SEPTEMBER 2010 | VOL 1 | NO 4

Cost-Effectiveness in the NewComparative Effectiveness LandscapeAfter some setbacks, now what?

REMS Regulation Provokes Angerin Provider CommunityPublic FDA meeting addresses concerns

©2010 Engage Healthcare Communications, LLC

Continued on page 20

Continued on page 5

Continued on page 12Comparative Effectiveness Researchin Oncology Is High PriorityGoal is to reflect care in real-world setting

By Wayne Kuznar

Chicago, IL—Oncology has been iden-tified as a high-priority area for com-parative effectiveness research (CER),given the accelerating pace of diagnos-tic and therapeutic interventions andthe often high costs attached to theseinterventions. CER in oncology was thesubject of a well-attended symposiumat the 2010 ASCO meeting.

The goal of CER is to reflect care inthe real-world setting, said Gary H.Lyman, MD, professor of medicine and

director of health services, effective-ness, and outcomes research in oncolo-gy, Duke Comprehensive CancerCenter, Durham, NC. This means goingbeyond the confines of study popula-tions to the broader context of real-lifeclinical practice.

The toolbox for comparative effec-tiveness contains randomized con-trolled trials (RCTs), which are consid-ered the gold standard of CER, as wellas systematic reviews and meta-analy-ses of RCTs. However, because mostclinical questions in oncology have not

By Margot J. Fromer

Silver Spring, MD—Risk Evaluationand Mitigation Strategies (REMS) arerequired from some drug manufactur-ers as part of a new US Food and DrugAdministration (FDA) regulation de -signed to draw the attention of spon-sors, providers, and patients to the like-lihood of severe adverse eventsaccompanying certain drugs and bio-logic 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 sideeffects

• When new safetydata are avail able

• If the drug or bio-logic agent is a newmolecular entity.Although the can cer community is

affected by REMS to the greatest extent,no one is pleased to be further entangledin government red tape. Negative reac-tions to REMS have been many andloud; therefore, the FDA held a meetingto address questions and concerns onJuly 27 and 28 at its Silver Spring, MD,headquarters.

The 250 attendees represented awide range of those affected—drugmanufacturers (also called “sponsors”under the legislation), providers, pro-fessional societies, and patient advoca-cy groups. The consensus was that

www.ValueBasedCancer.com

IN THIS ISSUE

SEPTEMBER 2010 VOL 1 NO 4

By Cherie Dewar

Boston, MA—Cost-effectiveness canstill add value in the comparative effec-tiveness landscape without it becomingwoven into the politically caustic con-cept of healthcare allocation, accordingto 4 experts from academia, industry,and governmental agencies. The futureof cost-effectiveness in the larger uni-verse of comparative effectivenessresearch in a post–healthcare reformworld was debated during a round-table discussion at the Acad emyHealthconference in Boston.

A Suddenly Toxic Methodology

Steven Pearson, MD, president andfounder of the In stitute for Clin ical and

Economic Re view,Harvard Me di calSchool, Bos ton,MA, noted therestrictions placedon the use of cost-effectiveness dur-ing the healthcarereform debate.“Wow, cost-effec-tiveness really took an arrow to theheart,” Dr Pearson said. As stated bythe new independent, non gov -ernmen tal Pa tient-Centered Out comesResearch Insti tute, healthcare policycannot “develop or use dollars perquality-adjusted life-year as a thresh-old to establish what type of healthcareis cost-effective or recommended.”

By Charles Bankhead

Chicago, IL—Taking part in clinicalresearch poses administrative, logistic,and financial challenges to communityoncology practices, but also presentsthese organizations with opportunitiesfor a more active role in shaping patientcare. There fore, community practicesthat venture into clinical research shouldstrive to follow emerging guidelinesaimed at establishing exemplary clinicaltrial sites, according to speakers at anAmerican Society of Clinical Oncol ogy

(ASCO) educationprogram.

Considerationsinvolved in devel-oping an exempla-ry research site in -clude the following:• Structuring and marketing a pro gram

for success• Organizing a team that recognizes its

critical role in the program’s success• Knowing the costs to bud get effective-

ly and negotiate contracts.Community oncology practices have a

vested interest in participating in clinicalresearch, according to Robin Zon, MD, a

Continued on page 8

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

Robin Zon, MD

Janet Woodcock, MD

To read the VBCC Perspective onthis story, please turn to page 9.

Fostering Clinical Research in the Community Setting

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

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

STARTS STRONG. LASTS LONG.

Proven CINV prevention in a single IV dose Powerful CINV prevention in the fi rst 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

Lasts long against nausea following moderately emetogenic chemotherapy3

Powerful acute CINV prevention following highly emetogenic chemotherapy4

Eisai offers a variety of support programs and resources

IndicationALOXI® (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

of its components

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 fi le. 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.

September 29-October 2 27th National Oncology EconomicsConference, St. LouisContact: Association of CommunityCancer Centers, 11600 Nebel Street, Suite201, Rockville, MD 20852Phone: 301-984-9496, ext. 219 [email protected].

September 30-October 3Third AACR Conference on The Science

of Cancer Health Disparities inRacial/Ethnic Minorities and theMedically Underserved, Miami, FLContact: AACR, 615 Chestnut Street, 17thFloor, Philadelphia, PA 19106. 215-440-9300or [email protected].

October 1-29th International Kidney CancerSymposium, ChicagoContact: Kidney Cancer Association, PO

Box 96503, Washington, DC 20090. 800-850-9132 or [email protected].

October 1-32010 Breast Cancer Symposium,National Harbor, MDContact: The American Society for ClinicalOncology, 2318 Mill Road, Suite 800,Alexandria, VA 22314. 571-483-1300 orhttp://breastcasymposium.org/Home.aspx.

October 1-42010 iSBTc Annual Meeting,Washington, DCContact: International Society forBiological Therapy of Cancer, 555 EastWells Street, Suite 1100, Milwaukee, WI53202. 414-271-2456 or [email protected].

October 8-9NCCN 5th Annual Congress:Hematologic Malignancies, New York, NYContact: National Comprehensive CancerNetwork, 275 Commerce Dr, Suite 300,Fort Washington, PA 19034. 866-788-NCCN (6226) orhttp://www.nccn.org/about/emailform.asp?department=meetings.

October 8-9Personalized Cancer Therapy andPrevention, HoustonContact: The University of Texas M. D.Anderson Cancer Center CME/Conference Services,Unit 1381, PO Box 301439, Houston, TX77230. 713-792-2223 or [email protected].

October 8-1235th ESMO Conference, Milan, ItalyContact: ESMO Head Office CongressDepartment, Via Luigi Taddei 4, CH-6962Viganello-Lugano, Switzerland. +41 (0)91 973 19 26 or [email protected].

October 18-20ASCO-NCI-EORTC Annual Meeting onMolecular Markers in Cancer,Hollywood, FLContact: ASCO, 2318 Mill Road, Suite 800,Alexandria, VA 22314. 571-483-1351 orwww.molecularcameeting.org

October 19-20ECRI Institute’s 17th Annual Conference:Personalized Medicine and ComparativeEffectiveness, Bethesda, MDContact: ECRI. 610-825-6000 orhttp://conferences.thehillgroup.com/CERandPMconference/registration.cfm

October 20-23Southwest Oncology Group Annual FallMeeting, ChicagoContact: SWOG, 14980 Omicron Drive,San Antonio, TX 78245. 210-677-8808 orwww.swog.org.

October 21-22AICR Annual Research Conference onFood, Nutrition, Physical Activity andCancer, Washington, DCContact: American Institute for CancerResearch, 1759 R Street, NW, Washington,DC 20009. 800-843-8114 or [email protected].

October 24–27The 32nd Annual Meeting of the Societyfor Medical Decision Making, Toronto,Ontario, CanadaContact: The Society for Medical DecisionMaking, 390 Amwell Road, Suite 402,Hillsborough, NJ 08844. 908-359-1184 [email protected].

October 27-30Colorectal Cancer: Biology to Therapy,PhiladelphiaContact: AACR, 615 Chestnut Street, 17thFloor, Philadelphia, PA 19106. 215-440-9300or [email protected].

October 31-November 4American Society for RadiationOncology Annual Meeting, San DiegoContact: ASTRO, 8280 Willow OaksCorporate Drive, Suite 500, Fairfax, VA22031. 703-502-1550 or www.astro.org

MEETINGS CALENDAR

3VOL. 1 NO. 4 www.ValueBasedCancer.com I

ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Chemotherapy-Induced Nausea and VomitingALOXI is indicated for:

DOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and Vomiting

Instructions for I.V. Administration

CONTRAINDICATIONS

[see Adverse Reactions (6) ]

WARNINGS AND PRECAUTIONSHypersensitivity

ADVERSE REACTIONS

≥

Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

Postmarketing Experience

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONSPregnancy

Labor and Delivery

Nursing Mothers

Pediatric Use

Geriatric Use

≥

≥ ≥

≥

Renal Impairment

Hepatic Impairment

Race

OVERDOSAGE

PATIENT COUNSELING INFORMATION FDA-Approved Patient Labeling (17.2) in

Instructions for Patients

see Adverse Reactions (6)

ALOXI®

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(N=194)

4 I VALUE-BASED CANCER CARE I September 2010 VOL. 1 I NO. 4

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Directors, Client ServicesJohn [email protected]

Phil [email protected]

Cristopher [email protected]

Editorial DirectorDalia [email protected]

Managing EditorColin [email protected]

Senior Production ManagerRobyn Jacobs

Business ManagerBlanche Marchitto

September 2010 Vol. 1 No. 4

VBCC Editorial Board

Mission StatementValue-Based Cancer Care provides a forum for payers,providers, and the entire oncology team to considerthe cost-value issues particular to cancer treatments.This unique focus is achieved through news coveragefrom major hematology/oncology meetings and thecancer literature, supplemented with commentariesand perspectives from those involved in evaluatingtherapies, treating patients, and paying for care.

