, FACP, in their editorials in this theme issue of American Health & Drug Benefits.

However, such rapid development and growth come with a high price tag, raising the question of how to pay for these expensive therapies. Indeed, cost in oncology has become a top concern not only for patients, but also for oncologists and, increasingly, for payers. Recent estimates put the cost of cancer care at $100 billion annually, and this is projected to rise to $200 billion by 2020.3 The growing cost of treating cancer has contributed to a heightened focus on evidence-based treatment and pathways to ensure appropriate use of therapies, minimize waste, and control costs. Thus enters “value” into the conversation at all oncology settings.

A unique attempt at defining value in oncology is presented in this issue in the report from the Steering Committee of the Third Annual Conference of the Association for Value-Based Cancer Care, which was held on May 2-5, 2013, and addressed “value” from the point of view of different stakeholders in oncology. The need for change in oncology reimbursement is a repeated theme in this discussion and has recently been echoed in the medical literature.4 Erin Zagadailov, PharmD, MS, and colleagues make an important contribution to the literature by highlight-

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ing the growing importance of patient-reported outcomes (PROs) in oncology drug management. The authors review cancer drugs that were approved with PRO information as a significant measure that may need to be taken into account by payer decisions. This important article brings to the fore the challenges and the opportunities of incorporating oncology-related PRO data into payer decision-making.

Rhonda Greenapple, MSPH, focuses on the introduction of new care delivery models in oncology and emerging payment models, based on results of a new payer survey. Anticipating a rapid expansion of innovative approaches to cancer management over the next 2 years, health plans are supporting new delivery models, such as pathways and palliative care, as well as new payment models, focusing on pay for performance as a cost-effective way to enhance outcomes.

Finally, Michael M. Wong, MD, PhD, and colleagues evaluate the increase in the economic burden of metastatic renal cell carcinoma (mRCC), looking for the most cost-effective way to control the cost of this tumor type and to guide treatment and policy decisions. Their analysis shows that targeted therapies are cost-effective in the setting of refractory mRCC, and that oral therapies have an economic advantage over intravenous agents. However, comparative effectiveness research is lacking and is sorely needed in this area.

Oncology continues to be an area with unique opportunities for reducing waste, cost-savings, and improving quality of care and outcomes. This theme issue provides a sample of key topics facing patients with cancer, oncologists, payers, and other stakeholders in the care conti­ nuum. The challenges are many, and yet they also present many opportunities for innovation and change.

References

1. PhRMA. More than 900 medicines and vaccines in clinical testing offer new hope in the fight against cancer. 2012 Report. www.phrma.org/sites/default/files/pdf/phrma medicinesindevelopmentcancer2012.pdf. Accessed July 10, 2013.

2. Centers for Disease Control and Prevention. Report to the nation finds continuing declines in cancer death rates since the early 1990s. www.cdc.gov/media/releases/ 2012/p0328_Cancer_deathrates.html. Accessed July 10, 2013.

3. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2012-2010. J Natl Cancer Inst. 2011;103:117-128.

4. Bach PB. Reforming the payment system for medical oncology. JAMA. 2013 July 1:257-258. [Epub ahead of print].

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EDITORIAL

Increasing Importance of Oncology Drug Management for Payers James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

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ncology management is coming into focus as a key strategy for payers within their specialty pharmacy management programs. Historically, oncology was unmanaged as a result of limited therapeutic options, and the majority of drugs were delivered to patients by infusion in the physicianâ&#x20AC;&#x2122;s office or in the hospital setting.

The approval of high-cost oral cancer agents in the past few years has increased the importance of oncology for payers, with managed care trend reports placing oncology as the third highest category of specialty drug spending, after rheumatoid arthritis and multiple sclerosis.1 More than 900 oncology drugs are currently in development, and more than 50% of these are oral agents.2 The 15 oral cancer drugs approved by the US Food and Drug Administration in the past 10 years are now targets for management by health plans. The utilization management (UM) programs that have been used for the traditional small molecules are now being expanded to cover specialty drugs, including oral and infusible oncology agents. Overall, health plans cover infused drugs under the medical benefit and oral drugs under the pharmacy benefit, which can pose management challenges, because the claim systems for each benefit typically do not communicate directly with one another. It requires manual systems and pharmacists or nurse case managers to implement these controls.

Specialty Pharmacy Specialty pharmacies will play a key role in the management of oral cancer drugs for health plans. These pharmacies provide effective product distribution, promote compliance, reduce waste, offer nursing and pharmacist expertise by disease and by drug, and deliver the drugs at a lower reimbursement rate than traditional retail pharmacies. They can also develop, manage, and implement UM programs for health plans, or the health plan can develop UM programs and let the specialty pharmacy operate them.

Specific control strategies include prior authorizations, step-edits, quantity limits, pathways, guidelines, increased patient cost-sharing, diagnostic testing, and preferred formularies driven by drug cost differences and manufacturer contracts. A prior authorization is the most effective method for driving appropriate use in oncology

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as plans restrict access based on the approved labeling, with restrictions by indication, and additional access may be allowed if the drug is listed in compendia or in published guidelines from credible groups, such as the National Comprehensive Cancer Network or the American Society of Clinical Oncology.

Step-edits are most often used for ancillary medications, including antinauseants or blood cell growth factor agents, in which interchanges of agents are well received by prescribers. Step-edits are growing in importance for oncology-specific categories in which a number of agents have been approved for the same indication, including chronic myelogenous leukemia (CML), renal-cell carcinoma, and castration-resistant metastatic prostate cancer. The recent approval of generic drugs for cancer, including letrozole and aromatase inhibitors, has allowed health plans to require the use of generics for first-line therapy before brand-name drugs in an effort to control costs. The pending launch of generic imatinib has several plans focusing attention on CML, promoting imatinib for first-line use now in anticipation of the potential savings when the generic equivalent becomes available.

The challenge to using generic cancer agents may be similar to the situation with HIV drugs, with newer brand-name drugs often replacing older ones before the generics are being launched, resulting in the value of generics being severely limited, because the standard of care has shifted to the newer, more targeted agents, and the generic drug is no longer a viable first-line option for newly diagnosed patients.

Molecular Diagnostics Genomic testing and molecular diagnostics provide additional guidance and support for the management of targeted cancer drugs, with health plans adding specific testing as part of the requirements for coverage of certain drugs. Certainly the use of molecular diagnostic assays or drug-specific diagnostics will enhance the appropriate use of agents and allow for the management of select therapies.

This is an area of potential growth and significant value, but we have a long way to go before it is routinely part of the treatment paradigm for most cancers. For example, tumor classification is unknown or, at best, is uncertain in more than 33% of patients with metastatic disease.3

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In general, health plans support diagnostic testing, provided that they affect care in a positive way either by directing a treatment approach or by changing an existing strategy for care. Perhaps the greatest potential for molecular diagnostics is the ability to avoid giving a patient a drug that will not work based on that patientâ&#x20AC;&#x2122;s genetic profile, and eliminate the potential side effects that would place the patient at risk for other medical complications and would also drive up costs.

coverage for oncology agents provided that there is a compendia listing or published clinical evidence to support the off-label use. These laws have discouraged some health plans from using any restrictions, based on the belief that any therapy that is restricted will likely be approved on appeal. Recently, the pressure of the growth in cancer drugs has reduced this concern among payers, and all payers are now using some level of UM programs for oncology drugs.

Copay and Coinsurance Standard quantity limits of 30-day supplies are routinely used as part of the specialty pharmacy distribution model. A typical oral cancer agent can cost â&#x2030;Ľ$6000 monthly, and plans want to avoid waste; in addition, side effects, lack of response, or change in the stage of cancer may make the continued use of an agent inappropriate.

Another common strategy is to use a short-fill or short-cycle dispensing program. In this case, the specialty pharmacy will ship a 1- or 2-week supply of a new medication and will communicate with the patient about his or her ability to tolerate the medication and allow for discontinuation of subsequent refills, as appropriate. The patient is charged a copay or coinsurance on the first fill, and subsequent refills adjust for any additional coinsurance as needed. Industry estimates suggest that a 25% savings in drug cost can be achieved with this type of program.

Increases in copays and coinsurance are occurring across all specialty drugs, as employers seek relief from high costs of drug benefits. Commercial plan members may have access to copay assistance programs, but Medicare patients are not allowed to participate in them.

A number of states have passed legislation to limit the out-of-pocket costs for consumers; in particular, the oral chemotherapy parity laws require the cost burden for patients to be equivalent for the medical benefit and the pharmacy benefit drugs. Recent trend surveys suggest that 50% of patients have a coinsurance in the medical benefit, which has been increasing steadily over the past 2 to 3 years. This will assist health plans in their efforts to manage pharmacy and medical benefit drugs used to treat the same cancer.

Pathways Pathway programs are an interesting new management approach designed to improve clinical and economic outcomes for specific cancer diagnoses by incorporating evidence-based information into treatment. To be successful, pathway programs need to include a formal treatment guideline; physician support (some experts suggest that an 80% concurrence rate is needed for success4); robust information technology systems; and clinical support from pharmacists, nurse case managers, and care coordinators.

Pathways decrease variation in care, promote quality, improve care coordination and communication among the treatment team, and optimize overall resources.

Pathways are physician-directed, require routine evaluation and evidence updates, empower patients, and may decrease litigation risk for providers, as a result of increased patient involvement in their treatment.

Formulary Management Plans can also use formulary management strategies to increase the utilization of preferred treatments. Benefit designs may limit restrictions on preferred agents by tier, require out-of-pocket differences, and impose higher restrictions on nonpreferred agents. Medicare plans are challenged by oncology agents as being a protected class by statute; however, they can still use some level of UM if managed carefully. Another challenge in formulary management involves state laws that mandate off-label

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Expanding Oncology Management It is evident that oncology management will continue to expand, and health plans will apply any reasonable UM strategies to promote appropriate use, improve clinical outcomes, and achieve cost-effectiveness. Several other types of therapy are also candidates for UM programs, including the use of palliative care, hospice care, pain management, and health and wellness programs, such as nutritional support and exercise. A coordinated care team will be needed to effectively manage patients with cancer throughout the course of their disease, from initial diagnosis to placement on an effective therapeutic regimen and any subsequent maintenance regimens.

Health plans welcome this challenge, and look forward to improvements in technology, medication development, and diagnostics to achieve greater success in the management of patients with cancer. n References

1. Express Scripts. Drug Trend Reportâ&#x20AC;&#x201D;Specialty trend by therapy class. Updated May 13. www.drugtrendreport.com/commercial/specialty-trend-by-therapy-class.

Accessed July 9, 2013.

2. Dearment A. PhRMA: 907 biotech drugs, vaccines under development. March 11, 2013. Drug Store News. http://drugstorenews.com/article/phrma-907-biotech-drugsvaccines-under-development. Accessed July 8, 2013.

3. Nystrom JS, Smith P. Potential clinical utility of gene expression profiling in identifying tumors of uncertain origin. J Oncopathol. 2013;1:35-46.

4. Phillips C. Clinical pathways in cancer care catching on. NCI Cancer Bulletin.

2012;9. www.cancer.gov/ncicancerbulletin/090412/page6. Accessed July 9, 2013.

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EDITORIAL

The Changing Face of Cancer Care: Evolution to a Collaborative Model

By Michael Kolodziej, MD, FACP Aetna National Medical Director for Oncology Solutions

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ncology has never been more exciting, or more challenging. At long last, the fruits of many years of labor in research investigating the basic science of cancer are being realized through genomic-based diagnostics and therapeutics as well as through highly active, novel immunotherapy. At the same time, the cost of medical care has skyrocketed, with cancer costs leading the way. In fact, the cost of care per patient with cancer exceeds that of all other medical conditions.

Given the aging of the US population and the number of people diagnosed with cancer, this clinical burden adds up to a very large healthcare bill. Serious questions abound regarding whether the money is being spent wisely and whether value is being delivered. Certainly, the delivery of cancer care has room for improvement, and this improvement can increase the quality of care and reduce the cost of care.

The Institute of Medicine has estimated that up to 30% of our nation’s healthcare spending is wasteful.1 Most of this waste is in areas of low-value, redundant, or futile care.1 It is safe to say that similar waste occurs in oncology care. For example, the cost is often lower for newly diagnosed patients as opposed to patients with recurrent disease, especially those in the last 6 to 12 months of life. Indeed, there is a disproportionate increase in hospitalization costs for symptoms of advanced malignancy at the end of life. Hospice services clearly reduce this pattern of care, and hospice use has increased. Still, almost half of all hospice-appropriate patients with cancer never receive this service.2-4 The cost of novel agents to treat cancer has become front-page news. Many of the new medications recently approved by the US Food and Drug Administration are targeted for subsets of patients with a specific molecular marker. Many of these agents are also oral, and cost more than $100,000 annually. At the June 2013 American Society of Clinical Oncology annual meeting, novel immunotherapies to treat melanoma, a notoriously difficult cancer to treat, generated tremendous excitement. It has been theorized that these novel agents will be used in combination and may actually cure a subset of patients—but with a projected price tag of close to $200,000 for an average course of treatment. So how can

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we ensure that we offer these highly active therapies to our patients, while confronting the challenges of uneven quality and uncontrolled costs of care?

Quality Improvement The answer may be as simple as approaching cancer care delivery as a continuous quality improvement process. To some extent, many oncology practices are already doing this. But the standardization of care, first by identifying and measuring the processes involved, followed by implementation of a quality improvement plan, then followed by measurement, will allow an individual practice to improve over time. In addition, standardi­ zation of care will allow benchmarking of practices to identify quality providers. Because the data needed to execute this strategy currently reside partially with providers and partially with payers, moving forward will require collaboration between providers and payers.

One way to move forward is to use clinical decision support tools, such as clinical pathways, as an enabling technology. These tools capture individual data and can identify clinically important subsets of patients, can report prospectively on compliance with evidence-based treatment guidelines, and can potentially link this information to downstream outcomes and resource consumption. Since the introduction of the National Comprehensive Cancer Network Clinical Guidelines®, evidence points to an increase in adherence to evidence-based treatment5; however, decision support tools provide additional value, because they can facilitate reporting and identify opportunities for improvement.

Provider–Payer Collaboration Once the lines of communication open up between providers and payers, and practices become comfortable with process improvement, other collaborative projects become possible. One such approach is the oncology patient-centered medical home. This treatment delivery reform focuses on transforming the oncology care delivery model, using patient-centered care, evidence-based treatment, enhanced services, and shared decision-making as the cornerstones. Under this model, quality improves.

Practices also will control costs by eliminating unneces-

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sary emergency department visits and hospitalizations.

Because of the enhanced care team–patient relationship, practices will more successfully address the difficult concerns surrounding quality-of-life and end-of-life issues.

The role of the payer is to facilitate data exchange, participate in discussions with engaged practices about opportunities for improvement, and perhaps most impor­ tant, restructure payment to reward successful practices.

This evolution in the processes of care will prepare oncology practices to survive, and even flourish, in the new world of integrated delivery systems and accountable care organizations. These transformed practices will be the exact partners in care who will be sought out by these delivery systems.

The Patient Patients must not get lost in transition. All of the reforms mentioned above will need to occur while preserving the best aspects of the patient–oncologist relationship. If the reforms are executed well, this relationship will be strengthened. Equally important, there will be new opportunities for transparency regarding quality.

Patient satisfaction and measurable outcomes will be required. Finally, patients will be able to participate in healthcare as informed decision makers.

Facing the Challenges There are surely challenges. The average oncology practice consists of 4 physicians. Providing enhanced

services simply may not be possible. To fill this gap, payers may develop enhanced patient services in collaboration with providers. These services may include a more focused case management approach, such as a virtual patient navigator, or a dedicated end-of-life support team. Even more challenging may be the electronic interfaces that will be required for real-time decisions and patient support.

The fact that multiple payers may bring many solutions could prove daunting for any individual practice.

The move to transparent cost and quality reporting will require a massive cultural transformation for patients, providers, and payers. These challenges should not derail the efforts to improve the quality and value of care.

Never have the potential benefits to providers, payers, and, most important, patients been greater. n

References

1. Institute of Medicine. Best care at lower cost: the path to continuously learning health care in America. September 6, 2012. http://iom.edu/Reports/2012/Best-Care-atLower-Cost-The-Path-to-Continuously-Learning-Health-Care-in-America.aspx.

Accessed July 9, 2013.

2. Fairfield KM, Murray KM, Wierman HR, et al. Disparities in hospice care among older women dying with ovarian cancer. Gynecol Oncol. 2012;125:14-18. Erratum in: Gynecol Oncol. 2012;126:509-510.

3. McCarthy EP, Burns RB, Ngo-Metzger Q, et al. Hospice use among Medicare managed care and fee-for-service patients dying with cancer. JAMA. 2003;289:2238-2245.

4. McCarthy EP, Burns RB, Davis RB, Phillips RS. Barriers to hospice care among older patients dying with lung and colorectal cancer. J Clin Oncol. 2003;21:728-735.

5. O’Grady MA, Gitelson E, Swaby RF, et al. Development and implementation of a medical oncology quality improvement tool for a regional community oncology network: the Fox Chase Cancer Center Partners initiative. J Natl Compr Canc Netw.

2007;5:875-882.

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Vol 6, No 5

In the fight against active, autoantibody-positive systemic lupus erythematosus (SLE) in adult patients receiving standard therapy

Add BENLYSTA to Help Make SLE More Manageable When added to standard therapy, BENLYSTA significantly reduced disease activity vs standard therapy alone at Week 521

•

BENLYSTA 10 mg/kg + standard therapy demonstrated superior efficacy vs placebo + standard therapy in reducing disease activity at Week 52 in 2 Phase III trials (Total N=1684)1-3

•

The primary endpoint was the percentage of patients meeting the SLE Responder Index (SRI) at Week 52. The SRI components measure reduction in disease activity defined as clinical improvement (SELENA-SLEDAI*) with no significant worsening in any organ system (BILAG†) and no worsening in overall patient condition (PGA‡)1

– •

A Phase II trial (Total N=449) did not meet the prespecified co-primary endpoints of percent change in SELENA-SLEDAI at Week 24 and time to first flare over 52 weeks. The Phase II trial led to the selection of a targeted autoantibody-positive population in the Phase III trials (28% of the Phase II trial population was autoantibody negative at baseline) 4

In Phase II and III clinical trials, 1458 patients with SLE have been exposed to BENLYSTA for a total of 1516 patient-years2-5

* SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index). † BILAG (British Isles Lupus Assessment Group). ‡ PGA (Physician’s Global Assessment).

Indication BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

How supplied: BENLYSTA is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.

Important Safety Information for BENLYSTA CONTRAINDICATION BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in BENLYSTA 1 mg/kg, 0/111 in BENLYSTA 4 mg/kg, and 6/674 in BENLYSTA 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.

SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with a history of chronic infections. Patients receiving therapy for a chronic infection should not receive BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while receiving BENLYSTA. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Please see additional Important Safety Information for BENLYSTA on following page.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

www.GSKSource.com

Important Safety Information for BENLYSTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk of malignancies.

HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS Hypersensitivity reactions, including anaphylaxis and death, have been reported with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions.

Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension.

In the event of an infusion reaction, the infusion rate may be slowed or interrupted.

Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

DEPRESSION In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations.

USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide.

Therefore, use of BENLYSTA is not recommended in combination with these therapies.

ADVERSE REACTIONS The most commonly reported adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Other Important Information for BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: Category C. BENLYSTA should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during BENLYSTA treatment and for at least 4 months after the last dose.

Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Effect in black/African American patients: In exploratory analyses of 2 Phase III trials, response rates were lower for black patients (N=148) in the BENLYSTA group relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the BENLYSTA group did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering BENLYSTA for black/African American patients.

References: 1. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012. 2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. 3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.

Arthritis Rheum. 2011;63(12):3918-3930. 4. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178. 5. Data on file, Human Genome Sciences, Inc.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

©2013 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. BN2289R0 February 2013

BRIEF SUMMARY BENLYSTA® (belimumab) for injection, for intravenous use only.

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.

BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide.

Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo.

Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo.

Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

Infusion Reactions In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity

reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions].

BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

Immunization Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. Patients received BENLYSTA at doses of 1 mg/kg (N=673), 4 mg/kg (N=111; Trial 1 only), or 10 mg/kg (N=674) or placebo (N=675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (Trial 2) treatment was given for 72 weeks [see Clinical Studies]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.

The population had a mean age of 39 (range 18-75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo.

The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions].

The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo).

Brief summary of Prescribing Information continued on reverse.

Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established.

Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Patients Treated With BENLYSTA 10 mg/kg Plus Standard of Care and at Least 1% More Frequently Than in Patients Receiving Placebo plus Standard of Care in 3 Controlled SLE Studies

Nursing Mothers It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Preferred Term Nausea Diarrhea Pyrexia Nasopharyngitis Bronchitis Insomnia Pain in extremity Depression Migraine Pharyngitis Cystitis Leukopenia Gastroenteritis viral

BENLYSTA 10 mg/kg + Standard of Care (n = 674) %

Placebo + Standard of Care (n = 675) %

15 12 10 9 9 7 6 5 5 5 4 4 3

12 9 8 7 5 5 4 4 4 3 3 2 1

Immunogenicity In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Pharmacokinetics].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment.

Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5 and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24% and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pediatric Use Safety and effectiveness of BENLYSTA have not been established in children.

Geriatric Use Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.

Race In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies]. Use with caution in black/AfricanAmerican patients.

OVERDOSAGE There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

PATIENT COUNSELING INFORMATION See Medication Guide.

Advice for the Patient Patients should be given the Medication Guide for BENLYSTA and provided an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.

Mortality: Patients should be advised that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions].

Serious Infections: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precautions]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection.

Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions].

Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes. [see Warnings and Precautions].

Immunizations: Patients should be informed that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired

by BENLYSTA [see Warnings and Precautions].

Pregnancy and Nursing Mothers: Patients should be informed that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations]. Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations].

BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline.

Manufactured by: Human Genome Sciences, Inc. Rockville, Maryland 20850 U.S. License No. 1820 Marketed by:

Human Genome Sciences, Inc. Rockville, MD 20850

GlaxoSmithKline Research Triangle Park, NC 27709

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

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

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

Clinical Topics of High Interest: Aging—With the aging of the US population there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people.

Allergies—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Under­treatment and lack of adherence are common obstacles to patient management.

Arthritis—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated.

Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs.

Cancer care—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

Cardiovascular disease—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

Diabetes, Obesity—The growing epidemics of these twin metabolic conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies.

Gastrointestinal conditions—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge.

Infectious Diseases—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance.

MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

Pain Management—Chronic pain is associated with many complicated medical disorders and an enormous economic burden, yet pain medications are still underused.

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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A Critical Connection Between B-Cell Signaling and the Tumor Microenvironment* Until recently, research of B-cell malignancies has been focused primarily on the B cell itself.1 However, new insights have revealed that there are important interactions between the B cell and the extracellular microenvironment that are dependent on intracellular signaling pathways mediated by various kinases including Bruton’s tyrosine kinase (BTK).2,3 These interactions suggest an important role in B-cell homing, adhesion, and migration.4,5 Further elucidation of these processes could change how we view and approach B-cell malignancies.

BTK signaling pathways and the microenvironment*† FDC BCR TLR T cell MyD88

BTK

Lyn

CXCR4/5 PI3K

MSC

PIP3

Syk

BTK

G G

Nucleus

PLCγ2

B cell

BTK

DAG NF-κB

IP3

PKC Ca2+

*

Based on in vitro data.

Illustrations not to scale.

†

Pharmacyclics, Inc., and Janssen Biotech, Inc., are currently investigating BTK in search of insights that could improve the lives of patients with B-cell malignancies.

Visit us at www.BCellSignals.com.

BCR

CD79A CD79B

Prosurvival Signals Lyn

Syk

BTK PLCγ2

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Normal and malignant B cells rely on multiple prosurvival pathways to avoid apoptosis.6-9 In B-cell malignancies, microenvironmental cues may inappropriately initiate signaling cascades through several kinases, including BTK, driving uncontrolled growth and survival of malignant B cells.5,10-13

NF-κB

B-Cell Homing Cells in the microenvironment secrete chemoattractant factors to promote the homing of B cells to lymphoid tissue.14 These factors act via signaling pathways involving BTK and other kinases.4,15

VCAM-1

Adhesion and Migration

VLA-4

The upregulation and increased migration of B cells may lead to retention of malignant cells in proliferative environments and the promotion of chemoresistance.16-18 BTK is an essential mediator of multiple adhesion and migration processes.4

References: 1. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103.

