SEPTEMBER 2010 | VOL 1 | NO 4 by Value-Based Cancer Care

SEPTEMBER 2010 VOL 1 NO 4

www.ValueBasedCancer.com

Cost-Effectiveness in the New REMS Regulation Provokes Anger Comparative Effectiveness Landscape in Provider Community After some setbacks, now what? By Cherie Dewar Boston, MA—Cost-effectiveness can still add value in the comparative effectiveness landscape without it becoming woven into the politically caustic concept of healthcare allocation, according to 4 experts from academia, industry, and governmental agencies. The future of cost-effectiveness in the larger universe of comparative effectiveness research in a post–healthcare reform world was debated during a roundtable discussion at the AcademyHealth conference in Boston. A Suddenly Toxic Methodology Steven Pearson, MD, president and founder of the Institute for Clinical and

Public FDA meeting addresses concerns Economic Review, Harvard Medical School, Boston, MA, noted the restrictions placed on the use of costeffectiveness during the healthcare reform debate. “Wow, cost-effectiveness really took an arrow to the heart,” Dr Pearson said. As stated by the new independent, nongovernmental Patient-Centered Outcomes Research Institute, healthcare policy cannot “develop or use dollars per quality-adjusted life-year as a threshold to establish what type of healthcare is cost-effective or recommended.” Continued on page 20

Comparative Effectiveness Research in Oncology Is High Priority Goal is to reflect care in real-world setting By Wayne Kuznar Chicago, IL—Oncology has been identified as a high-priority area for comparative effectiveness research (CER), given the accelerating pace of diagnostic and therapeutic interventions and the often high costs attached to these interventions. CER in oncology was the subject of a well-attended symposium at the 2010 ASCO meeting. The goal of CER is to reflect care in the real-world setting, said Gary H. Lyman, MD, professor of medicine and

director of health services, effectiveness, and outcomes research in oncology, Duke Comprehensive Cancer Center, Durham, NC. This means going beyond the confines of study populations to the broader context of real-life clinical practice. The toolbox for comparative effectiveness contains randomized controlled trials (RCTs), which are considered the gold standard of CER, as well as systematic reviews and meta-analyses of RCTs. However, because most clinical questions in oncology have not Continued on page 5

By Margot J. Fromer Silver Spring, MD—Risk Evaluation and Mitigation Strategies (REMS) are required from some drug manufacturers as part of a new US Food and Drug Administration (FDA) regulation designed to draw the attention of sponsors, providers, and patients to the likelihood of severe adverse events accompanying certain drugs and biologic agents. Going beyond the usual drug label, REMS are required for certain drugs, depending on: • Number of persons likely to use a drug • Severity of the disease for which the drug is intended • Expected benefit of a drug weighed against its possible adverse effects • Duration of treatment

• Seriousness of side effects • When new safety data are available • If the drug or biologic agent is a new Janet Woodcock, MD molecular entity. Although the cancer community is affected by REMS to the greatest extent, no one is pleased to be further entangled in government red tape. Negative reactions to REMS have been many and loud; therefore, the FDA held a meeting to address questions and concerns on July 27 and 28 at its Silver Spring, MD, headquarters. The 250 attendees represented a wide range of those affected—drug manufacturers (also called “sponsors” under the legislation), providers, professional societies, and patient advocacy groups. The consensus was that Continued on page 12

Fostering Clinical Research in the Community Setting By Charles Bankhead Chicago, IL—Taking part in clinical research poses administrative, logistic, and financial challenges to community oncology practices, but also presents these organizations with opportunities for a more active role in shaping patient care. Therefore, community practices that venture into clinical research should strive to follow emerging guidelines aimed at establishing exemplary clinical trial sites, according to speakers at an American Society of Clinical Oncology To read the VBCC Perspective on this story, please turn to page 9.

(ASCO) education program. Considerations involved in developing an exemplary research site in- Robin Zon, MD clude the following: • Structuring and marketing a program for success • Organizing a team that recognizes its critical role in the program’s success • Knowing the costs to budget effectively and negotiate contracts. Community oncology practices have a vested interest in participating in clinical research, according to Robin Zon, MD, a Continued on page 8

IN THIS ISSUE Jayson Slotnik explains preventive services rule changes .................... 14 Comparing VHA and fee-for-service cancer care ................................... 20 Continuing education on value-based benefit design ............................ 22 Reviewing new therapies for prostate cancer......................................... 25 ©2010 Engage Healthcare Communications, LLC

ALOXI provides powerful CINV prevention that can’t be ignored. ®

Proven CINV prevention in a single IV dose s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy 1,2 s Lasts long against nausea following moderately emetogenic chemotherapy 3 s Powerful acute CINV prevention following highly emetogenic chemotherapy 4 s Eisai offers a variety of support programs and resources

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

STARTS STRONG. LASTS LONG.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083A 08/10

MEETINGS CALENDAR September 29-October 2 27th National Oncology Economics Conference, St. Louis Contact: Association of Community Cancer Centers, 11600 Nebel Street, Suite 201, Rockville, MD 20852 Phone: 301-984-9496, ext. 219 or labankert@accc-cancer.org. September 30-October 3 Third AACR Conference on The Science

ALOXIÂŽ (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: L =23@/B3:G 3;3B=53<71 1/<13@ 163;=B63@/>G K >@3D3<B7=< =4 /1CB3 /<2 23:/G32 </CA3/ /<2 D=;7B7<5 /AA=17/B32 E7B6 7<7B7/: /<2 @3>3/B 1=C@A3A L 756:G 3;3B=53<71 1/<13@ 163;=B63@/>G K >@3D3<B7=< =4 /1CB3 </CA3/ /<2 D=;7B7<5 /AA=17/B32 E7B6 7<7B7/: /<2 @3>3/B 1=C@A3A DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting =A/53 4=@ 2C:BA / A7<5:3 ;5 ) 2=A3 /2;7<7AB3@32 =D3@ A31=<2A =A7<5 A6=C:2 =11C@ />>@=F7;/B3:G ;7<CB3A 034=@3 B63 AB/@B =4 163;=B63@/>G Instructions for I.V. Administration "+ 7A AC>>:732 @3/2G 4=@ 7<B@/D3<=CA 7<831B7=< "+ A6=C:2 <=B 03 ;7F32 E7B6 =B63@ 2@C5A :CA6 B63 7<4CA7=< :7<3 E7B6 <=@;/: A/:7<3 034=@3 /<2 /4B3@ /2;7<7AB@/B7=< =4 "+ #/@3<B3@/: 2@C5 >@=2C1BA A6=C:2 03 7<A>31B32 D7AC/::G 4=@ >/@B71C:/B3 ;/BB3@ /<2 27A1=:=@/B7=< 034=@3 /2;7<7AB@/B7=< E63<3D3@ A=:CB7=< /<2 1=<B/7<3@ >3@;7B CONTRAINDICATIONS "+ 7A 1=<B@/7<271/B32 7< >/B73<BA 9<=E< B= 6/D3 6G>3@A3<A7B7D7BG B= B63 2@C5 =@ /<G =4 7BA 1=;>=<3<BA [see Adverse Reactions (6) 7< 4C:: >@3A1@707<5 7<4=@;/B7=< ] WARNINGS AND PRECAUTIONS Hypersensitivity G>3@A3<A7B7D7BG @3/1B7=<A ;/G =11C@ 7< >/B73<BA E6= 6/D3 3F6707B32 6G>3@A3<A7B7D7BG B= =B63@ '

@313>B=@ /<B/5=<7ABA ADVERSE REACTIONS 31/CA3 1:7<71/: B@7/:A /@3 1=<2C1B32 C<23@ E723:G D/@G7<5 1=<27B7=<A /2D3@A3 @3/1B7=< @/B3A =0A3@D32 7< B63 1:7<71/: B@7/:A =4 / 2@C5 1/<<=B 03 27@31B:G 1=;>/@32 B= @/B3A 7< B63 1:7<71/: B@7/:A =4 /<=B63@ 2@C5 /<2 ;/G <=B @3J 31B B63 @/B3A @3>=@B32 7< >@/1B713 < 1:7<71/: B@7/:A 4=@ B63 >@3D3<B7=< =4 </CA3/ /<2 D=;7B7<5 7<2C132 0G ;=23@/B3:G =@ 6756:G 3;3B=53<71 163;=B63@/>G

/2C:B >/B73<BA @3137D32 >/:=<=A3B@=< 2D3@A3 @3/1B7=<A E3@3 A7;7:/@ 7< 4@3?C3<1G /<2 A3D3@7BG E7B6 "+ /<2 =<2/<A3B@=< =@ 2=:/A3B@=< =::=E7<5 7A / :7AB7<5 =4 /:: /2D3@A3 @3/1B7=<A @3>=@B32 0G â&#x2030;Ľ =4 >/B73<BA 7< B63A3 B@7/:A '/0:3 Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies â&#x2030;Ľ 2% in any Treatment Group ALOXI Ondansetron Dolasetron 0.25 mg 32 mg I.V. 100 mg I.V. Event (N=410) (N=633) (N=194) 3/2/163

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VOL. 1

NO. 4

of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, Miami, FL Contact: AACR, 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106. 215-440-9300 or meetings@aacr.org. October 1-2 9th International Kidney Cancer Symposium, Chicago Contact: Kidney Cancer Association, PO

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Box 96503, Washington, DC 20090. 800850-9132 or kidney.cancer@hotmail.com. October 1-3 2010 Breast Cancer Symposium, National Harbor, MD Contact: The American Society for Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 571-483-1300 or http://breastcasymposium.org/Home.aspx.

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E3@3 â&#x2030;Ľ G3/@A =:2 E67:3 E3@3 â&#x2030;Ľ G3/@A =:2 != =D3@/:: 27443@3<13A 7< A/43BG =@ 34431B7D3<3AA E3@3 =0A3@D32 03BE33< B63A3 AC0831BA /<2 B63 G=C<53@ AC0831BA 0CB 5@3/B3@ A3<A7B7D7BG 7< A=;3 =:23@ 7<27D72C/:A 1/<<=B 03 @C:32 =CB != 2=A3 /28CAB;3317/: ;=<7B=@7<5 /@3 @3?C7@32 4=@ 53@7/B@71 >/B73<BA "4 B63 /2C:B >/B73<BA 7< "+ #"!) 1:7<71/: ABC273A E3@3 â&#x2030;Ľ G3/@A =:2 != =D3@/:: 27443@3<13A 7< A/43BG E3@3 =0A3@D32 03BE33< =:23@ /<2 G=C<53@ AC0831BA 7< B63A3 ABC273A B6=C56 B63 >=AA707:7BG =4 63756B3<32 A3<A7B7D7BG 7< A=;3 =:23@ 7<27D72C/:A 1/<<=B 03 3F1:C232 != 27443@3<13A 7< 34I 1/1G E3@3 =0A3@D32 7< 53@7/B@71 >/B73<BA 4=@ B63 !) 7<271/B7=< /<2 <=<3 /@3 3F>31B32 4=@ 53@7/B@71 #"!) >/B73<BA =E3D3@ "+ 34I 1/1G 7< 53@7/B@71 >/B73<BA 6/A <=B 033< /23?C/B3:G 3D/:C/B32 Renal Impairment 7:2 B= ;=23@/B3 @3</: 7;>/7@;3/:=<=A3B@=< >6/@;/1=97<3B71 >/@/;3B3@A '=B/: AGAB3;71 3F>=AC@3 7<1@3/A32 0G />>@=F7;/B3:G 7< A3D3@3 @3</: 7;>/7@;3/B73<BA E7B6 /<G 235@33 =4 @3</: 7;>/7@;3/B71 7;>/7@;3/:=<=A3B@=< 1=;>/@32 B= B63 63/:B6G AC0831BA =A/53 /28CAB;3/B73<BA E7B6 /<G 235@33 =4 63>/B71 7;>/7@;3/:=<=A3B@=< >6/@;/1=97<3B71A E/A 16/@/1B3@7H32 7< BE3<BG 4=C@ 63/:B6G />/<3A3 AC0831BA =D3@ B63 2=A3 @/<53 =4 K ;15 95 '=B/: 0=2G 1:3/@/<13 E/A 67563@ 7< />/<3A3 AC0831BA 1=;>/@32 B= *67B3A 6=E3D3@ <= 2=A3 /28CAB;36/@;/1=97<3B71A =4 >/:=<=A3B@=< 7< :/19A 6/A <=B 033< /23?C/B3:G 16/@/1B3@7H32 OVERDOSAGE '63@3 7A <= 9<=E< /<B72=B3 B= "+ "D3@2=A3 A6=C:2 03 ;/</532 E7B6 AC>>=@B7D3 1/@3 74BG /2C:B 1/<13@ >/B73<BA E3@3 /2;7<7AB3@32 >/:=<=A3B@=/@B =4 / 2=A3 @/<57<5 ABC2G '67A 7A />>@=F7;/B3:G B7;3A B63 @31=;;3<232 2=A3 =4 ;5 '67A 2=A3 5@=C> 6/2 / A7;7:/@ 7<1723<13 =4 /2D3@A3 3D3<BA 1=;>/@32 B= B63 =B63@ 2=A3 5@=C>A /<2 <= 2=A3 @3A>=<A3 34431BA E3@3 =0A3@D32 7/:GA7A ABC273A 6/D3 <=B 033< >3@4=@;32 6=E3D3@ 2C3 B= B63 :/@53 D=:C;3 =4 27AB@70CB7=< 27/:GA7A 7A C<:793:G B= 03 /< 34431B7D3 B@3/B;3/:=<=A3B@=< =D3@2=A3 A7<5:3 7<B@/D3<=CA 2=A3 =4 >/:=<=A3B@=31B7D3:G 0/A32 =< 0=2G AC@4/13 /@3/ E/A :3B6/: B= @/BA /<2 ;713 '63 ;/8=@ A75<A =4 B=F717BG E3@3 1=<DC:A7=<A 5/A>7<5 >/::=@ 1G/<=A7A /<2 1=::/>A3 PATIENT COUNSELING INFORMATION &33 FDA-Approved Patient Labeling (17.2) in 4C:: >@3A1@707<5 7<4=@;/B7=< Instructions for Patients L #/B73<BA A6=C:2 03 /2D7A32 B= @3>=@B B= B637@ >6GA717/< /:: =4 B637@ ;3271/: 1=<27B7=<A /<G >/7< @32<3AA =@ AE3::7<5 7< /<2 /@=C<2 B63 7<4CA7=< A7B3 -see Adverse Reactions (6) 7< 4C:: >@3A1@707<5 7<4=@;/B7=<. L #/B73<BA A6=C:2 03 7<AB@C1B32 B= @3/2 B63 >/B736/@;/13CB71/:A :0C?C3@?C3 ! (& =@ #73@@3 /0@3 P271/;3<B #@=2C1B7=< 2@=< ?C7B/7<3 @/<13 /<2 3:A7<< 7@3F #6/@;/13CB71/:A C0:7< @3:/<2

ALOXIÂŽ 7A / @357AB3@32 B@/23;/@9 =4 3:A7<< 3/:B61/@3 & &E7BH3@:/<2 CA32 C<23@ :713<A3 7AB@70CB32 /<2 ;/@93B32 0G 7A/7 <1 *==21:744 /93 ! O 7A/7 <1 :: @756BA @3A3@D32 #@7<B32 7< (&