BPA Worldwide membership applied for August 2010.

Contact Information:For subscription and reprint information please contact: [email protected]: 732-992-1538 Fax: 732-992-1881

Permission requests to reprint all or part of any articlepublished in this magazine should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881.

Address all editorial correspondence to: [email protected] Telephone: 732-992-1536 Fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 6 times ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2010 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a trademark of EngageHealth care Communi cations, LLC. No part of thispublication may be reproduced or transmitted in anyform or by any means now or hereafter known, elec-tronic or mechanical, including photocopy, record-ing, or any informational storage and retrieval sys-tem, without written permission from the publisher.Printed in the United States of America.

The ideas and opinions expressed in Value-BasedCancer Care do not necessarily reflect those of theeditorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Cancer Care should not beconstrued as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the editorsnor the publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGEOF ADDRESS should be directed to CIRCULA-TION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIP-TION RATES: One year: $99.00 USD; Two years:$149.00 USD; Three years: $199.00 USD.

Bruce A. Cutter, MD, MMMCancer Care NorthwestSpokane, WA

Craig Deligdish, MDFlorida Comprehensive Cancer NetworkMelbourne, FL

Peter G. Ellis, MDUniversity of Pittsburgh School ofMedicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDITA PartnersPhiladelphia, PA

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and the American Enterprise InstituteNew York, NY

David Hom, MBASoluciaFarmington, CT

Philip E. Johnson, MS, RPh, CPhH. Lee Moffitt Cancer CenterTampa, FL

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhRegence Blue Cross Blue Shield of OregonPortland, OR

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Ed Pezalla, MD, MPHAetna Pharmacy ManagementHartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM. D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHFoley HoagWashington, DC

Brian K. Solow, MD, FAAFPPrescriptionSolutionsIrvine, CA

G. Rhys Williams, ScD, MSAmgenThousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSBioPharma Partners, LLCNew York, NY

Value Propositions

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

Determining the Value of CTC Screening forColorectal Cancer

Initial Prostate Cancer Treatment ChoiceImpacts Long-Term Costs

VBCC Perspective

9 Community Trials Essential to BroadKnowledge / Ed Pezalla, MD, MPH

ASCO Conference

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

Bevacizumab Cost-Effectiveness “in Line” with Other Therapies

Greater Role for Pharmacogenomics Ahead

11 ASCO Weighs in on CER

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

Technology Assessment

19 Does Robotic Surgery Make the Cut?

AcademyHealth Conference

20 Comparing VHA with Fee-for-Service Cancer Care

Continuing Education

22 The Evolving Role of Managed CarePharmacists in Value-Based Benefit Design:Strategies for Clinical and Economic Success

Focus On

25 New Compounds Hold Promise for Prostate Cancer

VBCC Perspectives

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

New Prostate Cancer Therapies Raise NewIssues / Lee Newcomer, MD

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 CancerTherapies Raise New Issues,” page 26

TABLE OF CONTENTS

been the subject of RCTs, the toolboxalso includes cohort studies; popula-tion studies; prognostic and predictivestudies; and modeling approaches.

Even RCTs have limitations for use incomparative effectiveness, Dr Lymansaid, because they are often short termand use surrogate efficacy outcomes;they have a limited sample size; a dura-tion of follow-up too short to addressimportant safety and toxicity questions;and they frequently exclude patientswith major but common comorbidities.

Clinical decision models (eg, Mar -kov models) are increasingly beingused as reasonable estimates of com-parative effectiveness, he said. Suchmodeling studies have the advantageof comparing efficacy over a range ofassumptions and can provide meas-ures of incremental effectiveness thatreflect quality of life and costs.

Imaging in cancer is in the top quar-tile of the 100 Institute of Medicine pri-ority topics for CER. The use of diag-nostic imaging in cancer care hasincreased by 40% to 50% per year since1999, said Neal J. Meropol, MD, chief,division of hematology/oncology,University Hospitals Case MedicalCenter and Case Western ReserveUniversity, Cleveland, OH.

Other priority needs for CER in can-cer screening and prevention aremolecular risk stratification, prescreen-ing molecular tests, risk modifiers, andthe optimal frequency of diagnostic

testing. Gene profiling also has takencenter stage of late and representsanother area that is ripe for CER.

“What we need are models that inte-grate clinical and molecular risk assess-

ment,” said Dr Meropol. Treatment must include more re -

search on adjuvant therapy decisions,selection of treatment intensity, and bet-ter knowledge on the best time to

change treatments. Obtaining supportfor many of the treatment studies “isdifficult when competing treatmentsare marketed by different entities,” he

Comparative Effectiveness Research... Continued from cover

ASCO CONFERENCE


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

First- and every-cycle Neulasta® achieved:

� 94% reduction in febrile neutropenia

(17% placebo vs 1% Neulasta®; P < 0.001).1,2

� 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 InformationDo 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. MC49047-A-1 04-10 www.neulasta.com

Continued on page 6

at a glanceComparative 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

“What we need are modelsthat integrate clinical andmolecular risk assessment.”

—Neal J. Meropol, MD

ASCO CONFERENCE


said, calling for more publicly fundedphase 3 trials in cancer research.

Alternatives to “Traditional” Studies

Katrina Armstrong, MD, associate di -

rector, outcomes and delivery research,Abramson Cancer Center, University ofPennsylvania, Phila delphia, elaboratedon alternatives to RCTs for conductingCER, focusing on observational studies

with the use of propensity scoring orinstrumental variable analysis, and evi-dence synthesis using decision analysis.

Propensity scoring is a method toadjust for differences between treat-

ment groups, and as such “can address90% of the bias in observational data,”she said. One example of using propen-sity scores to adjust for potential con-founders in observational studies is inthe treatment of localized prostate can-cer, in which Wong and colleaguesdetermined that men aged 65 to 80years experienced a survival advantagewith treatment versus observation.1

Instrumental variable analysis ad -justs for differences in groups whenrelevant differences between groupsare not available, said Dr Armstrong.One such example is an analysis thatsimulated the conditions of a ran-domized trial of chemotherapy forad vanced lung cancer in patientsolder than 65 years.2 The analysisshowed that chemotherapy in thispopulation led to a median survivalincrease of 33 days and a 1-year sur-vival rate of 9%.

Decision analysis is a quantitativeapproach to synthesizing evidence tocompare expected outcomes of differ-ent interventions. She cited her ownstudy, a Markov decision-analyticmodel, to determine that women withBRCA1/2 mutations should make deci-sions about the use of hormone replace-ment therapy after prophylacticoophorectomy based on quality-of-lifeissues rather than life expectancy.3

“Cost is a growing focus of compar-ative effectiveness research,” DrArmstrong said, adding that it isincreasingly being incorporated intoMarkov models. A recent example is aMarkov state-transition model aimedat determining how fracture riskshould be managed in men receivingandrogen-deprivation therapy for thetreatment of localized prostate can-cer.4 The authors concluded that inmen at higher risk for hip fracture,routine use of alendronate without abone mineral density test is a cost-effective strategy.

As more targeted therapies for cancerare developed, data collection will haveto change to include the presence ofbiological markers to conduct CER ofthese therapies, Dr Armstrong said. �

References1. Wong YN, Mitra N, Hudes G, et al. Survival associat-ed with treatment vs observation of localized prostatecancer in elderly men. JAMA. 2006;296:2683-2693.2. Earle CC, Tsai JS, Gelber RD, et al. Effectiveness ofchemotherapy for advanced lung cancer in the elderly:instrumental variable and propensity analysis. J ClinOncol. 2001;19:1064-1070.3. Armstrong K, Schwartz JS, Randall T, et al. Hormonereplacement therapy and life expectancy after prophy-lactic oophorectomy in women with BRCA1/2 muta-tions: a decision analysis. J Clin Oncol. 2004;22:1045-1054.4. Ito K, Elkin EB, Girotra M, Morris MJ. Cost-effective-ness of fracture prevention in men who receive andro-gen deprivation therapy for localized prostate cancer.Ann Intern Med. 2010;152:621-629.

BRIEF SUMMARY OF PRESCRIBING INFORMATIONNeulasta® (pegfilgrastim) injection, for subcutaneous use

INDICATIONS AND USAGENeulasta 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.

CONTRAINDICATIONSDo not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONSSplenic RuptureSplenic 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 SyndromeAcute 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 ReactionsSerious 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 DisordersSevere 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 CellsThe 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 REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary:

Warnings and Precautions] Warnings

and Precautions] Warnings and Precautions]

Warnings and Precautions]

Warnings and Precautions]The most common adverse reactions occurring in 5% of patients and with a between-group difference of 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.