2. Kil LP, de Bruijn MJW, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3:71-83. 3. Pighi C, Gu T-L, Dalai I, et al. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol (Dordr). 2011;34:141-153. 4. de Gorter DJJ, Beuling EA, Kersseboom R, et al. Bruton’s tyrosine kinase and phospholipase C 2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26:93-104. 5. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367-3375. 6. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175-1184. 7. Rauch M, Tussiwand R, Bosco N, Rolink AG. Crucial role for BAFF-BAFF-R signaling in the survival and maintenance of mature B cells.

PLoS One. 2009;4:e5456. 8. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol. 2007;85:471-475.

9. Grumont RJ, Rourke IJ, O’Reilly LA, et al. B lymphocytes differentially use the Rel and nuclear factor B1 (NF- B1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med. 1998;187:663-674. 10. Nishio M, Endo T, Tsukada N, et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1 . Blood. 2005;106:1012-1020. 11. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120:4684-4691. 12. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF- B activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563-574. 13. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88-92. 14. Okada T, Ngo VN, Ekland EH, et al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med. 2002;196:65-75. 15. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658-3667. 16. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113:4604-4613.

17. Binsky I, Lantner F, Grabovsky V, et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner.

J Immunol. 2010;184:4761-4769. 18. Kurtova AV, Balakrishnan K, Chen R, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114:4441-4450.

© Pharmacyclics, Inc. 2013 © Janssen Biotech, Inc. 2013 04/13 K08BR13002

3rd annual conference AVBCC 2013 Steering Committee Co-Chairs

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Burt Zweigenhaft, BS President and Chief Executive Officer OncoMed Onco360 Great Neck, NY

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

Gary M. Owens, MD President, Gary Owens Associates Glenn Mills, PA

L inda Bosserman, MD, FACP Medical Oncologist and President, Wilshire Oncology Medical Group Rancho Cucamonga, CA

ouglas S. Burgoyne, D PharmD President, VRx Pharmacy Services Salt Lake City, UT

John E. Hennessy, CMPE Vice President of Operations Sarah Cannon Cancer Services Nashville, TN

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

Kevin B. Knopf, MD, MPH Hematologist/Oncologist California Pacific Medical Center Sutter Health San Francisco, CA

J ames R. Lang, PharmD, MBA Vice President, Pharmacy Services BlueCross BlueShield of Michigan Detroit, MI

rant D. Lawless, MD, G RPh, FACP Program Director Associate Professor University of Southern California Los Angeles, CA

Douglas M. Long Vice President Industry Relations IMS Health Totowa, NJ

Jennifer Malin, MD, PhD Medical Director of Oncology WellPoint, Inc Los Angeles, CA

Thomas A. Marsland, MD President, Integrated Community Oncology Network (ICON) Orange Park, FL

atrick McKercher, RPh, P PhD President, Patient Access Network Foundation Washington, DC

Leonard Natelson Chief Executive Officer Hematology/Oncology Associates of Rockland Rockland, NY

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atthew C. Palmgren, PharmD M President Int’Ovation Signal Mountain, TN

L illie D. Shockney, RN, BS, MAS Administrative Director John Hopkins Medical Institutions Baltimore, MD

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC

F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare and Bentelligence Greenville, SC

Defining Value in Cancer Care:

AVBCC 2013 Steering Committee Report

T

he AVBCC Annual Meeting experiences expo­ nential growth in attendance and participation as oncologists, payers, employers, managed care executives, patient advocates, and drug manufacturers convened in Hollywood, FL, on May 2-5, 2013, for the Third Annual Conference of the Association for Value-Based Cancer Care (AVBCC). The conference presented an all-inclusive open forum for stakeholder dialogue and integration across the cancer care contin­ uum, facilitating an open dialogue among the various healthcare stakeholders to align their perspectives around the urgent need to address value in cancer care,

Group I: Pathways

Gary M. Owens; Grant D. Lawless; Jennifer Malin: The question of value from the perspective of pathways in oncology is focused on how to decrease care variabil­ ity to improve clinical outcomes at an acceptable and sustainable cost. Using pathways to eliminate care vari­ ability and to improve outcomes should ultimately result in cost efficiencies as well. Pathways must balance (1) population needs, which reflects how healthcare payers perceive the issue of pathways; (2) individual needs, which are dependent on the physician–patient relation­ ship; and (3) societal needs, which involve patient out­ comes and cost of care. The key value considerations related to oncology pathways involve: • Comparative efficacy, which allows us to compare various products and decide which product delivers the best efficacy

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costs, patient education, safety, outcomes, and quality.

The AVBCC 2013 Steering Committee was held on the first day of the conference to define value in cancer care. The committee was divided into 7 groups, each representing a key stakeholder in oncology. The goal of the Steering Committee was to define value from the particular point of view of each of the stakeholder groups and to suggest how that particular perspective can contribute to the value proposition in oncology, by balancing cost, quality, and access to care to improve overall patient outcomes. The following summary high­ lights the major points addressed by each group.

• Toxicity, which is directly related to efficacy and is directly related to the value of a product • Cost, which also must be incorporated into the defini­ tion of the value of pathways • Finally, pathways cannot be universal but must apply to specific populations (ie, population needs); path­ ways need to apply to 80% or 85% of the population, but there will always be the need to deviate from pathways to meet selected individuals’ parameters.

When discussing value, it is also necessary to ask who sets the pathway; is the pathway a national or a local standard? That is, is the pathway being set up by path­ ways companies that are in the business of promoting pathways and selling a product, or by a public organiza­ tion? We raised some of the pros and cons related to na­ tional versus regional pathways, whether private or public.

Pro: Pathways developed by national organizations

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can be authoritative. Theoretically, they could be un­ biased, and they would create uniformity across regions.

Variability of care as a problem has already been recog­ nized in the 1970s, and it is still a problem today. Na­ tional pathways would create uniformity of care, and such a large, authoritative source could drive compara­ tive effectiveness that does not exist now.

Con: National pathways would be slower to imple­ ment. Anything done at a national level is going to take more time. It might be hard to get all of the proper stake­ holders together on a national level. More important, a national guideline or a national pathways office has a large potential to do harm, because it is conducted on a national basis.

The goal of implementing pathways is to drive better outcomes and more costeffective care. For that, we need unbiased comparative effectiveness data on cost and outcomes. Pathways also need to be able to create payment models that align financial incentives across all stakeholders.

Pro: Regional pathways, similarly, could be unbiased, and a regional group would be easier to structure and put together to get the right stakeholders across the table.

Con: A regional pathway is going to result in varia­ tions of care by those regions. Because it will not be at the local level but rather at a regional level, regions may not have the power to drive effective activities that are so essential.

The goal of implementing pathways is to drive better outcomes and more cost-effective care. For that, we need unbiased comparative effectiveness data on cost and outcomes. Pathways also need to be able to create pay­ ment models that align financial incentives across all stakeholders, so that they are not inadvertently driving care based on financial drivers. We believe that advo­ cates could provide a supporting role for this by helping to reinforce pathways, because cancer care has evolved to the point where not every treatment choice needs to be available, regardless of cost.

In addition, end-of-life care concepts must be incorpo­ rated into pathways. The resources spent on unnecessary care at the end of life can be carefully monitored; they are often used unnecessarily and can better serve other pa­ tients who would benefit more from care. End-of-life care must be part of the pathways to prevent futile and poten­ tially unnecessary care, considering the limited resources.

Finally, pathways probably need to include branches

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to allow for proven precision (or personalized) medicine decisions. But we must insist on “proven” medicine, be­ cause many precision medicine tests are directional, or they do not necessarily create decision points. We need to make sure genetic tests can actually do what they promise to do before they are incorporated into path­ ways. Once they are established with evidence, they can be incorporated into the pathways. Therefore, pathways have to be a “dynamic process” that incorporates new products that come to market with appropriate evidence.

Group II: Reimbursement

Burt Zweigenhaft; John E. Hennessy; Douglas S. Burgoyne: Our discussion involved current payment methods and what they should be in the future, focusing on 2 key points. We need to move away from the oldschool fee for services that are inclusive and bundled to new approaches that will incorporate individual val­ ue-added services that are not currently covered and recognized, such as advance care directives, care plan­ ning, medication treatment management, drug adher­ ence, side-effect management, and educational services that carry value for patients with cancer. We probably all agree that our current system of payments and reimburse­ ments is not appropriate for the breadth of services that need to be incorporated into appropriate care today, as we need to improve how we pay for services. Recognizing and then scoring or monetizing individual components of care that have clinical utility is the greater part of the value proposition in oncology care tomorrow.

We probably all agree that our current system of payments and reimbursements is not appropriate for the breath of services that need to be incorporated into appropriate care today.

We are beginning to recognize the great value that multidisciplinary care team members and oncologists can provide in terms of clinical management, diagnos­ tics, and treatment, and not just dispensing drug thera­ py. So it will be important to measure and score clinical value-added activities to receive reimbursement for ad­ ditional cogitative services. We need to move to unbun­ dling or decoupling bundling from dispensing drugs, and start to demonstrate the value that oncologists and on­ cology treatments deliver for patients globally, by break­ ing the costs apart to recognize the value of each service; for example, administrative services improve outcomes in terms of patient compliance with oral therapies, but that service is currently not being reimbursed.

The provider will have to define what is fair market

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value for the additional clinical management services delivered. It is always nontransparent and extremely difficult to recognize the value of the entire treatment continuum when we are bundling so many services into the drug-dispensing margins. One novel idea would be paying a premium reimbursement modifier for the first time that an oncologist treats a new patient versus the eighth or tenth round of treatments. How do we assess the value of these differences in the care continuum, and how should the reimbursement reflect that difference?

We did not come up with the solutions to these ques­ tions, but these are the types of questions that should be raised in relation to value and quality of care in oncology.

We are, however, in agreement that we must recognize the differences in these services, and it is time to begin to pay for these different services. We need to separate the first encounter with a patient from other components of the treatment, and from reimbursement for drugs.

Group III: Regulatory/Government

Jayson Slotnik; Douglas M. Long: How does the federal government define value? The short answer is, it does not consider value in its decisions in oncology. So, our discussion quickly evolved into what the role of the federal government is in terms of value in cancer care.

However, although we said that the government does not define value, value is directly related to cost, and the government overall defines value as the lowest cost. But the government and everybody need to take a broader perspective of value so that cost is not the only compo­ nent of value.

In terms of value, we should be looking at patient care as a total engagement of the provider care and the global episode of care. We think that the Association for Val­ ue-Based Cancer Care should drive the conversation around value by making sure that the definition incorpo­ rates all related costs of cancer care, not only drug costs, as well as outcomes and measurements; we also need to provide tools to measure the outcomes in oncology. So, the definition of value from a regulatory perspective should include all of these components—total costs, outcomes, and measurements.

Mr Zweigenhaft: The Centers for Medicare & Med­ icaid Services (CMS), which is responsible for 45% of the patients with cancer in this country, is really the 800-lb gorilla we often talk about in healthcare. CMS truly influences the market, and your group believes that this regulatory body does not know where it is going, and it is not setting the tone in the industry; does this mean that the tone will be set outside of government services?

How do you see this evolving?

Mr Slotnik: CMS is a complicated entity, because of the rules that have been written for it by Congress on

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how CMS can provide access to care. Medicare coverage policies have evolved over time as a result of what Con­ gress has allowed CMS to do in terms of drug coverage (eg, in the case of fail-first drug coverage in Part B, or by trying to shift drugs over to Medicare Part D or vice versa). CMS is trying to limit what it has to pay for.

Nevertheless, over the past 7 or 8 years, we have seen a shift toward paying for value by Medicare, paying for what works, and paying for evidence. This began when the Medicare Modernization Act (MMA) of 2003 was passed. It has taken time to implement the MMA, be­ cause regulatory bodies, such as CMS, move slowly as a result of the politics around any change in policy, partic­ ularly as it relates to cancer care.

Value is directly related to cost, and the government overall defines value as the lowest cost. But the government and everybody need to take a broader perspective of value so that cost is not the only component of value.

But, over time, we will likely start to see more bound­ aries to expanded access to care. Certain things will be less accessible over time, and we have already seen this in policies evolving to limit what Medicare is paying for, using the approach of only paying for what works; how­ ever, CMS must first figure out what works, which com­ plicates things. Sometimes when we know we pay for something that does not work, if we cannot get it there, we do not go back; we just end up with more questions than answers. This is hard to balance.

Group IV: Advocacy Groups

Lillie D. Shockney; Patrick McKercher; F. Randy Vogenberg: From an advocacy group’s perspective, which represents the patient’s perspective, we deter­ mined that value has to be very patient-specific: what each individual thinks is important and has value. One patient sees one thing as important, and yet another pa­ tient may see that as not being important. Certainly both patients should receive patient-centered care, which is easy to say but not always easy to deliver. And that care should be provided at the right time, in the right setting, and obviously with the right treatment, based on evi­ dence-based medicine. There is a need to develop what we call “a new platform” that can guide patients and physicians in addressing a patient’s life goals.

One of the very first things we should do before we touch patients is to talk to them about their goals, their work, their plans, and find out who the patient is. For

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example, if the patient is planning to start a family next year, you need to consider fertility preservation to help her or him to be able to have a family after the chemo­ therapy. Incorporating the patient’s life goals into the treatment considerations is important.

Value for the patient includes getting decision-mak­ ing tools. In the case of patients who may become longterm survivors, we need to empower them to be able to participate in the decision-making about their treat­ ment. We must not have treatment done to the patient, but have treatment done with the patient. The same applies to patients with metastatic disease, in terms of decision tools, to give them the power to participate in, and have their voice heard about, their treatment. More treatment does not make it better treatment, especially in the metastatic setting.

A recent study showed that between 40% and 60% of patients with metastatic cancer believe that the chemo­ therapy they are getting will cure them, which indicates that there is no discussion with the patient.

Value for the patient includes getting decision-making tools. In the case of patients who may become long-term survivors, we need to empower them to be able to participate in the decision-making about their treatment. We must not have treatment done to the patient, but have treatment done with the patient.

We also have to promote survivorship care to begin at the time of diagnosis. We need to be proactive about side effects and try to prevent them, instead of telling pa­ tients to expect them. Fatigue is the number one struggle for patients with cancer. The evidence shows that if a patient with cancer is power walking 3 times weekly for 30 minutes, fatigue will be reduced significantly. So why are we not making sure patients do that?

There is also value in patients having a patient advo­ cate, which in most cases would be an oncology nurse advocator who understands the disease and the treat­ ment and can provide education and support, and iden­ tify barriers, including cultural or financial barriers.

It is crucial to change the goals of health insurance coverage. Rather than focusing on covering treatment, the value to patients is in coverage for preventive care, which promotes health. There is more value in paying for keeping people healthy than paying for sickness.

Another big value issue for patients (as well as for pro­ viders) is continuity of care. Value-based care must ensure

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that we are delivering care in an efficient way, that it is effective, that we are not overtreating or undertreating, and that patients have access to care, in terms of geogra­ phy and time. For example, many patients cannot afford to take time off from work to get a screening test. So that patient will not have the test. Geographic access and ex­ tended-hours access to a facility can improve overall care.

Finally, quality of life (QOL) must also be included in the patient’s definition of value. When QOL is poor, survival may not be what the patient perceives as value.

Patients without QOL often prefer not to survive. Sur­ vival without QOL is not the ultimate value for patients.

Group V: Oncology Practices

Linda Bosserman; Thomas A. Marsland; Leonard Natelson: Oncology care is provided in academic practic­ es and community practices but 80% of cancer care has been given in community practices. However, many of these practices are being bought up by hospitals that offer the opportunity to reduce fragmented care but will be challenged to maintain the innovation and engagement of entrepreneurial physicians. We believe that we are going to have a culture change in oncology. Until now, practices have been very physician-centric. Most physi­ cians within a private oncology practice have 4 driving principles: (1) they love to practice medicine; (2) they value “cowboy independence” in patient decision-making and in care innovations, which was drilled into all of us in medical school; (3) they have business interests in run­ ning the practice; and (4) they are interested in research.

But we now have a shortage of oncologists, and the question is, do we need physicians to run the business and do the negotiations, or do we need them to use their 14 years of training to lead teams that take care of pa­ tients, which no one else can do?

We believe that more systems of care are being creat­ ed because patients want to have integration and focus on their overall health. As we move toward a pa­ tient-centered system, we need to remember that pa­ tients do not care how their doctor gets paid. Patients want to get the care they need—the right care, at the right time, in the right setting, for the best price. Cancer care is no longer about the doctor, it is about the patient.

And it is moving from a focus on treatment at any cost to education and discussions with patients and payers about the overall health impact of care.

The physicians are willing to work in systems, and it does not matter if the system is owned by physicians (as in the Healthcare Partners, IPA), by Kaiser (when the payer owns the system), or by a hospital or hospital system. As systems compete, we are going to have real-world data and outcomes-based care that will allow us to continually re­ fine what is offered to achieve the best value, but the fact

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is that patients today want to go into a health system. In California, for example, we have 3 systems in the north: Sutter Health, Catholic Healthcare West, and Kaiser, and some outliers. San Diego also has 3 big systems. And al­ though our big region in southern California is fighting and arguing, everyone is going to come together quickly, because Kaiser has taken a 40% market share in Califor­ nia: this is a clear message from consumers that they want integrated and cost-effective care that is focused on their health, with easy web access to their clinicians, their data, and their individual health information.

In the Medicare Advantage plans in Kaiser, patients do not have a copayment for chemotherapy or radiation.

Other Medicare Advantage plans with smaller Individu­ al Practice Associations in California can have up to 20% copays; just recently, annual out-of-pocket maxi­ mums have been established. One of my patients with stage I breast cancer said, “If I have a recurrence, I don’t want to have copays. I’m switching to Kaiser.” We are seeing people with private PPO insurance, including professors and business professionals, switching to Kaiser for comprehensive, integrated care; these are people who would not have gone with Kaiser before. This is a culture change, and we all have to reengineer our practices to engage the patient, the payer, and our colleagues. To do that, we need to standardize care, we need to have care and payment integration, and we need to have scale.

It is possible that not every small private oncology practice will have to go out of business, but all practices are going to need some networked resources to empower them to have the right pathways and all of the latest information to be able to make decisions at the point of care, to provide patient education and patient resources online and in the community. We are going to have to rethink our systems and put the patient at the center, which is where value is in cancer care.

A physician does not have the expertise in every can­ cer and every new treatment in rare diseases, nor the administrative expertise and support for the business so­ phistication that we need, which will be based on per­ sonalized data. As the number of molecular markers continues to grow, who can remember every mutation?

Most oncologists work in general oncology. They do not have the luxury to specialize. Oncologists are going to need all of the tools to deliver value-based care. We need to know which mutation requires which drug to deliver the most cost-effective, value-based care.

We are going to have to decide what data we need and how to transfer the data into real-world information that is useful. This means that we have to standardize and learn to work in and provide leadership to teams, including nurse practitioners, physician assistants, regis­ tered and licensed vocational nurses, medical assistants,

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navigators, social workers, therapists, administrators, and payers to come to terms with new realities in oncology.

As a senior oncologist, the exciting reality is that the doctors we have interviewed over the past 3 years are exceptionally well trained and enthusiastic to work in a comprehensive team environment.

It is possible that not every small private oncology practice will have to go out of business, but all practices are going to need some networked resources to empower them....We are going to have to rethink our systems and put the patient at the center, which is where value is in cancer care.

Our partners in the pharmaceutical companies know what they currently need from a regulatory perspective to get a drug on the market, and they have been able to use data from clinical trial patients on progression-free survival, disease-free survival, and overall survival, with support for significant toxicities to get those drugs on the market. But they do not know where real-world data come into this picture: which real-world data, from whom, and for which comorbidities have what benefits, with what toxicities and preferences for impact on their overall health, especially in advanced terminal diseases.

These are all relevant questions.

We need our drug development partners to pay for all the new and expensive drugs and to figure out the value of those drugs with data that matter to patients. The value perspective means that we know what the cost is in relation to all the relevant outcomes and whose out­ come is going to be the most important. How can we begin to get honest data to patients? We have had a lot of data provided to doctors, and we have been incentiv­ ized to give drugs to patients, but we have not been in­ centivized to improve health. We are now moving to­ ward improving health. If patients with lung cancer in the real world live about 1 year, what educational mate­ rials should be provided to a patient at various ages, with various comorbidities, to discuss a therapy that may delay death but with significant risks of hospitalizations, suffer­ ing from toxicities, and the possibility of dying from the therapy? We have been incentivized and trained to focus on treatment using the few patients who might achieve an unusual long-term benefit while overlooking the many who suffer needlessly during the time they have left to live. As was noted in one example, we can reduce patient fatigue during chemotherapy by instituting power walking, which is treating to improve health—not a major focus of doctors.

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Most physicians have not been trained or able to focus their teams on the benefits of nutrition and exer­ cise on long-term health, despite all the data we have.

We need a different payment system that will recognize the components of care that patients need in these new systems.

Survivorship is just now starting to be addressed by phy­ sicians, yet it lowers recurrence risk and improves overall health outcomes. Most women with breast cancer are going to die of heart disease, not cancer. As oncologists, we have been incentivized only to focus on the risk of recurrent breast cancer and not to deal with other health issues, such as lipids, bone density, or cardiac risk that interact with adjuvant therapies to impact long-term health. That’s not treating for health.

Personalized medicine will require teamwork. We need to change the physician role. Young physicians are will­ ing to lead and participate in teams, and they want to practice medicine. They are happy to go into systems, but they need a fair compensation to lead an integrated team, regardless of whether it is with a pharmacist, nurse practitioners, physician assistants, or nurses, who are also undervalued in our system. Nurses are experts at compli­ ance, adherence, patient education, and overcoming barriers for our patients, but when the reimbursements for infusion and drugs were removed, that changed the role of nurses, who are now only administering chemo­ therapy. Nurses need to be better valued in the system for their knowledge and their skills.

Overall, hospitals consider value not by traditional economic terms of cost versus quality, but value by market share—how many patients they serve, how many doctors they have, the status of the doctors, the size of the hospital, and the hospital’s appeal to the patient, who is seen as a consumer.

We need a different payment system that will recog­ nize the components of care that patients need in these new systems. Our group had many challenges in deciding what the actual outcome end points should be. Until we standardize the data and demand real health outcomes from our care, we will remain challenged in our current delivery models, which are fragmented, with costs that are not sustainable now. As we see systems delivering integrated care with real-world data on health outcomes, we see consumers choosing them. That is stimulating others to come together in systems that can compete

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better on cost, quality, and care to improve value to consumers. As competition expands, we can all learn from each other as the German systems have done.

Mr Zweigenhaft: Do you believe that community oncology will be around in the future, or are we all going to be working in the systems?

Dr Bosserman: I think we will have many different models. Healthcare is still regional, but a community practice cannot do it alone anymore. They have to be a part of some system, which is empowered by an electron­ ic medical record system or a network. Telemedicine is going to have a bigger role. I think we will have big in­ tegrated systems with managed care, but primary care physicians do not want to manage cancer. That remains the role of the oncologists, and that is cost-effective.

Mr Zweigenhaft: Our group agreed that the reim­ bursement system has to change to recognize the value of nurses to patients. We also need to agree what the diag­ nostic value is for the patient. Is the first positron emission tomography (PET) scan worth more than the seventy-­ fifth scan? At a recent meeting’s survivorship session, a woman who had lost her husband to cancer asked, “How many PET scans do you think he had in his last 2 years of life? He had 75 scans. Was the value of the first scan the same as the value of the seventy fifth scan?” This is a sign of a broken system. We need to move to a system of reim­ bursement that only pays for value-based care.