October 1-4 2010 iSBTc Annual Meeting, Washington, DC Contact: International Society for Biological Therapy of Cancer, 555 East Wells Street, Suite 1100, Milwaukee, WI 53202. 414-271-2456 or info@isbtc.org. October 8-9 NCCN 5th Annual Congress: Hematologic Malignancies, New York, NY Contact: National Comprehensive Cancer Network, 275 Commerce Dr, Suite 300, Fort Washington, PA 19034. 866-788-NCCN (6226) or http://www.nccn.org/about/emailform.asp? department=meetings. October 8-9 Personalized Cancer Therapy and Prevention, Houston Contact: The University of Texas M. D. Anderson Cancer Center CME/ Conference Services, Unit 1381, PO Box 301439, Houston, TX 77230. 713-792-2223 or register@mdanderson.org. October 8-12 35th ESMO Conference, Milan, Italy Contact: ESMO Head Office Congress Department, Via Luigi Taddei 4, CH-6962 Viganello-Lugano, Switzerland. +41 (0)91 973 19 26 or congress@esmo.org. October 18-20 ASCO-NCI-EORTC Annual Meeting on Molecular Markers in Cancer, Hollywood, FL Contact: ASCO, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 571-483-1351 or www.molecularcameeting.org October 19-20 ECRI Instituteâ&#x20AC;&#x2122;s 17th Annual Conference: Personalized Medicine and Comparative Effectiveness, Bethesda, MD Contact: ECRI. 610-825-6000 or http://conferences.thehillgroup.com/CER andPMconference/registration.cfm October 20-23 Southwest Oncology Group Annual Fall Meeting, Chicago Contact: SWOG, 14980 Omicron Drive, San Antonio, TX 78245. 210-677-8808 or www.swog.org. October 21-22 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer, Washington, DC Contact: American Institute for Cancer Research, 1759 R Street, NW, Washington, DC 20009. 800-843-8114 or researchconference@aicr.org. October 24â&#x20AC;&#x201C;27 The 32nd Annual Meeting of the Society for Medical Decision Making, Toronto, Ontario, Canada Contact: The Society for Medical Decision Making, 390 Amwell Road, Suite 402, Hillsborough, NJ 08844. 908-359-1184 or info@smdm.org. October 27-30 Colorectal Cancer: Biology to Therapy, Philadelphia Contact: AACR, 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106. 215-440-9300 or meetings@aacr.org. October 31-November 4 American Society for Radiation Oncology Annual Meeting, San Diego Contact: ASTRO, 8280 Willow Oaks Corporate Drive, Suite 500, Fairfax, VA 22031. 703-502-1550 or www.astro.org

www.ValueBasedCancer.com

TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

September 2010 Value Propositions 7 Trastuzumab Extends Stomach Cancer Survival, But Is It Worth It?

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Managing Editor Colin Gittens colin@engagehc.com 732-992-1536

VBCC Perspective 9 Community Trials Essential to Broad Knowledge / Ed Pezalla, MD, MPH

Continuing Education 22 The Evolving Role of Managed Care Pharmacists in Value-Based Benefit Design: Strategies for Clinical and Economic Success

ASCO Conference 10 Active Surveillance Cost-Effective for Low-Risk Prostate Cancer

Focus On 25 New Compounds Hold Promise for Prostate Cancer

Senior Production Manager Robyn Jacobs

Bevacizumab Cost-Effectiveness “in Line” with Other Therapies

Business Manager Blanche Marchitto Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

11 ASCO Weighs in on CER

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

New Prostate Cancer Therapies Raise New Issues / Lee Newcomer, MD

Trial Participation Hampered by Costs ISPOR Conference 11 Incorporating Patient-Reported Data into the Pharma Sales Story Health Policy 14 Understanding the Preventative Services Rule Changes / Jason Slotnik, JD, MPH

In this issue...

“Using the therapy for patients who do not meet the precise indications is simply conducting a $93,000 clinical trial with 1 subject.” —Lee Newcomer, MD, from “New Prostate Cancer Therapies Raise New Issues,” page 26

Permission requests to reprint all or part of any article published in this magazine should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881. Address all editorial correspondence to: editor@valuebasedcare.com Telephone: 732-992-1536 Fax: 732-992-1881

VBCC Perspectives 26 The $93,000 Question / Yu-Ning Wong, MD, MSCE

Greater Role for Pharmacogenomics Ahead

BPA Worldwide membership applied for August 2010. Contact Information: For subscription and reprint information please contact: circulation@valuebasedcare.com Telephone: 732-992-1538 Fax: 732-992-1881

AcademyHealth Conference 20 Comparing VHA with Fee-for-Service Cancer Care

Initial Prostate Cancer Treatment Choice Impacts Long-Term Costs

Phil Pawelko phil@greenhillhc.com 732-992-1887

No. 4

Technology Assessment 19 Does Robotic Surgery Make the Cut?

Determining the Value of CTC Screening for Colorectal Cancer

Directors, Client Services John Hennessy john@greenhillhc.com 732-992-1886

Cristopher Pires cris@greenhillhc.com 732-992-1896

Vol. 1

VBCC Editorial Board Bruce A. Cutter, MD, MMM Cancer Care Northwest Spokane, WA

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX

Craig Deligdish, MD Florida Comprehensive Cancer Network Melbourne, FL

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Jayson Slotnik, JD, MPH Foley Hoag Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

Lynn Nishida, RPh Regence Blue Cross Blue Shield of Oregon Portland, OR

Brian K. Solow, MD, FAAFP PrescriptionSolutions Irvine, CA

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Naimish Pandya, MD University of Maryland Baltimore, MD

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

Ed Pezalla, MD, MPH Aetna Pharmacy Management Hartford, CT

Scott Gottlieb, MD Mount Sinai Medical Center and the American Enterprise Institute New York, NY

Denise K. Pierce DK Pierce & Associates Zionsville, IN

David Hom, MBA Solucia Farmington, CT

VALUE-BASED CANCER CARE

September 2010

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

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Comparative Effectiveness Research... been the subject of RCTs, the toolbox also includes cohort studies; population studies; prognostic and predictive studies; and modeling approaches. Even RCTs have limitations for use in comparative effectiveness, Dr Lyman said, because they are often short term and use surrogate efficacy outcomes; they have a limited sample size; a duration of follow-up too short to address important safety and toxicity questions; and they frequently exclude patients with major but common comorbidities.

testing. Gene profiling also has taken center stage of late and represents another area that is ripe for CER. “What we need are models that integrate clinical and molecular risk assess-

Continued from cover

ment,” said Dr Meropol. Treatment must include more research on adjuvant therapy decisions, selection of treatment intensity, and better knowledge on the best time to

change treatments. Obtaining support for many of the treatment studies “is difficult when competing treatments are marketed by different entities,” he Continued on page 6

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care

“What we need are models that integrate clinical and molecular risk assessment.”

First- and every-cycle Neulasta® achieved: ■ 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2

—Neal J. Meropol, MD Clinical decision models (eg, Markov models) are increasingly being used as reasonable estimates of comparative effectiveness, he said. Such modeling studies have the advantage of comparing efficacy over a range of assumptions and can provide measures of incremental effectiveness that reflect quality of life and costs. Imaging in cancer is in the top quartile of the 100 Institute of Medicine priority topics for CER. The use of diagnostic imaging in cancer care has increased by 40% to 50% per year since 1999, said Neal J. Meropol, MD, chief, division of hematology/oncology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH. Other priority needs for CER in cancer screening and prevention are molecular risk stratification, prescreening molecular tests, risk modifiers, and the optimal frequency of diagnostic

at a glance Comparative effectiveness research (CER) should foster real-world investigations CER may become increasingly important to the growing field of genetic profiling Models using propensity scoring and decision analysis techniques will become an increasingly important means of conducting CER

■ 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2 Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebo-treated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

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Comparative Effectiveness Research... said, calling for more publicly funded phase 3 trials in cancer research. Alternatives to “Traditional” Studies Katrina Armstrong, MD, associate diBRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary: s 3PLENIC 2UPTURE ;3EE Warnings and Precautions] s !CUTE 2ESPIRATORY $ISTRESS 3YNDROME ;3EE Warnings and Precautions] s 3ERIOUS !LLERGIC 2EACTIONS ;3EE Warnings and Precautions] s 5SE IN 0ATIENTS WITH 3ICKLE #ELL $ISORDERS ;3EE Warnings and Precautions] s 0OTENTIAL FOR 4UMOR 'ROWTH 3TIMULATORY %FFECTS ON -ALIGNANT #ELLS ;3EE Warnings and Precautions] The most common adverse reactions occurring in r 5% of patients and with a between-group difference of r 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer

rector, outcomes and delivery research, Abramson Cancer Center, University of Pennsylvania, Philadelphia, elaborated on alternatives to RCTs for conducting CER, focusing on observational studies receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain

26%

31%

Pain in extremity

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta. Gastro-intestinal disorders: 3PLENIC RUPTURE ;SEE Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis ;SEE Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS ;SEE Warnings and Precautions] General disorders and administration site conditions: Injection site reactions Skin and subcutaneous tissue disorders: Allergic reactions/ hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and FLUSHING ;SEE Warnings and Precautions] DRUG INTERACTIONS No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting boneimaging results. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during

VALUE-BASED CANCER CARE

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with the use of propensity scoring or instrumental variable analysis, and evidence synthesis using decision analysis. Propensity scoring is a method to adjust for differences between treatpregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/ developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard DEVIATION ;3$= SYSTEMIC EXPOSURE !5#0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

References 1. Wong YN, Mitra N, Hudes G, et al. Survival associated with treatment vs observation of localized prostate cancer in elderly men. JAMA. 2006;296:2683-2693. 2. Earle CC, Tsai JS, Gelber RD, et al. Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol. 2001;19:1064-1070. 3. Armstrong K, Schwartz JS, Randall T, et al. Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: a decision analysis. J Clin Oncol. 2004;22:1045-1054. 4. Ito K, Elkin EB, Girotra M, Morris MJ. Cost-effectiveness of fracture prevention in men who receive androgen deprivation therapy for localized prostate cancer. Ann Intern Med. 2010;152:621-629.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2010 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 11.0

September 2010

ment groups, and as such “can address 90% of the bias in observational data,” she said. One example of using propensity scores to adjust for potential confounders in observational studies is in the treatment of localized prostate cancer, in which Wong and colleagues determined that men aged 65 to 80 years experienced a survival advantage with treatment versus observation.1 Instrumental variable analysis adjusts for differences in groups when relevant differences between groups are not available, said Dr Armstrong. One such example is an analysis that simulated the conditions of a randomized trial of chemotherapy for advanced lung cancer in patients older than 65 years.2 The analysis showed that chemotherapy in this population led to a median survival increase of 33 days and a 1-year survival rate of 9%. Decision analysis is a quantitative approach to synthesizing evidence to compare expected outcomes of different interventions. She cited her own study, a Markov decision-analytic model, to determine that women with BRCA1/2 mutations should make decisions about the use of hormone replacement therapy after prophylactic oophorectomy based on quality-of-life issues rather than life expectancy.3 “Cost is a growing focus of comparative effectiveness research,” Dr Armstrong said, adding that it is increasingly being incorporated into Markov models. A recent example is a Markov state-transition model aimed at determining how fracture risk should be managed in men receiving androgen-deprivation therapy for the treatment of localized prostate cancer.4 The authors concluded that in men at higher risk for hip fracture, routine use of alendronate without a bone mineral density test is a costeffective strategy. As more targeted therapies for cancer are developed, data collection will have to change to include the presence of biological markers to conduct CER of these therapies, Dr Armstrong said. ■

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VALUE PROPOSITIONS Adding trastuzumab to standard cisplatinum/fluoropyrimidine chemotherapy for patients with HER2-positive advanced gastric cancer results in a median survival of 13.8 months, compared with 11.1 months with chemotherapy alone, according to a new study (Lancet. 2010;376 [9742]:687-97. Epub 2010 Aug 19). But an accompanying editorial questions whether that added survival is worth the cost. The multinational, randomized, controlled phase 3 trial included 584 patients (294 in the trastuzumab group, 290 in the chemotherapy group), and adverse event rates were similar in both groups. For those with high levels of HER2, the median survival was 16 months in the trastuzumab group and 11.8 months the chemotherapy only group. Commentators outside the study pointed to the £55,000 cost per life-year gained as a troubling fact of such new therapies.

Determining the Value of CTC Screening for Colorectal Cancer A simulation model to calculate lifetime costs and life expectancies for 15 colorectal cancer screening strategies finds that computed tomographic colonography (CTC) is not cost-effective if reimbursed at the same rate as colonoscopy (J Natl Cancer Inst. 2010;102[16]:1238-52. Epub 2010 Jul 27). Investigators examined whether CTC screening every 5 years could be cost effective compared to currently reimbursed colorectal screening tests in an unscreened cohort of Medicare beneficiaries. The number of life-years gained by CTC screening every 5 years was only slightly lower than the number gained from colonoscopy screening every 10 years. If CTC was reimbursed at the same rate as colonoscopy ($488), lifetime costs associated with this screening exceeded those of colonoscopy. The Centers for Medicare and Medicaid Services does not currently reimburse CTC screening. The authors point out that “comparative effectiveness research, and cost-effectiveness analyses in particular, can also be used to inform reimbursement levels.”

the Cochrane researchers say that there should be more studies measuring the direct health influence of these policies, especially in cases where there are no clear alternatives to the restricted drugs.

Initial Prostate Cancer Treatment Choice Impacts Long-Term Costs A study looking at short- and long-term costs associated with different prostate cancer treatments finds that treatments that are initially less expensive may incur higher long-term costs (Cancer. 2010 Aug 23. [Epub ahead of print]). The researchers looked at initial treatment approaches (watchful waiting, radiation, hormonal therapy, hormonal therapy plus radiation, and surgery) and costs short term (1-12 months), long-term (> 12 months) and overall (months 1-60). For most cases, costs were initially high, dropped sharply, and then remained steady. Watchful waiting had the lowest initial ($4270) and 5-year costs; initial costs were highest for hormonal therapy plus radiation ($17,474). Hormonal therapy had low initial costs but the highest 5-year costs ($26,896). Hormonal therapy plus radiation ($25,097) and surgery ($19,214) had the second and third highest 5-year total costs.

App Shortcut for Clinical Trial Adversity Printed information on the adverse events patients may face in clinical trials has been converted to digital form and formatted for use with the iPhone and iPod Touch. Researchers at the Center for Biomedical Informatics at The Children’s Hospital of Philadelphia created the app, which is free to download. The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) is a 200-page handbook in its most recent edition (version 4.0) and is used to help standardize record-keeping of side effects occurring in patients enrolled in clinical trials.

Credit: The Children's Hospital of Philadelphia

Trastuzumab Extends Stomach Cancer Survival, But Is It Worth It?

Users of this app can search these broad categories, which include specific types of adverse events in clinical trials.

Spending Grows, Mortality Remains Constant A retrospective database analysis of patients at 122 hospitals from 2000 and 2004 found little correlation between reduced mortality for 7 commonly diagnosed conditions (acute myocardial infarction [AMI], chronic obstructive pulmonary disease, community-acquired pneumonia, congestive heart failure, cerebrovascular accident, sepsis, or urinary tract infection) and increased spending on patients with those conditions. Absolute mortality decreased for all conditions between 2000 and 2004, and relative mortality reductions ranged from 1% (for sepsis) to 21% (for AMI). The greatest relative mortality reductions occurred in the diseases with active quality improvement and public reporting efforts (AMI, pneumonia, and heart failure). During the same time, inflation-adjusted costs increased for all diagnoses, with relative cost increases ranging from 26% for pneumonia to 60% for heart failure. The dollars spent, say the authors, have produced inconsistent value, with wide variation in the cost per life-year saved(Health Aff [Millwood]. 2010;29[8]:1523-1531).