Clinical Trials ExperienceBecause 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

pregnancy 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 MothersIt 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 UseSafety 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

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 UseOf 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 ImpairmentIn 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 ADMINISTRATIONThe 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.

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 4% 9%

LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

ImmunogenicityAs 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 ExperienceThe 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: Warnings and Precautions]Blood and lymphatic system disorder: Sickle cell crisis

Warnings and Precautions]Respiratory, thoracic, and mediastinal disorder: ARDS

Warnings and Precautions]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and

Warnings and Precautions]

DRUG INTERACTIONSNo 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 bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere 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

Neulasta® (pegfilgrastim)

Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, California 91320-1799

© 2010 Amgen Inc. All rights reserved.www.neulasta.com1-800-77-AMGEN (1-800-772-6436)

v 11.0

Comparative Effectiveness Research... Continued from page 5


VALUE PROPOSITIONS

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

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

Determining the Value of CTC Screening forColorectal Cancer

A simulation model to calculate lifetime costs and life expectancies for15 colorectal cancer screening strategies finds that computed tomograph-ic colonography (CTC) is not cost-effective if reimbursed at the same rateas colonoscopy (J Natl Cancer Inst. 2010;102[16]:1238-52. Epub 2010 Jul27). Investigators examined whether CTC screening every 5 years couldbe cost effective compared to currently reimbursed colorectal screeningtests in an unscreened cohort of Medicare beneficiaries. The number oflife-years gained by CTC screening every 5 years was only slightly lowerthan the number gained from colonoscopy screening every 10 years. IfCTC was reimbursed at the same rate as colonoscopy ($488), lifetimecosts associated with this screening exceeded those of colonoscopy. TheCenters for Medicare and Medicaid Services does not currently reim-burse CTC screening. The authors point out that “comparative effective-ness research, and cost-effectiveness analyses in particular, can also beused to inform reimbursement levels.”

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 com-monly diagnosed conditions (acute myocardial infarction [AMI], chronicobstructive pulmonary disease, community-acquired pneumonia, con-gestive heart failure, cerebrovascular accident, sepsis, or urinary tractinfection) 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% (forAMI). The greatest relative mortality reductions occurred in the diseaseswith active quality improvement and public reporting efforts (AMI,pneumonia, and heart failure). During the same time, inflation-adjustedcosts increased for all diagnoses, with relative cost increases rangingfrom 26% for pneumonia to 60% for heart failure. The dollars spent, saythe authors, have produced inconsistent value, with wide variation in thecost per life-year saved(Health Aff [Millwood]. 2010;29[8]:1523-1531).

Limiting Access, Cutting CostsRestricting 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, FortinPM, et al. Pharmaceutical policies: effects of restrictions on reimbursement.Cochrane Database Syst Rev. 2010;8:CD008654). The most common restric-tion was a prior authorization policy; in some cases, restricting reimburse-ment led to almost immediate cost savings and decreased drug use (ie, inthe case of branded gastric acid suppressants). In others (ie, brandedantipsychotic drugs), health services did increase and costs were notreduced. Although the policies do appear to save money in several studies,

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

Initial Prostate Cancer Treatment Choice ImpactsLong-Term Costs

A study looking at short- and long-term costs associated with differentprostate cancer treatments finds that treatments that are initially lessexpensive may incur higher long-term costs (Cancer. 2010 Aug 23. [Epubahead of print]). The researchers looked at initial treatment approaches(watchful waiting, radiation, hormonal therapy, hormonal therapy plusradiation, and surgery) and costs short term (1-12 months), long-term(> 12 months) and overall (months 1-60). For most cases, costs were ini-tially high, dropped sharply, and then remained steady. Watchful waitinghad the lowest initial ($4270) and 5-year costs; initial costs were highestfor hormonal therapy plus radiation ($17,474). Hormonal therapy hadlow initial costs but the highest 5-year costs ($26,896). Hormonal therapyplus radiation ($25,097) and surgery ($19,214) had the second and thirdhighest 5-year total costs.

App Shortcut for Clinical TrialAdversity

Printed information on the adverse eventspatients may face in clinical trials has been con-verted to digital form and formatted for use withthe iPhone and iPod Touch. Researchers at theCenter for Biomedical Informatics at TheChildren’s Hospital of Philadelphia created theapp, which is free to download. The NationalCancer Institute’s Common Terminology Criteria forAdverse Events (CTCAE) is a 200-page handbook inits most recent edition (version 4.0) and is used tohelp standardize record-keeping of side effectsoccurring in patients enrolled in clinical trials.

Pricey Premiums as Health Insurance Costs RiseThe annual premium for a family health plan sponsored by an employ-

er cost about 54% more in 2009 ($13,027) than it did in 2000 ($8437),according to inflation-adjusted figures from the Agency for HealthcareResearch and Quality. The annual premium cost for a single coverageplan rose by 41% (to $4669 from $3308) in that same time period. NewYork had the highest average premiums ($13,757 for family/$5121 forsingle); Ohio the lowest ($11,870 for family/$4261 for single). The aver-age annual employee contributions for health insurance premiums were$3474 for family coverage (which covered 26.7% of the average familypremium) and $957 for single coverage (20.5% of the average single pre-mium). Data were collected from the Medical Expenditure Panel Survey.

It’s Where You Are, Not What They KnowFor older patients with kidney failure, the type and intensity of treat-

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

Credit: The Children's Hospital of Philadelphia

Users of this app can searchthese broad categories, whichinclude specific types ofadverse events in clinical trials.


principal investigator with the NorthernIndiana Cancer Research Consortium inSouth Bend. “The ‘community,’ as a part-nership between the physician and thepatient, has the potential to make anenormous impact on the algorithm ofcancer care by increasing participation inclinical trials,” Dr Zon said. Never -theless, a clear disconnect exists betweeninterest and participation.

Clinicians in community oncologypractices care for 85% of oncologypatients, and 50% to 60% of patientaccrual in clinical trials comes fromthe community setting; however, lessthan 20% of oncologists and 2% to 7%of all patients with cancer participatein clinical trials.

The Ingredients for Success

Successful clinical research sites haveseveral common traits, which Dr Zonhighlighted. 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 stan-dards for exemplary clinical trial sites,which Dr Zon helped to write.1

First and foremost, exemplary clini-cal trial sites adhere to the clinical prac-tice guidelines of the InternationalConfer ence on Harmonisation of Tech -nical Requirements for Registration ofPharm aceuticals for Human Use, DrZon said. Adherence to the guidelinesis a requirement for participation infederally funded and industry-spon-sored clinical research.

The National Academy of SciencesInstitute of Medicine (IOM) has pub-lished 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, theIOM called on NCI to increase reim-bursement to trial sites and urged theAmerican Medical Association to devel-op a Current Procedural Terminology-4code that would increase reimburse-ment to providers who enroll patientsand participate in clinical trials. The IOMalso recommended that NCI work witha nonprofit foundation to develop a cer-tification program for clinical trial sites.

Among informational resources relat-ed to clinical trials, Dr Zon cited a seriesin the Journal of Oncology Practice thataddressed various aspects of clinicalresearch, such as exemplary attributes ofresearch sites, good clinical practice

research guidelines, quality assurance,and education.

Quality Teams Make for Quality

Research

The path to exemplary status as aresearch site begins with the creation of aresearch team that understands andstrives to create a culture that is support-ive to clinical research.

Physicians participating in clinicalresearch must have a strong commit-ment to it and be willing to spend the

extra time required to explain the trialprocess to patients, discuss treatmentoptions, and obtain appropriate consent.Most steps in the research process,including forms and documentation,require the participating physician tosign off on them. Research physiciansalso must be prepared to attend institu-tional and investigator meetings relatedto the clinical research program and spe-cific clinical trials.

“The main thing physicians have tooffer is our time,” said Gary I. Cohen,MD, director of clinical research at theBerman Cancer Center in Baltimore,MD. “Our time has value, and we don’twant to give it away. If we are going todo clinical trials, we certainly want tomanage our time properly, and having ateam allows us to get that done in themost efficient way.”

Although the titles and responsibili-ties of other clinical research teammembers may vary somewhat fromsite to site, most teams share severalkey members, including research asso-ciates, research nurses, pharmacy andsecretarial support, as well as physi-cian leaders.

Clinical research associates screenpatients and determine their eligibilityto participate in a trial, and also pre-pares a duplicate or “shadow” medicalchart for each trial participant. Theshadow chart is stored separately andused for audit purposes. The clinicalresearch pharmacist has responsibilityfor logging and monitoring use andstorage of investigational drugs anddistributes assigned study medications.

Physicians who participate in clini-cal research must have a strong com-mitment to research and be willing tospend the extra time required toexplain the trial process to patients,discuss treatment options, and obtainappropriate consent. Most steps in theresearch process, including forms and

documentation, require the participat-ing physician to sign off. Researchphysicians also must be prepared toattend institutional and investigatormeetings related to the clinical researchprogram and specific clinical trials.

Operating a clinical research siterequires a substantial financial com-mitment, Dr Cohen noted, and person-nel costs usually represent the largestoutlay. At his institution, salary andbenefits for various members of theresearch team can range from $39,000

for a medical assistant to $98,000 for aresearch nurse.

Personnel costs account for aboutthree fourths of expenditures for a site’sresearch program. Of equal importance,the clinical research team must have theresources necessary to carry out theirwork, including workspace, telephone/telecommunication support, and com-puter equipment and software, DrCohen added.