Groups VI: Hospitals

Kevin B. Knopf; Craig K. Deligdish: The ability of hospitals to deliver value is unclear. Hospitals are not focused on value as cost versus quality of care but on value as volume. In northern California, for example, there are 3 main systems: Kaiser has more than one third of the market share; Sutter Health system has 28 hospi­ tals in various foundations and different maturities; and Catholic Healthcare West is still surviving. There are also several academic centers. Sutter Health is looking for larger contracts and is focused on attracting patients with good insurance or Medicare, but not Medicaid. We had difficulty defining what a hospital actually is. The model is different with each system. In Kaiser, a hospital is part of a large staff model HMO, with alignment of outpatient and inpatient healthcare financially. Catholic Healthcare West has a private practice model with some interplay between the oncologists and the hospital sys­ tem. By contrast, Sutter Health, as well as Catholic Healthcare West, have a traditional hospital model, in which oncologists are separate from the hospital and so are the ancillary services. There is a growing movement toward “Foundation acquisition” of oncology practices in the Sutter Health system.

So, overall, hospitals consider value not by traditional

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economic terms of cost versus quality, but value by mar­ ket share—how many patients they serve, how many doctors they have, the status of the doctors, the size of the hospital, and the hospital’s appeal to the patient, who is seen as a consumer—the traditional “heads and beds” model. Therefore, buying a proton beam therapy machine, for example, to deliver radiation to patients with prostate cancer makes sense, because it gives the hospital status to have this expensive type of radiation, the healthcare system can charge a $50,000 premium per patient for this advanced technology, and it impresses people within the organization and can serve as a mar­ keting tool. The hospital can advertise that it has this advanced type of radiation, with no regard to whether it has true value to the patient or to the payer. Cost is not seen as part of the value equation.

Whether this will change depends on the payment system and on how hospitals and providers will be paid in the future. At present, hospitals are still looking at the number of beds that are being occupied by patients and the number of patients being treated, and in oncology the number of “chairs per person per day” being used for chemotherapy. They are not looking at the cost-effec­ tiveness of a particular chemotherapy regimen as much as how many patients are being treated daily. Hospitals are not yet in the habit of looking at overhead costs or even at patient outcomes.

A landmark development was when Leapfrog part­ nered with the CMS and another policy think tank to review hospitals based on their CMS violations and made this information available online to patients. The idea is that patients would be able to choose a hospital based on how many (or few) CMS violations it has and would go to the one with the best compliance. But, in many cases, patients still select a hospital based on their health plan.

We wonder when hospitals would start to look at value. We believe that hospitals would not look at value until they are forced to by reporting systems from the public about their outcomes. That may take a while until the outcomes from cancer services are reported, and the outcomes are based on what we can measure and what we, as oncologists, think are important things to mea­ sure. The value of these outcomes may not be public knowledge and may not be tracked for a while, even though we have increasingly better information systems.

Ultimately, we believe that value lies in patients’ out­ comes based on the treatment received.

The model that hospitals are using to define value remains based on the number of daily computed tomog­ raphy scans, the number of daily PET scans, and the number of patients in the hospital per bed per day rather than the value of the specific procedure or imaging study.

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Hospitals will change the way they define value de­ pending on future changes in healthcare, such as the implementation of accountable care organizations (ACOs) or competition among health systems. If sys­ tems begin to compete on costs, hospitals may begin to look at them.

Hospitals will change the way they define value depending on future changes in healthcare, such as the implementation of accountable care organizations or competition among health systems. If systems begin to compete on costs, hospitals may begin to look at them.

We had different views on whether pay for perfor­ mance will become the new payment system or whether it is a failed model. Patients today choose a hospital in part based on their perception of quality of care, which may be affected by the marketing efforts of hospitals rath­ er than on meaningful outcomes. Will that change in the future? How does the patient define quality of care?

This takes us to the providers and the way that they practice medicine today, which is changing, even in oncology. Many physicians today prefer to work in a hospital, where they work fewer hours than in private practice and are paid a set salary. They are not willing to take on administrative responsibilities or any risk. But there is a shortage of oncologists today, and we believe that nurse practitioners will play a bigger role in oncolo­ gy in the future. Their role in patient care may level out with that of oncologists at some point. It is not clear how this will affect oncologists in a hospital system.

Will hospitals start to tease apart the value of the care provided by oncologists? Evidence shows that the newer generation of doctors increase the cost of care, because, rather than thinking about what is possible, they tend to order many tests, which may reduce the value of care, when the testing is not necessary or is not cost-effective; this depends on the individual physician. This leads us to ask, “Will we eventually begin to measure the value of an individual physician or the value of the cost data?” We don’t have information systems ready to measure that at this point, and it is not clear when this may happen.

Mr Zweigenhaft: With regard to hospitals assuming risks, if they are currently focused on the number of pa­ tients and the number of “chair time” per day in cancer care, do they have the infrastructure to measure what oncologists do and to deal with risks when the current system falls apart? Are hospitals ready to manage risk?

Dr Deligdish: We do not believe that hospital systems

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are in a position to manage risk. In most communities, hospital systems drive the relationship between the health plan and the providers, and if they are unwilling to accept risk in the oncology arena, this indicates that they are not ready to assume risk management elsewhere. We are not aware of many situations in which hospitals have created relationships where they have agreed to accept downside risk. Some hospital systems have created relationships with health plans that are based on a profit-sharing type of arrangement, which is a different type of an ACO. These ACOs are specific to oncology (ie, they have no primary care patients), and they are based on a relationship in which the hospital has agreed to provide some services that potentially could measure quality or outcomes for providers who care for patients with cancer.

Another development in hospitals is that, in the past, an oncologist in a private clinic had access to all hospital systems. But recently, hospitals have been trying to cap­ ture physicians and restrict them to the specific hospital, where a provider is limited to one system. This is not fully enforced yet, but it could become an issue. This takes us back to the idea that to continue to be a com­ munity practice, the practice has to be large enough to be dominant in that particular community so that the hospital system cannot afford to not have the practice as part of their team.

Group VII: Managed Care Organizations

James R. Lang; James T. Kenney, Jr; Matthew C. Palmgren: We began the discussion by focusing on risk.

We are unaware of anyone taking downside risk in on­ cology. Oncologists are trying to survive, and some programs involve upside risk, especially related to path­ ways. There is downside risk for those who do not par­

There are many cases where managed care is driving down reimbursement collectively, forcing providers or patients to buy alternate types of drugs based on cost.

Can we avoid this? ticipate in pathways, because the standard fees have not changed over time, and the only increases are the path­ ways fees. In addition, inflation reduces payments for providers, but there is no true downside risk. Next, we discussed payment for quality, which for us means pay­ ment for HEDIS (Healthcare Effectiveness Data and Information Set) measures, not actual outcomes. Man­ aged care organizations (MCOs) are paying for various markers, which are not the same as true outcomes.

MCOs have enough data, or enough collected informa­ tion, to determine outcomes.

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Drug reimbursement is a big issue. Both CMS man­ aged care health plans have been squeezing reimburse­ ment. There are many cases where managed care is driving down reimbursement collectively, forcing pro­ viders or patients to buy alternate types of drugs based on cost. Can we avoid this? Blue Cross Blue Shield (BCBS) of Michigan, for example, as well as other plans, in­ creased the payments for generic chemotherapy drugs, so the payment for a small vial of generic 5-fluorouracil, for example, is small, but the overall treatment involves a much bigger reimbursement; that is, many plans are moving away from the “buy-and-bill” model for drugs to the bundling payments model.

Starting January 1, 2014, BCBS of Michigan will begin to reimburse nurses for managing the patient.

Starting January 1, 2014, BCBS of Michigan will begin to reimburse nurses for managing the patient. The patients will be identified by the plan, which will add extra reimbursement to the physician’s practice.

We are also seeing a significant increase in outpatient clinic costs. It is difficult for the health plan to try and manage this process, because the plan often has contracts with the hospital networks. When the plans squeeze the system in one place, it impacts the rest of the contracts.

The problem is that it is very difficult to isolate the out­ patient hospital reimbursement within the totality of the reimbursement contracts.

In addition, plans would like to incentivize home in­ fusion and ambulatory infusion, but this is often very difficult to do. In addition, there is not much effort today to educate patients about infusion, and there are no ben­ efits designed to help patients transition to home or ambulatory infusions.

With regard to drug innovation and companion diag­ nostics, the main issue is the lack of appropriate clinical data for companion diagnostics, especially in oncology.

There is a great need for more data and outcomes related to the use of diagnostics tests in association with specific oncolytics. The problem for health plans is that there is not enough evidence to try to understand the outcomes and make coverage decisions regarding what tests and what downstream drugs should be used and when.

A related topic is comparative effectiveness research (CER). Clearly health plans want CER-based evidence, but, to date, the information coming from this research is not comprehensive enough. A study may compare 1 drug versus another type of treatment or 2 drugs, but not the entire scope of therapies available for the same con­ dition. For example, there are at least 7 major therapies

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for prostate cancer, but the research only compared 2 or 3 treatments. That is not sufficient. Furthermore, there is not enough money to study all of these companion tests.

Doing a government-supported comparative effective­ ness study for these tests would require approximately $2 billion annually, and who has this type of money?

The role of formularies historically has been seen as getting the right drug to the right patient at the right time. Plans would like formularies to be evidence-based, but that is not always the case, because plans do not have all of the necessary evidence to make decisions based on it. Today, with health plans having 80% to 90% generic drug dispensing rates, or even higher in the case of Kai­ ser, formularies are going to change their approach to benefits from time to time. To address costs, we some­ times offer coupons for areas that include expensive brands. Currently, formularies have 3 to 5 tiers, and it is difficult to know where formularies will be in 3 years.

The use of prior authorizations is increasing in the medical benefit. Prior authorization is not easy, because plans are not used to dealing with claims data. The data are often not in real time, and therefore may not be ac­ curate, because the claims can come in 3 weeks after the patient received the medication or treatment. Neverthe­ less, plans are clearly focusing on prior authorization on the medical benefit side.

Mr Natelson: As a representative of small oncology private practices, we are being squeezed by health plans, and they refuse to negotiate an increase with us. Prior authorization is costing us money, but the payer will not increase our reimbursement, even though we have to hire staff to do the prior authorization. This pushes many oncologists to join a hospital, where they will not have to deal with all this. But payers will negotiate with the hospital, because hospitals are a lot bigger and have mar­ ket share, which makes it necessary for payers to deal with them. But the payer tells the private practice, “if you don’t play by our rules, we are going to not keep you in our network.” It is surprising that private insurance plans do not see that they should help community oncol­ ogy stay in business, because they are less expensive and deliver quality care at a lower cost.

A level 3 office visit in community oncology costs 60% of what a level 3 visit would cost in a hospital set­ ting. It costs the payer more, but the payer is forcing community oncology to sell out to a hospital. The reality is that hospitals can then put pressure on payers to in­ crease their reimbursement, because hospitals have mar­ ket share; if the payer is not complying, the hospital will find another payer.

So, the dilemma is why payers are squeezing commu­ nity oncology out of business, while they end up dealing with a hospital system that is bigger than they are and

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can therefore put pressure on the payer to increase their fees. How do you balance this gap?

Dr Lang: It is fair to ask how we can keep oncologists inside different plans. One way some plans try to do this is by the use of pathways, as was discussed earlier. Every­ one is trying to tie value to pathways, whether it is pay-for-performance pathways, pathways based on the National Comprehensive Cancer Network Guidelines®, or the pathways used by P4Health (by Cardinal Health) in Michigan. What they are all trying to do is bring value by changing the profit margins.

Our current payer system is broken, and we need to fix it. Most of the reimbursement in oncology today is based on drugs. The question is how to take advantage of that in the near future while changing the dynamics of the system later...and paying for value and quality.

Eliminating the margins altogether on drugs will take 5 or 6 years, because we have to come up with a new payment system. Many plans are using generics to adjust the margins. We are adjusting the margins based on the guidelines now, because this helps to use generics in on­ cology. Our current payer system is broken, and we need to fix it. Most of the reimbursement in oncology today is based on drugs. The question is how to take advantage of that in the near future while changing the dynamics of the system later, after getting rid of all the margins and paying for value and quality, as every group has been discussing here.

Mr Natelson: We need to get away from prior autho­ rization and use pathways to replace prior authorization.

Payers should tell community oncology that they are not going to increase their overhead and that they are going to work with the community oncology.

Dr Lang: That is where quality of management comes in. Payers are willing to replace prior authorization with pathways, mostly with pathways that follow the NCCN guidelines. Payers are telling providers that if they follow these pathways they will eliminate the prior authoriza­ tions and get rid of some of the administrative overhead that is caused by the payer. The truth is, we need a tool to ensure that doctors and pharmacists follow the best evidence; not all doctors and pharmacists follow the lat­ est information. That is what prior authorization does and what pathways based on clinical guidelines can do.

You are right that oncology is moving so fast, and the prior authorizations are changing almost every 6 months

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because of new evidence, new published research, and new evidence-based guidelines. Health plans have no intention of putting oncologists out of practice, but the system is moving too fast and we need time to adapt to new information. Payers have created some of the prob­ lems for oncology practices, but that is not their inten­ tion. There is a major shift in the dynamics of oncology.

As noted, BCBS of Michigan is rewarding for quality of care in its new program. Providers that are 80% com­ pliant get a 10% increase in payment. For oncologists, this could be up to 20%, and we are paying the increased margin on 13 generics. As mentioned before, on January 1, 2014, BCBS of Michigan is instituting provider-deliv­ ered care management fees, which will also pay for on­ cology nurses, who are not being paid today for their patient management.

The program started with 50 practices 3 years ago, paying for these fees for primary care physicians. A year ago, it expanded the coverage to 400 practices, and they have 400 nurses in the state of Michigan who are em­ ployed by these organizations. The third phase will be launched in January by paying these fees to oncology practices. It involves many changes to the practice, such as making nursing appointments and having space for nurses to see patients. This is not bulletproof, and it has taken much work to get started, but it is working and it is a major shift. The payment is on a patient-by-patient basis, and the plan sends monthly reports that indicate which patients are eligible. Again, this is not perfect, but the plan did not pay for these services at all before. It is a start in the right direction.

Value in Oncology

Dr Owens: Taking this discussion as a whole, 4 words have emerged from every group, identifying 4 major issues that are directly related to the definition of value in cancer care. The first word is change. Everybody here recognizes that the status quo cannot continue, and change looks very different for the various stakeholders. The next word is data. Each group mentioned data, and not just data, but data that can be turned into information that ultimately could be used to make reasonable clinical, economic, and management decisions. The third word is outcomes—un­ derstanding what outcomes the specific stakeholder is looking for, how they can be measured, and how to pro­ vide for them. Finally, the fourth word is cost. Clearly, cost is the elephant in the room. We know that the current cost trends are unsustainable. We know that we need more value out of what we spend. Cost is a concern for every single stakeholder in this room. Other important words that were mentioned today include quality and ac­ cess, and they are inherently related to the 4 key concepts we have just discussed.

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There are many other common important words or concepts that are relevant to the definition of value in oncology, but those 4 were the ones that registered for me across the entire discussion. This was a very impres­ sive attempt to define value, and the conversation should continue in the future to reflect on new develop­ ments in oncology.

Call to Action • Clinical pathways: Oncology pathways must incorpo­

rate the needs of the population, the individual patient, and society at large in determining the best allocation of resources. Pathways must also allow for some degree of variation, and should be informative not only for active treatment but for discontinuing unwarranted treatment. Pathways must always be a dynamic process to adapt to new evidence and to new clinical guidelines.

• Reimbursement: New models for reimbursement in oncology are needed, moving away from fee for ser­ vice. These models should consider the value of differ­ ent services, not only of the oncologist but also ser­ vices related to patient education and management provided by nurses, as well as cognitive services, ad­ ministrative duties, and other services that are not traditionally covered by insurance, and these should also seek to eliminate waste.

• Regulatory: The government should define value in oncology in a broad way to incorporate quality of care, access, and other significant measures of value, and not only cost, as is currently the case.

• Patient advocacy: The patient’s unique perception of value should be honored, recognizing that value for patients with cancer is not always to extend survival, but rather to maintain quality of life. Patients must also become wiser partners in shared decision-making.

• Oncology practice: Community oncology practices continue to be threatened, largely because of payment and reimbursement concerns; they must therefore reengineer their practice models to meet the changing needs and realities in healthcare overall and specifical­ ly in oncology.

• Hospitals: Hospitals that provide cancer care must rede­ fine themselves and their approach to the patient. They must become more transparent and be able to deliver value for patients and for society as their core principle.

They must also begin to look at cost and waste.

• Managed care organizations: Health plans must work in collaboration with providers and provide more sup­ port and better direction to oncologists. To improve outcomes, payers must be willing to partner with pro­ viders to meet current and increasing challenges in oncology. n

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NEW

For the treatment of elevated IOP

UNLOCK NEW TREATMENT POSSIBILITIES

SIMBRINZA™ Suspension provided additional 1-3 mm Hg IOP lowering compared to the individual components1 ■ IOP measured at 8 AM, 10 AM, 3 PM, and 5 PM was reduced by 21-35% at Month 32-4 ■ Efficacy proven in two pivotal Phase 3 randomized, multicenter, double-masked, parallel-group, 3-month, 3-arm, contribution-of-elements studies2,3 ■ The most frequently reported adverse reactions (3-5%) were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy1 ■ Only available beta-blocker-free fixed combination2,3 INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination indicated in the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Dosage and Administration The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use.

SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

IMPORTANT SAFETY INFORMATION Contraindications SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product and neonates and infants under the age of 2 years.

Warnings and Precautions Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and although administered topically, is absorbed systemically. Sulfonamide attributable adverse reactions may occur. Fatalities have occurred due to severe reactions to sulfonamides. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration.

If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

Corneal Endothelium—There is an increased potential for developing corneal edema in patients with low endothelial cell counts.

References: 1. SIMBRINZA™ Suspension Package Insert. 2. Katz G, DuBiner H, Samples J, et al. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2% [published online ahead of print April 11, 2013]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2013.188. 3. Nguyen QH, McMenemy MG, Realini T, et al.

Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixedcombination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3): 290-297. 4. Data on file, 2013.

© 2013 Novartis 4/13

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Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA™ Suspension has not been specifically studied in these patients and is not recommended.

Adverse Reactions In two clinical trials of 3 months’ duration with SIMBRINZA™ Suspension, the most frequent reactions associated with its use occurring in approximately 3-5% of patients in descending order of incidence included: blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with SIMBRINZA™ Suspension were comparable to those of the individual components. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients.

Drug Interactions—Consider the following when prescribing SIMBRINZA™ Suspension: Concomitant administration with oral carbonic anhydrase inhibitors is not recommended due to the potential additive effect. Use with high-dose salicylate may result in acid-base and electrolyte alterations. Use with CNS depressants may result in an additive or potentiating effect. Use with antihypertensives/cardiac glycosides may result in additive or potentiating effect on lowering blood pressure. Use with tricyclic antidepressants may blunt the hypotensive effect of systemic clonidine and it is unknown if use with this class of drugs interferes with IOP lowering. Use with monoamine oxidase inhibitors may result in increased hypotension.

For additional information about SIMBRINZA™ Suspension, please see Brief Summary of full Prescribing Information on adjacent page.

B:6.875” T:6.875” S:6.875” BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate.

CONTRAINDICATIONS Hypersensitivity - SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product.

Neonates and Infants (under the age of 2 years) - SIMBRINZA™ Suspension is contraindicated in neonates and infants (under the age of 2 years) see Use in Specific Populations WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA™ Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA™ Suspension.

Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information] Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts.

Caution should be used when prescribing SIMBRINZA™ Suspension to this group of patients.

Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZATM Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease.

Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients.

Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZATM Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA™ Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangitis obliterans.

Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information].

ADVERSE REACTIONS Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.

SIMBRINZA™ Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA™ Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA™ Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable.

Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients.

Other adverse reactions that have been reported with the individual components during clinical trials are listed below.

Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain.

The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope.

Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia.

Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications].

DRUG INTERACTIONS Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA™ Suspension. The concomitant administration of SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is not recommended.

High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA™ Suspension.

CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA™, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.

Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA™ Suspension is advised.

Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA™ Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/ kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral adminis-

AMCM3M0054_SIMBRINZA_JournalAd_PI_ASize_r5.indd 1

There are no adequate and well-controlled studies in pregnant women. SIMBRINZA™ Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/ kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk.

It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, 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 individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA™ Suspension is contraindicated in children under the age of 2 years [see Contraindications].

Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult patients.

OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion.

Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician.

Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA™ Suspension. Care should be exercised in operating machinery or driving a motor vehicle.

Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA™ Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness.

Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections.

Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.

Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.

Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension, but may be reinserted 15 minutes after instillation. ©2013 Novartis U.S. Patent No: 6,316,441 ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA 1-800-757-9195 alcon.medinfo@alcon.com

© 2013 Novartis 4/13

MG13003JAD

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T:9.875”

Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information].

Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.

Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.

B:9.875”

Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA™ Suspension has not been studied in patients with acute angle-closure glaucoma.

The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria.

tration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood.

S:9.875”

Severe Renal Impairment - SIMBRINZA™ Suspension has not been specifically studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA™ Suspension is not recommended in such patients.

Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis.

BUSINESS

Original Article

Rapid Expansion of New Oncology Care Delivery Payment Models: Results from a Payer Survey Rhonda Greenapple, MSPH Background: Oncology practices are seeking to adapt to new care delivery models, including accountable care organizations (ACOs), patient-centered medical homes (PCMHs) in oncology, and oncology pathways, as well as new payment models, such as bundled payments or pay-for-performance contracts.

Objective: Our survey sought to determine which payment models and care delivery models payers view as the most viable and the most potentially impactful in managing and reducing the cost of cancer care.

Methods: We conducted an online national survey of 49 payers, including 19 medical directors and 30 pharmacy directors, representing more than 100 million covered lives within national and regional plans, using a validated instrument comprised of approximately 120 questions. The survey was administered using the SurveyGizmo website. It was initiated on July 10, 2012, and completed on July 25, 2012. The survey included open- and closedended questions and probed payers about models of care that they, in collaboration with providers, are implementing or supporting to improve the quality of cancer care and to reduce the associated costs.

Results: Payers are rapidly moving to implement new reimbursement models to support new care delivery models, including ACOs and PCMHs. Based on the results of this survey, a minority of payers are experimenting with new oncology payment models, but most payers are evaluating various models, including bundled payments, capitation, shared savings, and pay for performance. Of the payers in this survey, 39% have already implemented oncology pathways, and 59% who have not already done so are planning to implement pathways in 2 years. Input from local oncology experts is an important resource for pathway development, and a substantial majority (95%) of payers will use pathways to address earlier initiation of palliative care discussions where appropriate.

Conclusion: Payers anticipate that there will be a rapid expansion of the use of innovative approaches to oncology cost management over the next 2 years. As payers and their network providers gain more experience in collaborative care delivery, it is expected that demonstration of cost-savings will become more robust and convincing, and a variety of approaches will become more widely adopted.

A

lthough patients with cancer represent only 1% of commercially insured patients, 10% of commercial health insurance expenditures is spent on this patient population.1 Throughout 2012, the conversation about mounting business pressures on oncology practices to address this discrepancy has been dominated by 3 topics—the viability of accountable care organizations (ACOs) as a model for delivery of oncology care, payer efforts to standardize cancer care through the im-

Ms Greenapple is President and Founder, Reimbursement Intelligence, Madison, NJ.