Pricey Premiums as Health Insurance Costs Rise The annual premium for a family health plan sponsored by an employer cost about 54% more in 2009 ($13,027) than it did in 2000 ($8437), according to inflation-adjusted figures from the Agency for Healthcare Research and Quality. The annual premium cost for a single coverage plan rose by 41% (to $4669 from $3308) in that same time period. New York had the highest average premiums ($13,757 for family/$5121 for single); Ohio the lowest ($11,870 for family/$4261 for single). The average annual employee contributions for health insurance premiums were $3474 for family coverage (which covered 26.7% of the average family premium) and $957 for single coverage (20.5% of the average single premium). Data were collected from the Medical Expenditure Panel Survey.

It’s Where You Are, Not What They Know Limiting Access, Cutting Costs Restricting access to some medications can save insurers money without causing a concomitant increase in other types of healthcare utilization, according to a meta-analysis of 29 studies (Green CJ, Maclure M, Fortin PM, et al. Pharmaceutical policies: effects of restrictions on reimbursement. Cochrane Database Syst Rev. 2010;8:CD008654). The most common restriction was a prior authorization policy; in some cases, restricting reimbursement led to almost immediate cost savings and decreased drug use (ie, in the case of branded gastric acid suppressants). In others (ie, branded antipsychotic drugs), health services did increase and costs were not reduced. Although the policies do appear to save money in several studies,

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For older patients with kidney failure, the type and intensity of treatment received depends less on evidence-based practice guidelines and patient preferences and more on the region in which they receive care (JAMA. 2010;304[2]:180-186). Regions with high-intensity end-of-life care had a higher density of nephrologists and higher rates of kidney failure, but patients with kidney failure in these regions were less likely to have seen a nephrologist before starting dialysis. The decision of when to start and stop receiving dialysis can be a difficult one, the researchers said, and the study points out the need for better training of kidney specialists and better team care with geriatricians and palliative care specialists. “We need to get serious about optimizing end-of-life care,” said senior author Manjula Kurella Tamura, MD.

www.ValueBasedCancer.com

ASCO CONFERENCE

Fostering Clinical Research in the Community... principal investigator with the Northern Indiana Cancer Research Consortium in South Bend. “The ‘community,’ as a partnership between the physician and the patient, has the potential to make an enormous impact on the algorithm of cancer care by increasing participation in clinical trials,” Dr Zon said. Nevertheless, a clear disconnect exists between interest and participation. Clinicians in community oncology practices care for 85% of oncology patients, and 50% to 60% of patient accrual in clinical trials comes from the community setting; however, less than 20% of oncologists and 2% to 7% of all patients with cancer participate in clinical trials. The Ingredients for Success Successful clinical research sites have several common traits, which Dr Zon highlighted. They include: • A committed staff • Financial resources • Accessible ancillary services • Institutional support • Respect for patients • An overarching commitment to patient safety. These principles are outlined in ASCO’s statement on minimum standards for exemplary clinical trial sites, which Dr Zon helped to write.1 First and foremost, exemplary clinical trial sites adhere to the clinical practice guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Dr Zon said. Adherence to the guidelines is a requirement for participation in federally funded and industry-sponsored clinical research. The National Academy of Sciences Institute of Medicine (IOM) has published a report that addresses needs, goals, and initiatives to “reinvigorate” the National Cancer Institute’s (NCI’s) cooperative group trials program (www.nap.edu/catalog/12879.html). Among other recommendations, the IOM called on NCI to increase reimbursement to trial sites and urged the American Medical Association to develop a Current Procedural Terminology-4 code that would increase reimbursement to providers who enroll patients and participate in clinical trials. The IOM also recommended that NCI work with a nonprofit foundation to develop a certification program for clinical trial sites. Among informational resources related to clinical trials, Dr Zon cited a series in the Journal of Oncology Practice that addressed various aspects of clinical research, such as exemplary attributes of research sites, good clinical practice

research guidelines, quality assurance, and education. Quality Teams Make for Quality Research The path to exemplary status as a research site begins with the creation of a research team that understands and strives to create a culture that is supportive to clinical research. Physicians participating in clinical research must have a strong commitment to it and be willing to spend the

documentation, require the participating physician to sign off. Research physicians also must be prepared to attend institutional and investigator meetings related to the clinical research program and specific clinical trials. Operating a clinical research site requires a substantial financial commitment, Dr Cohen noted, and personnel costs usually represent the largest outlay. At his institution, salary and benefits for various members of the research team can range from $39,000

“A partnership between the physician and the patient has the potential to make an enormous impact on the algorithm of cancer care by increasing participation in clinical trials.” —Robin Zon, MD extra time required to explain the trial process to patients, discuss treatment options, and obtain appropriate consent. Most steps in the research process, including forms and documentation, require the participating physician to sign off on them. Research physicians also must be prepared to attend institutional and investigator meetings related to the clinical research program and specific clinical trials. “The main thing physicians have to offer is our time,” said Gary I. Cohen, MD, director of clinical research at the Berman Cancer Center in Baltimore, MD. “Our time has value, and we don’t want to give it away. If we are going to do clinical trials, we certainly want to manage our time properly, and having a team allows us to get that done in the most efficient way.” Although the titles and responsibilities of other clinical research team members may vary somewhat from site to site, most teams share several key members, including research associates, research nurses, pharmacy and secretarial support, as well as physician leaders. Clinical research associates screen patients and determine their eligibility to participate in a trial, and also prepares a duplicate or “shadow” medical chart for each trial participant. The shadow chart is stored separately and used for audit purposes. The clinical research pharmacist has responsibility for logging and monitoring use and storage of investigational drugs and distributes assigned study medications. Physicians who participate in clinical research must have a strong commitment to research and be willing to spend the extra time required to explain the trial process to patients, discuss treatment options, and obtain appropriate consent. Most steps in the research process, including forms and

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for a medical assistant to $98,000 for a research nurse. Personnel costs account for about three fourths of expenditures for a site’s research program. Of equal importance, the clinical research team must have the resources necessary to carry out their work, including workspace, telephone/ telecommunication support, and computer equipment and software, Dr Cohen added. The considerable overhead costs associated with operating a clinical research site require income to offset those expenses. A site may not make money, but it also should not lose money, which necessitates a “cost-neutral” financial balancing act, Dr Cohen said. Budgeting and Paying for Trials Contract negotiation is the fulcrum in the balancing act, and the negotiation process has no hard and fast rules. “Sponsors will not pay more than fair market value for services,” said Dee Anna Smith, chief executive officer of the Sarah Cannon Research Institute in Nashville, TN. “There is no clear mechanism in the law or regulations for determining fair market value in the clinical research context,” she said. “Well-documented justification [of costs] increases the likelihood that a sponsor will agree to your budget.” The budget for a clinical trial allocates and documents financial responsibility among the sponsor, the research site, the patient, and insurance provider. An effective budget process should include a thorough review of the protocol and informed consent; careful justification of all costs; determination of institutional requirements; and a thorough delineation of all overhead costs, as well as

Continued from cover identification of hidden costs. One of the most difficult aspects of the process involves estimating or accounting for inflation in multiyear projects, Ms Smith noted. However, cost estimations of future required procedures must include an allowance for inflation. Identifying hidden costs is more problematic for new research sites than for experienced sites. Often overlooked are costs associated with site selection and visits, training the research staff, attendance at investigator meetings, development of study tools, and filing regulatory documents. Other costs that should be taken into account include recruitment, pharmacy review, laboratory setup, quality assurance, radiology setup, monitoring, administration of the study drug, and pathology fees. A research contract should clearly address indemnification, patient injury, and payment terms, Ms Smith said. Indemnification typically includes protection for the sponsor, institution, and research site; use of study results; and product liability. Allowances for patient injury typically include direct medical costs; emergent and long-term care; and possibly, a monetary cap. Most contracts do not have allowances for incidental expenses resulting from injury, lost wages, pain and suffering, or punitive damages. Payment terms will vary from site to site and sponsor to sponsor, but many agreements include some common traits. Ms Smith suggests that the terms stipulate advance payment of a nonrefundable fee for start-up costs, which most sponsors expect. Other issues commonly addressed in the agreement include: • Payment disputes • Defined escalation procedures • Operational issues (eg, information needed to process invoices) • Electronic payment versus use of paper checks • Payment frequency or schedule • Pass-through allowances • Process for dealing with insurance denials. “Understand the protocol, understand and document your costs, understand billing coverage, and understand when you will get cash,” Ms Smith said. “Don’t be mesmerized by the initial perpatient amount offered. Look for what is not in your contract, and don’t be afraid to negotiate. Finally, deliver on the study requirements.” ■

Reference 1. Zon R, Meropol NJ, Catalano RB, Schilsky RL. American Society of Clinical Oncology Statement on minimum standards and exemplary attributes of clinical trial sites. J Clin Oncol. 2008;26(15):2562-2567.

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VBCC PERSPECTIVE

Community Trials Essential to Broad Knowledge By Ed Pezalla, MD, MPH

everal sessions at the recent ASCO meeting considered new standards for community-based oncology research and the development of comparative effectiveness research (CER) methods. Community-based oncology trials play an important role in developing treatment strategies and options. In recent years, however, clinical trial participation in the United States has been on the decline, which limits the population available to researchers and makes it difficult to achieve the diversity needed to reflect the actual experience of patients across the country. Encouraging high-quality communitybased trials will remedy this and remove barriers such as the need to travel to major urban medical centers.

The development of sophisticated CER methodologies should also help to fill the gap for clinical trials since these approaches may augment, or in some cases, replace, the need for an expensive randomized controlled trial (RCT).

The development of sophisticated CER methodologies should also help to fill the gap for clinical trials. Problems of cost will continue to exist but we should note that for manufacturer-sponsored drug trials, the pharmaceutical firm will cover the cost of the experimental treatment and most insurers will cover the routine care needed for the treatment of cancer. In all cases, however, guidance from the health plan on reimbursement should be sought before enrolling in a trial. This may not make trial participation affordable for all but should go some ways towards helping many more patients join a trial. In addition, with the passage of the Patient Protection and Affordable Care Act in March 2010, insurers will be prohibited from dropping or limiting coverage because an individual chooses to participate in a clinical trial effective January 1, 2014. This applies to all clinical trials that treat cancer or other lifethreatening diseases. As noted in “Trial Participation Hampered by Costs” (see page 11), patients continue to express concerns about the cost of clinical trial participation, and Dr Weckstein’s prescriptions for mitigating these financial barriers appear sound. Covering the largely unseen costs of copays and deductibles through legislation would be a huge boon, as would public funding for patient costs associated with trial participation. Ed Pezalla, MD, MPH, is the national medical director for Pharmacy Policy and Strategy of Aetna Pharmacy Management, Hartford, CT, and an editorial board member of Value-Based Cancer Care.

It is my hope that a combination of renewed interest in clinical trials at the community level with alternatives to RCTs in the case of already approved drugs will yield better medical evidence and better patient outcomes. ■

We are here, where you need us most We are committed to the discovery and development of innovative immunotherapeutic approaches aimed at helping patients fight cancers, such as advanced melanoma. Together, we can make a difference.

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www.ValueBasedCancer.com

ASCO CONFERENCE

Active Surveillance Cost-Effective for Low-Risk Prostate Cancer By Wayne Kuznar Chicago, IL—Active surveillance is a cost-effective option for low-risk clinically localized prostate cancer. The number of quality-adjusted lifeyears (QALYs) was highest with active surveillance compared with radical prostatectomy, radiation therapy, brachytherapy, and proton beam therapy, according to data presented by Julia H. Hayes, MD, instructor in medicine at Harvard Medical School, and attending physician at Dana-Farber Cancer Institute, Boston, MA, during a poster presentation at the 2010 meeting of the American Society of Clinical Oncology. “In the age of PSA [prostate-specific antigen] screening, more than 50% of men with clinical localized disease are overtreated, meaning that they are treated unnecessarily, and treatment is associated with significant side effects,” she said. Modeling Care and Costs Dr Hayes used a Markov Monte Carlo model to estimate costs and QALYs of 5 different therapeutic strategies for clinically localized, low-risk prostate cancer. The model considered active surveillance (a policy of following men closely and treating them at the first sign of progression with intent to cure) or immediate treatment with any 1 of the following: radical prostatectomy, intensity-modulated radiation therapy (IMRT), brachytherapy, or proton beam therapy. Costs included Medicare reimbursement rates for treatment and costs associated with side effects, treatment, visits, biopsies, and patient time costs in 2008 US dollars. Cost and QALYs were discounted at 3% annually. The model assumed equivalent prostate cancer–related outcomes, and then the risk of dying from prostate cancer was varied. For a 65-year-old man, brachytherapy was the least expensive treatment option when considering total costs ($25,606), whereas proton beam therapy was the most expensive ($53,828). Active surveillance was associated with the highest quality-adjusted life expectancy (QALE), at 8.58 QALYs. Compared with radical prostatectomy, active surveillance provided an additional 9.1 months of QALE, at an incremental cost-effectiveness ratio of $2729 per QALY. Brachytherapy and IMRT had similar QALE benefit, but IMRT cost $21,050 compared with $10,174 for brachytherapy. “The reason that active surveillance cost more than brachytherapy was

because everybody who progressed on active surveillance, which was about 60% of men over the course of their lives, went on to IMRT, and IMRT cost about $20,000 and brachytherapy cost about $10,000,” said Dr Hayes

ical prostatectomy, it actually became the most effective and least expensive,” he said. For a 55-year-old man, active surveillance provided an additional 4.7 months of QALYs compared with radical prosta-

“In the age of PSA [prostate-specific antigen] screening, more than 50% of men with clinical localized disease are overtreated...and treatment is associated with significant side effects.” —Julia H. Hayes, MD “If we assumed that men on active surveillance got brachytherapy or rad-

tectomy, at an incremental cost-effectiveness ratio of $829 per QALY.

Active surveillance remained the most effective strategy, even if the risk of disease progression doubled, the risk of symptoms on active surveillance doubled, and the risk of side effects of treatment was reduced by half (from 53% to 26%). The risk of prostate cancer–specific death on active surveillance would have to be 60% higher than after initial treatment (16% vs 9%) to eliminate the QALE advantage of active surveillance compared with immediate treatment. “You would have to almost double the risk of dying from prostate cancer on active surveillance in order to make initial treatment favored in terms of QALE,” Dr Hayes said. ■

Bevacizumab Cost-Effectiveness “in Line” with Other Therapies Chicago, IL—The cost-effectiveness of adding bevacizumab (Avastin) to firstline chemotherapy for the treatment of metastatic colorectal cancer is comparable to that of many other therapies for metastatic cancer. Although the acquisition cost of bevacizumab is high, it has improved the cost-effectiveness of systemic therapy (irinotecan [Camptosar]- or oxaliplatin-based regimens), said the study’s lead investigator, Diego Villa, MD, MPH, of the British Columbia Cancer Agency, Vancouver, Canada. He presented the results at the 2010 ASCO meeting. Adding bevacizumab to chemotherapy has previously been shown to significantly improve overall survival in metastatic colorectal cancer, but “the

cost of therapy with bevacizumab for advanced colorectal cancer is $44,000 to $55,000 per patient over 10 months of treatment,” Dr Villa said. Dr Villa performed a populationbased analysis using a Markov model that tracked major clinical and treatment events in the natural history of the disease. He compared outcomes and costs in the pre-bevacizumab era with those in the bevacizumab era. The database was comprised of patients with newly diagnosed metastatic colorectal cancer between 2003 and 2004 (pre-bevacizumab era) and 2006 (bevacizumab era) who were referred to the British Columbia Cancer Agency. Of the 943 patients included, 611 were from the pre-bevacizumab era and 332 were from the bevacizumab era.