The considerable overhead costs asso-ciated with operating a clinical researchsite require income to offset thoseexpenses. A site may not make money,but it also should not lose money, whichnecessitates a “cost-neutral” financialbalancing act, Dr Cohen said.

Budgeting and Paying for Trials

Contract negotiation is the fulcrum inthe balancing act, and the negotiationprocess has no hard and fast rules.

“Sponsors willnot pay more thanfair market valuefor services,” saidDee Anna Smith,chief executive offi-cer of the SarahCannon Research

Institute in Nashville, TN. “There is noclear mechanism in the law or regula-tions for determining fair market valuein the clinical research context,” she said.“Well-documented justification [of costs]increases the likelihood that a sponsorwill agree to your budget.”

The budget for a clinical trial allocatesand documents financial responsibilityamong the sponsor, the research site, thepatient, and insurance provider. Aneffective budget process should includea thorough review of the protocol andinformed consent; careful justification ofall costs; determination of institutionalrequirements; and a thorough delin-eation of all overhead costs, as well as

identification of hidden costs. One of themost difficult aspects of the processinvolves estimating or accounting forinflation in multiyear projects, Ms Smithnoted. However, cost estimations offuture required procedures must includean allowance for inflation.

Identifying hidden costs is moreproblematic for new research sites thanfor experienced sites. Often overlookedare costs associated with site selectionand visits, training the research staff,attendance at investigator meetings,development of study tools, and filingregulatory documents.

Other costs that should be taken intoaccount include recruitment, pharma-cy review, laboratory setup, qualityassurance, radiology setup, monitor-ing, administration of the study drug,and pathology fees.

A research contract should clearlyaddress indemnification, patient injury,and payment terms, Ms Smith said.

Indemnification typically includesprotection for the sponsor, institution,and research site; use of study results;and product liability. Allowances forpatient injury typically include directmedical costs; emergent and long-termcare; and possibly, a monetary cap.Most contracts do not have allowancesfor incidental expenses resulting frominjury, lost wages, pain and suffering,or punitive damages.

Payment terms will vary from site tosite and sponsor to sponsor, but manyagreements include some common traits.Ms Smith suggests that the terms stipu-late advance payment of a nonrefund-able fee for start-up costs, which mostsponsors expect. Other issues commonlyaddressed 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, under-

stand and document your costs, under-stand billing coverage, and understandwhen you will get cash,” Ms Smith said.“Don’t be mesmerized by the initial per-patient amount offered. Look for what isnot in your contract, and don’t be afraidto negotiate. Finally, deliver on the studyrequirements.” �

Reference1. Zon R, Meropol NJ, Catalano RB, Schilsky RL.American Society of Clinical Oncology Statement on min-imum standards and exemplary attributes of clinical trialsites. J Clin Oncol. 2008;26(15):2562-2567.

Fostering Clinical Research in the Community... Continued from cover

“A partnership between the physician and the patient hasthe potential to make an enormous impact on the algorithmof cancer care by increasing participation in clinical trials.”

—Robin Zon, MD

ASCO CONFERENCE


VBCC PERSPECTIVE

By Ed Pezalla, MD, MPH

Several sessions at the recentASCO meeting considered newstandards for community-based

oncology research and the develop-ment of comparative effectivenessresearch (CER) methods.

Community-based oncology trialsplay an important role in developingtreatment strategies and options. Inrecent years, however, clinical trial par-ticipation in the United States has beenon the decline, which limits the popu-lation available to researchers andmakes it difficult to achieve the diversi-ty needed to reflect the actual experi-ence of patients across the country.Encouraging high-quality community-based trials will remedy this andremove barriers such as the need totravel to major urban medical centers.

Problems of cost will continue toexist but we should note that for man-ufacturer-sponsored drug trials, thepharmaceutical firm will cover the costof the experimental treatment andmost insurers will cover the routinecare needed for the treatment of cancer.In all cases, however, guidance fromthe health plan on reimbursementshould be sought before enrolling in atrial. This may not make trial participa-tion affordable for all but should gosome ways towards helping manymore patients join a trial. In addition,with the passage of the Patient Pro -tection and Affordable Care Act inMarch 2010, insurers will be prohibitedfrom dropping or limiting coveragebecause an individual chooses to par-ticipate in a clinical trial effectiveJanuary 1, 2014. This applies to all clin-ical trials that treat cancer or other life-threatening diseases.

As noted in “Trial ParticipationHampered by Costs” (see page 11),patients continue to express concernsabout the cost of clinical trial participa-tion, and Dr Weckstein’s prescriptionsfor mitigating these financial barriersappear sound. Covering the largelyunseen costs of copays and deductiblesthrough legislation would be a hugeboon, as would public funding forpatient costs associated with trial par-ticipation.

The development of sophisticatedCER methodologies should also help tofill the gap for clinical trials since theseapproaches may augment, or in somecases, replace, the need for an expen-sive randomized controlled trial (RCT).

It is my hope that a combination ofrenewed interest in clinical trials at thecommunity level with alternatives toRCTs in the case of already approveddrugs will yield better medical evi-dence and better patient outcomes. �

©2010 Bristol-Myers Squibb. All rights reserved. 731US10AB00724 4/10

We are committed to the discovery and development of

innovative immunotherapeutic approaches aimed at helping

patients ght cancers, such as advanced melanoma.

Together, we can make a difference.

We are here, where youneed us most

The development of sophis -ticated CER methodologiesshould also help to fill the gap for clinical trials.

Community Trials Essential to Broad Knowledge

Ed Pezalla, MD, MPH, is the national medical direc -tor for Pharmacy Policy and Strategy of AetnaPharmacy Management, Hartford, CT, and an edito-rial board member of Value-Based Cancer Care.

ASCO CONFERENCE


By Wayne Kuznar

Chicago, IL—Active surveillance is acost-effective option for low-risk clini-cally localized prostate cancer.

The number of quality-adjusted life-years (QALYs) was highest with activesurveillance compared with radicalprostatectomy, radiation therapy, bra -chytherapy, and proton beam therapy,according to data presented by Julia H.Hayes, MD, instructor in medicine atHarvard Medical School, and attendingphysician at Dana-Farber Cancer Insti -tute, Boston, MA, during a poster pres-entation at the 2010 meeting of theAmer ican Society of Clinical Oncology.

“In the age of PSA [prostate-specificantigen] screening, more than 50% ofmen with clinical localized disease areovertreated, meaning that they aretreated unnecessarily, and treatmentis associated with significant sideeffects,” she said.

Modeling Care and Costs

Dr Hayes used a Markov MonteCarlo model to estimate costs andQALYs of 5 different therapeutic strate-gies for clinically localized, low-riskprostate cancer. The model consideredactive surveillance (a policy of follow-ing men closely and treating them atthe first sign of progression with intentto cure) or immediate treatment withany 1 of the following: radical prostate-ctomy, intensity-modulated radiationtherapy (IMRT), brachytherapy, or pro-ton beam therapy. Costs includedMedicare reimbursement rates fortreatment and costs associated withside effects, treatment, visits, biopsies,and patient time costs in 2008 US dol-lars. Cost and QALYs were discountedat 3% annually.

The model assumed equivalentprostate cancer–related outcomes, andthen the risk of dying from prostatecancer was varied.

For a 65-year-old man, brachytherapywas the least expensive treatment optionwhen considering total costs ($25,606),whereas proton beam therapy was themost expensive ($53,828). Active surveil-lance was associated with the highestquality-adjusted life expectancy (QALE),at 8.58 QALYs. Compared with radicalprostatectomy, active surveillance pro-vided an additional 9.1 months ofQALE, at an incremental cost-effective-ness ratio of $2729 per QALY.

Brachytherapy and IMRT had simi-lar QALE benefit, but IMRT cost$21,050 compared with $10,174 forbrachytherapy.

“The reason that active surveillancecost more than brachytherapy was

because everybody who progressed onactive surveillance, which was about60% 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

“If we assumed that men on activesurveillance got brachytherapy or rad-

ical prostatectomy, it actually becamethe most effective and least expensive,”he said.

For a 55-year-old man, active surveil-lance provided an additional 4.7 monthsof QALYs compared with radical prosta-

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

Active surveillance remained themost effective strategy, even if the riskof disease progression doubled, therisk of symptoms on active surveil-lance doubled, and the risk of sideeffects of treatment was reduced byhalf (from 53% to 26%).

The risk of prostate cancer–specificdeath on active surveillance wouldhave to be 60% higher than after ini-tial treatment (16% vs 9%) to elimi-nate the QALE advantage of activesurveillance compared with immedi-ate treatment. “You would have toalmost double the risk of dying fromprostate cancer on active surveil-lance in order to make initial treat-ment favored in terms of QALE,” DrHayes said. �

Active Surveillance Cost-Effective for Low-Risk Prostate Cancer

Chicago, IL—The cost-effectiveness ofadding bevacizumab (Avastin) to first-line chemotherapy for the treatment ofmetastatic colorectal cancer is compa-rable to that of many other therapiesfor metastatic cancer.

Although the acquisition cost ofbevacizumab is high, it has improvedthe cost-effectiveness of systemic thera-py (irinotecan [Camptosar]- or oxali-platin-based regimens), said the study’slead investigator, Diego Villa, MD,MPH, of the British Columbia CancerAgency, Vancouver, Canada. He pre-sented the results at the 2010 ASCOmeeting.