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2013;6(5):249-256 www.AHDBonline.com Disclosures are at end of text

plementation of oncology clinical pathways, and how these emerging care delivery systems would affect oncology payment models.2 The June 2012 announcement of the launch of the first oncology ACO in Florida—a 3-party collaboration between the Miami-Dade region’s Florida Blue, Baptist Health South Florida (a hospital group), and Advanced Medical Specialties (a multisite oncology practice)— made national healthcare business headlines.3,4 To date, at least 8 other oncology ACOs and health plans exploring oncology payment redesign have emerged in this vanguard.5 By the end of 2012, Florida Blue, formerly Blue

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BUSINESS

Key Points Oncology practices are transitioning to new care delivery models (eg, ACOs, oncology medical home, and pathways) to control the escalating cost of cancer care. ➤ This article presents responses from a recent survey of 19 medical directors and 30 pharmacy directors regarding which of these models healthcare payers view as most viable. ➤ Results show that payers are adopting clinical pathways as a first step toward implementing the principles of healthcare reform to the real-life management of oncology care. ➤ Payers value payer–provider collaboration and recognize the need to change incentives and reimbursement structures in oncology. ➤ The cost-savings expected from an oncology ACO are seen as inherently linked to the use of clinical pathways: 39% of plans surveyed have already implemented oncology pathways, and 59% of plans are planning to do so in 2 years. ➤ Payers believe that pathways can reduce clinical variation in care, improve care quality, and reduce costs, mainly by reducing end-of-life costs. ➤ Payers anticipate a rapid expansion of the use of innovative approaches to cost management and reimbursement in oncology over the next 2 years. ➤

Cross and Blue Shield of Florida, followed with the launch of an ACO for patients with cancer at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, FL.6 Results from the Cancer Center Business Summit 2012 survey on positioning and payment for oncology, which was specific to accountable care initiatives, showed expected trends in the coming years, including acceleration in payer experimentation beyond clinical pathways, with potential incorporation of emergency department management and advance care planning; increased interest in oncology practices that are positioned as specialist collaborators within primary care medical homes; clinically integrated treatment pathways with health information exchange reporting capabilities to increase connectivity; and increased experimentation with bundled pricing for oncology.1 Bundled pricing in oncology provides payments for multiple services, designated as an “episode of care,” where the full team of providers is compensated with a bundled payment (thereby averting the add-on administrative cost of multiple claim submissions) in addition to potential savings through standardization of care.7 A UnitedHealthcare bundled payment pilot program

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brought together 5 physician groups to evaluate varied treatments and associated costs, to reduce variations, and to implement a bundled payment structure. Outcomes from these programs point to drug cost evaluation, provider involvement, and coordination of care as critical success factors.7 Payer efforts to standardize care through the implementation of oncology clinical pathways require physician participation and acceptance to achieve measurable success. Publication of the preliminary success of a statewide collaborative clinical pathway program, which detailed the integral role of oncology providers in the provider network, offered a framework for avoiding the potential pitfalls of externally imposed standardization of care.2 Data from Cardinal Health presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) revealed an overall cost reduction of 15% for patients with breast, colon, or lung cancer in a clinical pathways pilot program launched in 2008.8 Our organization set out to learn how payers are seeking to initiate or to expand on the development of some of these potentially game-changing new business models for the delivery of more cost-effective, higher-quality oncology care. Reaching out to executive-level decision makers within our database of payers, we conducted an in-depth survey of payers representing more than 100 million US covered lives to gain firsthand insights about how payers are seeking to bend the currently unsustainable oncology cost curve. This article summarizes our findings and suggests the potential implications of these payer-led initiatives for the oncology providers in their networks.

Methods Survey Content and Development We developed our survey on the basis of a detailed review of the published literature about payer cost-management strategies for oncology care, as well as in consultation with an expert focus group panel of senior medical directors and other executive-level decision makers with leading regional integrated delivery systems and regional and national payer organizations. The survey was field tested with a sample group of medical and pharmacy directors who responded, and was revised based on feedback received from the test group regarding the usability of the survey and the clarity of the questions. The final survey consisted of a 120-item questionnaire divided into 3 major sections—the adoption of clinical pathways, the implementation of new oncology payment models, and the creation of new oncology care delivery models, such as an ACO or an oncology medical home model. The survey included open- and closed-ended questions and incorporated separate but parallel questionnaire tracks based on whether payers had adopted oncology clinical pathways.

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Payers Expand Oncology Care Delivery Payment Models

Table Demographics of Payer Survey Respondents Health plan characteristic Respondent’s title

Plan size

Channel (public/private) National vs regional

Segment

Respondents, N (%)

Covered lives, N (%)

Medical director

19 (39)

42,780,000 (39)

Pharmacy director

30 (61)

65,714,500 (61)

Small: <750,000

19 (39)

5,874,498 (5)

Medium: 750,000-2.5 million

14 (28)

17,680,000 (17)

Large: >2.5 million

16 (33)

84,940,000 (78)

Commercial

31 (63)

72,882,500 (67)

Medicare

8 (7)

21,992,000 (20)

Medicaid

10 (20)

13,620,000 (13)

National

16 (33)

49,664,500 (46)

Regional

22 (67)

58,730,000 (54)

Total

49 (100)

Survey Sample and Administration The survey was administered online using the SurveyGizmo website (www.surveygizmo.com). Our sample was culled from US payer organizations within our proprietary database of qualified payer organization members who have responded to previous surveys conducted by our organization. The survey was initiated on July 10, 2012, and data collection was completed on July 25, 2012. Respondents received an honorarium for participation in the survey.

Results Respondent and Organizational Characteristics An initial invitation to participate in the electronic survey was sent to the payer organization members who are responsible for implementation of oncology therapy evaluation and management, stipulating that participation was limited to the first 50 respondents; 49 invitees completed the survey. The respondents included 19 (39%) medical directors and 30 (61%) pharmacy directors (Table). The sample included 19 (39%) smaller plans (with <750,000 covered lives), 14 (28%) medium-sized plans (with 750,000-2.5 million covered lives), and 16 (33%) large plans (with >2.5 million covered lives). In aggregate, the respondents represent more than 100 million covered lives, including commercial (63%), Medicaid (20%), and Medicare (7%) participants. A majority (67%) of the respondents represent regional plans and 33% represent national payer organizations.

Rapid Uptake of New Delivery Models in Oncology Our survey confirms that health plans are moving rapidly to implement new care delivery models, including ACOs and patient-centered medical homes

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(PCMHs). Payers generally agreed that the ACO and PCMH models offered structures and processes that would facilitate the delivery of coordinated oncology care, which they believe would improve care quality and reduce wasteful or duplicated care. Among the surveyed plans, 21% currently have an ACO and 56% anticipate having an ACO in 2 years. Of the payers who have formed a Medicare ACO, approximately 66% plan to expand it to include commercial plans. Of plans with an ACO, 75% of the respondents said they are forming legal partnerships with providers. Of the total plans surveyed, 38% currently have a PCMH and 35% anticipate that they will have a PCMH in 2 years.

When asked about the potential sources for cost-savings in an oncology ACO, the respondents rated “better coordination of care” as the strongest potential contributor to savings, followed by “earlier institution of palliative care where appropriate” and “reduce inappropriate uses of therapies” (Figure 1). Reductions in hospitalizations, emergency department visits, and the use of diagnostic imaging and other tests also were rated as impor­ tant areas for potential savings.

This suggests that health plans will focus their initial oncology cost-reduction efforts on the elimination of wasteful and inappropriate care, particularly by improving the management of transitional care. Respondents anticipate that savings will start slowly and will accrue over time as payers and providers gain more experience in collaborative care delivery. The majority (70%) of the responding payers anticipate savings between 6% and 15% at 3 years after the formation of an ACO. The payers agreed that community oncology practices are a core resource for inclusion in an ACO, in addition to hospitals, physician–hospital organizations, and long-

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Figure 1 P otential Sources of Cost Reductions within an Oncology ACO Q: Where will cost reductions in oncology come from within the ACO? Please rate on a scale of 1-5 (1 = weak contributor, 5 = strong contributor).

Earlier institution of palliative care where appropriate

4.1

Better coordination of care

4.4

Reduce overall oncologic drug spending

4.0

Reduce emergency department visits Reduce diagnostic tests (imaging)

3.4 3.8

Reduce hospitalizations

3.7

Reduce inappropriate uses of therapies

4.2 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Mean rating

ACO indicates accountable care organization.

term care facilities. Practices with complete electronic medical records (EMRs) were identified by payers as the types of oncology practices that have joined or are likely to join an ACO. Other practice characteristics that payers cited as relevant for ACO participation are being part of an integrated delivery network and participation in an integrated oncology network.

Our survey also confirms that payers view cost-savings from an oncology-focused ACO as being inherently intertwined with the adoption of oncology pathways. Although ACOs will drive better coordination of care, thereby eliminating duplicate testing and unnecessary care, oncology pathways will be one of the primary means that will support standardization of care across the provider network within these new models.

Adoption of Oncology Clinical Pathways Payers view clinical pathways as an important tool for managing cancer drug costs, especially in tumor types that can carry high treatment costs, including breast, lung, prostate, and colorectal cancers, as well as multiple myeloma. However, only 39% of payers reported having implemented a pathways program in oncology at the time of the survey. A disproportionate number of health plans using pathways are commercial plans (48%) rather than Medicare (30%) or Medicaid (22%).

Among plans that did not yet have pathways in place, 31% are planning to implement oncology pathways within 1 to 2 years, and 28% are planning to implement

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pathways in ≥2 years. This finding suggests that by 2014, approximately 60% of payers will be using oncology clinical pathways to help them manage oncology care costs.

One recent study estimates that by 2015, oncology pathways could expand to include 25% of all covered lives in the United States.9 The 2 main drivers of payers’ adoption of oncology pathways are the desire to reduce clinical variation in care across their provider network and to improve quality of care. Regardless of the payer size or the plan type, reducing costs associated with end-of-life care is also an important consideration for establishing clinical pathways in oncology.

These findings have important implications for oncology practices and providers. Most important, they suggest that there is a window of opportunity of perhaps 12 months to 24 months for providers within an oncology practice to conduct an internal process audit to determine their level of “pathway readiness.” The goal of such an audit would be to assess differences in what individual physicians within the practice are doing with specific patients, and to evaluate the extent to which care processes and treatment algorithms are aligned with evidence-based clinical guidelines. The recently published results of a collaborative statewide oncology pathway initiative in Michigan suggest that prepathway physician practices closely followed pathway guidelines, and that, regardless of the number of different therapy combinations that were on pathway for breast, colon, and lung cancer (the 3 tumor types selected by the program steering committee), the vast majority of patients were treated with 1 of 30 regimens.2 A second important finding for oncology providers is that payers universally perceive provider input on oncology clinical pathways as a vital element of successful pathway implementation. Although evidence-based resources, such as national guidelines and the medical literature, were identified by payers as important resources for pathway development, input from local oncology experts was identified by 68% of the surveyed payers as a resource for pathway development (Figure 2).

Of note, only a small minority (11%) of payers identified outside vendors as a resource, suggesting that despite the widespread availability of prepackaged oncology clinical pathways, payers recognize the value of a collaborative development process that gives network providers a clear and prominent voice. Similarly, responding payers identified local oncology experts as the major stakeholders involved in guiding adjustments to clinical pathways, based on new therapeutic or diagnostic options, as well as the regular meeting of the pathway steering committee to review emerging clinical data and new studies.

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Figure 2 Resources that Payers Engage to Develop Oncology Clinical Pathways Q: What resources have you used to develop pathways?

Please check all that apply.

100

95%

90

84%

80

Respondents, %

A third key finding for oncology providers is that payers have realistic expectations for provider adherence to pathways, with 75% of payers reporting a provider adherence target of 80% or 90%, which is aligned with the real-world experience of organizations such as Blue Cross Blue Shield of Michigan, which has implemented pathway programs.1 The payers identified the 3 tools that are their most effective mechanisms for maintaining pathway adherence as (1) traditional management tools (eg, prior authorization and step-edits), (2) technology-based management via electronic order entry, and (3) the use of EMRs. Overall, surveyed payers expressed modest expectations of the actual cost-savings that can be achieved with clinical pathways, with the majority of payers (50%75%, depending on tumor type) anticipating savings in the 6% to 20% range for most tumor types. A notable exception is metastatic melanoma, for which 35% of payers anticipate a potential drug savings of >30%.

Overall, payers anticipate the greatest potential drug-­ spending savings in breast cancer, with 75% of surveyed payers expecting a savings of ≥11%.

One of the key ways in which payers anticipate that clinical pathways will help manage oncology care costs is by reducing the costs at end of life. This will be accomplished by providing concrete direction for providers within pathways regarding palliative care, and by potentially limiting the use of third-line therapy and later lines of therapy where appropriate. Among plans that have implemented oncology clinical pathways, nearly all (95%) indicated that palliative care is being addressed in pathways (Figure 3).

Responding payers were split regarding how strongly pathways would emphasize palliative care, but 47% said that palliative care would be recommended by their plan as a course of action. Payers anticipate that their plan’s role will be to educate providers through evidence-based clinical pathways that advocate for the appropriate initiation of palliative care discussions.

A slight majority (55%) of payers stated that oncology pathways will limit the use of third-line therapies, with executives at large payer organizations and Medicare-­ focused payers seeing the greatest potential for pathways to limit the use of later lines of therapy. For providers, this suggests that payers will focus on restricting the use of high-cost drugs that offer little benefit in terms of extended overall survival to treat advanced disease.

By providing a rational, evidence-based framework for reducing variation in clinical practice among network providers, oncology clinical pathways are viewed by payers as essential building blocks for driving change in provider behavior. Because of the difficulty in measuring cost-savings that are directly attributable to

68%

70 60 50 40 30 20 0

16%

11%

10 Guidelines

Medical Outside literature vendors

Manufacturers Local experts

Figure 3 How Payers Address Palliative Care in Oncology Clinical Pathways Q: How will palliative care be addressed by pathways?

Palliative care will not be referenced in pathways Reference but with low mention only

Concrete provider direction

5% 16%

32%

47%

Recommended as a course of action

pathway implementation, some experts suggest that sustained reductions in clinical variation are, in themselves, a surrogate measure for cost-savings.2 As more provider groups embark on pathway-based practices, payers will become more skilled at gathering and analyzing data gleaned from EMRs and electronic decision-support systems; furthermore, payers will be able to provide more accurate assessment of the financial cost-savings achievable through a more standardized approach to cancer care.

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ncology Payment Models Under Consideration Figure 4 O

by Payers Q: What oncology payment models, if any, are under consideration? Please check all that apply.

Capitation

32%

Pay for performance

29%

Shared savings

29%

Bundled payments for defined episodes of care

41%

No payment models are under consideration

27% 0 5 10 15 20 25 30 35 40 45

Respondents, %

On the Horizon: Payers View New Oncology Payment Models A minority (16%) of payers are experimenting with new oncology payment models that move reimbursement away from traditional fee for service, and most of this exploration is taking place in Medicare-focused plans. Based on this survey, among health plans that have not implemented new payment models, 73% are considering various models, including bundled payments for defined episodes of care (41%), capitation (32%), shared savings (29%), and pay for performance (29%), as shown in Figure 4.

The time frame for implementation of new payment models varies. Overall, 41% of payers anticipate that they will be piloting new oncology payment models within the next 1 to 2 years, with 45% of large plans considering implementation within this time frame.

There has been much discussion of how provider quality metrics will be integrated into new payment models.

Our survey showed that payers rate hospitalization statistics and adherence to pathways as the most relevant quality metrics. Slightly less important are the use of supporting therapies, outcome metrics, emergency department visits, and process measurements, such as the use of EMRs. Payer emphasis on measuring provider adherence to oncology pathways highlights the intrinsic link between the demonstration of quality care and the adoption of evidence-based standards for practice. Pathways provide ongoing standards, guidance, and a tool for ongoing evaluation of a practice’s delivery of quality care.

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Discussion As payers, in collaboration with providers, continue to experiment on how to improve oncology care, contain costs, and redistribute incentives, novel oncology care delivery and payment models are continuing to emerge.10 Although the traditional fee-for-service model remains relatively intact, payers recognize that they need to continue to work with providers to change incentives and compensation so practices and providers are less dependent on margins from the drugs that are administered and are being appropriately compensated for managing patient care.7 Providers also are beginning to rethink their approaches to care management, and are evaluating operational changes that will allow them to more actively participate in the reduction of emergency department visits and of potentially avoidable hospitalizations. These changes include triage programs; mandatory chemotherapy patient education; and around-the-clock, 7-days-a-­ week access to oncology nurse practitioners for the management of side effects and other chemotherapy-­ related complications.10 Although our survey suggests that payers recognize the vital role that oncology providers play in advancing the timing of conversations about palliative care and in limiting futile late-line treatment, it is unclear how payers will revamp their payment models to ensure that oncology providers are fairly compensated for the additional care they will need to deliver. The 2010 ASCO guidance statement on advanced cancer notes that the transition from curative care to palliative care occurs too late in the treatment process, and that a better understanding of palliative care can produce higher-quality care while reducing costs.11 The payment model needs to change to engage providers in the process of transforming the delivery of care within their own practices.12 Oncology pathways, medical homes, and ACOs are interlocking pieces of the oncology cost-savings puzzle.12 Oncology clinical pathways, together with EMRs and electronic decision-support systems, are proved methods of gaining provider agreement on the standardization of clinical care, as well as practical methods of monitoring real-life clinical practice and identifying and adjudicating exceptions.10,12 However, clinical pathways are inherently non–patient-centric, and in this regard, oncology medical homes are a better model for the delivery of integrated and collaborative care.

Consultants in Medical Oncology and Hematology, a 9-physician oncology practice near Philadelphia, PA, that became the first oncology practice to be recognized by the National Committee for Quality Assurance as a level III PCMH, has demonstrated the effectiveness of the oncology PCMH model in minimizing the use of

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unnecessary resources.12 Since Consultants in Medical Oncology and Hematology launched its oncology PCMH, it has reported a 68% reduction in emergency department visits, a 51% reduction in hospital admissions per patient receiving chemotherapy, and a 21% reduction in length of stay for admitted patients.12 ACOs and reengineered oncology payment models will provide the mechanisms for new and more rational alignment of incentives among all stakeholders in cancer care delivery.10 The eventual integration of these principles into the oncology practice model is inevitable, because the current fee-for-service approach is creating an unsustainable business environment for community-­ based oncology practices and is driving ongoing consolidation and shifting of care to the institutional setting. In an editorial on the value of the oncology PCMH, Dr John D. Sprandio noted, “Community-based physicians have not led the response to the current economic challenges confronting their practices,” suggesting that the primary beneficiaries of the early wave of change in oncology care have been third-party vendors of pathway programs and institutional-based cancer programs.12 Our survey confirms that payers are turning to the adoption of clinical pathways as a first step in their efforts to bring the principles of healthcare reform to the real-­ life management of oncology care. Payers are engaging in thoughtful, active collaborations with their network of oncology providers to ensure engagement and support adherence, and are building pathways with sufficient flexibility to empower the personalization of care based on provider and individual patient decisions.

However, payers also recognize that oncology pathways alone are not the solution, and are starting to evaluate and experiment with alternative oncology care delivery models—including ACOs and oncology PCMHs—as a means to put more responsibility and accountability in the hands of their providers.

The development and implementation of reformed oncology payment models—whether a bundled episode of care or a further evolution of modified fee for service—is clearly on the horizon, although payers responding to our survey recognize that they are only starting down that road. As the results of the UnitedHealthcare bundled payment experiment are reported, and as other oncology payment pilot initiatives are put to the test, payers will begin reaching out to initiate a dialogue with their network providers about redefining how they can collaborate to deliver the best possible care without breaking the healthcare system’s fragile financial equilibrium.

Limitations In general, survey research poses certain limitations.

Survey data rely on responders and, therefore, potential bias is inherent in all survey-based research.

In addition, because the sample size in this study was subdivided between medical and pharmacy directors and between 3 plan sizes (Table), the generalizability of insights and decision-making to a broader scope of plans is limited. Although our proprietary database of qualified payer organizations allows for timely access to member

Our survey confirms that payers are turning to the adoption of clinical pathways as a first step in their efforts to bring the principles of healthcare reform to the real-­life management of oncology care. insights, the sample was limited to 19 medical directors and 30 pharmacy directors. The smaller number of medical directors in this study reflects the greater coverage of oral cancer therapies by the pharmacy benefit and the increasing movement of oral cancer therapy to pharmacy benefit management.

Conclusion Although fee for service continues to be the base model for providers and health plans, payers recognize the need for provider collaboration to change incentives and compensation structures. Similarly, this evolving dynamic encourages providers to actively participate in operational changes that could greatly impact cost.

Given the evolving environment and collaborative responsiveness between payers and providers, rapid uptake of new care delivery models will likely continue; cost-savings are anticipated to become more robust with subsequent adoption of a wide range of approaches to oncology care. n Author Disclosure Statement Ms Greenapple has reported no conflicts of interest.

References

1. Barkley R. Where does oncology fit in the scheme of accountable care? J Oncol Pract. 2012;8:71-74.

2. Feinberg BA, Lang J, Grzegorczyk J, et al. Implementation of cancer clinical care pathways: a successful model of collaboration between payers and providers. Am J Manag Care. 2012;18:e194-e199.

3. Regan T. Accountable care organizations come to oncology. Oncol Biotech News.

October 17, 2012. www.onclive.com/publications/obtn/2012/september-2012/ accountable-care-organizations-come-to-oncology/1. Accessed December 26, 2012.

4. Anderson C. Oncology ACO launched. Healthc Finance News. June 13, 2012. www.healthcarefinancenews.com/news/oncology-aco-launched. Accessed December 26, 2012.

5. Barkley RR. The rapidly evolving ACO world. OBR Green. September 2012. http://obroncology.com/obrgreen/article/The-Rapidly-Evolving-ACO-World. Accessed June 11, 2013.

6. Elliott VS. Disease-specific ACOs make their debut. Am Med News. January 28, 2013. www.amednews.com/article/20130128/business/130129958/6/. Accessed May 9, 2013.

7. Cantlupe J. Bundled payments come to cancer care. HealthLeaders Media. January/­

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February 2013. March 11, 2013. www.healthleadersmedia.com/page-1/HEP-289965/ Bundled-Payments-Come-to-Cancer-Care. Accessed June 6, 2013.

8. Beasley D. Analysis: new cancer breakthroughs add pressure to control costs.

Reuters.com. June 5, 2013. http://uk.reuters.com/article/2013/06/05/us-cancer-­ costs-analysis-idUKBRE95405U20130605. Accessed June 6, 2013.

9. McKinsey & Company. Strategies in oncology: spotlight on clinical pathways.

Oncology Knowledge Bulletin. January 2012. www.mckinsey.com/~/media/mckinsey/ dotcom/client_service/pharma%20and%20medical%20products/pmp%20new/ pdfs/786594_strategies_in_oncology.ashx. Accessed December 28, 2012.

10. Lederman L. Are medical homes and ACOs the future of cancer care? OBR Green. 2012;6. http://obroncology.com/obrgreen/article/Are-Medical-Homes-andACOs-the-Future-of-Cancer-Care? Accessed January 2, 2012.

11. Peppercorn JM, Smith TJ, Helft PR, et al, for the American Society of Clinical Oncology Ethics Committee and Taskforce on the Cost of Cancer Care. American Society of Clinical Oncology Statement: toward individualized care for patients with advanced cancer. J Clin Oncol. 2011;29:755-760.

12. Sprandio JD. Oncology patient-centered medical home. J Oncol Pract. 2012;8(3 suppl):47S-49S.

Stakeholder Perspective New Oncology Care Delivery Payment Models to Enhance Care Efficiency

By Gary M. Owens, MD President, Gary Owens Associates, Glen Mills, PA

More than 13 million people are living with cancer in the United States today.1 That number will continue to grow as advances in the detection, treatment, and follow-up of cancer continue to improve. The American Cancer Society estimates that >1.6 million cases of cancer will be newly diagnosed in 2013, and that >580,000 people in the United States will die of cancer this year.2 The estimated economic burden of cancer is >$201 billion, and of this >$77 billion is direct medical costs.3 Finally, the National Cancer Institute projects that by 2020 there will be >18 million cancer survivors in the country, with direct medical cost that is likely to exceed $157 billion.4 MEDICAL/PHARMACY DIRECTORS: Therefore, the treatment of cancer and its associated costs is of major importance for health plans. Plan leaders are aware of the multiple inefficiencies in the current system, and they are looking for innovative solutions for them.

An illustrative example of system inefficiencies was published in June.5 This analysis of treatments for prostate cancer in >50,000 men showed that the use of advanced technologies for low-risk disease rose from 32% in 2004 to 44% in 2009; moreover, among men at high risk for death from noncancer causes within 10 years, the use of these technologies increased from 36% to 57%.5 Overall, advanced technologies rose from 13% to 24%, with no evidence that these newer, more expensive technologies improved outcomes.5 It is in this setting that plans are looking for alternate systems of care and payment methodologies for cancer care.

The article by Ms Greenapple outlines the results of a survey of 49 payers, representing >100 million covered lives. In that survey, “Payers generally agreed that the ACO [accountable care organization] and PCMH [patient-centered medical home] models offered structures and processes that would facilitate the delivery of coor-

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dinated oncology care, which they believe would improve care quality and reduce wasteful or duplicated care.” Payers anticipate that newer payment methods will help reduce inefficient care and, at times, the wasteful use of resources. Although most payers are still reimbursing cancer care using the traditional fee-for-service model, the majority of payers are willing to explore alternative payment methods, according to this survey, and their uptake is likely to be adopted rapidly.