When considering the costs associated with diagnosis and staging; surgery; systemic therapy; and radiation therapy, the weighted average cost of treatment per patient increased from $34,972 in the pre-bevacizumab era to $38,764 after bevacizumab was introduced. Median overall survival for patients initiating chemotherapy improved from 15.6 months in the pre-bevacizumab era to 19.5 months in the bevacizumab era. The cost-effectiveness ratio of bevacizumab for this indication was calculated at $15,617 per life-year gained, or $62,468 per quality-adjusted life-year gained, which is “in line with many other therapies for metastatic cancer,” Dr Villa noted. —WK ■

Greater Role for Pharmacogenomics Ahead Chicago, IL—Using genetic and pharmacogenomic information to treat patients with cancer in optimal fashion has advanced in the past several years, and the clinical utility of this approach should continue to improve as genetic research continues, said several panelists at a 2010 ASCO session on evaluating the evidence and marketing of genomic tests. Unfortunately, clinicians too often pick the therapy they’re “most comfortable with, as opposed to the one the patient’s biology is driving us towards,” said Howard L. McLeod, PharmD, of University of North Carolina at Chapel

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Hill. “We’re moving toward an era where it’s less of our choice and more of the tumor’s choice.” Information on what therapy may impact a tumor has grown more common, Dr McLeod noted, emphasizing that many therapies, including irinotecan, cetuximab, and panitumumab, include pharmacogenomic information in the label. In addition, recent drug label updates have increased the amount of information provided, including, most importantly, actionable recommendations that impact clinical care. Michael L. Maitland, MD, PhD, concentrated on these practical aspects of

care. Noting that the current cost of sequencing an individual’s genome sequence is about $10,000, he indicated that by 2013, that cost should have dropped to $1000. Although not widely used at the moment, avoiding use of genetic information is becoming unacceptable, he argued. A question from the audience highlighted the “in-between” state of pharmacogenomics in practice. Asked by a practicing oncologist if he should be testing his patients for CYP2D6 to guide care, Dr Maitland stated that “there’s not going to be a yes or no answer to that question.” ■

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ISPOR CONFERENCE

Incorporating Patient-Reported Data into the Pharma Sales Story By Daniel Vollaro Atlanta, GA—Offering practical advice about how and when to use patientreported outcomes (PROs) to make supportable claims in the marketing of new drugs and products, a workshop directed mainly to new product developers at the International Society for Pharmacoeconomics and Outcomes Research meeting in Atlanta clarified some of the basic issues surrounding the use of this type of research instrument. The workshop reviewed the labeling and approval histories of several products, including Advair (fluticasone propionate and salmeterol xinafoate; GlaxoSmith Kline) and the human growth hormone somatropin, to show how manufacturers make claims using PROs, as well as the different standards Germany, England, and the United States use to evaluate PROs. Attendees also heard the merits of a claim-centered approach to using PROs to support marketing claims. A Useful By-Product PROs are data gathered directly

from patients as part of a clinical trial, usually in the form of a questionnaire. These are often the only instrument that measures patients’ feelings about, and overall satisfaction with, the therapy in a typical clinical trial. PROs provide valuable data for researchers and for marketing departments, sometimes serving as evidence to support claims that a drug was efficacious or superior to another product in the marketplace. Warning that the US Food and Drug Administration (FDA) scrutinizes comparative claims carefully and is inclined to view them suspiciously, United BioSource Corporation (UBC) Senior Research Scientist Asha Hareendran, PhD, explained that all promotional claims “must be supported by substantial evidence or substantial clinical evidence,” and the evidence required for comparative claims, or claims of superiority, “would include adequate and well-controlled trials designed to establish superiority of one treatment over another.” This requirement shapes the way drug companies market their products, Dr Hareendran said, because if they want to make a comparative claim,

they must use PROs from randomized controlled trials—a higher standard of evidence than is required for noncomparative claims. She suggested that drug developers can use less costly conjoint analysis studies to support noncomparative promotional claims.

“What do you want to see in the Wall Street Journal or on the FDA’s label claim?” —William Lenderking, PhD Dr Hareendran showed several examples of patient satisfaction evidence included in product marketing materials for several inhaler products designed to treat chronic obstructive pulmonary disease and offered some guidance on choosing the appropriate PROs for promotional materials. Begin at the End “When you are aiming for a labeling claim, it’s not something that you

can decide at the extremes,” Dr Hareendran said. “Most of my colleagues in the pharmaceutical industry would say, select the instrument based on the concept that you want to claim on, and then make sure all the properties on the instrument meet the requirements of the 2009 FDA guidelines.’” Dr Hareendran’s colleague at UBC, William Lenderking, PhD, echoed her call for a strategic approach to supporting promotional claims. Dr Lenderking, senior research leader at UBC, outlined clear priorities for how drug companies should support an advertising claim with the appropriate PRO evidence: begin with a clear sense of the “claim” or “story” you want to tell. “It’s just such a basic concept—you need to know where you are going,” Dr Lenderking said. “What do you want to see in the Wall Street Journal, or on the FDA’s label claim, or what are the conclusions you want in the NICE [National Institute for Health and Clinical Excellence] appraisal?” Think about that, he advised, and then “work backwards from there.” ■

ASCO CONFERENCE

ASCO Weighs in on CER By Colin Gittens

he American Society of Clinical Oncology (ASCO) stated that comparative effectiveness research (CER) should draw on approaches currently used for clinical trials, highlighting its stake in the matter by pointing out that CER is integral to oncology research. ASCO’s statement came in response to a request from the US Department of Health and Human Services (HHS) for information on developing an inventory of CER. “The extensive federally funded clinical trials network is a gold standard for CER,” wrote ASCO President George W. Sledge, Jr, MD, in a letter dated August 9, 2010. The letter pushes for a single repository containing links to the many types of studies that will be used in CER. Such a repository would foster awareness in the research community of trials under way. As with the ClinicalTrials.gov website, CER studies should be registered at their outset, which would

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guard against publication bias.In addition, withholding of federal funds until the time of registration could be used as an incentive for participation, Dr Sledge wrote. The HHS should also stratify studies based on design, and indicate whether data were peer reviewed, so that users can evaluate the strength of the evidence, Dr Sledge stated. Sustaining CER efforts over time is also essential, the ASCO president wrote. “Linking the inventory to the newly created Patient-Centered Outcomes Research [PCOR] Institute may be one method to enable sustainability,” said Dr Sledge. The PCOR Institute has dedicated funding and incorporates a public–private partnership, attributes that “may create more buyin among stakeholders in the research community.” Finally, the letter urges that the CER inventory should be delayed until the HHS receives input and feedback from the PCOR Institute’s Board of Governors and Methodology Committee. ■

Trial Participation Hampered by Costs By Charles Bankhead

ost-related factors are a chief reason for patients declining to participate in a clinical trial, a survey of 4 community oncology practices showed. Overall, 28% of patients cited cost as a factor in their refusal to participate in clinical trials, and 12% said cost was the primary reason for not participating. “Cost is an issue,” Douglas Weckstein, MD, of New Hampshire Oncology-Hematology in Hooksett, concluded during a poster presentation at the American Society of Clinical Oncology meeting. Some patients reported that they did not have health insurance and others said they cover the cost of copayments or deductibles. In some cases, insurers refused to cover treatment provided through a clinical trial. The findings came from a survey of patients and physicians at 4 community cancer clinics in New England. The primary objective was to determine the proportion of patients who decline to participate in clinical trials because of costs associated with participation.

Secondary objectives were to identify other reasons for not participating and to determine how often physicians at the clinics do not discuss clinical trial opportunities with patients. A total of 213 trial-eligible patients at the 4 clinics did not participate in clinical trials. Aside from the cost factor, of the 120 patients who cited specific reasons, 50% expressed concern about possible side effects, 44% cited concern about randomization, and 33% said they were too overwhelmed and did not have the time. Survey responses from Dr Weckstein’s clinic also showed that 40% of trial-eligible patients did not recall their physicians telling them about clinical trial opportunities. According to Dr Weckstein, 3 potential actions could mitigate financial barriers to patients’ participation in clinical trials: • Legislation to cover quality trials, including coverage for deductibles and copays • Consideration of costly testing in trial design • Public funding for patient costs to participate in trials. ■

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HEALTH POLICY

REMS Regulation Provokes... the FDA is teetering on a tightrope between protecting patient safety and imposing new barriers to access. The latter provoked much scarcely contained anger from attendees. Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, acknowledged the problems. “FDA regulates sponsors, but we have no control over how they influence providers and prescribers,” she said. “REMS is not perfect, but it’s enforceable. We can order compliance with those who agree to abide by the restrictions, but we cannot make people agree to participate in the REMS program. It’s awkward.”

at a glance REMS programs negotiate a delicate balance between protecting patient safety and imposing new barriers to access REMS program components include a medication guide, a communication plan, and elements to assure safe use Many fear that REMS will add significantly to the costs of drug manufacturing, prescribing, dispensing, and providing patient care

Background The FDA Amendments Act (FDAAA) of 2007 created REMS. In essence, it permits the FDA to establish stronger regulations, which require sponsors to ensure that the benefits of a drug outweigh its risks. REMS applies to new drug applications as well as to already approved drugs that are deemed by the FDA to carry significant risk. REMS requirements include a medication guide (MG), a communication plan (CP), and elements to assure safe use (ETASU). The MG is similar to a drug label but provides more extensive information and is dispensed with the drug. This must be given to patients to inform them of possible serious adverse events, as well as the importance of strict adherence to the dosing regimen. The CP is designed for healthcare providers. It explains safety protocols and contains information about training materials; prescribing procedures; patient–physician agreements; informed consent; patient education materials; medical monitoring; and data collection forms and procedures.

Continued from cover

The ETASU are a series of additional requirements that must be commensurate with a specific, serious risk but must not be unduly burdensome to patients. They require that the pre-

and certification programs and monitor REMS. It has no control, however, over other participants in the system, and cannot force them to comply with REMS requirements.

“The medication guides emphasize only risks. If patients read that they might die from taking ESAs, they might refuse them—and then miss the clear benefits of these drugs.” —Thomas H. Hostetter, MD scriber and pharmacist be educated about the specific risks of a drug and be certified to prescribe and/or dispense it. In some cases, prescribers are required to counsel patients about risk, enroll them in a registry, ask that they sign a prescriber–patient agreement to ensure full awareness of risk, and monitor them closely for signs of toxicity. Furthermore, some drugs with ETASU requirements are only permitted to be dispensed from certain registered pharmacies. ETASU is the most stringent REMS requirement, and can preclude approval if the sponsor does not comply. All REMS include a timetable for submission of risk and benefit assessment at 18 months, 3 years, and 7 years. Drugs with ETASU requirements can have more frequent assessments. The onus of assessment falls on the manufacturer.

The FDA Acknowledges Problems Even before the July meeting, the FDA recognized problems and attempted to set a course by drafting guidance for industry.1 This document considered issues such as the goal of REMS programs and what factors are pertinent to REMS (and how can they be measured). Other considerations include how ETASU will affect patients’ access to some drugs. Will they really improve safety—or diminish it? Can they be standardized? And how will they affect the healthcare delivery system? Other issues noted by Dr Woodcock include the advantages and disadvantages of various REMS drug distribution systems; monitoring and assessment; ameliorating the burden of cost to all participants; and maintaining patient privacy.

Concerns and Problems During the 2 years after the FDAAA became effective on March 25, 2008, the FDA approved 110 REMS for new drugs and biologic agents. The majority (68%) required an MG only, and just 10 necessitated ETASU. Nevertheless, stakeholders across the healthcare system have expressed concerns about REMS. Many see REMS as a burden on the provision of care. Prescribers complain about having to enroll in several programs, obtain a variety of certifications, and provide additional counseling to patients. These restrictions can interfere with the way medicine is practiced, and they are costly—and not reimbursed, according to some physicians. Another concern is REMS’ potential negative effect on patient access to therapies. Advocacy groups are concerned that physicians may choose to not participate in REMS, thus denying patients access to certain drugs. Pharmacy organizations have complained about the fact that there is no compensation for the extra work stemming from REMS regulations. Manufacturers also perceive the burden of REMS as substantial. A drug’s sponsor must establish the education

Panelists Voice Concerns Sandra Adamson Fryhofer, MD, an internist in Atlanta, GA, and member of the American Medical Association (AMA) Council on Science and Public Health, agreed with the FDA that REMS is probably necessary, but said that the AMA is concerned about the process of implementation and the significant burdens it will place on physicians. She noted that the organization polled its members and found that 50% of them will refuse to prescribe drugs that require REMS. “One third of oncologists say they won’t even register as REMS prescribers,” she added. Mitchell S.Y. Cohen, Esq, an attorney at Kaiser Permanente, and Jeffrey K. Francer, Esq, Assistant General Counsel for the Pharmaceutical Research and Manufacturers of America, agreed that 3 major principles should guide REMS implementation. These include: • The process of calculating risks and benefits should be easy for patients to understand • Data about evaluation of REMS should be shared with all concerned, as should efforts taken to mitigate burdens on all participants • Use of MGs and CPs should be rea-

VALUE-BASED CANCER CARE

September 2010

sonable, and confidentiality of patient information must be ensured. Several speakers were concerned that patients might refuse a drug after reading the MG. Thomas H. Hostetter, MD, a practicing nephrologist and past president of the American Society of Nephrology, was the most outspoken. In discussing erythropoiesis-stimulating agents (ESAs), he noted that there are 350,000 patients undergoing dialysis in the United States, and they all receive ESAs in varying doses. “The medication guides emphasize only risks, and if patients read, in practically the first sentence, that they might die from taking ESAs, they might refuse them—and then miss the clear benefits of these drugs,” he said. Michael Lazarus, MD, a nephrologist at Fresenius Medical Care North America in Waltham, MA, added that ESAs are used in oncology as well as nephrology, but in much higher doses; therefore, the risks are greater. “But the medication guide does not distinguish among types of ESA use, and the same guide is given to all patients, regardless of diagnosis and treatment plan,” Dr Lazarus said. “This is confusing.” Every speaker noted that REMS will add significantly to the costs of drug manufacturing, prescribing, dispensing, and providing patient care. Several concerns were generated by ETASU. According to Dr Fryhofer, their rigor may make physicians shy away from certain drugs and use less effective ones. “The purpose of REMS is increased safety, not decreased access to therapy,” she said. “Therefore, ETASUs should be developed with input from specialty physicians.” In addition, ETASU will erect new barriers between patients and providers, and worsen the ones that already exist, noted Karen Kiefer, of the New Jersey chapter of the American Pain Management Nurse/Physician Association. Several pharmacists said that restrictive distribution programs can interfere with pharmacy practice. They advocated for compensation to pharmacies for the additional cost of administering REMS in general, and ETASU in particular. Others voiced concern that, because ETASU are not standardized, they can increase administrative, evaluative, and safety problems. Also, everyone affected by ETASU will experience increased demands on their time. ■ Reference 1. Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications. Rockville, MD; Food and Drug Administration: September 2009.