Adding bevacizumab to chemother-apy has previously been shown to sig-nificantly improve overall survival inmetastatic colorectal cancer, but “the

cost of therapy with bevacizumab foradvanced colorectal cancer is $44,000 to$55,000 per patient over 10 months oftreatment,” Dr Villa said.

Dr Villa performed a population-based analysis using a Markov modelthat tracked major clinical and treat-ment events in the natural history ofthe disease. He compared outcomesand costs in the pre-bevacizumab erawith those in the bevacizumab era. Thedatabase was comprised of patientswith newly diagnosed metastatic col-orectal cancer between 2003 and 2004(pre-bevacizumab era) and 2006 (beva-cizumab era) who were referred to theBritish Columbia Cancer Agency. Ofthe 943 patients included, 611 werefrom the pre-bevacizumab era and 332were from the bevacizumab era.

When considering the costs associ-ated with diagnosis and staging; sur-gery; systemic therapy; and radiationtherapy, the weighted average cost oftreatment per patient increased from$34,972 in the pre-bevacizumab erato $38,764 after bevacizumab wasintroduced.

Median overall survival for patientsinitiating chemotherapy improvedfrom 15.6 months in the pre-beva-cizumab era to 19.5 months in thebevacizumab era.

The cost-effectiveness ratio of beva-cizumab for this indication was calcu-lated at $15,617 per life-year gained, or$62,468 per quality-adjusted life-yeargained, which is “in line with manyother therapies for metastatic cancer,”Dr Villa noted. —WK �

Chicago, IL—Using genetic and phar-macogenomic information to treatpatients with cancer in optimal fashionhas advanced in the past several years,and the clinical utility of this approachshould continue to improve as geneticresearch continues, said several pan-elists at a 2010 ASCO session on evalu-ating the evidence and marketing ofgenomic tests.

Unfortunately, clinicians too oftenpick the therapy they’re “most comfort-able with, as opposed to the one thepatient’s biology is driving us to wards,”said Howard L. McLeod, PharmD, ofUniversity of North Carolina at Chapel

Hill. “We’re moving toward an era whereit’s less of our choice and more of thetumor’s choice.”

Information on what therapy mayimpact a tumor has grown more com-mon, Dr McLeod noted, emphasizingthat many therapies, including irinote-can, cetuximab, and panitumumab,include pharmacogenomic informationin the label. In addition, recent drug labelupdates have increased the amount ofinformation provided, including, mostimportantly, actionable recommenda-tions that impact clinical care.

Michael L. Maitland, MD, PhD, con-centrated on these practical aspects of

care. Noting that the current cost ofsequencing an individual’s genomesequence is about $10,000, he indicatedthat by 2013, that cost should havedropped to $1000. Although not wide-ly used at the moment, avoiding use ofgenetic information is becoming unac-ceptable, he argued.

A question from the audience high-lighted the “in-between” state of phar-macogenomics in practice. Asked by apracticing oncologist if he should betesting his patients for CYP2D6 toguide care, Dr Maitland stated that“there’s not going to be a yes or noanswer to that question.” �

Bevacizumab Cost-Effectiveness “in Line” with Other Therapies

Greater Role for Pharmacogenomics Ahead

“In the age of PSA [prostate-specificantigen] screening, more than 50% ofmen with clinical localized disease areovertreated...and treatment is associatedwith significant side effects.”

—Julia H. Hayes, MD

ISPOR CONFERENCE


By Daniel Vollaro

Atlanta, GA—Offering practical adviceabout how and when to use patient-reported outcomes (PROs) to make sup-portable claims in the marketing of newdrugs and products, a workshop direct-ed mainly to new product developers atthe International Society for Pharma -coeconomics and Outcomes Researchmeeting in Atlanta clarified some of thebasic issues surrounding the use of thistype of research instrument.

The workshop reviewed the labelingand approval histories of several prod-ucts, including Advair (fluticasone pro-pionate and salmeterol xinafoate;GlaxoSmith Kline) and the humangrowth hormone somatropin, to showhow manufacturers make claims usingPROs, as well as the different stan-dards Germany, England, and theUnited States use to evaluate PROs.Attendees also heard the merits of aclaim-centered ap proach to usingPROs 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 instrumentthat measures patients’ feelings about,and overall satisfaction with, the thera-py in a typical clinical trial. PROs pro-vide valuable data for researchers andfor marketing departments, sometimesserving as evidence to support claimsthat a drug was efficacious or superiorto another product in the marketplace.

Warning that the US Food and DrugAdministration (FDA) scrutinizes com -parative claims carefully and is in clinedto view them suspiciously, UnitedBioSource Corporation (UBC) SeniorResearch Scientist Asha Hareendran,PhD, explained that all promotionalclaims “must be supported by substan-tial evidence or substantial clinical evi-dence,” and the evidence required forcomparative claims, or claims of superi-ority, “would include adequate andwell-controlled trials designed to estab-lish superiority of one treatment overanother.” This requirement shapes theway drug companies market their prod-ucts, Dr Hareendran said, because ifthey want to make a comparative claim,

they must use PROs from randomizedcontrolled trials—a higher standard ofevidence than is required for noncom-parative claims. She suggested thatdrug developers can use less costly con-joint analysis studies to support non-comparative promotional claims.

Dr Hareendran showed severalexamples of patient satisfaction evi-dence included in product marketingmaterials for several inhaler productsdesigned to treat chronic obstructivepulmonary disease and offered someguidance on choosing the appropriatePROs for promotional materials.

Begin at the End

“When you are aiming for a label -ing claim, it’s not something that you

can decide at the extremes,” DrHareendran said. “Most of my col-leagues in the pharmaceutical indus-try would say, select the instrumentbased on the concept that you wantto claim on, and then make sure allthe properties on the instrumentmeet the requirements of the 2009FDA guidelines.’”

Dr Hareendran’s colleague at UBC,William Lenderking, PhD, echoed hercall for a strategic approach to sup-porting promotional claims. DrLenderking, senior research leader atUBC, outlined clear priorities for howdrug companies should support anadvertising claim with the appropriatePRO evidence: begin with a clear senseof the “claim” or “story” you want to tell.

“It’s just such a basic concept—youneed to know where you are going,”Dr Lenderking said. “What do youwant to see in the Wall Street Journal, oron the FDA’s label claim, or what arethe conclusions you want in the NICE[National Institute for Health andClinical Excellence] appraisal?” Thinkabout that, he advised, and then “workbackwards from there.” �

Incorporating Patient-Reported Data into the Pharma Sales Story

“What do you want to seein the Wall Street Journalor on the FDA’s labelclaim?”

—William Lenderking, PhD

ASCO Weighs in on CERBy Colin Gittens

The American Society of ClinicalOncology (ASCO) stated thatcomparative effectiveness re -

search (CER) should draw onapproaches currently used for clinicaltrials, highlighting its stake in thematter by pointing out that CER isintegral to oncology research.ASCO’s statement came in responseto a request from the US Departmentof Health and Human Services(HHS) for information on developingan inventory of CER.

“The extensive federally fundedclinical trials network is a gold stan-dard for CER,” wrote ASCO Presi -dent George W. Sledge, Jr, MD, in aletter dated August 9, 2010.

The letter pushes for a singlerepository containing links to themany types of studies that will beused in CER. Such a repositorywould foster awareness in theresearch community of trials underway. As with the ClinicalTrials.govwebsite, CER studies should be regis-tered at their outset, which would

guard against publication bias.Inaddition, withholding of federal fundsuntil the time of registration could beused as an incentive for participation,Dr Sledge wrote.

The HHS should also stratifystudies based on design, and indi-cate whether data were peer re -viewed, so that users can evaluatethe strength of the evidence, DrSledge stated.

Sustaining CER efforts over time isalso essential, the ASCO presidentwrote. “Linking the inventory to thenewly created Patient-Centered Out -comes Re search [PCOR] Institute maybe one method to enable sustainabili-ty,” said Dr Sledge. The PCOR Institutehas dedicated funding and incorpo-rates a public–private partnership,attributes that “may create more buy-in among stakeholders in the researchcommunity.”

Finally, the letter urges that theCER inventory should be delayeduntil the HHS receives input andfeedback from the PCOR Institute’sBoard of Governors and Metho -dology Committee. �

Trial Participation Hampered by CostsBy Charles Bankhead

Cost-related factors are a chiefreason for patients declining toparticipate in a clinical trial, a

survey of 4 community oncology prac-tices showed. Overall, 28% of patientscited cost as a factor in their refusal toparticipate in clinical trials, and 12%said cost was the primary reason for notparticipating.

“Cost is an issue,” DouglasWeckstein, MD, of New HampshireOncology-Hematology in Hooksett,concluded during a poster presenta-tion at the American Society of ClinicalOncology meeting.

Some patients reported that theydid not have health insurance andothers said they cover the cost ofcopayments or deductibles. In somecases, insurers refused to cover treat-ment provided through a clinical trial.

The findings came from a survey ofpatients and physicians at 4 communi-ty cancer clinics in New England. Theprimary objective was to determine theproportion of patients who decline toparticipate in clinical trials because ofcosts associated with participation.