With the economic burden of cancer care growing at a rapid rate, it is essential that payers and providers work collaboratively to develop and to ultimately adopt systems of care that can meet the triple aim of improving the patient experience of care for patients with cancer (including quality and satisfaction), improving the net health of patients with cancer, and reducing or moderating the trend of the cost of care.

The next few years are likely to see the adoption of alternate delivery and payment models for cancer care.

Not all of these will be successful, and there will likely be many modifications of these systems as we search for better solutions to our current inefficient and costly healthcare system. Payers and providers should be encouraged to work collaboratively to develop these new models of care, because without such initiatives the burden of cancer care will continue to grow at an unsustainable rate. n 1. American Cancer Society. Cancer prevalence: how many people have cancer?

Revised October 23, 2012. www.cancer.org/cancer/cancerbasics/cancer-prevalence.

Accessed July 7, 2013.

2. American Cancer Society. Cancer facts and figures 2013. 2013. www.cancer.org/ acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845. pdf. Accessed July 7, 2013.

3. American Cancer Society. Economic impact of cancer. Revised February 1, 2013. www.cancer.org/cancer/cancerbasics/economic-impact-of-cancer. Accessed July 7, 2013.

4. National Cancer Institute. Cancer prevalence and cost of care projections. http:// costprojections.cancer.gov/. Accessed July 7, 2013.

5. Jacobs BL, Zhang Y, Schroeck FR, et al. Use of advanced treatment technologies among men at low risk of dying from prostate cancer. JAMA. 2013;309:2587-2595.

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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 AND PRECAUTIONS (continued) WARNINGS AND PRECAUTIONS (continued) Dizziness and Confusional State: of patients experienced dizziness and of patients experienced a confusional Dizziness and Confusional State: 18% of18% patients experienced dizziness and 12% of12% patients experienced a confusional state; state;

1% of patients experienced grade 3/4 dizziness, 3% of patients experienced grade 3/4 confusional state. Instruct patients 1% of patients experienced grade 3/4 dizziness, and 3%and of patients experienced grade 3/4 confusional state. Instruct patients avoid situations where dizziness or confusion be a problem not to takemedications other medications that maydizziness cause dizziness to avoidtosituations where dizziness or confusion may bemay a problem and notand to take other that may cause or confusion adequate or confusion withoutwithout adequate medicalmedical advice.advice.

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

Therenowere noofcases Neuropathy: 18% of18% patients experienced neuropathy (approximately 9% peripheral neuropathy).

There were cases gradeof grade 3 or higher neuropathy reactions reported.

3 or higher neuropathy adverseadverse reactions reported. of Second Primary Malignancies: acute myelogenous leukemia havereported been reported in patients receiving Risk ofRisk Second Primary Malignancies: Cases ofCases acuteofmyelogenous leukemia have been in patients receiving POMALYST as an investigational of multiple myeloma.

POMALYST as an investigational therapytherapy outsideoutside of multiple myeloma.

ADVERSE REACTIONS ADVERSE REACTIONS

INTERACTIONS DRUGDRUG INTERACTIONS No formal drug interaction haveconducted been conducted with POMALYST. Pomalidomide is primarily metabolized

by CYP1A2 No formal drug interaction studiesstudies have been with POMALYST. Pomalidomide is primarily metabolized

by CYP1A2 and and Pomalidomide also a substrate for P-glycoprotein Coadministration of POMALYST withthat drugs are strong CYP3A.CYP3A. Pomalidomide is also aissubstrate for P-glycoprotein (P-gp).(P-gp).

Coadministration of POMALYST with drugs arethat strong inhibitors or inducers of CYP1A2, P-gp should be avoided.

Cigarette smoking may reduce pomalidomide exposure inhibitors or inducers of CYP1A2, CYP3A,CYP3A, or P-gporshould be avoided.

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

Patients be advised that smoking may reduce of pomalidomide. to CYP1A2 induction.

Patients should should be advised that smoking may reduce the effithe cacyeffi ofcacy pomalidomide.

USE IN SPECIFIC POPULATIONS USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy doesduring occur during treatment, immediately discontinue theand drug andpatient refer patient to an obstetrician/ Pregnancy: If pregnancy does occur treatment, immediately discontinue the drug refer to an obstetrician/

gynecologist experienced in reproductive for further evaluation and counseling. any suspected fetal exposure gynecologist experienced in reproductive toxicitytoxicity for further evaluation and counseling.

Report Report any suspected fetal exposure to POMALYST to the the MedWatch program at 1-800-332-1088 and to Celgene Corporation at 1-888-423-5436. to POMALYST to the FDA viaFDA the via MedWatch program at 1-800-332-1088 and also to also Celgene Corporation at 1-888-423-5436.

Nursing Mothers: is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the Nursing Mothers: It is notItknown if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of milk of lactating rats. Because manyare drugs are excreted in human milk and because of the potential for adverse reactions in nursing lactating rats. Because many drugs excreted in human milk and because of the potential for adverse reactions in nursing from POMALYST, a decision made whether to discontinue or to discontinue thetaking drug, taking infantsinfants from POMALYST, a decision should should be madebewhether to discontinue nursingnursing or to discontinue the drug, into into the importance of thetodrug to the mother. accountaccount the importance of the drug the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under agehave of 18not have notestablished. been established.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the agethe of 18 been Geriatric No dosage adjustment is required for POMALYST based age. Patients to 65ofyears Geriatric Use: NoUse: dosage adjustment is required for POMALYST based on age.on Patients greatergreater than orthan equalortoequal 65 years age of age werelikely morethan likelypatients than patients lessorthan to 65ofyears of experience age to experience pneumonia. were more less than equalortoequal 65 years age to pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in thePomalidomide liver. Pomalidomide its metabolites are primarily Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. and its and metabolites are primarily excreted by the kidneys. inflof uence renal and hepatic impairment on the safety, effiand cacy, and pharmacokinetics of excreted by the kidneys.

The inflThe uence renalofand hepatic impairment on the safety, efficacy, pharmacokinetics of pomalidomide notevaluated. been evaluated.

Avoid POMALYST in patients with a creatinine serum creatinine >3.0 mg/dL. Avoid POMALYST in pomalidomide has nothas been Avoid POMALYST in patients with a serum >3.0 mg/dL. Avoid POMALYST in patients with bilirubin serum bilirubin >2.0 and mg/dL and AST/ALT >3.0 x ULN. patients with serum >2.0 mg/dL AST/ALT >3.0 x ULN. full Prescribing Information, including WARNINGS, CONTRAINDICATIONS, WARNINGS PleasePlease see fullsee Prescribing Information, including Boxed Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND AND PRECAUTIONS, and ADVERSE REACTIONS. PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation.

POMALYST® is a registered trademark of Celgene Corporation.

POMALYST is a trademark of Celgene Corporation.

POMALYST REMS™ isREMS™ a trademark of Celgene Corporation. ©2013 Celgene Corporation US-POM120044 ©2013 Celgene Corporation 02/13 02/13 US-POM120044

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In the clinical of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone In the clinical trial of trial 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had atone least one treatment-emergent reaction. (low-dose dex) (n=112), all patients had at least treatment-emergent adverseadverse reaction.

In the POMALYST alone POMALYST versus POMALYST + lowdexamethasone dose dexamethasone arms, respectively, most common reactions • In the• POMALYST alone versus + low dose arms, respectively, most common adverseadverse reactions included and asthenia (55%,neutropenia 63%), neutropenia (52%,anemia 47%), anemia (38%,constipation 39%), constipation (36%, 35%), (≥30%)(≥30%) included fatiguefatigue and asthenia (55%, 63%), (52%, 47%), (38%, 39%), (36%, 35%), (36%,diarrhea 22%), diarrhea (34%,dyspnea 33%), dyspnea (34%,upper 45%),respiratory upper respiratory tract infection (32%,back 25%),pain back pain nauseanausea (36%, 22%), (34%, 33%), (34%, 45%), tract infection (32%, 25%), (32%,and 30%), and pyrexia (19%, 30%) (32%, 30%), pyrexia (19%, 30%) • 90% of patients with POMALYST alone and of patients with POMALYST + low-dose had atone least one • 90% of patients treatedtreated with POMALYST alone and 88% of88% patients treatedtreated with POMALYST + low-dose dex haddex at least treatment-emergent CTC3Grade 3 or 4 adverse reaction treatment-emergent NCI CTCNCI Grade or 4 adverse reaction In the POMALYST alone POMALYST versus POMALYST + lowdexamethasone dose dexamethasone arms, respectively, most common Grade 3/4 adverse • In the• POMALYST alone versus + low dose arms, respectively, most common Grade 3/4 adverse reactions included neutropenia (47%,anemia 38%), anemia (22%,thrombocytopenia 21%), thrombocytopenia (22%,and 19%), and pneumonia reactions (≥15%)(≥15%) included neutropenia (47%, 38%), (22%, 21%), (22%, 19%), pneumonia (16%,For 23%).

ForGrade other3Grade 3 or 4 toxicities neutropenia and thrombocytopenia, hold treatment and restart treatment at (16%, 23%). other or 4 toxicities besidesbesides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less the previous dosetoxicity when toxicity has resolved to less at the physician’s discretion 1 mg less than thethan previous dose when has resolved to less than orthan equalortoequal Gradeto2Grade at the2physician’s discretion • 67% of patients with POMALYST and of patients with POMALYST + low-dose had atone least one • 67% of patients treatedtreated with POMALYST and 62% of62% patients treatedtreated with POMALYST + low-dose dex haddex at least treatment-emergent reaction treatment-emergent seriousserious adverseadverse reaction In the POMALYST alone POMALYST versus POMALYST + lowdexamethasone dose dexamethasone arms, respectively, most common • In the• POMALYST alone versus + low dose arms, respectively, most common seriousserious adverseadverse reactions (≥5%)pneumonia were pneumonia (14%,renal 19%),failure renal failure (8%,dyspnea 6%), dyspnea (5%,sepsis 6%), (6%, sepsis3%), (6%,pyrexia 3%), pyrexia (3%, 5%) reactions (≥5%) were (14%, 19%), (8%, 6%), (5%, 6%), (3%, 5%) dehydration (5%,hypercalcemia 3%), hypercalcemia (5%,urinary 2%), urinary tract infection (0%,and 5%), and febrile neutropenia (5%, 1%) dehydration (5%, 3%), (5%, 2%), tract infection (0%, 5%), febrile neutropenia (5%, 1%)

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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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17 ( 16)

Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)

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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,

CLINICAL CLINICAL

Review Article

Patient-Reported Outcomes Are Changing the Landscape in Oncology Care: Challenges and Opportunities for Payers Erin Zagadailov, PharmD, MS; Michael Fine, MD; Alan Shields, PhD

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2013;6(5):264-274 www.AHDBonline.com Disclosures are at end of text

Background: A patient-reported outcome (PRO) is a subjective report that comes from a patient without interpretation by a clinician. Because of the increasingly significant role of PROs in the development and evaluation of new medicines, the US Food and Drug Administration (FDA) issued a formal guidance to describe how PRO instruments will be reviewed and evaluated with respect to claims in approved medical product labeling. Meanwhile, PROs continue to appear in oncology clinical trials more frequently; however, it is unclear how payers and policymakers can use PRO data in the context of decision-making for cancer treatments.

Objective: The objective of this article is to discuss the challenges and opportunities of incorporating oncology-related PRO data into payer decision-making.

Discussion: Payer concerns with PRO instruments are often related to issues regarding measurement, relevance, quality, and interpretability of PROs. Payers may dismiss PROs that do not independently predict improved outcomes. The FDA guidance released in 2009 demonstrates, as evidenced by the case of ruxolitinib, how PRO questionnaires can be generated in a relevant, trustworthy, and meaningful way, which provides an opportunity for payers and policy decision makers to focus on how to use PRO data in their decision-making.

This is particularly relevant in oncology, where a recent and sizable number of clinical trials include PRO measures.

Conclusion: As an increasing number of oncology medications enter the market with product labeling claims that contain PRO data, payers will need to better familiarize themselves with the opportunities associated with PRO questionnaires when making coverage decisions.

PRO measures will continue to provide valuable information regarding the risk–benefit profile of novel agents. As such, PRO measures may provide evidence that should be considered in payers’ decisions and discussions; however, the formal role of PROs and the pertinence of PROs in decision-making has yet to be understood.

A

patient-reported outcome (PRO) is a subjective report that comes directly from a patient in regard to his or her health condition or treatment without interpretation by a clinician or anyone else.1 PROs have long provided a unique insight into the effectiveness of novel medical treatments.2 Indeed, PRO questionnaires have been developed to quantify a patient’s self-reported health status in a variety of areas, including symptoms, functioning, quality of life (QOL), and health-related QOL. In addition, PRO questionDr Zagadailov is Manager of Global Health Economics Outcomes Research, Xcenda, Chicago, IL; Dr Fine is Medical Director, HealthNet, Huntington Beach, CA; and Dr Shields is Director of Endpoint Development and Outcomes Assessment, Adelphi Values, Boston, MA.

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naires have been developed to assess other health-related outcomes, such as treatment adherence and satisfaction.

Because of its increasingly significant role in the development and evaluation of new medicines,2-4 the US Food and Drug Administration (FDA), in conjunction with industry and academic experts, published a formal guidance, “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims,” in 2009 to describe how the FDA will review and will evaluate the existing, modified, or newly created PRO instruments in support of the claims contained in FDA-approved drug labeling.1 The guidance was in development since early 2000 when select members of the FDA, the International Society for Quality of Life Research, the International Society for Pharmacoeconomics and Outcomes Research, Pharmaceutical Research

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and Manufacturers of America (PhRMA), and the European Regulatory Issues on Quality of Life Assessment Group began meeting to discuss how PRO data could be incorporated into drug labeling claims.5 The FDA released its draft guidance document in 2006 and its subsequent final guidance in 2009 after receiving and responding to public commentary on the guidance.

By establishing a set of standards and parameters for the use and development of PROs, the FDA has clearly acknowledged and accepted PROs as important and trustworthy means for evaluating drugs, biologics, and medical devices. Furthermore, the FDA guidance may ultimately lead to the more efficient and more appropriate use of these tools; increased collaboration has been seen among measurement-focused researchers to offer suggestions for best practice with respect to the development, implementation, and evaluation of PROs across a variety of therapeutic areas.5-10 The impact of the FDA’s PRO guidance has been felt in oncology, as evidenced by a rapidly growing body of literature regarding the development, interpretation, and incorporation of PROs into oncology. More specifically, several publications have focused on the use of PROs to support product claims labeling as a means of demonstrating further product differentiation in oncology.5,11-15 With the number of cancer survivors currently at 10 million and growing in the United States, it is clear that patients with cancer are living longer as a result of improvements in survival rates for several cancers thanks to new treatment options that have demonstrated control in tumor growth and reduced cancer-related morbidity and mortality.12 In addition, an increasing number of therapies offer equivalent survival benefits; however, there may be differences in the type and severity of adverse events or in the way the drug affects patient functioning. Often, these differences are material for patients, and they markedly influence the clinician’s choice of therapy for corresponding malignancies from the perspective of the physician and payer. Furthermore, the difference in impact on patient-specific factors, in the absence of a substantial difference of survival benefits, has led to an emphasis on the totality of a patient’s treatment experience and an enhanced understanding of how to balance the benefits of therapy with the risks associated with treatment.

Building on safety, efficacy, and health economics data, PROs further inform decision-making by contributing evidence that is reflective of the patient experience.

PRO measures also add considerable value to treatment decisions made between providers and patients when they enable providers to address relevant decision-related questions (eg, does a new therapy deliver significant clinical benefit above and beyond the primary registra-

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Key Points In 2009, the FDA published a formal guidance on the review and evaluation of patient-reported outcomes (PROs) related to claims included in FDA-approved medical product labeling. ➤ Payers are concerned with issues related to relevance, quality, and interpretability of PROs when evaluating data from these instruments. ➤ Cancer drugs currently in clinical trials are increasingly incorporating PRO measures and may soon be entering the market with product labeling claims containing PRO data. ➤ PRO measures can provide evidence that should be considered in payers’ drug coverage decisions and providers’ discussions with patients regarding drug choice. ➤ The case of ruxolitinib, to date the only cancer drug that has followed the FDA guidance for the development of a PRO instrument and received a PRO-based product labeling, is a good model for marketing applications of PRO-related measures. ➤ Payers need to become more familiar with the FDA PRO guidance and the various PRO measures for coverage decisions to determine how each measure fits in a drug’s overall risk–benefit profile. ➤

tion trial clinical end point, from the patient’s perspective?).15 PRO symptom measures can also be useful in predicting later-stage disease progression and survival.12 The association between PRO symptom assessments and drug-related toxicity can be valuable when determining the risk–benefit profile of a treatment.12 The use of PROs in clinical trials is increasingly necessary and accepted. Furthermore, as more oncology treatments that extend life or provide palliative care become available, PROs will continue to appear as end points in oncology trials. It is unclear, however, how payers and policymakers can use PRO data in the context of decision-making for cancer treatments,15 and, to date, there is a paucity of literature from the perspective of the payer and policy decision maker.

To begin filling this gap, the objective of this article is to discuss the challenges and opportunities of incorporating oncology-related PRO data into payer decision-making. In turn, this will help third-party payers (public and private) understand the role and the potential added value that PRO data could have in determining a product’s overall risk versus benefit. We use a case study to describe the value of PRO data from the payer’s perspective for a novel oncology product (ie, ruxolitinib in patients with intermediate- or high-risk myelofibrosis) and

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Table 1 Examples of Frequently Used PRO Instruments in Oncology Type of tool PRO instrument Health-related quality of life Generic • EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) • FACT-G (Functional Assessment of Cancer Therapy-General) • SF-36 (Short Form 36-Item) • PROMIS (Patient-Reported Outcomes Measurement Information System) Cancer-specific • FLIC (Functional Living Index-Cancer) • EORTC QLQ-BN20 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and Brain) • EORTC QLQ-BR23 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Breast) • EORTC QLQ-LC13 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung) • FACT-L (Functional Assessment of Cancer Therapy-Lung) • FACT-B (Functional Assessment of Cancer Therapy-Breast) Symptoms and symptom burden • Visual analog scale Generic • Symptom Distress Scale • Memorial Pain Assessment Card • Rotterdam Symptom Checklist Cancer-specific • LCSS (Lung Cancer Symptom Scale) • MDASI (Monroe Dunaway Anderson Symptom Assessment Inventory) PRO indicates patient-reported outcome. how PRO data were incorporated into its product labeling in accordance with US regulatory guidance.

Historical Context and Current Status of PROs in Oncology PRO questionnaires collect information about the patient that can best, or only, be known by the patient (eg, pain) and cannot be evaluated through objective (eg, laboratory or marker) measurement. Many PROs are utilized in oncology: Table 1 describes a sample of PRO measures such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-General (FACT-G).

The number of oncology products and new technologies incorporating PRO measures into clinical trials and seeking PRO-related product labeling claims continue to increase. A 2010 analysis of all trials registered at ClinicalTrials.gov since 2004 showed that 12% of industry-sponsored trials and more than 15% of non–industry-sponsored trials incorporated some form of PRO assessment.16 In an earlier, 2007 analysis of clinical trials between 2002 and 2006 registered at ClinicalTrials.gov focusing only on oncology trials, 12% of all industry-sponsored trials reported the inclusion of PRO mea-

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sures.12 To our knowledge, there have not been any more current estimates than these 2 analyses.

With this in mind, and considering the FDA guidance that was released in 2009, we used a similar search strategy to what Gondek and colleagues used in 200712 to determine the more current utilization of PRO measures in oncology clinical trials. Among a total of 636 oncology registered trials on ClinicalTrials.gov between September 2006 and June 2012, we found 545 oncology trials that incorporated PROs (Table 2). This reveals much higher utilization of PRO measures in recent oncology trials than what was reported by Gondek and colleagues in 200712 or by Doward and colleagues in 2010,16 and translates to approximately 85% of recent oncology trials that incorporate some form of PROs that evaluate health-related QOL or symptom measures.

With respect to product labeling, several reviews have evaluated the frequency of PROs in FDA-approved product labeling.2-4 In a review of end points that were included in product labeling for all new molecular entities from 1997 to 2002, 30% of product labels included a PRO.2 In a separate systematic review from 2006 to 2010, 21% of FDA-approved drugs (93 of 432 total approvals) contained PROs.3 Gnanasakthy and colleagues found similar results: 24% of product labels between

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Table 2 Oncology Clinical Trials by Disease, with Quality of Life, Symptom Measures, or PROs as Study End Points Total cancer Trials with any Cancer type trials, N PRO measures, N HRQOL Symptoms Other PROsa 6 5 4 2 1 Multiple 69 55 46 11 6 Breast 6 5 5 4 – Bone 37 36 28 6 4 Colorectal 31 19 18 2 1 Lymphoma 42 31 27 1 4 Leukemia 100 94 83 28 10 Lung 26 21 19 4 2 Pancreas 45 41 36 12 2 Prostate 22 19 14 7 4 Kidney 28 28 27 6 2 Liver 26 24 22 3 – Brain 18 17 15 4 – Head/neck 9 8 8 – – Melanoma 26 24 21 4 3 Ovarian b 42 37 35 11 2 Hematologic c 103 81 71 26 4 Other 636 545 – – – Total Includes general PRO instruments that do not directly capture HRQOL or symptoms (eg, Cancer Therapy Satis­ faction Questionnaire, patient preference) and trials that did not specify the PRO end point or a nonspecific term of PRO was used. b Hematologic cancers include, but are not limited to, myelofibrosis, polycythemia vera, multiple myeloma, and mye­ lodysplastic syndromes. c Other cancers include, but are not limited to, uterine, gastrointestinal, thyroid, and bladder.

HRQOL indicates health-related quality of life; PRO, patient-reported outcome. a

2006 and 2010 contained PRO claims, and the largest percentage of product claims was in oncology.4 Before the FDA guidance, selecting a PRO questionnaire for incorporation into a clinical trial was often based on the questionnaire’s previous use. Because questionnaire selection should be based on the relevance of the content (ie, what the questionnaire measures) and the strength of its psychometric performance in the specific target patient population, the approach to selecting a questionnaire based on previous use is seen as inadequate.16 The continued use of older generic instruments, such as the Short Form 36-Item (SF-36) health survey questionnaire, is often disputed. Older PRO instruments may also predate advances in measurement science; these advances have led to the development of PROs that measure meaningful changes in a specific disease following the new FDA guidance.16 Before the publication of the FDA’s PRO guidance in

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2009, the majority of oncology agents with PRO claims were based on generic- or symptom-related assessments, some of which might not have been published or evaluated for content validity or for psychometric performance (eg, reliability, construct-related validity, and sensitivity to change) within a given disease. This is the case for many of the oncology products with QOL or PRO claims before the development and release of the FDA guidance, as described in Table 3.