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Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

ÂŠ Centocor Ortho Biotech Inc. 2010 4/10 08ADA10012

HEALTH POLICY

Understanding the Preventive Services Rule Changes are plans that existed at the time of enactment. According to estimates by the Departments (based on Kaiser data), 82% of large employers and 70% of small employers will remain

grandfathered in 2011. By 2013, 55% of large employers and 34% of small employers will remain grandfathered. So it is unclear how many plans will be affected by this provision because

of grandfathering and the fact that some plans already provide coverage of, and eliminate cost-sharing for, preventive services (either by State law, or voluntarily).

Indication ZOMETA is indicated for the treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

By Jayson Slotnik, JD, MPH

n July 14, 2010, the Departments of Treasury, Labor, and Health and Human Services issued interim final rules for group health plans and health insurance issuers to provide detail on how those entities are to cover the preventive services required under the Patient Protection and Affordable Care Act (PPACA). It is important for readers of this publication to be aware of these rules and to understand how these changes will impact their business and patient care going forward. PPACA requires insured and selfinsured group health plans as well as health insurance issuers in the group and individual markets to provide cov-

Highlights from the Important Safety Information ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient. In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.

Some plans already provide coverage of, and eliminate cost-sharing for, preventive services. erage of, and eliminate cost-sharing for, the following preventive services: 1) Services/items with an ‘A’ or ‘B’ rating from the US Preventive Services Task Force (USPSTF). Cancer-specific recommendations in this category include BRCA screening and counseling; breast cancer preventive medications; breast, cervical, and colorectal cancer screening; and tobacco use counseling. 2) Immunizations with recommendations from the Advisory Committee on Immunization Practices of the CDC; 3) Preventive care and screening for infants, children, and adolescents provided by Health Resources and Services Administration (HRSA) guidelines; and 4) With respect to women, preventive care and screening provided by HRSA (except breast cancer screening recommendations issued in November 2009). These provisions, however, do not apply to grandfathered plans, which

Please see brief summary on the following page. References: 1. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98:962969. 2. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 3. Aredia Prescribing Information. Novartis Pharmaceuticals Corporation. 4. Actonel Prescribing Information. Procter & Gamble Pharmaceuticals. 5. Boniva Prescribing Information. Roche Laboratories Inc. 6. Didronel Prescribing Information. Procter & Gamble Pharmaceuticals. 7. Fosamax Prescribing Information. Merck & Co. 8. Skelid Prescribing Information. sanofiaventis US LLC. 9. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88: 1082-1090.

Jayson Slotnik, JD, is an attorney at Foley Hoag, LLP and an editorial board member of Value-Based Cancer Care.

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HEALTH POLICY Interpreting the Rules So what will the Interim Final Rules on Preventive Services mean for practitioners and payers? First, if preventive services are billed jointly with an office visit, copays may be imposed if the primary purpose of the visit was something other than the preventive services. However, if the primary purpose was

to obtain preventive services, copays are not allowed. Note that “primary purpose” is not defined, which could lead to confusion regarding billing for such visits. In addition, if preventive services are billed separately, the copay is waived for such service (but copays for the office visit still apply). On the health plan side, plans are not

required to provide coverage of, and may impose cost-sharing for, preventive services provided out-of-network. Also, if a recommendation/guideline for preventive services fails to specify the frequency, method, treatment, or setting, the plan may use “reasonable medical management” to determine coverage rules. The provision applies to plan years

beginning on or after September 23, 2010, or the first plan year beginning on or after the date that is 1 year after the recommendation/guideline goes into effect. For an employer plan beginning on July 1, 2011, the employer would not have to provide coverage of, and eliminate cost sharing for, that service until July 1, 2012. ■

Because skeletal-related events (SREs)† can have devastating consequences, help protect your patients with ZOMETA • ZOMETA may help reduce and delay SREs in more malignancies than any other bone-targeted agent1-8

Metastatic breast cancer

Metastatic hormone-refractory prostate cancer

Multiple myeloma

Metastatic lung cancer and other solid tumors

Metastatic renal cell carcinoma

*ZOMETA should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy. † SRE=skeletal-related event, defined as pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and the need for radiation or surgery to the bone.9

More than

April 2010

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YEARS of real-world experience C-ZOM-100050

www.ValueBasedCancer.com

ZOMETA

® (zoledronic acid) Injection Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range of measured albumin in mg/dL). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 µmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 µmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in preand postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3. Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zometa Pamidronate 4 mg 90 mg n (%) n (%) Patients Studied Total No. of Patients Studied 86 (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea 25 (29) 28 (27) Constipation 23 (27) 13 (13) Diarrhea 15 (17) 17 (17) Abdominal Pain 14 (16) 13 (13) Vomiting 12 (14) 17 (17) Anorexia 8 (9) 14 (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2) Hypokalemia 10 (12) 16 (16) Hypomagnesemia 9 (11) 5 (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia 13 (15) 10 (10) Anxiety 12 (14) 8 (8) Confusion 11 (13) 13 (13) Agitation 11 (13) 8 (8) Respiratory Dyspnea 19 (22) 20 (19) Coughing 10 (12) 12 (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

n/N

(%)

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Table 5. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Table 7. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases

Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Grade 3

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

Laboratory Parameter n/N Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

1Grade

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)]. Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6. Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

Patients Studied Total No. of Patients Total No. of Patients with any AE Blood and Lymphatic Anemia Neutropenia Thrombocytopenia Gastrointestinal Nausea Vomiting Constipation Diarrhea Abdominal Pain Dyspepsia Stomatitis Sore Throat General Disorders and Administration Site Fatigue Pyrexia Weakness Edema Lower Limb Rigors Infections Urinary Tract Infection Upper Respiratory Tract Infection Metabolism Anorexia Weight Decreased Dehydration Appetite Decreased Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb Neoplasms Malignant Neoplasm Aggravated

Zometa 4 mg

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

Placebo

1031 (100) 1015 (98)

556 (100) 548 (99)

455 (100) 445 (98)

344 (33) 124 (12) 102 (10)

175 83 53

(32) (15) (10)

128 (28) 35 (8) 20 (4)

476 333 320 249 143 105 86 82

(46) (32) (31) (24) (14) (10) (8) (8)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

398 328 252 215 112

(39) (32) (24) (21) (11)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

124 (12) 101 (10)

50 82

(9) (15)

41 30

(9) (7)

231 164 145 130

81 50 60 48

(15) (9) (11) (9)

105 61 59 45

(23) (13) (13) (10)

n (%)

(%)

7/529 6/973 115/973 19/971 1/971

(55) (23) (21) (15) (14)

205 (20)

316 143 131 106 84 97

(57) (26) (24) (19) (15) (17)

284 74 73 40 52

(62) (16) (16) (9) (11)

89 (20)

Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

Psychiatric Depression Anxiety Confusion

146 (14) 112 (11) 74 (7)

95 73 39

(17) (13) (7)

49 (11) 37 (8) 47 (10)

Respiratory Dyspnea Cough

282 (27) 224 (22)

155 129

(28) (23)

107 (24) 65 (14)

Skin Alopecia Dermatitis

125 (12) 114 (11)

80 74

(14) (13)

36 38

(11) (13) (16) (8) (10)

(8) (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8.

Placebo

(%)

4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

n/N

(%)

4/241 0/415 14/415 8/415 1/415

(2%) — (3%) (2%) (<1%)

1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L)

Table 8. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

(<1%) (<1%) — — (<1%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9. Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Zometa 4 mg n/N Normal Abnormal Total Solid Tumors

569 239 216 156 143

n/N

(1%) (<1%) (12%) (2%) (<1%)

Multiple Myeloma and Breast Cancer

(22) (16) (14) (13)

Pamidronate 90 mg

27/246 (11%) 2/26 (8%) 29/272 (11%) Zometa 4 mg n/N

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

(%)

17/154 (11%) 1/11 (9%) 18/165 (11%) Zometa 4 mg n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

Pamidronate 90 mg n/N

(%)

23/246 (9%) 2/22 (9%) 25/268 (9%) Placebo n/N

(%)

10/143 (7%) 1/20 (5%) 11/163 (7%) Placebo n/N

(%)

8/68 (12%) 2/10 (20%) 10/78 (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include:

CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in-vivo drug interaction studies have been performed. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials. 7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide In multiple myeloma patients, the risk of renal dysfunction may be increased when Zometa is used in combination with thalidomide. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonateclass effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the highdose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the lowdose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman. 8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

REV: OCTOBER 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2009-101

TECHNOLOGY ASSESSMENT

Does Robotic Surgery Make the Cut? Conference explores science and marketing of new device By Robertson Paton

ver the past decade, polarized opinion has abounded regarding robot-assisted laparoscopy. On one side, many of the surgeons who pioneered the use of the da Vinci surgical robot (Intuitive Surgical, Sunnyvale, CA) in Germany and the United States described it as “revolutionary,” heralding “a new era,” and creating a “paradigm shift.”1-3 “We are convinced that it will totally change the future of urological surgery,” researchers at the University of Heidelberg, Germany, wrote in May 2001.3 The technology was rapidly adopted—it went from being used in 2648 radical prostatectomies in 2003 to 73,000 in 2009—about 85% of the total performed in the United States, according to an article in the New York Times.4 Some urologists, however, were deeply skeptical about the da Vinci robot’s benefits. Some surgeons take issue with the robot’s high costs—as much as $1.4 million for the unit, several hundred thousand dollars annually for maintenance contracts, and nearly $2000 per procedure for consumables. Others question the comparative effectiveness of robot-assisted surgery and are frustrated with what they view as the slow pace of improvement in the technology. To bolster their views, they point to studies indicating that robotassisted surgery is no more effective than well-established open procedures and standard laparoscopy.

The Pennsylvania Hospital Experience A recent media seminar and expert panel convened at Pennsylvania Hospital, Philadelphia, to help assess whether robotic surgery is an advance in modern medicine or just effective marketing. Although the seminar did not necessarily provide the answer to this question, it did provide a background as to how the technology works and the experiences of the institution and the surgical teams in employing it. Laparoscopy, whether robotic or standard, results in smaller incisions; less pain and blood loss; fewer transfusions; and faster discharge and recovery times, said Daniel Eun, MD, assistant professor of urology in surgery and director of minimally invasive and robotic urologic oncology and reconstruction at the University of Pennsylvania School of Medicine, Philadelphia. The drawbacks of laparoscopic procedures include less surgical dexterity, limitations on the kinds of procedures that can be per-

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formed, and generally longer times in the operating room, he said. During standard laparoscopy, the surgeon must stand over the patient but look at a 2-dimensional image on a monitor, usually located overhead. The instruments are long and awkward, with no “wristed” movement. “It’s counterintuitive,” Dr Eun said. “It’s like operating with chopsticks.” The instruments also amplify movement and are more likely to cause “instrument tremor.” Ergonomically, standard laparoscopy results in greater surgeon fatigue than open or robot-assisted surgeries.

Other panelists were enthusiastic about robot-assisted surgery. “The robot can work in places you can’t get your hands in. This technology is really in its infancy,” said William Welch, MD, professor of neurosurgery at the University of Pennsylvania School of Medicine. Use Ahead of the Evidence Despite the generally positive reaction to the technology at Pennsylvania Hospital, at least one cautionary note was struck. John Y.K. Lee, MD, assistant professor of neurosurgery at the University of Pennsylvania School of

“The robot is a tool. The surgeon is the one who selects the patients and produces the results.” —Daniel Eun, MD In contrast, the da Vinci surgical robot offers a 3-dimensional vision system, computerized tremor filtering, and automatic scaling down of large motions of the surgeon’s hand to the confined surgical domain. The surgeon sits at a console, using a foot-operated clutch that supplements the hand controls to conduct the operation. Even though members of his team are qualified, Dr Eun makes all incisions. Robot-assisted procedures performed by Dr Eun rarely have to be converted to open surgical techniques. “The open incision is a thing of the past in my care,” he said. Although Dr Eun is an advocate of robot-assisted procedures, having performed 4500 during his career, he does not perform them unless, based on previous experience, the expected “outcome [will be] at least equal to an open operation.” “The robot is a tool,” Dr Eun concluded. “The surgeon is the one who selects the patients and produces the results.” Jonathan D. Moreno, MD, David and Lyn Silfen University Professor of Medical Ethics, University of Pennsylvania School of Medicine, seconded this conclusion. “Perhaps it’s better to think of this as device-assisted surgery, an extension of the kinds of tools surgeons have used for a long time,” he said. “A true robot is autonomous.” Despite the state of the US economy, Dr Moreno said he expects that plenty of money will be invested in new medical technology, including enhancements to the da Vinci robot and the development of new robotic systems. “In 25 years, we’ll have a device that will be able to interact with [the surgeon],” he said.

Medicine and medical director of the Gamma Knife Center at Pennsylvania Hospital, remarked on the difficulties of performing comparative effectiveness studies. “How do we get randomized studies? It’s very difficult,” he said, pointing out that this is particularly the case for the rare tumors seen in neurology. “The patient doesn’t want to be randomized to open or endoscopic [surgery]. They want the least invasive or maximally effective [procedure]. We’ll never have comparative effectiveness studies for these types of tumors.” Outside of the institution, studies of the merits of robot-assisted surgery have emerged, and although some have been inconclusive, some researchers have taken definite stands on the comparative effectiveness of the technology. Hu and colleagues performed a populationbased observational cohort study using information from a national cancer database.5 They determined that patients who underwent minimally invasive radical prostatectomy (standard and robot-assisted) experienced shorter length of stay and fewer miscellaneous surgical complications and strictures

than patients in the open prostatectomy group, but experienced more genitourinary complications, incontinence, and erectile dysfunction. The researchers concluded that patients “had been enamored of new technology” in choosing minimally invasive surgery instead of the established gold standard of open radical prostatectomy.4 When Breitenstein and colleagues conducted a case-matched study of robot-assisted versus standard laparoscopic cholecystectomy, they found similar outcomes, but hospital costs were 28% higher for the robot-assisted cholecystectomies.6 “Costs of robots…are high and do not justify the use of this technology considering the lack of benefits for patients,” the authors concluded. The debate will certainly continue. When more experience is gained with robotic technology, outcomes should improve and costs should drop as the technology improves and competitors enter the field. In the meantime, the da Vinci robot should not be seen as a miraculous device that can overcome the limitations of an inexperienced surgeon, according to Vipul Patel, MD, medical director of the Global Robotics Institute at Florida Hospital, Orlando. Dr Patel, who did not attend the meeting, commented in a separate interview that “the robot is an enabling technology. It makes a good surgeon better; it doesn’t make a bad surgeon good.” ■ References 1. Bräutigam WM, Engl T, Bentas W, et al. Roboticassisted laparoscopic radical prostatectomy: the Frankfurt technique. World J Urol. 2003;21(3):128-132. 2. Bentas W, Wolfram M, Jones J, et al. Robotic technology and the translation of open radical prostatectomy to laparoscopy: the early Frankfurt experience with robotic radical prostatectomy and 1-year follow-up. Eur Urol. 2003;44(2):175-181. 3. Rassweiler J, Binder J, Frede I. Robotic and telesurgery: will they change our future? Curr Opin Urol. 2001;11(3):309-320. 4. Kolata G. Results unproven, robotic surgery wins converts. New York Times. February 14, 2010;A1. 5. Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009;302(14):1557-1564. 6. Breitenstein S, Nocito A, Puhan M, et al. Roboticassisted versus laparoscopic cholecystectomy: outcome and cost analyses of a case-matched control study. Ann Surg. 2008;247(6):987-993.