Secondary objectives were to identifyother reasons for not participating andto determine how often physicians atthe clinics do not discuss clinical trialopportunities with patients.

A total of 213 trial-eligible patients atthe 4 clinics did not participate in clin-ical trials. Aside from the cost factor, ofthe 120 patients who cited specific rea-sons, 50% expressed concern aboutpossible side effects, 44% cited concernabout randomization, and 33% saidthey were too overwhelmed and didnot have the time.

Survey responses from DrWeckstein’s clinic also showed that40% of trial-eligible patients did notrecall their physicians telling themabout clinical trial opportunities.

According to Dr Weckstein, 3 poten-tial actions could mitigate financial bar-riers to patients’ participation in clini-cal trials:• Legislation to cover quality trials,

including coverage for deductiblesand copays

• Consideration of costly testing intrial design

• Public funding for patient costs toparticipate in trials. �

ASCO CONFERENCE


HEALTH POLICY

the FDA is teetering on a tightropebetween protecting patient safety andimposing new barriers to access. Thelatter provoked much scarcely con-tained anger from attendees.

Janet Woodcock, MD, director of theFDA Center for Drug Evaluation andResearch, acknowledged the problems.“FDA regulates sponsors, but we haveno control over how they influenceproviders and prescribers,” she said.“REMS is not perfect, but it’s enforce-able. We can order compliance withthose who agree to abide by the restric-tions, but we cannot make peopleagree to participate in the REMS pro-gram. It’s awkward.”

Background

The FDA Amendments Act (FDAAA)of 2007 created REMS. In essence, it per-mits the FDA to establish stronger regu-lations, which require sponsors toensure that the benefits of a drug out-weigh its risks. REMS applies to newdrug applications as well as to alreadyapproved drugs that are deemed by theFDA to carry significant risk.

REMS requirements include a med-ication guide (MG), a communicationplan (CP), and elements to assure safeuse (ETASU).

The MG is similar to a drug label butprovides more extensive informationand is dispensed with the drug. Thismust be given to patients to informthem of possible serious adverseevents, as well as the importance ofstrict adherence to the dosing regimen.

The CP is designed for healthcareproviders. It explains safety protocolsand contains information about train-ing materials; prescribing proce dures;patient–physician agreements; in formedconsent; patient education materials;medical monitoring; and data collec-tion forms and procedures.

The ETASU are a series of additionalrequirements that must be commensu-rate with a specific, serious risk butmust not be unduly burdensome topatients. They require that the pre-

scriber and pharmacist be educatedabout the specific risks of a drug and becertified to prescribe and/or dispense it.In some cases, prescribers are requiredto counsel patients about risk, enrollthem in a registry, ask that they sign aprescriber–patient agreement to ensurefull awareness of risk, and monitorthem closely for signs of toxicity.

Furthermore, some drugs withETASU requirements are only permit-ted to be dispensed from certain regis-tered pharmacies. ETASU is the moststringent REMS requirement, and canpreclude approval if the sponsor doesnot comply.

All REMS include a timetable for sub-mission of risk and benefit assessment at18 months, 3 years, and 7 years. Drugswith ETASU requirements can havemore frequent assessments. The onus ofassessment falls on the manufacturer.

Concerns and Problems

During the 2 years after the FDAAAbecame effective on March 25, 2008, theFDA approved 110 REMS for new drugsand biologic agents. The majority (68%)required an MG only, and just 10 neces-sitated ETASU. Nevertheless, stakehold-ers across the healthcare system haveexpressed concerns about REMS.

Many see REMS as a burden on theprovision of care. Prescribers complainabout having to enroll in several pro-grams, obtain a variety of certifications,and provide additional counseling topatients. These restrictions can interferewith the way medicine is practiced, andthey are costly—and not reimbursed,according to some physicians.

Another concern is REMS’ potentialnegative effect on patient access totherapies. Advocacy groups are con-cerned that physicians may choose tonot participate in REMS, thus denyingpatients access to certain drugs.

Pharmacy organizations have com-plained about the fact that there is nocompensation for the extra work stem-ming from REMS regulations.

Manufacturers also perceive the bur-den of REMS as substantial. A drug’ssponsor must establish the education

and certification programs and moni-tor REMS. It has no control, however,over other participants in the system,and cannot force them to comply withREMS requirements.

The FDA Acknowledges Problems

Even before the July meeting, theFDA recognized problems and at -tempted to set a course by draftingguidance for industry.1 This documentconsidered issues such as the goal ofREMS programs and what factors arepertinent to REMS (and how can theybe measured).

Other considerations include howETASU will affect patients’ access tosome drugs. Will they really improvesafety—or diminish it? Can they bestandardized? And how will theyaffect the healthcare delivery system?

Other issues noted by Dr Woodcockinclude the advantages and disadvan-tages of various REMS drug distribu-tion systems; monitoring and assess-ment; ameliorating the burden of costto all participants; and maintainingpatient privacy.

Panelists Voice Concerns

Sandra Adamson Fryhofer, MD, aninternist in Atlanta, GA, and memberof the American Medical Association(AMA) Council on Science and PublicHealth, agreed with the FDA thatREMS is probably necessary, but saidthat the AMA is concerned about theprocess of implementation and the sig-nificant burdens it will place on physi-cians. She noted that the organizationpolled its members and found that 50%of them will refuse to prescribe drugsthat require REMS. “One third ofoncologists say they won’t even regis-ter as REMS prescribers,” she added.

Mitchell S.Y. Cohen, Esq, an attorneyat Kaiser Permanente, and Jeffrey K.Francer, Esq, Assistant General Coun -sel for the Pharmaceutical Researchand Manufacturers of America, agreedthat 3 major principles should guideREMS implementation. These include:• The process of calculating risks and

benefits should be easy for patientsto understand

• Data about evaluation of REMSshould be shared with all concerned,as should efforts taken to mitigateburdens on all participants

• Use of MGs and CPs should be rea-

sonable, and confidentiality of pa -tient information must be ensured.Several speakers were concerned

that patients might refuse a drug afterreading the MG. Thomas H. Hostetter,MD, a practicing nephrologist and pastpresident of the American Society ofNephrology, was the most outspoken.In discussing erythropoiesis-stimulat-ing agents (ESAs), he noted that thereare 350,000 patients undergoing dialy-sis in the United States, and they allreceive ESAs in varying doses. “Themedication guides emphasize onlyrisks, and if patients read, in practicallythe first sentence, that they might diefrom taking ESAs, they might refusethem—and then miss the clear benefitsof these drugs,” he said.

Michael Lazarus, MD, a nephrolo-gist at Fresenius Medical Care NorthAmerica in Waltham, MA, added thatESAs are used in oncology as well asnephrology, but in much higher doses;therefore, the risks are greater. “But themedication guide does not distinguishamong types of ESA use, and the sameguide is given to all patients, regardlessof diagnosis and treatment plan,” DrLazarus said. “This is confusing.”

Every speaker noted that REMS willadd significantly to the costs of drugmanufacturing, prescribing, dispens-ing, and providing patient care.

Several concerns were generated byETASU. According to Dr Fryhofer,their rigor may make physicians shyaway from certain drugs and use lesseffective ones. “The purpose of REMSis increased safety, not decreased accessto therapy,” she said. “Therefore,ETASUs should be developed withinput from specialty physicians.”

In addition, ETASU will erect newbarriers between patients and providers,and worsen the ones that already exist,noted Karen Kiefer, of the New Jerseychapter of the American Pain Man age -ment Nurse/Physician Association.

Several pharmacists said that restric-tive distribution programs can inter-fere with pharmacy practice. Theyadvocated for compensation to phar-macies for the additional cost ofadministering REMS in general, andETASU in particular.

Others voiced concern that, becauseETASU are not standardized, they canincrease administrative, evaluative,and safety problems. Also, everyoneaffected by ETASU will experienceincreased demands on their time. �

Reference1. Guidance for Industry Format and Content of ProposedRisk Evaluation and Mitigation Strategies (REMS),REMS Assessments, and Proposed REMS Modifications.Rockville, MD; Food and Drug Administration:September 2009.

REMS Regulation Provokes... Continued from cover

“The medication guides emphasize only risks.If patients read that they might die fromtaking ESAs, they might refuse them—andthen miss the clear benefits of these drugs.”

—Thomas H. Hostetter, MD

at a glanceREMS 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

sig n if icantly to the costs of drug

man u fac turing, prescribing,

dispensing, and providing

patient care

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

HEALTH POLICY


By Jayson Slotnik, JD, MPH

On July 14, 2010, the Depart -ments of Treasury, Labor, andHealth and Human Services

issued interim final rules for grouphealth plans and health insuranceissuers to provide detail on how thoseentities are to cover the preventiveservices required under the PatientProtection and Affordable Care Act(PPACA). It is important for readers ofthis publication to be aware of theserules and to understand how thesechanges will impact their business andpatient care going forward.

PPACA requires insured and self-insured group health plans as well ashealth insurance issuers in the groupand individual markets to provide cov-

erage of, and eliminate cost-sharing for,the following preventive services:

1) Services/items with an ‘A’ or ‘B’rating from the US Preventive ServicesTask Force (USPSTF). Cancer-specificrecommendations in this categoryinclude BRCA screening and counsel-ing; breast cancer preventive medica-tions; breast, cervical, and colorectalcancer screening; and tobacco usecounseling.