For example, topotecan was granted PRO-based product labeling claims for symptom improvement using a Symptom Distress Scale in patients with small-cell lung cancer. The 4-category symptom scale measures shortness of breath, interference with daily activity, fatigue, hoarseness, cough, insomnia, anorexia, chest pain, and hemoptysis.17 Improvement was defined as a change in 1 category from baseline and sustained during 2 courses of treatment. Overall, patients receiving topotecan had

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Table 3 FDA Oncology Drug Approvals with a PRO Claim in the Label Generic Therapeutic PRO end (brand name) Manufacturer indications points Preâ&#x20AC;&#x201C;FDA guidance Gemcitabine Eli Lilly Carcinoma HRQOL hydrochloride NSCLC Clinical benefit (Gemzar) response, a Pancreatic measure of neoplasms clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change Imatinib Novartis Chronic Improvement mesylate myeloid in symptoms of (Gleevec) leukemia, acute interferon lymphoblastic toxicity leukemia HRQOL Irinotecan Pfizer Colorectal HRQOL hydrochloride neoplasms (Camptosar) Leuprolide Atrix Prostatic Improvement acetate Laboratories neoplasms in bone pain, (Eligard) urinary pain, and urinary signs and symptoms Mitoxantrone (Novantrone)

Immunex Corporation

Prostatic Improvement neoplasms, acute in pain and nonlymphocytic analgesic use leukemia

Paclitaxel (Taxol)

Mead Johnson, a Bristol-Myers Squibb Company

Carcinoma NSCLC

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HRQOL

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Approval date

PRO instruments

HRQOL was assessed using May 1996 FACT-L, EORTC QLQ-C30, and EORTC QLQ-LC13 Pain intensity was assessed using Memorial Pain Assessment Card

FACT-BRM questionnaire

May 2001

EORTC QLQ-C30

June 1996

Both bone pain and urinary pain were assessed by patients using a VAS ranging from 1 (no pain) to 10 (worst pain possible) Urination symptoms were assessed on a VAS ranging from 1 (no difficulty) to 10 (very difficult) Pain intensity was measured using the Symptom Distress Scale pain item 2, a 5-point scale Analgesic use was measured using a 5-point scale where 0 = no analgesics, 1 = nonnarcotics taken occasionally, 2 = nonnarcotic analgesics taken regularly, 3 = narcotic analgesics taken occasionally, and 4 = narcotic analgesics taken regularly The pain scale was derived from the present pain intensity of the McGill Pain Questionnaire Quality of life was evaluated using the FACT-L questionnaire

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Table 3 FDA Oncology Drug Approvals with a PRO Claim in the Label (Continued) Generic Therapeutic PRO end (brand name) Manufacturer indications points PRO instruments Pamidronate Novartis Osteolytic bone Pain narcotic Pain score was calculated as the disodium metastases of use product of pain severity times (Aredia) breast cancer pain frequency Osteolytic Both were assessed on a 4-point lesions of scale, where 0 = none to 3 = multiple severe for pain severity and from myeloma 0 = none to 3 = constant (most of the time) for pain frequency Narcotic score was also assessed using a 4-point scale, from 0 = none to 3 = strong narcotic Thyrotropin alfa Genzyme Thyroid HRQOL HRQOL was measured using the (Thyrogen) neoplasm SF-36 health survey Topotecan GlaxoSmithKline Small-cell lung Symptom Data were collected on patients’ hydrochloride cancer improvement self-assessed scores for 9 (Hycamtin) symptoms of disease: shortness of Metastatic breath, interference with daily ovarian activity, fatigue, hoarseness, carcinoma cough, insomnia, anorexia, chest pain, and hemoptysis. Each symptom was rated on a 4-category scale Ligand Kaposi’s Treatment Alitretinoin Patients were asked about their (Panretin) Pharmaceuticals sarcoma satisfaction overall satisfaction with the The subjective treatment, which was 1 item of a 9-item QOL questionnaire assessment of lesions The subjective assessment of all treated lesions was scored by patients using a 7-point ordinal scale Bicalutamide AstraZeneca Prostatic HRQOL Self-administered patient (Casodex) neoplasms questionnaires on pain, social functioning, emotional well-being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment-related symptoms No additional detail was provided Post–FDA guidance Ruxolitinib Incyte Myelofibrosis Reduction in Myelofibrosis Symptom (Jakafi) total symptom Assessment Form score

Approval date October 1991

November 1998 May 1996

February 1999

October 1995

November 2011

EORTC QLQ-C30 indicates European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ-LC13, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung; FACT-BRM, Functional Assessment of Cancer Therapy-Biologic Response Modifiers; FACT-L, Functional Assessment of Cancer Therapy-Lung; FDA, US Food and Drug Administration; HRQOL, health-related quality of life; NSCLC, non–smallcell lung cancer; PRO, patient-reported outcome; QOL, quality of life; SF-36, Short Form 36-Item; VAS, visual analog scale.

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lower symptom scores in 8 of the 9 items.17 No statistical comparisons with respect to differences in symptom improvement between topotecan and the trial comparator regimen, cyclophosphamide plus doxorubicin and vincristine were reported in the approved product labeling17; however, the results of a statistical comparison was previously reported by von Pawel and colleagues.18 The case of topotecan provides an example of an oncology agent with challenges regarding PRO labeling claims. First, the scale used to collect the PRO data has limited published evidence regarding the psychometric properties of the scores produced by this scale in patients with lung cancer, such as test–retest reliability and construct-related validity. Second, the prescribing information for topotecan states that the rating scale has limitations in interpretation and that responses precluded a formal statistical analysis.17 In addition, the published results from the trial reporting these symptom outcomes also indicate that the questionnaire was not a validated QOL instrument.18

Case Study of Ruxolitinib To date, only 1 oncology medication—ruxolitinib—has followed the FDA guidance for the development of a PRO instrument to obtain a PRO-based product labeling claim.

Furthermore, the FDA indicated that the example of ruxolitinib provides a model for future marketing applications and may foster more frequent use of PRO instruments.19 Ruxolitinib is an oral Janus kinase (JAK)1 and JAK2 inhibitor approved by the FDA for the treatment of patients with intermediate- or high-risk myelofibrosis.20 The results of 2 phase 3 trials (COMFORT-I and COMFORT-II) provided support for FDA approval.19 COMFORT-I was a randomized, multinational, double-blind, placebo-controlled, phase 3 study, and COMFORT-II was an open-label, randomized, phase 3 study comparing ruxolitinib with best available therapy.20 The primary end point of both trials was a reduction in spleen volume (biologic end point), and COMFORT-I incorporated a key secondary end point based on a PRO instrument designed specifically for this population: ≥50% improvement from baseline to week 24 in total symptom score (TSS) based on the modified Myelofibrosis Symptom Assessment Form version 2.0 (MFSAF v2.0).20 The modified MFSAF v2.0 diary captures a patient’s symptom severity (ie, night sweats, itching, abdominal discomfort, pain under ribs, early satiety, bone/muscle pain, and inactivity) on a scale of 0 (absent) to 10 (worst imaginable), with TSS as the sum of the individual symptom scores (with the exception of inactivity).20 In the COMFORT-I trial, TSS continued to worsen over time for patients receiving placebo. After 24 weeks of

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treatment, 45.9% of patients treated with ruxolitinib and 5.3% of patients receiving placebo achieved ≥50% improvement from baseline in TSS.20 In each individual symptom score, a greater proportion of patients taking ruxolitinib achieved ≥50% improvement compared with the patients receiving placebo.20 The presence of constitutional symptoms such as night sweats, fever, and weight loss have shown to be prognostic factors for reduced survival that are included in the International Prognostic Scoring System for mye­ lofibrosis21; therefore, measuring a drug’s ability to reduce symptom burden can be important in overall efficacy evaluations. Substantial symptom improvement was observed early in the first few patients treated with ruxolitinib in the phase 1/2 trial, and discussions with the FDA’s Division of Drug Oncology Products (DDOP) indicated that one other clinically relevant benefit, such as symptom improvement, may support registration, along with objectively measured spleen size.22 Therefore, a symptom assessment tool (an early version of the MFSAF) was incorporated into the phase 1/2 trial. This instrument was developed by a group of the study investigators22 and was supported by symptom data from a cross-sectional survey of 458 patients with myelofibrosis.23 Subsequent feedback from the FDA, cognitive testing, and patient interviews contributed to the further refinement of this symptom questionnaire to support the modified MFSAF v2.0 used in the COMFORT-I study.

In addition, to demonstrate whether the modified MFSAF v2.0 correlated with clinically meaningful improvements, the study sponsor grouped patients into TSS “responders” or “nonresponders” based on the key secondary end point in COMFORT-I, and these groups were categorized based on Patients’ Global Impression of Change (PGIC) scores at week 24.22 The PGIC asks patients, “Since the start of the treatment you’ve received in this study, your myelofibrosis symptoms are (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse, or (7) very much worse?”22 More than 90% of patients categorized as responders reported a PGIC score of “much improved” or “very much improved,” supporting the ability of the modified MFSAF v2.0 to measure clinically meaningful changes in the symptoms of myelofibrosis.22

Challenges with PROs from the Payer Perspective In the United States, payer concerns regarding the added value of PRO instruments are rooted in the meaning (ie, what is being measured?), relevance (ie, how important is what is being measured to the disease?), technical quality (ie, can I trust the scores produced by the questionnaire?), and interpretability (ie, at what

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point does an observed change in scores begin to reflect a bona fide treatment gain?) of PROs.15 Concern that PROs do not independently predict improved patient outcomes is also a barrier from the payer perspective.

Additional challenges germane to non-PRO and PRO data alike, such as unblinded trials, missing or incomplete data, the multiplicity of end points, and inconsistent findings, provide further barriers regarding the acceptance of PROs.5,24 The potential dearth of appreciation for the clinical impact associated with aggregate symptom burden in rare disease states may also be a contributing factor.

Aside from these challenges, the use of poorly designed questionnaires that do not specifically assess the disease result in a missed opportunity to determine a patient-based treatment benefit that may be valuable in the context of payer decision-making. For example, the symptom scale used to evaluate topotecan lacks published information about the symptom scale, and the prescribing information reports limitations in the symptom scale; therefore, the PRO labeling claims may lack credibility and value from the payer perspective.

Payer Survey Results Recent quantitative and qualitative payer market research conducted by Xcenda, LLC, in 2012,25 has described payers’ challenges with PRO data, such as the lack of familiarity with PRO measures, the perceived lack of value in using PRO data to support evidence regarding unmet needs, and the lack of impact that PRO data may have on decision-making; all of the above factors are accentuated in rare diseases. In the quantitative payer market research, a survey of 49 US payers, representing approximately 142 million covered lives, was used to determine payer perceptions of PRO data in oncology. This sample of payers represented 27 pharmacy directors, 16 medical directors (national or regional), and 6 other policy decision makers. The survey respondents represented national or regional health plans, including 3 integrated delivery systems, 6 pharmacy benefit managers, 27 managed care organizations, 4 preferred provider organizations, and 9 others.25 When asked about their familiarity with PRO data in oncology, the average response on a numeric rating scale (1, not familiar at all; 7, extremely familiar) was 3.6 (slightly below a neutral response of 4), indicating that many of the payers were not familiar with these types of data. Overall, most payers (N = 13) provided a value of 5, followed by values of 3 (N = 12), 4 (N = 8), 2 (N = 7), 6 (N = 4), and 1 (N = 5).25 The payers were also asked to what degree they believe PRO data can provide sufficient evidence that a drug is meeting an unmet need in oncology (1, do not

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believe evidence is sufficient; 7, strong belief that evidence is sufficient); the average response was also 3.6.

Most payers (N = 13) provided a value of 4, followed by values of 5 (N = 12), 2 (N = 10), 3 (N = 9), 6 (N = 3), and 1 (N =2); no payers provided a value of 7.25 This suggests that payers, although mostly neutral on the topic, may not believe that PRO data can provide sufficient evidence that a drug is meeting an unmet need.

More important, when asked if PRO data provide value in making formulary decisions for oncology drugs (1, no value; 7, extreme value), the average response was 2.8. Most payers (N = 18) provided a value of 2, followed by values of 4 (N = 17), 1 (N = 16), and 3 (N = 5). No payers responded with a value of 7 or 6. This indicates that payers place little value on PRO data in the context of coverage decision-making, which may be related to the challenges with PRO data noted earlier or with payers’ lack of familiarity with PRO data in oncology.25

Feedback from a Payer Focus Group Additional qualitative market research in the form of a double-blind focus group (ie, the study sponsor and the focus group participants do not know the identity of each other) included 13 payers, including pharmacy directors (N = 6), medical directors (N = 5), and other policymakers (N = 2) from national or regional plans.

This sample of 13 payers represented approximately 114 million covered lives.

Although qualitative results with a small sample size are difficult to validate, several key insights were derived from this focus group. The first key insight was that payers often mistakenly consider PROs to be synonymous with QOL, but this is incorrect. Although QOL can be assessed by PRO methods, QOL’s broad definition (an evaluation of the effect of all aspects of life on general well-being) typically precludes regulatory consideration for QOL-based medical claims.1 However, the FDA will consider other PRO data for labeling, especially in cases where the concepts of measurement are well defined (eg, symptoms) or if they characterize the specific effect of treatment on disease-related symptoms and physical, psychological, and social aspects of life (eg, health-related QOL).

The second key finding from the payer focus group was that payers’ internal committees and decision-making groups have not defined what PROs mean for their organizations or decision-making processes. Based on the recent FDA guidance, this is in contrast to the increasing importance of PROs to health authority regulatory scientists at the FDA,1 the FDA’s DDOP, healthcare providers, and patients. Subsequently, PRO data may be discarded or not considered as part of the evidence package for consideration when making key decisions in oncolo-

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gy. Third, none of the payers were familiar with or had read the FDA guidance regarding the incorporation of PRO claims in product labeling.

Despite this, several payers were willing to evaluate PRO data in the context of understanding the comprehensive risks and benefits of a given oncology therapy.

Therefore, an opportunity to increase awareness among payers will be a critical initiative. Ultimately, payers continue to manage members with larger populations in mind, which may explain why many payers do not perceive PRO data as valuable in the context of decision-making; however, PRO data also present several opportunities for payers to use in decision-making.

Opportunities Associated with PROs in Decision-Making The FDA’s guidance on the development, implementation, and interpretation of PRO measures directly supports PRO medical claims in product labeling, while also mitigating the challenges associated with PRO data.1 In this way, payers and policy decision makers can have increasing confidence that the data generated by PRO questionnaires have been demonstrated to be relevant, trustworthy, and meaningful, which provides an opportunity to focus on how to use PRO data in decision-making. For example, during discussion in the focus group, some of the payers indicated that PRO data can be useful to differentiate treatments with similar efficacy or comparable toxicity profiles. Similarly, several publications have focused on this specific benefit of PROs, because growing cost pressure has created an increasing need for product differentiation.5,14,16 In the focus group, payers provided caution against shifting focus away from conventionally used end points, such as survival or surrogates of survival (eg, progression-free survival), and continuing to maintain PROs as a secondary measure. Consistent with this payer perception, PROs present an opportunity to incorporate patient-perceived effects as an adjunct to clinical efficacy measures in an era of oncology where there is an increasing number of therapies offering equivalent survival or other clinical end points.12,16 The payers in the focus group also viewed PROs as an opportunity to identify oncology products that may directly impact healthcare utilization. Rooted in the fact that several oncology treatments have high toxicity profiles (especially when compared with nonantineoplastic medicines), payers see PROs as an opportunity to identify potentially costly events reported by patients in the trials. Therefore, treatments with reduced toxicity that can demonstrate a positive impact on PROs may influence payer decision-making for the treatments with supporting PRO data. For example, PROs measuring

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bone pain and/or muscle pain may be more directly related to the utilization of pain medications; PROs measuring nausea may be related to the utilization of antiemetic treatments; and PROs capturing side effects, such as diarrhea, may correlate to substantive dehydration and subsequent hospitalization costs.

FDA-evaluated PRO questionnaires such as the MFSAF present an opportunity for payers to evaluate relevant, disease-specific treatment benefits in the context of important risk–benefit decisions that directly impact the livelihood of patients with cancer. In addition, instruments created in collaboration with and approved by the FDA may lead to increased confidence and less scrutiny than payers previously had. As more PRO label claims are approved, payers may see, and should be prepared to react to, symptom data in labels. Some health plans, such as WellPoint, have already issued formulary guidance regarding the effectiveness in improving patients’ QOL.16 A recent review of PROs in labels discovered that between 2006 and 2010, 85.7% of PRO label claims were for symptoms.4 Ultimately, payers will have to start evaluating and incorporating these data into the decision-making process despite the findings from the payer focus group that suggest that several payers may not be familiar with the volume of PRO evidence in development or with their subsequent inclusion into medical claims labeling. Therefore, in an attempt to further incorporate PRO data into product labeling claims and formulary decision-making processes, efforts to increase awareness of PROs among all stakeholders in oncology—­ specifically payers—will be necessary.

As evidenced by direct feedback in the focus group, payers anticipate that PROs could be incorporated into decision-making in several ways. First, payers specifically value PROs that could be used to direct treatment decisions in terms of continuation versus discontinuation of treatment. PROs that are related to or are incorporated into response criteria, prognostic scales, or other formal decision-making algorithms may be used to determine continued access to treatment.

Second, products with positive PRO data could be granted preferred status for agents within the same class (ie, in comparison with agents with similar mechanisms and indications but lacking PRO evidence).

Third, products that demonstrate a marked difference in adverse events may aid payers in managing these events at a population level.

Finally, payers should strongly anticipate that PROs will have the largest impact on drug selection between individual patients and their physicians or healthcare providers at the clinical care delivery level, which is consistent with an increasing emphasis on patient-centered medical homes and palliative care.

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Call to Action: Incorporating PRO Data into Coverage Decision-Making • Familiarize yourself and your committees with the FDA guidance on PROs • Gather stakeholders within your organization to internally define PROs and to establish how PROs will impact your decision-making process • For FDA-approved product labeling claims regarding PROs, determine how each PRO measure fits within the overall treatment risk–benefit profile • Determine if the PRO measure will be related to changes in healthcare utilization • Determine if PRO measures could be used to inform continuation or discontinuation of the therapy.

Conclusions The 2009 FDA guidance and the subsequent example of incorporation of PRO labeling claims in the successful clinical development of ruxolitinib (leading to its approval for the treatment of intermediate- or high-risk myelofibrosis) have paved the way for drug manufacturers to develop and to disseminate PRO measures related to treatment benefit and/or risk in oncology. The growing body of literature regarding the incorporation of PRO claims into FDA labeling for oncology products has focused largely on the patient, regulatory, industry, and provider perspectives; however, the payer perspective and the impact of PRO labeling claims on decision-making has been of a lesser focus. More resources and tools regarding the use of PROs in oncology trials will be necessary for payers to further understand the value of PRO data in treatment decisions and of the identification of preferred pathways. Additional case studies need to be conducted to understand how payers and policymakers will use PRO measures and other secondary measures in coverage decisions and how PRO data will impact the future of cancer outcomes research.

Study Funding This study was supported by funding from Incyte Corporation.

Author Disclosure Statement Dr Zagadailov is an employee of Xcenda, which provides consulting services to pharmaceutical companies. Dr Fine has reported no conflicts of interest. Dr Shields is an employee of Adelphi Values, which provides consulting services to pharmaceutical companies, and was previously a consultant to Incyte, but was not compensated for this research.

References

1. US Food and Drug Administration. Guidance for Industry. Patient-Reported

Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed April 19, 2013.

2. Willke RJ, Burke LB, Erickson P. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels.

Control Clin Trials. 2004;25:535-552.

3. Marquis P, Caron M, Emery M, et al. The role of health-related quality of life data in the drug approval processes in the US and Europe: a review of guidance documents and authorizations of medicinal products from 2006 to 2010. Pharm Med. 2011;25:147-160.

4. Gnanasakthy A, Mordin M, Clark M, et al. A review of patient-reported outcome labels in the United States: 2006 to 2010. Value Health. 2012;15:437-442.

5. Hao Y. Patient-reported outcomes in support of oncology product labeling claims: regulatory context and challenges. Expert Rev Pharmacoecon Outcomes Res. 2010;10: 407-420.

6. Shields A, Gwaltney C, Tiplady B, et al. Grasping the FDA’s PRO guidance: what the agency requires to support the selection of patient-reported outcome instruments.

Applied Clin Trials. 2006;15:69-77.

7. Coons SJ, Gwaltney CJ, Hays RD, et al. Recommendations on evidence needed to support measurement equivalence between electronic and paper-based patient-reported outcome (PRO) measures: ISPOR ePRO Good Research Practices Task Force report. Value Health. 2009;12:419-429.

8. Rothman M, Burke L, Erickson P, et al. Use of existing patient-reported outcome (PRO) instruments and their modification: the ISPOR Good Research Practices for Evaluating and Documenting Content Validity for the Use of Existing Instruments and Their Modification PRO Task Force report. Value Health. 2009;12:1075-1083.

9. Patrick DL, Burke LB, Gwaltney CJ, et al. Content validity—establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force report: Part 1—eliciting concepts for a new PRO instrument. Value Health.

2011;14:967-977.

10. Patrick DL, Burke LB, Gwaltney CJ, et al. Content validity—establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force report: Part II—assessing respondent understanding. Value Health. 2011;14:578-588.

11. Bruner DW, Bryan CJ, Aaronson N, et al. Issues and challenges with integrating patient-reported outcomes in clinical trials supported by the National Cancer Institute-sponsored clinical trials networks. J Clin Oncol. 2007;25:5051-5057.

12. Gondek K, Sagnier PP, Gilchrist K, Woolley JM. Current status of patient-­ reported outcomes in industry-sponsored oncology clinical trials and product labels.

J Clin Oncol. 2007;25:5087-5093.

13. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol. 2003;21:1404-1411.

14. Kitchen H, Rofail D, Caron M, Emery MP. Oncology patient-reported claims: maximising the chance for success. Ecancermedicalscience. 2011;5:212.

15. Lipscomb J, Reeve BB, Clauser SB, et al. Patient-reported outcomes assessment in cancer trials: taking stock, moving forward. J Clin Oncol. 2007;25:5133-5140.

16. Doward L, Gnanasakthy A, Baker M. Patient reported outcomes: looking beyond the label claim. Health Qual Life Outcomes. 2010;8:89-97.

17. Hycamtin [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.

18. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17:658-667.

19. Deisseroth A, Kaminskas E, Grillo J, et al. US Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high risk myelofibrosis. Clin Cancer Res. 2012;18:3212-3217.

20. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2012.

21. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.

22. Falcone CR, Levy RS. Approval of Jakafi (ruxolitinib) based on a home-grown, patient-reported outcome instrument: a case study. Regulatory Focus website. June 2012. www.raps.org/focus-online/quality-and-compliance/quality-and-compliance-­ article/article/1854/approval-of-jakafi-ruxolitinib-based-on-a-home-grown-patientreported-outcome-i.aspx. Accessed January 7, 2013.

23. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.

24. Rock EP, Scott JA, Kennedy DL, et al. Challenges to use of health-related quality of life for Food and Drug Administration approval of anticancer products. J Natl Cancer Inst Monogr. 2007;37:27-30.

25. Xcenda. Patient-reported outcomes in oncology focus group. April 17, 2012.

Unpublished data.

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Stakeholder Perspective Assessing the Value of Patient-Reported Outcomes

By Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services, SelectHealth, Salt Lake City, UT

The article by Zagadailov and colleagues addresses interesting points about the implications of patient-­ reported outcomes (PROs) for drug coverage and treatment decisions, as well as the associated challenges and opportunities.

PAYERS: When evaluating the coverage of drugs, particularly novel drugs, the 3 main factors considered by payers are efficacy, safety, and cost. In the assessment of efficacy outcomes, primary outcomes carry the most weight and, fittingly, secondary outcomes carry less weight. Historically, PROs have been included as secondary outcome measures within pivotal as well as nonpivotal studies that contribute to the literature that is evaluated by payers for coverage decisions.

There are many primary end points within each therapeutic class, and even more when considering all therapeutic classes. The large variety of objective, consistent primary outcomes makes consensus among payer evaluations difficult. Whereas one payer may define the true value of a pharmaceutical intervention by the reduction of a negative event, such as a myocardial infarction (MI), another payer may give credence to a drug with a more potent reduction of a surrogate marker, such as low-density lipoprotein lowering. Using both criteria, a number needed to treat and a relatively simple, cost-effective measure may be calculated. In this example of cardiovascular disease, symptoms of disease progression, as well as medication side effects, are relatively benign, and therefore PROs are not as relevant as in symptomatic conditions or in side-effect–heavy treatments. However, without consensus on the relative value of more traditional, objective measures, how are payers expected to agree on the relative value of subjective PROs? This question, of course, assumes that payers agree that PROs carry enough value to justify the time spent on their evaluation.

Zagadailov and colleagues focus on oncology care, an area where PROs are beginning to have an impact in drug development. But even within the evaluation of cancer therapies, several common primary outcome measures exist, including, but not limited to, overall survival (OS), progression-free survival, and overall response rate. Again, there is no consensus among payers on the most important measure or on the relative value of incremental differences within each measure. For instance, one payer may assign high value to a drug that demonstrates 6 months of OS improvement, whereas another payer may attribute

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similar value to a drug that adds only 4 months of OS for the treatment of the same cancer type. To reiterate, even with objective outcomes for cancer therapies, assigning an economic value for payers is more difficult than assessing the value of MI prevention. The enormity of different types of PROs further creates difficulties in understanding the measures and in assigning value to these measures in an arena as complicated as cancer care.