Economic and Outcome Answers on the Way A study examining the effectiveness of robotic versus standard prostatectomy for prostate cancer is presently under way. Principal investigator Martin G. Sanda, MD, the director of the Beth Israel Deaconess Medical Center Prostate Cancer Care Center, will examine health-related quality of life before and after surgery, and will look at

how surgeon experience relates to outcomes, and whether robotic assistance reduces variance. Finally, the study will compare costs and cost effectiveness between standard and robot-assisted prostatectomy using quality adjusted life-year models. Preliminary results will be submitted to a peer reviewed publication this fall, Dr Sanda said.

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ACADEMYHEALTH CONFERENCE

Cost-Effectiveness in the New Comparative... If that is the case, does cost-effectiveness analysis (CEA) have a future? “We’re on a precipice…a policy window of sorts, and while that window is open, lots of creative activities can take place,” said Jean Slutsky, director of the Centers for Outcomes and Evidence, Agency for Healthcare Research and Quality, Rockville, MD. Given this new reality, Dr Pearson suggested that “impact on service” is one way that patients would find CEA helpful. “Certain prostate cancer therapies involve 1 overnight hospital stay and a few doctor visits

at a glance Cost and comparative effectiveness have become loaded terms that nevertheless are valuable concepts Transparency in cost-effectiveness decisions is needed to foster public trust and understanding of them

value from cost-effectiveness is used to determine the benefits his company provides. UnitedHealth Group’s different committees research the clinical value of a procedure, device, or drug by asking questions including: • Does it work? • How strong is the evidence? • What are the outcomes? • How does it work in the real world?

down the road; others involve a daily doctor’s visit for up to 6 to 8 weeks,” he noted. “Just putting that down can be powerful.” Assessing the cost to reduce side effects is another example. “If you’ve got 2 different agents [for] the same thing and one has a lower rate of side effects but is more expensive, how much are we spending to reduce that risk of a side effect?” he wondered. Ms Slutsky asserted that CEA desperately needs to overhaul its public image. “We’ve allowed all these tags to be associated with it, and it’s now become a public relations game, not an information game,” she said. Acknowledging that “it’s the terminology that gets a little tricky,” she said that “transparency is needed so the public knows how we come to cost conclusions. I really can’t emphasize enough how much we need effective communication so it comes across in a nonthreatening way.” Putting Cost-Effectiveness in the Equation Lewis Sandy, MD, senior vice president of clinical advancement at UnitedHealth Group, Minneapolis, MN, described how separating clinical

benefit level and structure?” Dr Sandy expressed hope that CEA will be in the examination room in the future, when the patient needs to make a high-stakes choice. “Comparative effectiveness needs to support optimal decisionmaking between doctors and patients,” he argued, adding that it should foster “a dialogue about evidence and an elicitation of preferences.”

“Comparative effectiveness needs to support optimal decision-making between doctors and patients.” —Lewis Sandy, MD “This clinical value calculus affects coverage decisions,” he said. “Is the product included in the envelope for benefit coverage? Cost-effectiveness can affect how it is covered—what is the

Hemal Shah, PharmD, executive director of health economics and outcomes research at Boehringer Ingelheim, Ridgefield, CT, concurred with Dr Sandy that cost and value should be

evaluated only after clinical outcomes are assessed. Using CEA to determine a one-size-fits-all measure of value is impractical, she argued, and instead should be done at regional or local levels. “Depending on the region and practice patterns, you’ll see very different ways cost and utilization are observed,” Dr Shah noted. Dr Pearson summed up the future of cost-effectiveness. “The United States has largely ignored how it uses its resources for healthcare,” he said. “If we feel we’re on an unsustainable path, what are the ways we can engage the public in a dialogue about some of those issues? Cost-effectiveness is not thought of as a method, it’s thought of as a form of decisionmaking. We may want to rename it and think of it in new terms.” ■

Comparing VHA with Fee-for-Service Cancer Care Implications for cancer care outside the VHA By Cherie Dewar

Although complex, comparative effectiveness analysis could provide value for patient-level decision-making

Continued from cover

Boston, MA—The work of 3 Harvard Medical School researchers presented at June’s AcademyHealth Conference provided a snapshot of how cancer care outcomes compare between the Veterans Health Administration (VHA) and the fee-for-service Medicare community. In this case, the notion of “you get what you pay for” may not necessarily be true.

After coinvestigator Elizabeth Lamont, MD, MS, established statistically that the VHA’s data were accurate, Nancy Keating, MD, MPH, presented findings on the quality of cancer care in the VHA versus the private sector. Showing a graph depicting a higher rate of stage I colon cancer diagnosis at the VHA compared with SEER (29.6% and 24.5%, respectively), Dr Keating noted, “this is consistent with other studies that demonstrate the

“The VHA’s less aggressive care for advanced cancer should be considered for healthcare reform.” —Mary Beth Landrum, PhD As the largest integrated delivery system in the world, the VHA provided free or low-cost healthcare to 5.5 million veterans in 2007. The papers presented at this session focused on male patients aged >65 years with cancer diagnosed or their first course of treatment received at the VHA between 2001 and 2004. This cohort was compared with a similar population identified from the Surveillance, Epidemiology, and End Results (SEER) Medicare database, whose regions cover about 25% of the United States. The researchers’ analytic strategy and sensitivity analysis accounted for observed differences seen between the 2 populations (eg, the higher percentage of blacks in the veteran population and a lower median income among veterans’ ZIP codes).

VHA has higher rates of early screening than the private sector.” Dr Keating then compared the VHA and SEER’s propensity scores for standard treatments, including chemotherapy, surgery, radiation, and bisphosphonates for 6 cancer types: colon, small-cell lung, non–small-cell lung, prostate, non-Hodgkin lymphoma (NHL), and myeloma. The results showed the VHA and SEER exchanging the lead position of higher propensity scores for the different procedures. For example, the VHA’s tendency to perform curative surgery for non–small-cell lung cancer was 60.2% versus 65.6% for SEER. Conversely, the propensity score of CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], and prednisone/prednisolone) treatments to diffuse large B-

cell NHL at the VHA was 71.2% versus 60.7% for SEER. Taking a closer look at instances when the VHA did not appear to perform as well as the private sector, Dr Keating’s team adjusted for unobserved factors, such as the higher smoking rate, lower education level, and more severe comorbidities that veterans are known to have. “If we account for the severity of comorbid illness within the VA population, particularly with chronic obstructive pulmonary disease, we see the differences in treatment erased, or even reversed,” she said. Is Aggressive End-of-Life Care Better? Treatment of older patients with cancer at the end of life has become increasingly aggressive over time, despite the absence of evidence that aggressive care at the end of life is associated with better outcomes, according to a second paper presented by Dr Keating, entitled “Cancer Care at the End of Life in the VHA Versus the Private Sector.” Dr Keating’s team looked at 3 measures of end-of-life care for stage IV colorectal and lung cancer: chemotherapy within 14 days of death, admission to the intensive care unit in the last month of life, and >1 emergency department visit in the last month of life. The VHA had a lower propensity score for all 3 measures, but Dr Keating postulated that this may not necessarily be a bad thing. “These are indicators for care that are not Continued on page 21

VALUE-BASED CANCER CARE

September 2010

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ACADEMYHEALTH CONFERENCE

Comparing VHA with Fee-for-Service... potentially useful,” she said. “These lower rates are probably better, although there are some that might argue that.” Dr Keating surmised that the VHA is less aggressive with end-oflife care perhaps “due to the absence of financial incentives for end-of-life measures, or the integrated delivery system may be better structured to limit potentially futile medical care.”

Dr Keating proposed that “large capital outlay may not translate to better survivability. Comparative effectiveness can provide some good data to determine the better route.” ■

Continued from page 20

Reference 1. Keating NL, Landrum MB, Lamont EB, et al. Endof-life care for older cancer patients in the Veterans Health Administration versus the private sector. Cancer. 2010;116(15):3732-3739.

“Large capital outlay may not translate to better survivability. Comparative effectiveness can provide some good data to determine the better route.” —Nancy Keating, MD, MPH These end-of-life care statistics do not appear to jeopardize survival at the VHA. Mary Beth Landrum, PhD, presented research indicating that survival for older men with colorectal or lung cancer was comparable or better at the VHA when weighed against the private sector.1 However, Dr Landrum acknowledged, “We don’t really understand the relationship between aggressive end-oflife care and patients’ preferences. Ongoing work is looking at that.” When asked how their studies’ results may impact the larger world of cancer care, Dr Landrum suggested that “the VHA’s less-aggressive care for advanced cancer should be considered for healthcare reform.” Citing the VHA’s quick uptake of expensive medicinal options (eg, rituximab-CHOP chemotherapy) versus its slower implementation of complex equipment that requires highly trained workers (eg, 3dimensional conformal radiotherapy and intensity-modulated radiotherapy),

at a glance The VHA often has higher rates of early cancer screening than the private sector Apparent poorer outcomes for some measures in the VHA versus private plans disappeared when severity adjustments were made End-of-life care in the VHA system is often less aggressive, but this did not seem to impact survival

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CONTINUING EDUCATION

The Evolving Role of Managed Care Pharmacists in Value-Based Benefit Design: Strategies for Clinical and Economic Success This CE activity is based on a satellite symposium held in conjunction with the Academy of Managed Care Pharmacy’s 22nd Annual Meeting and Showcase, April 7-10, 2010.

TARGET AUDIENCE

PROGRAM P10024

LEARNING OBjECTIVES

Initial Release Date: September 15, 2010 • Expiration Date: September 15, 2011. Estimated time to complete activity: 1 hour. SPONSOR

This activity is jointly sponsored by Medical Learning Institute, Inc. (a nonprofit medical accreditation company), and Center of Excellence Media, LLC.

This activity was developed for oncology pharmacists and other healthcare professionals. Upon completion of this activity, the participant will be able to: • Describe how a well-planned value-based benefit design can provide oncology patients improved outcomes with few barriers. • Illustrate how nontraditional outcome measures, such as quality adjusted life-years, can play a role in developing value-based benefit designs for oncology drugs • Discuss strategies for overcoming barriers to implementing clinical pathways

Value-Based Oncology Benefits By Michael Jacobs, RPh

alue in healthcare is defined as health outcome/dollar of cost expended.1 From a payer’s perspective, this simply means that if more resources are expended, improved health outcomes should follow within a reasonable time period. Likewise, if consistently good health outcomes can be achieved by investing a predictable amount of resources (ie, by following a narrow clinical pathway to treat a given disease or condition), payers will attempt to establish a benefit design and cost-sharing philosophy that provides those outcomes with as few barriers as possible to patients and caregivers. Several steps must be taken in the healthcare system to provide value-based benefits in oncology. These include: Michael Jacobs, RPh, is national clinical practice leader for Buck Consultants, LLC, A Xerox Company, Atlanta, GA.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc. INSTRUCTIONS FOR CREDIT

There is no fee for this activity. After reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/10024.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

• Designing benefits that arrange costsharing based on the weight of scientific evidence • Selecting networks and providers based on historic performance and delivery of desired health outcomes at financially acceptable levels • Providing recognition (ie, compensation) for high-performing components of the healthcare system.2

Designing benefits that align the interests and incentives of all parties in oncology care is no simple task. Designing benefits that align the interests and incentives of all parties in oncology care is no simple task. This is partly because a number of payers do not know where, or how much, they are spending for many of these therapies.3 Some payers cover oncology therapies in the medical benefit, some cover them in the pharmacy benefit, and still others are paying for them through a coding system (J codes) that does not identify the specific therapies administered to

for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-10-027-HO1-P. For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc, at 609-333-1693 or cgusack@ mlicme.org. DISCLOSURES

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions.

PHARMACISTS’ DESIGNATION

Medical Learning Institute, Inc, is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides

the patients, instead listing only the charges for these therapies. Along with these billing options, today’s patients have more choices of where to receive oncology therapies. These drugs can be provided through a hospital setting, a physician’s office, an infusion center, a specialty pharmacy provider, or a local pharmacy provider, just to name a few.

• Michael Jacobs, RPh, has nothing to disclose. • Bruce A. Cutter, MD, MMM, is on the speaker’s bureau for Pfizer.

Managing Complex Care With more than 800 new oncology pharmaceutical drug entities in development, and many of these classified as specialty medications,4 cost is becoming an increasing concern for payers. It is estimated that as many as 400 of these new therapies could cost in excess of $50,000 per course of therapy, which raises the following question for many payers: will the health outcomes produced by these expensive medica-

• Kavita V. Nair, PhD, is a consultant and researcher for Centocor and a researcher for Amgen, Novartis, and Daiichi Sankyo. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Trade names used in this supplement are for the learner’s reference only. No promotion of or bias toward any product should be inferred.

tions justify the added investment? Payer concerns regarding health outcomes and healthcare costs have led many to accept the concept that following evidence-based, consensus-driven treatment protocols and pathways may be the most appropriate way to go, especially in oncology. This approach allows payers and clinicians to collect data, compare results, and identify potential care improvements as physicians begin prescribing new agents, as well as to begin achieving therapeutic predictability. With this collected information, payers can better plan benefits and share costs; identify the highest quality providers, provider networks, and distribution channels; and reward these high-quality providers for their efforts. But payers, physicians, and patients also need to move beyond these efforts. Concerns have been raised about how to determine, with a reasonable certainty, that a given therapy will produce a positive result in a particular patient. The opposite is also true—how do we identify the patients in whom a given therapy will not produce the desired results? In some cases, pharmacogenomics can play a role. For example, women with certain breast cancer tumors possessing a genetic variant that causes overexpression of the HER2 protein will benefit if trastuzumab is part of their therapeutic regimen.5 On the other hand, women with estrogen receptornegative/progesterone receptor-negative (ER-/PgR-) tumors will not benefit from endocrine therapy, such as tamoxifen.6 Another example of the benefit of pharmacogenetics has recently been evidenced in multiple myeloma. Even as the ability of bortezomib therapy to overcome the high-prognostic risk associated with a deletion of chromosome 13 has been relatively well documented, several studies suggest that patients who have this deletion do not benefit from thalidomide.7-10 As more information is gained regarding the molecular Continued on page 23

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Value-Based Oncology... pathogenesis of cancer and more targeted therapies are developed, the pharmacogenomics industry will continue to develop tests to identify patients that will benefit (or not benefit) from these agents. Pharmacogenomic tests promise better targeting of care, but are also indicative of how complex cancer care has become. Aside from complicating the practices of pharmacy and medicine, pharmacogenomics raises questions regarding how best to manage these therapies, given the involved laboratory testing, physician input, and specialty pharmacy distribution of the drug component of therapy. In addition, ancillary services, such as support for caregivers, emotional support, and financial considerations, may be beyond the primary insurance coverage. One patient care management model