2) Immunizations with recommen-dations from the Advisory Committeeon Immunization Practices of the CDC;

3) Preventive care and screening forinfants, children, and adolescents pro-vided by Health Resources and Ser -vices Administration (HRSA) guide-lines; and

4) With respect to women, preven-tive care and screening provided byHRSA (except breast cancer screen-ing recommendations issued inNovember 2009).

These provisions, however, do notapply to grandfathered plans, which

are plans that existed at the time ofenactment. According to estimates bythe Departments (based on Kaiserdata), 82% of large employers and70% of small employers will remain

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

of grandfathering and the fact thatsome plans already provide coverageof, and eliminate cost-sharing for, pre-ventive services (either by State law,or voluntarily).

Understanding the Preventive Services Rule Changes

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.

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.

Please see brief summary on the following page.

B

Z

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;98:962-969. 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. sanofi-aventis 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.

© 2010 NovartisJayson Slotnik, JD, is an attorney at Foley Hoag,LLP and an editorial board member of Value-BasedCancer Care.

Some plans already providecoverage of, and eliminatecost-sharing for, preventiveservices.

HEALTH POLICY


Interpreting the Rules

So what will the Interim Final Ruleson Preventive Services mean for practi-tioners and payers? First, if preventiveservices are billed jointly with an officevisit, copays may be imposed if the pri-mary purpose of the visit was some-thing other than the preventive services.

However, if the primary purpose was

to obtain preventive services, copays arenot allowed. Note that “primary pur-pose” is not defined, which could leadto confusion regarding billing for suchvisits. In addition, if preventive servicesare billed separately, the copay iswaived for such service (but copays forthe office visit still apply).

On the health plan side, plans are not

required to provide coverage of, and mayimpose cost-sharing for, preventive serv-ices provided out-of-network. Also, if arecommendation/guideline for preven-tive services fails to specify the frequency,method, treatment, or setting, the planmay use “reasonable medical manage-ment” to determine coverage rules.

The provision applies to plan years

beginning on or after September 23,2010, or the first plan year beginning onor after the date that is 1 year after therecommendation/guideline goes intoeffect. For an employer plan beginningon July 1, 2011, the employer would nothave to provide coverage of, and elimi-nate cost sharing for, that service untilJuly 1, 2012. �

Morethan of real-world

experience

YEARS

Metastatic renal cell carcinoma

Multiple myeloma

Metastatic breast cancer

Metastatic lung cancer and other solid tumors

Metastatic hormone-refractory prostate cancer

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

April 2010 C-ZOM-100050

* 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

ZOMETA® (zoledronic acid) InjectionConcentrate for Intravenous InfusionInitial U.S. Approval: 2001BRIEF SUMMARY: Please see package insert for full prescribing information.1 INDICATIONS AND USAGE

1.1 Hypercalcemia of MalignancyZometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected cal-cium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range ofmeasured 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 bonemetastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer shouldhave 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 orwith other nontumor-related conditions has not been established.

4 CONTRAINDICATIONS4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphy-lactic reaction/shock have been reported [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treatedwith 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 cau-tion in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution withother nephrotoxic drugs.Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, andmagnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy withZometa. If hypocalcemia, hypo phosphatemia, or hypomagnesemia occur, short-term supplemental therapymay be necessary.

5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adversereactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limitedin 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 factorsfor subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydra-tion 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 beconsidered only after evaluating the risks and benefits of treatment. In the clinical studies, patients withserum 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. Inthe clinical studies, patients with serum creatinine >265 µmol/L or >3.0 mg/dL were excluded and therewere 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 ClinicalPharmacology (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 intravenousbisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and cortico-steroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greaterfrequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dentalstatus (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reportsof 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 den-tistry prior to treatment with bisphosphonates.While on treatment, these patients should avoid invasive dental procedures if possible. For patients whodevelop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patientsrequiring dental procedures, there are no data available to suggest whether discontinuation of bisphospho-nate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the man-agement 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 administeredto a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in pre-and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malforma-tions. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, thepatient 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 hasbeen reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time toonset of symptoms varied from one day to several months after starting the drug. Discontinue use if severesymptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symp-toms 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 broncho constriction in aspirinsensitive patients receiving bisphosphonates.

5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patientswith hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or howto safely use Zometa in these patients.

6 ADVERSE REACTIONS6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.

Hypercalcemia of MalignancyThe safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who receivedeither 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 mggiven as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusionhas not been adequately studied in controlled clinical trials.Renal ToxicityAdministration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in anincreased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renalfailure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg isgiven as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over noless than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full pre-scribing information].The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (seeTable 3).Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumedcausality to study drug.

Table 3. Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Zometa Pamidronate4 mg 90 mgn (%) n (%)

Patients StudiedTotal No. of Patients Studied 86 (100) 103 (100)Total No. of Patients with any AE 81 (94) 95 (92)

Body as a WholeFever 38 (44) 34 (33)Progression of Cancer 14 (16) 21 (20)

CardiovascularHypotension 9 (11) 2 (2)

DigestiveNausea 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 SystemAnemia 19 (22) 18 (18)

InfectionsMoniliasis 10 (12) 4 (4)

Laboratory AbnormalitiesHypophosphatemia 11 (13) 2 (2)Hypokalemia 10 (12) 16 (16)Hypomagnesemia 9 (11) 5 (5)

MusculoskeletalSkeletal Pain 10 (12) 10 (10)

NervousInsomnia 13 (15) 10 (10)Anxiety 12 (14) 8 (8)Confusion 11 (13) 13 (13)Agitation 11 (13) 8 (8)

RespiratoryDyspnea 19 (22) 20 (19)Coughing 10 (12) 12 (12)

UrogenitalUrinary Tract Infection 12 (14) 15 (15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by agreater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with afrequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of pre-sumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulo cytopenia,thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headacheand somnolence.Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like EventsSymptoms 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 Zometa4 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 AbnormalitiesElectrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, canoccur with bisphosphonate use.Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, andserum 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 3Laboratory Parameter Zometa Pamidronate

4 mg 90 mgn/N (%) n/N (%)

Serum Creatinine1 2/86 (2%) 3/100 (3%)Hypocalcemia2 1/86 (1%) 2/100 (2%)Hypophosphatemia3 36/70 (51%) 27/81 (33%)Hypomagnesemia4 0/71 — 0/84 —

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

Grade 4Laboratory Parameter Zometa Pamidronate

4 mg 90 mgn/N (%) n/N (%)

Serum Creatinine1 0/86 — 1/100 (1%)Hypocalcemia2 0/86 — 0/100 —Hypophosphatemia3 1/70 (1%) 4/81 (5%)Hypomagnesemia4 0/71 — 1/84 (1%)1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal)2Grade 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)

Injection Site ReactionsLocal 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 EventsOcular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. Nocases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seenin postmarketing use [see Adverse Reactions (6.2)].Multiple Myeloma and Bone Metastases of Solid TumorsThe safety analysis includes patients treated in the core and extension phases of the trials. The analysisincludes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlledmulticenter 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 phasesand were followed for 2 years (or 21 months for the other solid tumor patients). The median duration ofexposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast can-cer 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 regard-less 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

Zometa Pamidronate Placebo4 mg 90 mgn (%) n (%) n (%)

Patients StudiedTotal No. of Patients 1031 (100) 556 (100) 455 (100)Total No. of Patients with any AE 1015 (98) 548 (99) 445 (98)

Blood and LymphaticAnemia 344 (33) 175 (32) 128 (28)Neutropenia 124 (12) 83 (15) 35 (8)Thrombocytopenia 102 (10) 53 (10) 20 (4)

Gastrointestinal Nausea 476 (46) 266 (48) 171 (38)Vomiting 333 (32) 183 (33) 122 (27)Constipation 320 (31) 162 (29) 174 (38)Diarrhea 249 (24) 162 (29) 83 (18)Abdominal Pain 143 (14) 81 (15) 48 (11)Dyspepsia 105 (10) 74 (13) 31 (7)Stomatitis 86 (8) 65 (12) 14 (3)Sore Throat 82 (8) 61 (11) 17 (4)

General Disorders and Administration SiteFatigue 398 (39) 240 (43) 130 (29)Pyrexia 328 (32) 172 (31) 89 (20)Weakness 252 (24) 108 (19) 114 (25)Edema Lower Limb 215 (21) 126 (23) 84 (19)Rigors 112 (11) 62 (11) 28 (6)

InfectionsUrinary Tract Infection 124 (12) 50 (9) 41 (9)Upper Respiratory Tract Infection 101 (10) 82 (15) 30 (7)

MetabolismAnorexia 231 (22) 81 (15) 105 (23)Weight Decreased 164 (16) 50 (9) 61 (13)Dehydration 145 (14) 60 (11) 59 (13)Appetite Decreased 130 (13) 48 (9) 45 (10)

MusculoskeletalBone Pain 569 (55) 316 (57) 284 (62)Myalgia 239 (23) 143 (26) 74 (16)Arthralgia 216 (21) 131 (24) 73 (16)Back Pain 156 (15) 106 (19) 40 (9)Pain in Limb 143 (14) 84 (15) 52 (11)

NeoplasmsMalignant Neoplasm Aggravated 205 (20) 97 (17) 89 (20)