For many payers, the US Food and Drug Administration’s pathway to drug approval is a moot point. State mandatory coverage regulations may leave payers little wiggle room to manage oncolytic therapies. The Centers for Medicare & Medicaid Services also has regulations that may prohibit a payer from designating coverage preference for one drug or another, even if the drug’s PROs are seemingly superior to other drugs’.

Nevertheless, PROs are not going away any time soon, and payers need to spend time becoming familiar with their different types. Payers will also need to determine if more recent PROs bring significant value to formulary and coverage decisions. This may take some real-world validation of health resource utilization that is tied to the outcomes of PROs. PROVIDERS: In oncology, many of the objective measures within clinical trials can be evaluated for individual patients, such as time to disease progression.

Many providers will capture some type of PRO, which may be as simple as assessing activities of daily living or screening patients with the Patient Health Questionnaire-9 scale for depression.

In the case of ruxolitinib that is cited in the present article, the Myelofibrosis Symptom Assessment Form version 2.0 (MFSAF v2.0) was evaluated as a secondary end point. It is my assumption that few providers complete a routine analysis of the MFSAF v2.0 for every patient with myelofibrosis. Providers will also need to assess the real-­ world applicability of PROs in their practices and determine how PROs fit into their therapy selection decision.

PROs could possibly contribute to the oncologist’s selection process and could even contribute to the decision to place a drug on a pathway, which may affect payers.

PATIENTS: Overall, patients with cancer are most concerned with their quality of life and length of life.

The assessment of quality of life may be better done through PROs, which can add an important perspective to treatment decisions. n

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Original Article

Review of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy Michael K. Wong, MD, PhD; Xufang Wang, MD, MBA; Maruit J. Chulikavit, MPH; Zhimei Liu, PhD Background: In 2006, the economic burden of metastatic renal cell carcinoma (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually. With the continuing increase of the economic burden of this disease in the United States, there is a growing need for economic analyses to guide treatment and policy decisions for this patient population.

Objective: To evaluate available comparative economic data on targeted therapies for patients with mRCC who have failed first-line targeted therapies.

Method: A broad and comprehensive literature review was conducted of US-based studies between January 1, 2005, and February 11, 2013, evaluating comparative economic evidence for targeted agents that are used as second-line therapy or beyond. Based on the specific search parameters that focused on cost-effectiveness and economic comparisons between vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) inhibitors and mammalian target of rapamycin (mTOR) inhibitors, only 7 relevant, US-based economic evaluations were found appropriate for inclusion in the analysis. All authors, who are experts in the health economics and outcomes research field, reviewed the search results. Studies of interest were those with a targeted agent, VEGF/VEGFr or mTOR inhibitor, in at least 1 study arm.

Discussion: As a group, targeted therapies were found to be cost-effective options in treating patients with refractory mRCC in the United States. Oral therapies showed an economic advantage over intravenous agents, presumably because oral therapies have a lower impact on outpatient resources. Based on 3 studies, everolimus has been shown to have an economic advantage over temsirolimus and to be cost-effective compared with sorafenib. No economic comparison between everolimus and axitinib, the only 2 drugs with a National Comprehensive Cancer Network category 1 recommendation for use after the failure of VEGFr tyrosine kinase inhibitors, is available.

Conclusion: The limited and heterogeneous sum of the currently available economic evidence does not allow firm conclusions to be drawn about the most cost-effective targeted treatment option in the second-line setting and beyond in patients with mRCC. It is hoped that ongoing head-to-head therapeutic trials and biomarker studies will help improve the economic efficiency of these expensive agents.

R

enal cell carcinoma (RCC) comprises 92% of all kidney cancers and has a poor prognosis, with approximately 10% of patients with metastatic

Dr Wong is Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; Dr Wang is Director, Worldwide Health Outcomes, Value & Access, Novartis Pharmaceuticals, and Dr Liu is Director, Oncology US Health Economics & Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ; Mr Chulikavit is Associate Director, LA-SER Analytica International, New York, NY.

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2013;6(5):275-286 www.AHDBonline.com Disclosures are at end of text

disease surviving beyond 5 years.1 In 2006, the economic burden of metastatic RCC (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually.2 A recent review reported that the economic burden of RCC in the United States ranges from $600 million to $5.19 billion, with annual per-patient medical costs of between $16,488 and $43,805.3 Furthermore, these costs will likely increase with the expanded use of targeted agents, based on a 2011 pharmacoeconomic analysis showing that the annual costs to treat patients with RCC receiving these agents are 3- to 4-fold greater than

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Key Points The growing economic burden of renal cell carcinoma (RCC) in the United States indicates the need for economic analyses of current therapies to guide treatment decisions for this disease. ➤ This article is based on a comprehensive review of 7 studies that were identified within the search criteria for US-based economic data related to targeted therapies for metastatic RCC (mRCC) after failure of first-line therapies. ➤ Targeted therapies were shown to be cost-effective for the treatment of refractory mRCC. ➤ Oral therapies showed an economic advantage over intravenous agents, presumably because of their lower impact on outpatient resources. ➤ No economic comparison is yet available for the only 2 drugs (ie, everolimus and axitinib) with an NCCN category 1 recommendation for use after a vascular endothelial growth factor receptor TKI. ➤ Ongoing head-to-head therapeutic trials and biomarker studies may help to improve the economic efficiency of targeted treatments in the second-line setting and beyond for mRCC. ➤

the costs to treat patients who are not receiving targeted therapies.4 In addition, the incidence and prevalence of RCC are rising, in part because of improved and earlier detection, and because of increases in related risk factors, such as hypertension, diabetes, and obesity.5-7 Clear-cell RCC, the most common histology, constitutes 75% of cases of RCC.8 The majority of patients with clear-cell RCC experience a loss of the functional von Hippel-Lindau gene, resulting in the accumulation of hypoxia-inducible factor-1α, an angiogenic factor whose protein synthesis is regulated by mammalian target of rapamycin (mTOR).9 The net effect is overproduction of downstream proteins that promote RCC progression by stimulating cell growth and proliferation, cellular metabolism, and angiogenesis (ie, vascular endothelial growth factor [VEGF], platelet-derived growth factor, and epidermal growth factor).9 Abnormal functioning of the mTOR pathway is therefore thought to play a role in the pathogenesis of RCC; inhibition of mTOR globally decreases protein production, suppresses VEGF synthesis, and induces cell cycle arrest.10 Knowledge of the critical role of VEGF and mTOR in RCC pathogenesis drove the development of targeted agents in the treatment of this disease.

The US Food and Drug Administration (FDA) approval of axitinib in January 2012 brings the total of approved

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targeted agents for RCC to 7 in the past 7 years, making this one of the most prolific areas of cancer drug development (Table 1).11-25 The need for clarity regarding the optimal sequential use of these agents is stronger than ever, particularly given the high price of these agents.

The oral VEGF receptor tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib and pazopanib, the VEGF monoclonal antibody bevacizumab plus (subcutaneously injected) interferon-α, and the intravenous (IV) mTOR inhibitor temsirolimus are recommended by the National Comprehensive Cancer Network (NCCN) as firstline therapies for the treatment of mRCC (Table 2).26 The VEGFr-TKI sorafenib is recommended for select patients only. Despite efficacy in mRCC, agents targeted against VEGF only “inhibit” the disease, making resistance almost inevitable and universal, thereby necessitating second-line therapy after the failure of initial VEGF inhibition.18,19,22-24 Because curing metastatic disease with these agents is rare, most patients require lifelong therapy and are destined to cycle through the available treatment options.

Guidelines on sequential therapy for the second-line treatment of mRCC and beyond are limited, indicating a lack of clinical trial–based comparative evidence and/or consensus in this area. In the NCCN guidelines, the oral agents everolimus and axitinib are category 1 recommendations for second-line therapy (Table 2).26 Despite their clinically proven benefit in extending progression-free survival (PFS), the cost of these agents and their lack of proven survival benefit have led to controversial government reimbursement decisions in some parts of the world (eg, by the National Institute for Health and Care Excellence in the United Kingdom27).

Given the lack of prospectively collected data sets assessing the optimal sequence of targeted therapies, as well as the high price of these agents, economic analyses provide important insights into the overall costs versus benefits of targeted therapies, thus helping to inform treatment decisions. In this review, we identify comparative economic evidence beyond the first-line treatment of mRCC and discuss the potential implications of the findings.

Method Literature Search of Comparative Economic Studies Although we did not conduct a systematic review, we did conduct a broad, inclusive search of comparative economic evidence for targeted therapies used in the treatment of patients with mRCC after failure of initial therapy. Our search parameters were: • The time frame was from January 1, 2005, to February 11, 2013 (lower boundary coincided with the introduction of sorafenib to the US market, marking the beginning of the targeted-therapy era in RCC)

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Table 1 Targeted Agents Approved for RCC and Pivotal Phase 3 Clinical Trials Drug, route of administration, approval date RCC indication Design of pivotal trial Advanced RCC TARGET: randomized, doubleSorafenib, oral11 December 20, 2005 blind study of sorafenib (n = 451) vs placebo (n = 452) in patients treated with 1 previous systemic therapy (primarily cytokines)18 Advanced RCC Randomized, open-label study Sunitinib, oral12 February 2, 2007 of sunitinib (n = 375) vs IFN-α (n = 375) in treatmentnaive patients19 Temsirolimus, IV13 May 30, 2007

Advanced RCC

Everolimus, oral14 March 30, 2009

RCC therapy after failure of treatment with sunitinib or sorafenib Metastatic RCC with IFN-α

PFS in the overall population of pivotal trial • Median, 5.5 mo with sorafenib vs 2.8 mo with placebo • HR, 0.44 (95% CI, 0.35-0.55; P <.001) • Median, 11 mo with sunitinib vs 5 mo with IFN-α • HR, 0.539 (95% CI, 0.4510.643; P <.001) • Median, 3.8 mo with temsirolimus vs 1.9 mo with temsirolimus + IFN-α vs 3.7 mo with temsirolimus + IFN-α • HR, not available

ARCC: randomized, open-label study of temsirolimus (n = 209) vs IFN-α (n = 207) vs temsirolimus + IFN-α (n = 210) in treatment-naive patients with ≥3 of 6 predictors of short survival20 RECORD-1: randomized, double-blind study of everolimus (n = 277) vs placebo (n = 139) in patients previously treated with sunitinib and/or sorafenib21 AVOREN: randomized, doubleblind study of bevacizumab + IFN-α (n = 327) vs placebo + IFN-α (n = 322) in treatmentnaive patients22

• Median, 4.9 mo with everolimus vs 1.9 mo with placebo • HR, 0.33 (95% CI, 0.25-0.43; P <.001)

• Median, 10.2 mo with bevacizumab + IFN-α vs 5.4 mo with placebo + IFN-α • HR, 0.63 (95% CI, 0.52-0.75; P = .001) • Median, 8.5 mo with CALGB 90206: randomized, bevacizumab + IFN-α vs 5.2 mo open-label study of bevacizumab with IFN-α + IFN-α (n = 369) vs IFN-α (n = 363) in treatment-naive • HR, 0.72 (95% CI, 0.61-0.83; patients23 P <.001) 16 Adults for first-line Randomized, double-blind study • Median, 9.2 mo with pazopanib Pazopanib, oral October 19, 2009 treatment of vs 4.2 mo with placebo of pazopanib (n = 290) vs advanced RCC placebo (n = 145) in treatment- • HR, 0.46 (95% CI, 0.34-0.62; and for patients naive and cytokine-pretreated P <.001) who have received patients24 previous cytokine therapy for advanced disease 17 Treatment of RCC AXIS: randomized, open-label • Median, 6.7 mo with axitinib Axitinib, oral January 27, 2012 after failure of 1 vs 4.7 mo with sorafenib study of axitinib (n = 361) vs previous systemic sorafenib (n = 362) in patients • HR, 0.665 (95% CI, 0.544therapy treated with 1 previous 0.812; P <.001) systemic therapy25 CI indicates confidence interval; HR, hazard ratio; IFN, interferon; IV, intravenous; PFS, progression-free survival; RCC, renal cell carcinoma; SC, subcutaneous.

Bevacizumab, IV, plus IFN-α, SC15 August 3, 2009

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CCN Treatment Guidelines for mRCC, by Phase 3 Table 2 N Evidence Setting Category 1 evidence Sunitinib Good or Pazopanib a Treatment naïve intermediate risk Bevacizumab + IFN-α Temsirolimus Poor riska Sorafenib Sunitinib Previous cytokine Pazopanib Axitinibb Previously treated Previous tyrosine Everolimus kinase inhibitor Axitinibb Previous mTOR Unknown inhibitor a Memorial Sloan-Kettering Cancer Center risk category. b Axitinib has a category 1 recommendation for treatment of patients who have failed ≥1 previous systemic therapy.

IFN indicates interferon; mRCC, metastatic renal cell carcinoma; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network.

Source: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).

Kidney cancer. Version 1.2013. 2013.

• The databases that were searched included PubMed/ MEDLINE and Ovid/EMBASE; abstracts and industry-­ sponsored articles were allowed • The conference proceedings that were searched (to account for relevant data that were not published in the peer-reviewed literature) included the American Society of Clinical Oncology (ASCO), the Genitourinary Cancers Symposium, the International Society for Pharmacoeconomics and Outcomes Research, the Academy of Managed Care Pharmacy, the American Society of Health-System Pharmacists, the American Urological Association, and the International Society for Quality of Life Research • The search was limited to studies in the English language and US-based studies (because national policy directly influences healthcare expenditures, and these agents entered the US pharmacopeia soon after FDA approval) • The search terms included “metastatic renal-cell carcinoma or mRCC or advanced renal-cell carcinoma or aRCC or stage 4 RCC,” “second-line therapy,” “targeted therapy or everolimus or RAD001 or temsirolimus or sorafenib or sunitinib or axitinib or pazopanib or bevacizumab or mTOR inhibitor or tyrosine kinase inhibitor or TKI or vascular endothelial growth factor inhibitor or VEGF inhibitor,” and “health-related quality of life, or HRQOL, or health

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economics or health outcomes or cost-effective” or “cost-effectiveness” (see Glossary).

All authors, who are experts in the health economics and outcomes research field, reviewed the search results. After this initial individual review, a group discussion was held to confirm which studies met our criteria and would be covered in this article. Studies of interest were those with a targeted agent—VEGF/ VEGFr or mTOR inhibitor—in at least 1 study arm.

Comparative outcomes of interest were health economics and outcomes research measures derived from any budget impact, cost minimization, cost-resource utilization comparison, or cost-effectiveness and cost utility analyses. Studies related to the economic burden (cost) of illness were excluded from this analysis.

Glossary Select Health Economics Outcomes Research Terms Health economics outcomes research: A broad term encompassing “a discipline that describes, interprets, and predicts the impact of various influences, especially interventions, on final end points (from survival to satisfaction with care) that matter to decision makers (from patients to society at large)”a Cost-effectiveness analysis: Analysis in which the consequences associated with a health technology are measured in terms of healthb Incremental cost-effectiveness ratio: The ratio of the difference in costs between 2 alternative health technologies to the difference in effectiveness between these 2 technologiesb Quality-adjusted life-year (QALY): Quantitatively measures the value of 1 year of life (a QALY of 1 = 1 year with normal health; a QALY of 0 = death)b Sensitivity analysis: Analysis that aims to assess and to determine the influence of input parameters on the outcomes of the economic evaluation studyb Deterministic sensitivity analysis: Point estimates are assigned to the input parametersb Probabilistic sensitivity analysis: Probability distributions are applied to the ranges for a model’s input parameters, and samples from these distributions are drawn at random to generate an empirical distribution of the relevant measure of cost-effectivenessb Apolone G. Health Qual Life Outcomes. 2003;1:3.

Andronis L, et al. Health Technol Assess. 2009;13:iii,ix-xi,­­ 1-61. a

b

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Key Findings of Identified Studies Because of the restrictive nature of our search, the overall number of results identified was low, and only 7 studies, which are summarized in Table 3, met our criteria of interest and were included here.28-35 Of these 7 studies, 3 compared one VEGF or VEGFr inhibitor with another and 4 compared one mTOR inhibitor with another or with a VEGF or VEGFr inhibitor. The studies were heterogeneous in design, with the incremental cost-effectiveness ratios (ICERs) or quality-adjusted life-years (QALYs) associated with various treatments (Glossary) the most common economic benchmarks utilized. Both clinical trial–based and observational-based studies were identified and included. No economic studies including pazopanib were identified using the search criteria. The key findings from each of the identified studies are presented below.

One cost-effectiveness analysis, which was presented at the 2006 ASCO annual meeting, evaluated sorafenib plus best supportive care versus best supportive care alone using a decision analytic Markov model to project lifetime survival and associated costs for patients with advanced RCC.28 Of note, this analysis was based on findings from the phase 3 TARGET trial, in which the majority of patients had received previous cytokine therapy.36 Findings showed lifetime per-patient costs to be $85,571 for sorafenib plus best supportive care and $36,634 for best supportive care alone.28 Treatment with sorafenib plus best supportive care resulted in an ICER of $75,354 per life-year gained.28 Because this ICER is within the societal willingness-to-pay threshold in the United States,37 the study authors concluded that sorafenib was a cost-effective treatment option for patients with advanced RCC. The second study was a retrospective comparison of costs associated with 2 sequences of the oral VEGFr-­ TKIs sorafenib and sunitinib using claims in the MarketScan research database.29 This analysis, which was published in abstract form in conjunction with the 2010 ASCO annual meeting, showed that the univariate incremental total per-patient monthly medical cost for patients who first received sunitinib and then sorafenib was $1639 more than the per-patient monthly cost for the patients who first received sorafenib and then sunit­ inib (P = .003). This represented an annual cost-savings of $19,668 for patients treated with sorafenib initially, which was primarily attributable to outpatient costs.29 The third study that was identified (and was published in a peer-reviewed journal) reported the results of an indirect analysis designed to evaluate the cost-effectiveness of everolimus versus sorafenib for the treatment of sunitinib-refractory mRCC based on the RECORD-1 patient population.31 The drug costs for everolimus and

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sorafenib were based on dosages from the RECORD-1 trial21 and a phase 2 study of sorafenib.38 Using Markov modeling with deterministic and probabilistic sensitivity analyses, the superior cost-effectiveness of everolimus over sorafenib was demonstrated, with a difference of $81,643 in the total average per-patient cost of treatment with everolimus versus sorafenib; this difference was primarily driven by drug acquisition costs (80%).31 Compared with sorafenib treatment, patients treated with everolimus had an estimated gain in life-years of 1.273 and a gain in QALYs of 0.916, resulting in an ICER of $64,155 per life-year gained, or $89,160 per QALY.31 The estimated ICER in this pretreated popu­ lation fell below the cost per QALY for many other oncology medications in widespread use. Compared with sorafenib, everolimus had a high probability of being considered cost-effective at a willingness-to-pay threshold of $100,000 per QALY in patients with advanced RCC who failed therapy with sunitinib.

An indirect model–based analysis comparing temsirolimus with everolimus after failure with sunitinib or with sorafenib over a 3-year time horizon was presented at the 2010 Genitourinary Cancers Symposium.32 The estimated average monthly cost of treatment was $5248 with everolimus and $5597 with temsirolimus, resulting in annual cost-savings of $4188 for treatment with everolimus.32 The cost difference was related to the route of administration for these 2 agents (oral for everolimus vs IV for temsirolimus, or outpatient vs in-clinic management) and the need for antihistamine premedication, which is often performed in a higher acuity setting, to prevent infusion reactions with IV temsirolimus therapy.

In addition, a retrospective resource utilization study of the US Oncology Network’s iKnowMed electronic medical record (EMR) system that was published in a peer-reviewed journal suggests that everolimus is associated with a lower patient burden in terms of outpatient and laboratory visits compared with temsirolimus among patients with mRCC.34 Patients receiving everolimus had significantly fewer monthly outpatient visits and monthly laboratory frequency monitoring compared with those receiving temsirolimus (mean, 1.19 vs 1.60 and 1.25 vs 2.23, respectively; both P <.05).34 Finally, data from multiple regression analyses that were presented at the 2010 meeting of the European Society of Medical Oncology (ESMO) revealed that patients receiving temsirolimus had a 28% higher frequency of outpatient visits and a 58% increase in the utilization of laboratory procedures compared with patients receiving everolimus.35 Although not a direct economic evaluation, results from this analysis provide additional evidence for differences in economic burden between the agents.

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Table 3 US-Based Cost-Effectiveness and Resource Utilization Studies with VEGF/VEGFr and mTOR Inhibitors Study (drugs evaluated; Outcomes sponsor) Study design assessed Findings Implications 28 Gao et al • Markov model to project • FACT-G, • Lifetime per-patient costs • T he ICER was within (sorafenib; Bayer the lifetime survival and FKSI (2004 US$): the established threshold Pharmaceuticals) cost associated with that society is willing to • Sorafenib + best • Life-years sorafenib + best supportive pay ($50,000-$100,000 supportive care: $85,571 gained care vs best supportive care per life-year or per • Best supportive care alone QALY). Therefore, alone: $36,634 sorafenib + best • 3 disease states (per • ICER: $75,354 per/lifesupportive care appears 3-month period): PFS, year gained to be cost-effective in progression, death • Key drivers of the model the management of • Resource utilization acresults were survival after advanced RCC counted for drugs, adminprogression and PFS istrations, physician visits, probabilities for both monitoring, and AEs treatment grounds 29 • Retrospective claims • Incremental • U Moyneur et al nivariate PMPM total •C ompared with sunitinib, (sorafenib, database analysis using PMPM medical costs: $9159 treatment with sorafenib sunitinib; Bayer MarketScan to evaluate medical costs (sunitinib > sorafenib) vs initially resulted in HealthCare) the costs of second-line $7520 (sorafenib > statistically significantly • Outpatient therapy with sorafenib or sunitinib) lower costs in patients costs sunitinib in the treatment • Inpatient with RCC, primarily •O utpatient costs: $3400 of patients with RCC because of outpatient vs $2148 (P <.001) costs costs • Person-time approach was • Pharmacy • I npatient costs: $1755 vs used in patients who had $1582 costs ≥1 switch in therapy from •P harmacy costs: $4004 vs sunitinib to sorafenib or $3790 sorafenib to sunitinib 30 • Total costs • Total per-patient costs: • Compared with axitinib, Ozer-Stillman et al • Survival partition model (axitinib, to estimate direct lifetime • Life-years $127,808 for sorafenib vs treatment with sorafenib sorafenib; Bayer medical costs and clinical gained $159,800 for axitinib after sunitinib failure is HealthCare) outcomes for sunitinibless expensive and • QALYs • Life-years gained: 1.440 refractory patients starting provides a similar benefit gained for sorafenib vs 1.423 for second-line therapy in terms of life-years and axitinib QALYs • Patients partitioned into 3 • QALYs gained: 1.016 for health states (PFS, sorafenib vs 1.015 for postprogression survival, axitinib and death) using OS and PFS Kaplan-Meier curves from AXIS 31 • Markov model to simulate • Cost per Casciano et al • Total average per-patient • Everolimus was projected (everolimus, cohort of patients with incremental cost of treatment with to be a cost-effective sorafenib; advanced RCC who failed life-year everolimus vs sorafenib treatment relative to Novartis therapy with sunitinib gained was $81,643, primarily sorafenib for patients Pharmaceuticals) • Cohorts modeled over because of acquisition with advanced RCC who • QALYs costs (80%) fail sunitinib 6-year time horizon in gained 8-week cycles from • Patients treated with • Estimated ICER fell everolimus or sorafenib everolimus had an estimatbelow the cost per initiation ed life-year gained of QALY for many 1.273 and QALY of 0.916 oncology medicines in • Markov disease states over sorafenib, resulting widespread use included stable disease in an ICER of $64,155 without AEs, stable • Compared with per life-year gained or disease with AEs, disease sorafenib, everolimus had $89,160 per QALY progression, and death a high probability of • Sensitivity analysis being considered costdemonstrated that results effective at a willingnesswere robust to parameters to-pay threshold of of high uncertainty $100,000 per QALY

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Table 3 US-Based Cost-Effectiveness and Resource Utilization Studies with VEGF/VEGFr and mTOR Inhibitors (Continued) Study (drugs evaluated; sponsor) Chulikavit et al32 (everolimus, temsirolimus; Novartis Pharmaceuticals)

Lopes et al33 (everolimus; Novartis Pharmaceuticals)

Vogelzang et al35 Liu et al35 (everolimus, temsirolimus; Novartis Pharmaceuticals)

Outcomes Study design assessed • Model-based analysis to • Average estimate the average monthly monthly cost of treatment cost of patients with advanced RCC with everolimus vs temsirolimus • Drug costs (2009 WAC), drug administration, treatment of underlying disease (physician visits and tests), AEs, and palliative care were included • Excel-based budget impact • PMPM and model for a hypothetical PMPY costs health plan with 1 million members and a prevalence of 203 patients with advanced RCC, where 90% of patients receive treatment

• Retrospective analysis • Outpatient using US Oncology’s visits iKnowMed electronic • Inpatient medical records data from visits 462 identified patients • Frequency of with mRCC who initiated laboratory therapy with everolimus assessments (oral mTOR) or temsirolimus (IV mTOR) • Patients followed for 6 months or until treatment discontinuation, whichever occurred earlier

Findings Implications • Average monthly costs: • Everolimus likely • Everolimus: $5248 provides a less costly treatment option for • Temsirolimus: $5597 patients with advanced • Difference resulted RCC who fail treatment from drug and infusion with sunitinib or costs sorafenib • Annual cost-savings of $4188 for treatment with everolimus vs temsirolimus • Total cost of drugs, • The introduction of administration, and AE everolimus as a secondmanagement: or third-line agent to VEGF-TKI resulted in a • Market before minimal budget impact everolimus launch (April 2008- March 2009), $7,050,157 • Market after everolimus launch (October 2009September 2010), $6,741,642 • Cost-savings of $308,515 • Mean monthly outpatient • T he oral mTOR visits: everolimus 1.19 vs inhibitor everolimus is temsirolimus 1.60 (P <.05) associated with a lower patient burden in terms • Mean monthly laboratory of outpatient and visits: everolimus 1.25 vs laboratory visits temsirolimus 2.23 (P <.05) compared with the IV • I n multiple regression mTOR inhibitor analyses, temsirolimus temsirolimus was associated with a 28% higher frequency (95% CI, 7%-50%) of outpatient visits and a 58% increased utilization (95% CI, 30%-86%) of laboratory procedures compared with patients receiving everolimus

AE indicates adverse event; FACT-G, Functional Assessment of Cancer Therapy-General; FKSI, FACT Kidney Symptom Index; ICER, incremental cost-effectiveness ratio; IV, intravenous; mRCC, metastatic renal cell carcinoma; mTOR, mammalian target of rapamycin; OS, overall survival; PFS, progression-free survival; PMPM, per-member per-month; PMPY, per-member per-year; QALY, quality-adjusted life-year; RCC, renal-cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFr, vascular endothelial growth factor receptor; WAC, wholesale acquisition cost.