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being discussed (and in some cases, put into practice) by payers is the medical home. With this approach, pharmacologic therapy is provided by the lowestcost provider, the oncologist provides the medical component of therapy, and a case management firm coordinates between these providers while also involving home caregivers to ensure emotional support for those who need it. For this approach to be successful, however, the healthcare system will have to evolve and will require an integrated health record, among other resources. A Vision of the Future For payers to provide these new oncology technologies and therapies effectively and appropriately, they will have to make increased demands on providers that will impact all aspects of oncology treatment. Payers may insist

that newly introduced therapies have solid outcomes data and predictable results for specific disease and tumor types before they will be fully reimbursed. This requirement may be accompanied by required pharmacogenomic tests (with the accompanying expense of these tests). Total patient management will be in greater demand, and a leveling of the playing field for distribution channels is expected, so that “gaming” of the system will be eliminated. Benefit designs that foster a patient’s preventive activities will become more common, with barriers to prevention and wellness being removed from healthcare benefits. Lastly, the use and acceptance of clinical pathways will become a standard component of oncologic therapies. ■ References 1. Porter ME, Teisberg EO. Redefining Health Care: Creating Value-Based Competition on Results. Boston, MA: Harvard Business School Press; 2006. 2. National Business Group on Health. Evidence-

based benefits: a strategic checklist for employers. Washington, DC; 2007. www.businessgrouphealth.org/ login.cfm?destinationURL=%2Fmembers%2FsecureD ocument%2Ecfm&destinationParms=docID%3D825. (password protected site). Accessed August 18, 2010. 3. Buck Consultants. Second Annual Prescription Drug Benefit Survey. San Francisco, CA; 2009:33. 4. Pharmaceutical Research and Manufacturers of America. 2009 Report Medicines in Development for Cancer. www.phrma.org/files/attachments/09-046 PhRMACancer09_0331.pdf. Accessed August 18, 2010. 5. Herceptin [package insert]. South San Francisco, CA: Genentech, Inc; 2009. 6. Dowsett M, Houghton J, Iden C, et al. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol. 2006;17(5):818-826. 7. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21:151-157. 8. Sagaster V, Ludwig H, Kaufmann H, et al. Bortezomib in relapsed multiple myeloma: response rates and duration are independent of a chromosome 13q-deletion. Leukemia. 2007; 21:164-168. 9. Attal M, Harousseau J-L, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 10. Sahebi F, Speilberger R, Kogut NM, et al. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Mar Transpl. 2006;37:825-829.

Defining Value in Oncology By Kavita V. Nair, PhD

variety of strategies—including value-based benefit design, payment reform, and comparative effectiveness research (CER)—are being used by payers, providers, and employers to address the central issue of value in healthcare. In general, healthcare value can be defined as “improving the net ratio of benefits obtained per dollar spent on healthcare”1; when attempting to define value for specific disease states, oncology has been largely ignored. Under healthcare reform, however, the provision of healthcare is now a mandate, with employers required to provide health insurance, payers required to cover all individuals, and consumers required to purchase health insurance or face financial penalties. This legislation has therefore triggered an urgent need to find ways to define value in oncology for several key reasons. First, there are substantial costs associated with treating an oncology patient. A recent study of multiple myeloma costs showed that the direct medical costs for 1 therapeutic course of bortezomib, bortezomib plus doxorubicin, thalidomide plus low-dose dexamethasone, and lenalidomide plus low-dose dexamethasone ranged from $33,966 to $47,002.2 In addition, the management of complications such Kavita V. Nair, PhD is associate professor and director, graduate studies (pharmaceutical outcomes research track) at the School of Pharmacy, University of Colorado, Denver.

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as hypercalcemia, anemia, bone lesions and fractures, and renal failure can themselves be quite high.3 Second, there is an urgency associated with treating oncology patients. The individualized and emotional nature of this disease has resulted in a “one-sizedoes-not-fit-all” approach to how it is currently managed. Oncologists may feel the need to treat patients with the newest (and most expensive) agents

complicated—it is not enough to determine if one drug is better than another; evaluations must consider whether a drug regimen may be superior to an alternative regimen or surgical option. In addition, it is unclear who will bear the cost of these evaluations. Are payers or pharmaceutical manufacturers willing to develop randomized clinical trials to gather evidence of comparative effectiveness or do oncology practices have

The sheer complexity of oncology management has deterred many innovators from pursuing efforts to demonstrate value. that may extend survival for only a few months. The sheer complexity of oncology management has deterred many innovators from pursuing efforts to demonstrate value. The goal of this article is to provide a broad overview on how value can be defined in oncology management. Many Means of Establishing Value One of the first steps in defining value is to conduct CER for drug therapies, technologies, and surgical options. CER compares the benefits, risks, and costs of strategies for the treatment of a specific disease. The Comparative Effectiveness Research Act of 2009 allocated $1.1 billion in preliminary funding, and launches plans for more formal CER.4 Although the high cost of cancer drug therapies and treatment options make this disease area ripe for CER studies, conducting these within oncology poses challenges. The multifaceted therapy options used to treat cancer make CER

to do so within their own individual practices? Related to the issue of gathering CER data is the adoption of practice guidelines for the cost-effective utilization of oncology drugs. The manner in which drug therapies are made available to oncology patients is another defining value issue. Oncology drugs are unique in that both oncologists and pharmacy directors can acquire and dispense the drug. Oncologists employ a “buy-and-bill” approach, whereas pharmacy payers dispense oncology drugs through specialty pharmacies and tiered formularies. Therefore, the 2 common approaches for accessing oncology drugs are through the medical benefit (typically through oncology practices) and through the pharmacy benefit. Each approach has downsides, including increased patient cost-sharing if drugs are purchased through the pharmacy benefit, and possible delayed access to therapy if patients have to wait for their

physicians to acquire their medications. The unique nature of oncology drug management and the dichotomy of this distribution has prompted discussions about newer value-based benefit design options and integrated care models for oncology medication management. Another means of establishing value in oncology management is outcomes measurement. In oncology clinical trials, the primary goal typically is to obtain evidence regarding the benefitto-risk profile of the experimental intervention relative to an existing standard of care. Although the efficacy of oncology drugs has historically been measured by overall survival, surrogate endpoints, such as time-to-progression (TTP) and progression-free-survival have been more frequently utilized over the last decade.5 Other end points, such as tolerability of side effects, patient quality of life, cost effectiveness of drug therapies (ie, quality-adjusted life-years and incremental rate ratios can be utilized before starting treatment to determine the utility of using a new and expensive drug therapy. For example, the VISTA trial compared bortezomib plus melphalan/prednisone (VMP) with melphalan/prednisone (MP) in newly-diagnosed multiple myeloma patients ineligible for stemcell transplant.6 VMP was found to be superior to MP for TTP, the primary endpoint for the trial. VMP also provided a substantial survival benefit. An incremental cost analysis was conducted to compare lifetime health outcomes and cost effectiveness of VMP comContinued on page 24

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CONTINUING EDUCATION

Defining Value in... pared with MP. Although the total lifetime direct medical costs for VMP may be more than twice those for MP, the cost per life-year was approximately 18% less while providing more qualityadjusted-life-years.7 Payment reform in primary care has also been investigated. Pay-for-performance (P4P) models, in which physicians are provided financial incentives for improving outcomes of care, have emerged across the nation. Although these P4P models have traditionally been used in primary care to reward physicians for improving such clinical measures as glycemic control in diabetes, for example, they can also start to be utilized in oncology management. One option under discussion is pre-

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ferred tiered provider networks, wherein providers are rewarded for achieving lower-cost care with better clinical outcomes. P4P options, however, can only be developed in oncology management when there is better evidence about which drug therapy or surgical options provide the best outcomes. Another way of defining value is in the area of cancer prevention. Screening rates for prostate and colon cancer are between 50% and 60% nationwide, well below expected levels. Increasing screening compliance rates has the potential to demonstrate value for employers in terms of early detection, lower direct medical costs, and fewer losses in productivity. Although cancer screening has not

traditionally been a focus for employer prevention efforts (because of the small prevalence of disease), focusing on increasing screening rates for high-risk populations can result in significant medical cost savings and limit productivity losses for employers and payers. Finally, in the oncology value equation, awareness and communication of the true cost of a drug therapy or a procedure and its expected benefits (within the context of costs) for both the practicing oncologist and the patient can help facilitate informed decisionmaking. Understanding the cost-sharing levels a patient may face with a particular drug or procedure, and making that part of the physician–patient discussion, will provide more value in choosing the right option. ■

References 1. Schickedanz A, rapporteur. Assessing and Improving Value in Cancer Care. Workshop Summary. Washington, DC: The National Academies Press; 2009. http:// www.nap.edu/catalog/12644.html. 2. Fullerton DSP, Trautman H, Huang H, et al. A budget impact model comparing resource utilization of four approved therapies for multiple myeloma (MM) in the US. Blood. 2007;110(suppl):abstract 3324. 3. Cook R. Economic and clinical impact of multiple myeloma to managed care. J Manag Care Pharm. 2008; 14(7 suppl):19-25. 4. Available at: http://thomas.loc.gov. 5. Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Aff (Millwood). 2005; 24(1):67-78. 6. San Miguel JF, Schlag R, Khuageva NK, et al; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 7. Wang S-T, Huang H, Shi H, et al. The cost-effectiveness of bortezomib for the initial treatment of multiple myeloma in the United States. Blood (ASH Annual Meeting Abstracts). 2009;114(22):561. Abstract 1379. 8. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System Survey Data. Atlanta, Georgia: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2007.

Putting Multiple Myeloma on the Clinical Pathway By Bruce Cutter, MD, MMM

reatment of multiple myeloma (MM) has evolved rapidly in recent years, from a relatively simple, cheap, and somewhat effective regimen (melphalan hydrochloride and prednisone), to high-dose chemotherapy with autologous stem cell transplantation, to new and more effective agents.1 Although we are now seeing impressive responses and significantly improved survival times, this progress has not come without cost. The newer agents (eg, thalidomide, lenalidomide, and bortezomib) have their own toxicities, and considerable price tags have accompanied treatment advances. In addition, some of these agents are delivered orally, which raises unique issues regarding cost, accessibility, and system that are beyond the scope of this article.

cancer treatments; at its core, the issue is “bang for the buck.” Clinical pathways are an important means of addressing the large value deficit in oncology. Clinical Pathways: Components and Processes At the most fundamental level, clinical pathways represent an agreement by oncologists to treat a patient with a certain disease in a certain way; they are a tool to standardize care and reduce unexplained variation. Clinical pathways hold the promise of helping to drive fundamental change in the current system of oncology care and remedy the existing value deficit. They possess a number of beneficial qualities, including: • Being physician (provider) developed and owned • Being narrowly structured (ie, they are a pathway, not a menu)

Clinical pathways hold the promise of helping to drive fundamental change in oncology care. Looking ahead, we need to understand how best to combine these new agents, among themselves and with older medications, and to determine the role autotransplantation will continue to play. As our understanding of MM’s cellular pathways and molecular genetics continues to improve, additional effective treatments will likely be developed. Along with the clinical challenge presented by MM, today’s clinician also must deal with matters of value and sustainability. Value (defined as quality and outcomes divided by costs) is central to the availability and success of Bruce Cutter, MD, MMM, is a consultant in Spokane, WA.

• Being supportive of clinical research and knowledge advancement (eg, clinical trials are always “on pathway”) • Being based on Institute of Medicine quality principles, including being effective (evidence-based), safe, patient-centered, timely, efficient, and equitable • Having physician accountability as a central component • Having an opt-out (“off pathway”) mechanism to allow for appropriate variation based on clinical needs • Containing an ongoing review process to assist with accountability and to modify treatment as needed • Being transparent and auditable • Addressing both the numerator and

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denominator of the value equation. A clinical pathway for MM (or any other cancer) would be formulated and implemented by a group of oncologists, preferably in collaboration with a health plan, who would look at the evidence for MM treatment and decide, based on clinical outcomes and other patient-centered factors (ie, toxicity and convenience), the most appropriate treatment(s) for the disease. Cost would be considered next, to help determine what treatment(s) are to be “on pathway”; cost, however, never trumps clinical criteria. The pathway would then be adopted by a practice and operationally “rolled out,” with a prospective review mechanism by physician peers to assure compliance and accountability, and to allow for the patient to be treated “off pathway” if clinical circumstances warrant (as reviewed and agreed upon by physician peers). Pathway compliance and the reasons for treating a patient “offpathway” are documented, and retrospective data monitoring takes place to assess pathway appropriateness and accountability. A thorough pathway review is undertaken at least yearly, or more frequently if necessary, to adjust for changes in clinical practice and the literature. The Cancer Care Northwest Pathway Experience In our practice, Cancer Care Northwest, a pharmacy and therapeutics committee is charged with pathway development and physician accountability. The Cancer Care Northwest pathways are part of a larger quality initiative called Foundations of Quality, developed in close collaboration with Premera Blue Cross, a regional

health plan, beginning in 2002. This clinical quality program has been paired with a pay-for-quality contract that created physician incentives and rewards for the value we bring to the table. Explicit in this program’s development was the belief that this model of standardizing care and reducing unexplained variation will enhance the value of care provided to our patients. Although this belief is yet unproved, data in support of this value hypothesis are beginning to appear in the literature. So far, we have developed a “proof of concept,” in which providers and health plans collaborate in a teambased fashion to develop delivery system innovation that promises to enhance patient quality of care, address value, and promote sustainability for the system, the providers, and health plans. Although clinical pathways can help to standardize care and reduce unexplained variation, changes necessary to address the value deficit in oncology will require fundamental culture change for providers and health plans. The major barriers to adoption of pathways and other tools to address the value deficit involve culture, leadership, and change management, not operations. Because pathways are evidence-based, quality-driven, and valuefocused—in addition to being operationally viable and scalable—they speak to the needs and values of both providers and health plans. More importantly they speak to the real needs of patients. ■ Reference 1. Jagannath S, Kyle RA, Palumbo A, et al. The current status and future of multiple myeloma in the clinic. Clin Lymphoma Myeloma Leuk. 2010;10(1):28-43.

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FOCUS ON

New Compounds Hold Promise for Prostate Cancer

To read the VBCC Perspectives on this article, please turn to page 26.

Several options arriving, with some unique mechanisms of action By Caroline Helwick

irtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease (CRPC). Docetaxel, the standard of care for these patients, provides a modest prolongation of survival, but there is an urgent need for novel treatment strategies. Recently, the biological and molecular mechanisms driving prostate cancer growth and progression have become better understood, and this has resulted in widespread clinical testing of numerous new targeted therapies. At least some of these may extend and ideally even save the lives of the 218,000 men who develop this disease annually, some 32,000 of whom will die of prostate cancer under current therapies.1 September is National Prostate Cancer Awareness Month, a time in which cancer organizations emphasize prevention and symptom recognition in the hopes of saving lives. In 2010, the message is also one of therapeutic optimism, as agents capitalizing on unique mechanisms of action begin to enter the marketplace.