An Excel-based economic model comparing 2 market scenarios that was published in a peer-reviewed journal found that introducing everolimus as a second- or thirdline therapy after VEGFr-TKIs results in a minimal budget impact.33 In this hypothetical plan of 1 million covered lives, with a 0.023% prevalence of mRCC and 90% of patients receiving treatment for mRCC across

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first-, second-, and third-line treatments, the total cost of drugs, administration, and adverse event management (from April 2008 through March 2009) was $7,050,157 before the launch of everolimus. After the launch of everolimus, the total cost was $6,741,642 (from October 2009 through September 2010), resulting in a savings of $308,515.33 These trends remained consistent across

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scenario analyses in which everolimus replaced various combinations of comparators, as well as across sensitivity analyses. However, the sensitivity analysis that evaluated inclusion of the postapproval uptake lag period (April 2009-March 2010) and set the adverse event management costs to $0 yielded lower savings in comparison with the base-case analysis.33 Axitinib is a potent VEGFr-TKI and is the only drug other than everolimus that is included in the NCCN guidelines with category 1 evidence for use in patients with mRCC after initial failure with a VEGFr-TKI.26 This recommendation is predominantly based on data that were derived from the AXIS trial.25 An economic evaluation of sorafenib versus axitinib in the AXIS trial, which was presented at ESMO 2012, was based on a partitioned survival model with 3 health states—PFS, postprogression survival, and death—that was constructed to estimate the direct lifetime medical costs and clinical outcomes for patients starting second-line therapy.30 This model was populated with the Kaplan-Meier– derived overall survival and PFS data from the AXIS trial.

The investigators estimated lifetime per-patient costs to be $123,171 for sorafenib and $152,013 for axitinib, with the $28,842 cost difference mainly attributable to the higher medication cost of axitinib.30 Although the AXIS trial showed that axitinib significantly prolonged PFS compared with sorafenib (median, 6.7 vs 4.7 months; hazard ratio, 0.665; 95% confidence interval, 0.544-0.812; one-sided P <.001),25 this partition model found similar benefit in terms of life-years and QALYs for both drugs but a lower total per-patient cost for sorafenib.30

Discussion Health economics research aimed at evaluating the comparative costs, cost-effectiveness, and budget impact of cancer therapies is an increasing area of focus, but large gaps remain,39 as evidenced by our comprehensive search returning only 7 studies. However, themes related to drug costs, IV versus oral therapies, oral mTOR salvage therapy, and the promising impact of molecular personalization of RCC therapy emerged from our analysis of the literature. Although drug price is a major driver of overall costs, there appears to be an advantage for oral therapies for the treatment of mRCC over those administered intravenously, presumably because of a lower economic impact on outpatient care.

Using data from a large US health insurance claims database, a retrospective analysis restricted to the period of first angiogenesis inhibitor use demonstrated that mean total cost per member per month for IV bevaciz­ umab was approximately 2 times higher than for oral sorafenib and approximately 1.6 times higher than for oral sunitinib.40 The annualized total costs of therapy

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(adjusted to 2007 US dollars), including inpatient, outpatient, and drug costs, for patients with RCC who were treated with bevacizumab, sorafenib, and sunitinib were $160,212, $83,976, and $98,556 per patient, respectively.40 Therefore, the use of IV bevacizumab led to a cost increase of 56% to 71% more than the use of oral angiogenesis inhibitors.40 However, the clinical implications of this finding are not clear-cut. Although orally administered agents may result in lower outpatient costs, they may also be more likely to be associated with lower adherence and persistence rates, with a resultant negative impact on effectiveness. The data comparing adherence among oral and IV therapies are limited, and at least 1 retrospective claims database analysis suggests that schedule compliance with everolimus is higher than that with temsiro­ limus as second-line therapy for patients with mRCC (medication possession ratios of 0.93 vs 0.86, respectively; P <.001).41 The data on temsirolimus suggested the presence of higher toxicity than oral therapies (ie, infusion reactions), potentially generating higher monitoring demands and, as such, increasing costs.34 These hypotheses are congruent with data from other areas of medicine, but selection bias is one factor that may not be adequately captured in the reviewed literature. For example, the use of bevacizumab may be motivated by its more favorable toxicity profile, whereas the selection of temsirolimus may reflect the desire to use this drug in patients with poor performance status, as recommended in the current treatment guidelines.26 Although the data show that the oral mTOR inhibitor everolimus offers several economic options compared with other therapies in the second-line treatment setting of mRCC, a clear, economically favorable therapeutic path cannot be identified from the currently available data. This is a significant knowledge gap considering that the majority of patients receiving first-line anti-VEGF therapy will progress, at least 32.9% of patients receiving second-line therapy will experience treatment failure, and at least 16.6% of these patients will progress to receive third-line treatment.42 Although firm conclusions are not possible, our analysis is useful in that it raises several important testable hypotheses.

Of note, comparative economic analyses across treatments for mRCC are known to be problematic for numerous reasons, including the lack of available clinical comparative effectiveness data, as well as differing study designs, patient populations, clinical definitions, and instrumen­t­ ation used for patient-reported outcomes. Such factors complicate the ability to compare economic data across multiple studies. In addition, interpretation of cost-effectiveness analyses differs depending on the determination of the willingness-to-pay threshold. Studies found in our

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Table 4 Ongoing and Recently Completed Head-to-Head Sequencing Clinical Trials in Patients with mRCC Study design; planned Primary end NCT identifier enrollment Treatment arms point Secondary end points NCT00903175 Phase 2, • Everolimus 10 mg once daily orally PFS after PFS after second-line (RECORD-3) open-label, followed by sunitinib 50 mg once first-line treatment, ORR, randomized, daily orally (4 wks on/2 wks off) treatment duration of response, multicenter OS, and safety • Sunitinib 50 mg once daily orally trial (n = 390) (4 wks on/2 wks off) followed by everolimus 10 mg once daily orally NCT00720941 P hase 3, • Sunitinib 50 mg once daily orally PFS OS, ORR, duration of (COMPARZ) open-label, (4 wks on/2 wks off) response, safety, randomized, health outcomes • Pazopanib 800 mg once daily multicenter analysis orally trial NCT00474786 P hase 3, In patients who failed first-line Safety and PFS by investigator (INTORSECT) open-label, sunitinib therapy: tolerability assessment, RR, OS, randomized, • Sorafenib 400 mg twice daily PFS (central proportion of patients multicenter with PFS at 12, 24, orally assessment) trial and 36 wks by • Temsirolimus 25 mg IV once independent weekly assessment, duration of response NCT00732914 Phase 3, • Sunitinib 50 mg once daily Total PFS TTP, OS, disease (SWITCH) open-label, (4 wks on/2 wks off) followed by control rate, randomized, sorafenib 400 mg twice daily cardiotoxicity multicenter • Sorafenib 400 mg twice daily trial followed by sunitinib 50 mg once daily (4 wks on/2 wks off) NCT01613846 Phase 3, • Sorafenib 400 mg twice daily Total PFS TTP, PFS in first and (SWITCH-II) open-label, followed by pazopanib 800 mg second line, OS, randomized, once daily disease control rate, multicenter HRQOL • Pazopanib 800 mg once daily trial followed by sorafenib 400 mg twice daily HRQOL indicates health-related quality of life; IV, intravenous; mRCC, metastatic renal cell carcinoma; NCT, National Clinical Trial; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression. literature search reported ICERs ranging from $64,155 to $89,160. These fit within the range of willingness-to-pay thresholds often cited in US sources ($50,000-$100,000 per QALY gained)37; however, the accepted threshold can vary drastically among decision makers.43,44 The pivotal trials summarized in Table 1 established the efficacy and safety of individual targeted therapies; nevertheless, there is a general lack of head-to-head comparisons relevant to everyday clinical practice. Specific to second-line therapy, there are no prospectively collected data comparing the efficacy and safety of evero­ limus with those of axitinib, the 2 agents that are recommended at a class 1 level in the NCCN guidelines.26

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Coupled with the lack of head-to-head randomized trials in which the optimal sequence of treatments for mRCC is the primary outcome, comparisons of economic analyses are difficult.

Frequently, comparators are drawn from historical data sets. For example, in the recent phase 3 AXIS trial, a small subset of patients received axitinib after previous failure with sunitinib.25 The trial showed a favorable clinical response for axitinib based on median PFS25; however, during the formal discussion period that followed the initial presentation of the AXIS results at ASCO 2011, a number of discussants pointed out that the degree of benefit appears to approximate that of

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sorafenib historically. Indeed, the analysis by Ozer-Stillman and colleagues points to a similar benefit in terms of life-years and QALYs for sorafenib and axitinib, with the lower cost for sorafenib tipping the scale in its favor.30 It is hoped that current research that is underway involving several head-to-head and/or treatment sequencing trials will provide answers and will provide balanced prospective data that are sufficiently robust to draw meaningful conclusions, both on the usual clinical end points and on economic impact (Table 4).

The identification of specific biomarkers predictive of efficacy in patients with mRCC is a prolific area of research. This so-called personalized medicine has the potential to have a great impact on the existing therapeutic and, consequently, on economic paradigm. Theoretically, the successful identification of patient-specific sensitivity pathways would permit the exclusion of nonresponders before treatment is initiated, thereby favorably affecting cost versus benefit for that agent. Even with personalized medicine, it is likely that patients will require multiple lines of therapy, indicating that optimizing sequencing will remain critical. Unfortunately, the availability of mature data from biomarker and sequencing studies is likely many years away, and critical methodologic issues remain to be solved.45 As additional data flow from therapeutic clinical trials, one approach that may provide a more immediate answer to the appropriate second-line therapy is to leverage the current global adoption of EMRs. The proliferation of EMRs has allowed an unprecedented ability to access treatment data, which are, for the first time, robustly linked to resource utilization and costs through their built-in payer billing functionality. This will also allow a cross-sectional approach that can include both academic centers and community practices. The latter group is underrepresented in published studies but represents the majority of oncologic care in the United States.

This “real-world” approach of conducting chart reviews and/or evaluating EMR databases to address payer and provider issues for the armamentarium of treatment options for mRCC could provide a first approximation of the economic burden of various treatment sequences for mRCC in the current vacuum of head-to-head comparisons. Unfortunately, very little evidence is available to address whether outcomes research really affects drug pol­ icy or clinical practice.46 Further studies are warranted to improve clinical decision-making for the treatment of mRCC in the context of new targeted therapies and emerging research possibilities for biomarker identification.

Limitations Our review revealed that comparative economic evidence in the treatment of mRCC in patients who have

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failed initial therapy with targeted agents is very limited.

Our extensive search of the published literature identified only 3 studies that were published in peer-reviewed journals. To account for relevant data that were not published in the peer-reviewed literature, abstracts of several major conferences and meetings were searched, yielding an additional 4 studies that met our inclusion criteria. The designs of these studies were also heterogeneous. This lack of publicly available data and the heterogeneous nature of the data that are available minimize the conclusions that can be drawn from these studies. Furthermore, the potential pitfalls of using observational studies (eg, selection bias) to make conclusive treatment decisions or recommendations for sequencing and the choice of second-line targeted therapies need to be recognized.

The 7 studies we reviewed analyze the economic impact of the care of patients with RCC using a diverse array of approaches, each with inherent strengths and weaknesses. For example, cost-effectiveness models pre­ sent methodologic challenges from the standpoint of extrapolation of outcomes data beyond trial completion.

Health economics and outcomes research measures, such as QALYs, express aggregate individual utility and are considered to be the most applicable to research- or population-based decision-making rather than day-to-day use. The aggregate nature of the QALY makes it useful for comparisons of outcomes across multiple studies. As such, economic analyses based on clinical trials may not directly reflect costs in the real-world clinical practice setting. With 7 potential choices at present, it is possible that lifestyle considerations, the adverse event profile, convenience, and hidden economic incentives may begin to play a role in drug selection.

Claims database analyses, budget impact analyses, and model-based cost comparisons present their own methodologic challenges. For example, claims database analyses generally use International Classification of Diseases, Ninth Revision codes that can potentially lead to the inclusion of false-positive cases, and only costs from the perspective of the payer are included.40 Budget impact analyses are primarily intended to inform healthcare decision makers; therefore, similar to cost-effectiveness analyses, the analyses do not include cost implications from the societal perspective.33 The limitations of model-­ based cost comparisons include a lack of generalizability of results to all patients with RCC, given that the probabilities are generally taken from clinical trials and are often based on a series of assumptions, which may underestimate or overestimate costs and benefits.31 The dearth of head-to-head comparator studies of RCC and consensus methodologies for economic analyses represents a major limitation and a key research opportunity in this field at the present time.

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Conclusion The limited number of economic studies related to targeted treatment options in the second-line setting and beyond in patients with mRCC does not allow firm conclusions to be drawn about the most cost-effective targeted treatment option in this setting. We hope that ongoing head-to-head therapeutic trials and biomarker studies will improve our ability to evaluate the economic efficiency of these expensive agents. Analysis of real-world utilization data may provide a more accurate understanding of the economic impact of these medications in the use of patients outside the controlled environment of clinical trials. However, this needs to be balanced against the potential pitfalls of using observational studies (eg, selection bias) to make conclusive treatment decisions or recommendations for the sequencing and the choice of second-line targeted therapies.

Acknowledgments The authors would like to thank Denise Balog, PharmD, and Melanie Leiby, PhD, of ApotheCom, for their medical editorial assistance, and Novartis Pharma­ ceuticals for funding medical editorial assistance.

Study Funding Novartis Pharmaceuticals provided funding for editorial support and for data acquisition and primary analysis by LA-SER Analytica International. All authors retained independent control of the manuscript.

Author Disclosure Statement Dr Wong is on the advisory boards of Merck, Genentech, and Bristol-Myers Squibb. Drs Wang and Liu are employees and stockholders of Novartis Pharmaceuticals. Mr Chulikavit is an employee of LA-SER Analytica International and a consultant to Novartis Pharmaceuticals.

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20. Hudes G, Carducci M, Tomczak P, et al; for the Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356:2271-2281.

21. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-4265.

22. Escudier B, Pluzanska A, Koralewski P, et al; for the AVOREN Trial Investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-2111.

23. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26:5422-5428.

24. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol.

2010;28:1061-1068.

25. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.

Lancet. 2011;378:1931-1939. Erratum in: Lancet. 2012;380:1818.

26. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Kidney cancer. Version 1.2013. 2013. www.nccn. org/professionals/physician_gls/pdf/kidney.pdf. Accessed June 25, 2013.

27. National Institute for Health and Care Excellence. Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma August 26, 2009. www.nice.org.uk/Search.do?searchText=%22renal+cell+carcinoma%22&newsearch= true&x=0&y=0#/search/?reload. Accessed July 3, 2013.

28. Gao X, Reddy P, Dhanda R, et al. Cost-effectiveness of sorafenib versus best supportive care in advanced renal cell carcinoma. J Clin Oncol. 2006;24(18 suppl): Abstract 4604.

29. Moyneur E, Dorff TB, Barghout V, et al. Retrospective claims database cost analysis of second-line sorafenib (SR) or sunitinib (SR) therapy in treatment of patients (pts) with renal cell carcinoma (RCC). J Clin Oncol. 2010;28(15 suppl):Abstract e16521.

30. Ozer-Stillman I, Keyser R, Ambavane A, Cislo P. Sorafenib versus axitinib for second-line treatment of patients with advanced renal cell carcinoma (RCC) in the United States (US): An economic evaluation. Poster presented at the ESMO Congress; September 28-October 2, 2012, Vienna, Austria. Poster 856P. 31. Casciano R, Chulikavit M, Di Lorenzo G, et al. Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib. Value Health. 2011;14:846-851.

32. Chulikavit M, Casciano R, Stern L, Liu Z, Rogerio JW. Cost of treating patients with advanced renal cell carcinoma with everolimus versus temsirolimus after failure on sunitinib or sorafenib. Poster presented at the Genitourinary Cancers Symposium; March 5-7, 2010; San Francisco, CA. Poster 411.

33. Lopes M, Chulikavit M, Parikh R, et al. Budget impact of everolimus in the treatment of metastatic renal cell carcinoma. Am J Pharm Benefits. 2012;4(special issue):SP41-SP48.

34. Vogelzang NJ, Bhor M, Liu Z, et al. Everolimus vs. temsirolimus for advanced renal cell carcinoma: use and use of resources in the US Oncology Network. Clin Genitourin Cancer. 2013;11:115-120.

35. Liu Z, Gruschkus SK, Chen C, et al. Comparative outpatient resource utilization study of metastatic renal cell carcinoma patients receiving oral vs. intravenous mTOR inhibitors. Poster presented at the ESMO Congress; October 8-12, 2010; Milan, Italy. Poster 914P 36. Escudier B, Eisen T, Stadler WM, et al; for the TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. Erratum in: N Engl J Med. 2007;357:203.

37. Eichler HG, Kong SX, Gerth WC, et al. Use of cost-effectiveness analysis in health-care resource allocation decision-making: how are cost-effectiveness thresh-

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olds expected to emerge? Value Health. 2004;7:518-528.

38. Di Lorenzo G, Cartenì G, Autorino R, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27:4469-4474.

39. Tengs TO. Cost-effectiveness versus cost-utility analysis of interventions for cancer: does adjusting for health-related quality of life really matter? Value Health.

2004;7:70-78.

40. Duh MS, Dial E, Choueiri TK, et al. Cost implications of IV versus oral anti-­ angiogenesis therapies in patients with advanced renal cell carcinoma: retrospective claims database analysis. Curr Med Res Opin. 2009;25:2081-2090.

41. Hess GP, Chen CC, Hill JW, et al. Metastatic renal cell carcinoma: patient characteristics, treatment patterns, and schedule compliance in clinical practice.

Kidney Cancer J. 2011;9:84-89.

42. Hess GP, Chen C, Liu Z, et al. Risk of treatment failure after first-line tyrosine kinase inhibitors (TKI) therapy in patients with metastatic renal cell carcinoma. J Clin Oncol. 2011;29(15 suppl):Abstract e15114.

43. Nadler E, Eckert B, Neumann PJ. Do oncologists believe new cancer drugs offer good value? Oncologist. 2006;11:90-95.

44. Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ. 1992;146:473-481.

45. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-892.

46. Apolone G. Clinical and outcome research in oncology: the need for integration.

Health Qual Life Outcomes. 2003;1:3.

Stakeholder Perspective Cost and Effectiveness of Therapies for Advanced Kidney Cancer: The Need for Economic and Clinical Analyses

By Nicholas J. Vogelzang, MD Executive Medical Director, Associate Chair, Developmental Therapeutics and Genitourinary Committees, US Oncology Research, Houston, TX, and Comprehensive Cancer Centers of Nevada, Las Vegas

The profusion of new therapies for advanced kidney cancer—there are now 8 drugs available to treat the disease with the promise of more in development—has raised many questions, including their comparative effectiveness, quality of life, sequencing, and the cost of current and future therapies. Wong and colleagues have analyzed 7 studies that compared the cost of these therapies, showing that intravenous therapies with bevaciz­ umab and temsirolimus were more costly than the oral therapies sorafenib and everolimus; however, these drugs are now mostly second-, third-, or fourth-line agents.

PAYERS: Wong and colleagues point out that cost comparisons of the most frequently used frontline oral agents, sunitinib and pazopanib, and the most frequently used second-line agents, everolimus and axitinib, have not been published or conducted. I expect that the Comparing the Efficacy, Safety, and Tolerability of Pazopanib versus Sunitinib (COMPARZ) study will be analyzed from a cost perspective. Because these drugs are equivalent in progression-free survival and overall survival and are similarly priced, it would be surprising if there was much difference in their drug acquisition costs. However, the apparent improved quality of life and patient acceptance of pazopanib could paradoxically increase its overall cost, because of the resultant longer duration of use of pazopanib (defined as a higher “persistence rate” for pazopanib). Ideally, other studies, perhaps using payer databases, will soon compare the 2 market leaders pazopanib and sunitinib.

More than 50% of US patients receive second-line therapy for advanced renal cancer, most often with

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sorafenib, everolimus, or axitinib. The drug acquisition costs may be significantly different among these agents.

Sorafenib is dosed at 400 mg twice daily and is frequently dose de-escalated because of hand-foot syndrome.

Everolimus is dosed at 10 mg daily and is also often dose de-escalated to 5 mg daily. However, axitinib is often dose-escalated from 5 mg twice daily to 10 mg twice daily, with a potential doubling of the drug acquisition cost. In addition, axitinib may have a higher persistence rate.

The analysis of the costs of therapy with everolimus versus sorafenib will need to take into account treatment for diarrhea, stomatitis, and rash (ie, common toxicities of both agents), and the cost of axitinib must factor in the cost of blood pressure control (its most common toxicity).

Overall, approximately 20% to 25% of patients with advanced renal cancer receive third-line therapy, hence the economic impact is likely to be low; however, some patients have long duration (>1 year) of responses to third-, fourth-, or fifth-line therapy; therefore, the economic impact cannot be dismissed.

RESEARCHERS: There is much important work to be done in this field. The data from integrated health networks, such as US Oncology, Kaiser, Intermountain Healthcare, Carolinas HealthCare System, and many others, should be analyzed and published in peer-­ reviewed journals. Only then will we have a robust database that will allow researchers to draw firmer conclusions. Such information will also allow third-party payers to understand the value that they are providing to their members. n

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Vol 6, No 5

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

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