Immunotherapy Several forms of immunotherapy made news in 2010, most strikingly the antigen-specific product sipuleucel-T (Provenge; Dendreon Corporation), which became US Food and Drug Administration (FDA)-approved on April 29, 2010, for metastatic CRPC based on survival benefits shown in phase 3 trials. Sipuleucel-T is an active cellular immunotherapy, ie, a type of therapeutic cancer vaccine. It is derived from autologous peripheral blood cells that are collected during leukapheresis to contain only antigen-presenting cells. This product is cultured ex vivo with a recombinant fusion protein containing prostatic acid phosphatase (a prostate antigen) and granulocyte-macrophage colony-stimulating factor to produce the vaccine that is infused into the patient to boost T-cell response against prostate cancer cells. In the phase 3 IMPACT trial, patients receiving the vaccine had a median survival time of 25.8 months and 3-year survival of 32.1%, compared with 21.7 months and 23%, respectively, for patients receiving placebo.2 While this amounted to a 22% relative reduction in risk of death, the vaccine did not delay disease progression, which occurred in approximately 14 weeks in each arm. Treating men with an immunotherapy when they have metastatic and castration-resistant disease is “an uphill

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battle that probably involves barriers that have not yet been defined,” according to Dan Longo, MD, of the National Institute on Aging, who wrote an accompanying editorial to the publication of the IMPACT results. He noted that a 22% reduction in mortality in this challenging group may bode well for use of the drug earlier in the disease, although he felt the lack of an effect on progression is concerning. Benefits to be gained from this drug may become clearer with the final results of the ongoing phase 2 ProACT trial.

durable responses (ie, median time to PSA progression of 71 weeks) in 58% of chemo-naive CRPC patients receiving abiraterone5 and prolonged remissions in patients with <5 circulating tumor cells after 1 month of abiraterone treatment.6 Also showing promise in this class of agents is MDV3100 (Medivation/ Astellas). MDV3100 is a small-molecule androgen receptor antagonist that inhibits androgen receptor function by blocking nuclear translocation of the receptor and DNA binding. The drug’s

In 2010, the message is one of therapeutic optimism, as agents capitalizing on unique mechanisms of action begin to enter the marketplace. Androgen Receptor Targeting Prostate cancer is a hormonally sensitive disease that can be controlled for long periods with androgen-deprivation therapy. The androgen receptor plays a critical role in maintaining the proliferation of prostate cancer cells, not only before androgen ablation but also after hormonal treatments fail. Novel therapeutic strategies aim to inhibit and destabilize the function of this receptor and its interaction with key proteins. Early success with these oral compounds is being observed. Abiraterone acetate (Cougar Biotech/ Johnson & Johnson) is an orally administered small molecule that irreversibly and specifically inhibits cytochrome P17, a key enzyme in the generation of androgens and thus the production of testosterone. Testosterone levels in the testes and adrenals are thought to stimulate the growth of prostate cancer cells. Therefore, by selectively inhibiting the target enzyme, abiraterone consequently blocks testosterone production in both the adrenals and testes and suppresses cancer cell growth. Abiraterone has proven highly active in some men, with responses ranging from 45% in heavily pretreated patients to 75% in patients without extensive secondary hormonal therapy or chemotherapy.3 In a phase 2 trial reported this year by investigators from the United Kingdom, half of the 47 docetaxel-treated patients had ≥50% declines in prostatespecific antigen (PSA), and median time to PSA progression was 169 days.4 One fourth of the patients were still benefiting from the treatment after almost 1 year. Additional studies recently reported at the 2010 meeting of the American Society of Clinical Oncology showed

researchers claim that MDV3100 differs from other antiandrogens in its robust affinity for the androgen receptor and its multifaceted approach to stifling androgen production and activity. It works by 3 complementary actions: blocking testosterone binding to the androgen receptor, impeding movement of the androgen receptor to the nucleus of prostate cancer cells, and inhibiting the binding to DNA. In a recent phase 1/2 trial, more than half the patients with CRPC had ≥50% reduction in PSA, and median time to progression was 47 weeks.7 In addition, 22% of patients had soft-tissue responses and 56% had stabilized bone disease. “We were encouraged to see antitumor activity in men whose disease had spread after either becoming resistant to previous hormone treatments or progressing following chemotherapy,” said the study’s lead author Howard Scher, MD, of Memorial Sloan-Kettering Cancer Center, in a press release. “These findings strengthen the drug’s potential to change the outlook for a group of patients who currently have limited effective treatment options.” MDV3100 is being further evaluated in the 1200-patient AFFIRM trial. Histone deacetylase inhibitors also target androgen receptor activity, and clinical trials are evaluating vorinostat (Zolinza; Merck) and panobinostat (LBH589; Novartis) within this class. New Taxane The FDA recently granted approval to a promising new taxane, cabazitaxel (Jevtana; sanofi-aventis), for the treatment of metastatic CRPC after docetaxel fails. Cabazitaxel works by disrupting the microtubular network that is

essential for mitotic and interphase cellular functions and causes inhibition of cell division and cell death. Cabazitaxel showed a highly significant 30% reduction in mortality over mitoxantrone in the phase 3 TROPIC trial.8 In the final analysis of the study, median overall survival was improved from 12.7 months with mitoxantrone to 15.1 months with cabazitaxel.9 In a press statement, Richard Pazdur, MD, Director of the Office of Oncology Drug Products at the FDA, commented on the potential value of cabazitaxel by stating, “The FDA was able to review and approve the application for Jevtana in 11 weeks, expediting the availability of this drug to men with prostate cancer.” Future studies will evaluate the drug in less-advanced disease. Endothelial Receptor Antagonists Endothelins have been implicated in numerous physiologic and pathologic conditions. In prostate cancer, levels of endothelin-1 are increased, heightening the peptide’s ability to modulate mitogenesis and apoptosis upon binding to the endothelin-A receptor. Endothelin antagonism, therefore, may be useful in that it blocks the activation of endothelin-A and thereby inhibits tumor growth. The investigational oral endothelin receptor antagonists have shown some biologic activity but have not yet improved clinical outcomes in CRPC. In phase 3 trials of atrasentan (Xinlay; Abbott), clinical efficacy was minimal although responses in PSA and other biomarkers were observed.10-11 The phase 3 SWOG S0421 trial is currently investigating docetaxel plus atrasentan. Similarly, zibotentan (AstraZeneca) has been shown safe when coupled with docetaxel in preliminary studies, but clinical efficacy of zibotentan has not yet been established.12 Treatment with zibotentan plus docetaxel is being further evaluated in an ongoing phase 3 program that includes patients with nonmetastatic disease (ENTHUSE M0), asymptomatic metastatic CRPC (ENTHUSE M1), and symptomatic metastatic CRPC (ENTHUSE M1C). ■ References 1 . National Institutes of Health. Prostate Cancer. http://www.cancer.gov/cancertopics/types/prostate. Accessed August 19, 2010. 2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 3. Ryan CJ, Rosenberg J, Lin A, et al. Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer. Presented at the 2007 American Society of Clinical Oncology Prostate Cancer Symposium. Abstract 278.

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VBCC PERSPECTIVES

The $93,000 Question

By Yu-Ning Wong, MD, MSCE

ipuleucel-T (Provenge) and cabazitaxel (Jevtana) have drawn much attention both for being the first new treatments for advanced prostate cancer since docetaxel (Taxotere) was approved in 2004, and for their high costs. As described in Dr Newcomer’s accompanying piece, they will add significantly to the cost of care for prostate cancer patients. Ironically, although $93,000 for a course of sipuleucel-T and $8000 per dose of cabazitaxel seem high, these figures aren’t completely surprising when placed in the context of new therapies that have been approved in recent years for other disease sites. In many ways, we are victims of our own success. We now talk about cancer as a “chronic disease,” where patients are sequenced through multiple different therapies. With each FDA approval, there is a new “line” of therapy. For example, there have been 6 new agents approved for advanced renal cell cancer since late 2005, of which several cost $8000 to $10,000 per month. This does not include surveillance blood work, supportive care medications, or other treatment-related costs. Therefore, even though we don’t spend the whole Yu-Ning Wong, MD, MSCE, is assistant professor, Fox Chase Cancer Center and adjunct senior fellow, Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA and an editorial board member for Value-Based Cancer Care.

$93,000 price tag up front, we can easily approach that with several months. The survival benefit for each individual treatment is often modest (generally between 2-4 months), but the additive benefits resulting from this “daisy chain” fashion has lead to the significant improvement in survival for many advanced cancers. For example the life expectancy of patients treated with sequential new therapies for advanced colorectal cancer now exceeds 2 years; prior to 1996 there was only 1 active agent and life expectancy for these patients was only about 12

tions, supportive care drugs, imaging studies, and doctors’ visits. It places patients in the impossible position of having to make complex financial decisions alongside medical ones. Oncologists are trained to counsel patients about risks and benefits, including treatment-associated survival improvements and toxicities. However, even as we are encouraged to promote “shared decision-making,” physicians are ill prepared to add the “cost and value” dimension to these discussions. Framing these issues in the context of median- and long-term survival rates

Even as we are encouraged to promote “shared decisionmaking,” physicians are ill prepared to add the “cost and value” dimension to these discussions. months. As a practicing physician, I know of many patients who have benefited from these treatments; although many have died, I believe that they lived longer than they would have without these new drugs. Many continue to work and care for their families. These are the successes that keep me and other oncologists motivated to continue to take care of patients with incurable diseases. However, is making available every possible treatment for every patient “worth it?” It was easy when the economy was doing well. However, it’s the $93,000 question that has drawn a great deal more attention as the economy worsens. The current system is terribly broken. It allows well-insured patients access to the most expensive therapies but implicitly rations care to patients who are uninsured or underinsured. Many patients are facing increased cost-sharing for anticancer medica-

is nearly impossible. (Imagine asking “Would you spend your child’s college savings for a 15% chance that you’ll be alive in 2 years to see him graduate from high school?”) As a society, we need to have an uncomfortable discussion about how we will address these issues. Although insured patients rarely face the full cost of care, we all pay for these treatments through taxes and premiums. As long as we have publicly funded insurance and share risk with our colleagues through employer-sponsored commercial insurance plans, these should be shared discussions as well. Instead of asking an individual what she is willing to pay for care, we should be asking as a society what we are willing to sacrifice to make the newest treatment available. Are we willing to pay more in taxes and premiums? Are we willing to cut coverage for other services? Are we willing to ask

investors to accept lower profits as a result of lower prices? Are we willing to ask doctors and patients to go through more bureaucratic hurdles to ensure that these resources are used for those who are most likely to benefit? I doubt that the United States will go the way of the United Kingdom’s National Health Service, which has made the difficult decision to refuse to adopt certain cancer treatments due to their high cost and modest efficacy. However, there are other things we can do to better define the “value” of the treatments we are prescribing. As discussed in 2 recent editorials,1,2 we need to improve our clinical trial process to identify which drugs have the best chance of helping patients. In addition, we must do a better job in the postapproval setting of collecting data about the efficacy and toxicity of these new drugs. Although most are approved based on their first- or secondline data, many have broad indications and are often used in patients who have been heavily pretreated. Since only 5% of patients enroll in clinical trials, most patients receive costly and toxic therapy of unknown benefit for which little, if any primary data are collected to further clarify the treatments’ risks and benefits for future patients. I am curious to see how American insurers and policymakers will address the $93,000 question. While sipuleucelT may be the most costly example to date, it should be seen as the treatment that has forced this conversation, not as an exception. ■ References 1. Young RC. Cancer clinical trials—a chronic but curable crisis. N Engl J Med. 2010;363(4):306-309. 2. Dilts DM. Early warning: an ailing canary in the mine. J Clin Oncol. 2010;28(24):3799-3800.

New Prostate Cancer Therapies Raise New Issues By Lee Newcomer, MD

cost $93,000 for the 3 required infusions and cabazitaxel is priced at $8000 per infusion. To put this in perspective, the

rostate cancer patients have 2 new therapeutic options this summer with the approvals of sipuleucel-T and cabazitaxel. The former drug is an important scientific advance as one of the pioneering cancer vaccines to show a prolongation of survival. The latter is not a new scientific breakthrough, but it does offer another option for patients who have failed docetaxel. Both drugs, however, spotlight the Lee Newcomer, MD, is business leader, oncology services, for United Healthcare, Edina, MN and an editorial board member for Value-Based Cancer Care.

Is that fair value? That decision is one for society to debate and decide. In the interim everyone will pay for the

Using the therapy for patients who do not meet the precise indications is simply conducting a $93,000 clinical trial with 1 subject.

unsolved flaw in our national healthcare policy. The nation has not decided how much it is willing to pay for an additional year of life. Sipuleucel-T will

VALUE-BASED CANCER CARE

September 2010

average total cost of care for a prostate cancer patient at United Healthcare from diagnosis to death is $67,254. Treatment with just these 2 new drugs will increase the total cost of care by 210%. For that increased expenditure, those few patients fortunate enough to get a response would gain an additional 6.5 months of life.

indecision with higher taxes and a higher premium for privately insured patients. Failing to address the issue is simply not sustainable. In the interim, clinicians can help by being responsible stewards as they consider these therapies for patients. Sipuleucel-T was tested on a highly Continued on page 27

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New Prostate Cancer Therapies... selected group of patients with a hormonally resistant disease, no visceral involvement, no opioid usage for 6 months, no chemotherapy for 3 months, opioid and an ECOG performance status of 0 or 1. The current manufacturing shortage will restrain off-label usage this year. Next year will be more challenging as the therapy becomes widely available. Using the therapy for patients who do not meet the precise indications is simply conducting a $93,000 clinical trial with 1 subject. It would be a waste of precious resources. Second, patients should be monitored closely for progression with cabazitaxel therapy. It’s not often that insurers call for more testing, but at $8000 per treat-

ment, a radiologic examination is an inexpensive way to ensure that the next treatment course is indicated. Finally, these 2 drugs raise the question of regulation for pharmaceutical

Continued from page 26 pricing. There is no competition for these products and the manufacturers are free to set any price they desire. In a free market where the patient was deciding how to spend his own money,

this would be a fair practice. In today’s system, however, patients make the decision with the public’s money. Perhaps the public should decide what constitutes a fair price. ■

FOCUS ON

New Prostate Cancer Therapies... Continued from page 25 4. Reid AHM, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28: 1489-1495. 5. Ryan CJ, Smith MR, Logothetis C, et al. Median time to progression in chemotherapy-naïve patients with castration-resistant prostate cancer treated with abiraterone acetate and low-dose prednisone. Presented at the 2010 American Society of Clinical Oncology. Abstract 4671. 6. Danila DC, Anand A, Sung CC, et al. Molecular profiling of circulating tumor cells in patients with castrate metastatic prostate cancer receiving abiraterone acetate after failure of docetaxel-based chemotherapy. Presented at the 2010 American Society of Clinical Oncology. Abstract 4635. 7. Sher HI, Beer TM, Higano CS, et al. Antitumor activity of MDV3100 in castration-resistant prostate cancer: a phase I-II study. Lancet. 2010;375:1437-1446. 8. Sartor AO, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: final results of a multinational phase 3 trial (TROPIC). Presented at the 2010 Genitourinary Cancers Symposium. Abstract 9. 9. De Bono JS, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). Presented at the 2010 Annual Meeting of the American Society of Clinical Oncology. Abstract 4508. 10. Michaelson MD, Kaufman DS, Kantoff P, et al. Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer. 2006;107:530-535. 11. Nelson JB, Love W, Chin JL, et al. for the Atrasentran Phase 3 Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-1966. 12. Trump DL, Payne H, Miller K, et al. Phase I study of the specific endothelin A receptor antagonist zibotentan combined with docetaxel in patients with metastatic castration-resistant prostate cancer: assessment of efficacy, pain, and safety. Presented at the 2010 American Society of Clinical Oncology. Abstract 4664.

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Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

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