NervousHeadache 191 (19) 149 (27) 50 (11)Dizziness (excluding vertigo) 180 (18) 91 (16) 58 (13)Insomnia 166 (16) 111 (20) 73 (16)Paresthesia 149 (15) 85 (15) 35 (8)Hypoesthesia 127 (12) 65 (12) 43 (10)

PsychiatricDepression 146 (14) 95 (17) 49 (11)Anxiety 112 (11) 73 (13) 37 (8)Confusion 74 (7) 39 (7) 47 (10)

RespiratoryDyspnea 282 (27) 155 (28) 107 (24)Cough 224 (22) 129 (23) 65 (14)

SkinAlopecia 125 (12) 80 (14) 36 (8)Dermatitis 114 (11) 74 (13) 38 (8)

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

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 3Laboratory Parameter Zometa Pamidronate Placebo

4 mg 90 mgn/N (%) n/N (%) n/N (%)

Serum Creatinine1* 7/529 (1%) 4/268 (2%) 4/241 (2%)Hypocalcemia2 6/973 (<1%) 4/536 (<1%) 0/415 —Hypophosphatemia3 115/973 (12%) 38/537 (7%) 14/415 (3%)Hypermagnesemia4 19/971 (2%) 2/535 (<1%) 8/415 (2%)Hypomagnesemia5 1/971 (<1%) 0/535 — 1/415 (<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 amendment2Grade 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 4Laboratory Parameter Zometa Pamidronate Placebo

4 mg 90 mgn/N (%) n/N (%) n/N (%)

Serum Creatinine1* 2/529 (<1%) 1/268 (<1%) 0/241 —Hypocalcemia2 7/973 (<1%) 3/536 (<1%) 2/415 (<1%)Hypophosphatemia3 5/973 (<1%) 0/537 — 1/415 (<1%)Hypermagnesemia4 0/971 — 0/535 — 2/415 (<1%)Hypomagnesemia5 2/971 (<1%) 1/535 (<1%) 0/415 —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 amendment2Grade 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)

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-likeillness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mgand pamidronate groups) compared to the placebo group.Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreasedweight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in thepamidronate 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 ofthese small differences is not clear.Renal ToxicityIn the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients withnormal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baselinecreatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receivingZometa 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 CreatinineMultiple Myeloma and Breast Cancer Zometa 4 mg Pamidronate 90 mg

n/N (%) n/N (%)Normal 27/246 (11%) 23/246 (9%)Abnormal 2/26 (8%) 2/22 (9%)Total 29/272 (11%) 25/268 (9%)Solid Tumors Zometa 4 mg Placebo

n/N (%) n/N (%)Normal 17/154 (11%) 10/143 (7%)Abnormal 1/11 (9%) 1/20 (5%)Total 18/165 (11%) 11/163 (7%)Prostate Cancer Zometa 4 mg Placebo

n/N (%) n/N (%)Normal 12/82 (15%) 8/68 (12%)Abnormal 4/10 (40%) 2/10 (20%)Total 16/92 (17%) 10/78 (13%)*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened theinfusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients werereceiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis haveoccurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mginfused 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 thesereports are from a population of uncertain size and are subject to confounding factors, it is not possible toreliably estimate their frequency or establish a causal relationship to drug exposure.Osteonecrosis of the JawCases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patientstreated with intravenous bisphosphonates including Zometa. Many of these patients were also receivingchemotherapy and cortico steroids 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 WarningsAnd Precautions (5)].Musculoskeletal PainSevere and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphospho-nate use [see Warnings And Precautions (5)].Ocular Adverse EventsCases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edemahave been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity ReactionsThere have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, andbronchoconstriction. 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: drymouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, brady-cardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlyingrisk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders andAdministration Site: weight increase; Laboratory Abnormalities: hyperkalemia, hypernatremia.

7 DRUG INTERACTIONSIn-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro stud-ies also indicate that zoledronic acid does not inhibit micro somal CYP450 enzymes. In-vivo studies showedthat zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in-vivodrug interaction studies have been performed.

7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents mayhave an additive effect to lower serum calcium level for prolonged periods. This effect has not been reportedin Zometa clinical trials.

7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increasedrisk 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 combi-nation with thalidomide.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women usingZometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the poten-tial harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [seeWarnings And Precautions (5.4)]. Pregnancy Category DBisphosphonates are incorporated into the bone matrix, from where they are gradually released over periodsof weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount avail-able for release back into the systemic circulation, is directly related to the total dose and duration of bisphos-phonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm inanimals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into mater-nal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a womanbecomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such astime between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, andthe 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 daysbefore mating and continuing through gestation, the number of stillbirths was increased and survival ofneonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure fol-lowing an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observedin all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following anintravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortalityin pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition ofskeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gesta-tion, 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 postimplantationlosses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletaleffects 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 high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reductionof lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenousdose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dosegroup and included reduced body weights and food consumption, indicating that maximal exposure levelswere achieved in this study.In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day duringgestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surfaceareas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatmentgroups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative bodysurface areas). Adverse maternal effects were associated with, and may have been caused by, drug-inducedhypocalcemia.

8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in humanmilk, and because Zometa binds to bone long term, Zometa should not be administered to a nursingwoman.

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 pedi-atric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesisimperfecta, 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 oneyear, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD inindividual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for frac-ture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in chil-dren did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemiaof malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patientsincluded 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 commonwith repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if thepotential 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 concentrationtime profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed inadult 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 patientsreceiving 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 efficacyand safety in older and younger patients. Because decreased renal function occurs more commonly in theelderly, special care should be taken to monitor renal function.

10 OVERDOSAGEClinical 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 maycause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevantreductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenousadministration 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 single48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episodeof hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patientwas discharged seven days after the overdose.A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for atotal dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increasedGGT (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 hasbeen shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minuteintravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with anincreased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenousinfusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [seeDosage 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 T2009-101Manufactured by:Novartis Pharma Stein AGStein, Switzerland forNovartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©Novartis

TECHNOLOGY ASSESSMENT


By Robertson Paton

Over the past decade, polarizedopinion has abounded regard-ing robot-assisted laparoscopy.

On one side, many of the surgeons whopioneered the use of the da Vinci surgi-cal robot (Intuitive Surgical, Sunnyvale,CA) in Germany and the United Statesdescribed it as “revolutionary,” herald-ing “a new era,” and creating a “para-digm shift.”1-3 “We are convinced that itwill totally change the future of urolog-ical surgery,” researchers at theUniversity of Heidelberg, Germany,wrote in May 2001.3 The technologywas rapidly adopted—it went frombeing used in 2648 radical prostatec-tomies in 2003 to 73,000 in 2009—about85% of the total performed in theUnited States, according to an article inthe New York Times.4

Some urologists, however, weredeeply skeptical about the da Vincirobot’s benefits. Some surgeons takeissue with the robot’s high costs—asmuch as $1.4 million for the unit, sever-al hundred thousand dollars annuallyfor maintenance contracts, and nearly$2000 per procedure for consumables.Others question the comparative effec-tiveness of robot-assisted surgery andare frustrated with what they view asthe slow pace of improvement in thetechnology. To bolster their views, theypoint to studies indicating that robot-assisted surgery is no more effectivethan well-established open proceduresand standard laparoscopy.

The Pennsylvania Hospital

Experience

A recent media seminar and expertpanel convened at Pennsylvania Hos -pital, Philadelphia, to help assess whe -ther robotic surgery is an advance inmodern medicine or just effective mar-keting. Although the seminar did notnecessarily provide the answer to thisquestion, it did provide a backgroundas to how the technology works and theexperiences of the institution and thesurgical teams in employing it.

Laparoscopy, whether robotic or stan-dard, results in smaller incisions; lesspain and blood loss; fewer transfusions;and faster discharge and recovery times,said Daniel Eun, MD, assistant profes-sor of urology in surgery and director ofminimally invasive and robotic urologiconcology and recon struction at theUniversity of Penn sylvania School ofMedicine, Philadel phia. The drawbacksof laparoscopic procedures include lesssurgical dexterity, limitations on thekinds of procedures that can be per-

formed, and generally longer times inthe operating room, he said.

During standard laparoscopy, the sur-geon must stand over the patient butlook at a 2-dimensional image on a mon-itor, usually located overhead. The in -struments are long and awkward, withno “wristed” movement. “It’s counter -intuitive,” Dr Eun said. “It’s like operat-ing with chopsticks.” The instrumentsalso amplify movement and are morelikely to cause “instrument tremor.”Ergo nomically, standard laparoscopyresults in greater surgeon fatigue thanopen or robot-assisted surgeries.

In contrast, the da Vinci surgicalrobot offers a 3-dimensional vision sys-tem, computerized tremor filtering,and automatic scaling down of largemotions of the surgeon’s hand to theconfined surgical domain. The surgeonsits at a console, using a foot-operatedclutch that supplements the hand con-trols to conduct the operation.

Even though members of his teamare qualified, Dr Eun makes all inci-sions. Robot-assisted procedures per-formed by Dr Eun rarely have to beconverted to open surgical techniques.“The open incision is a thing of the pastin my care,” he said. Although Dr Eunis an advocate of robot-assisted proce-dures, having performed 4500 duringhis career, he does not perform themunless, based on previous experience,the expected “outcome [will be] at leastequal to an open operation.”

“The robot is a tool,” Dr Eun conclud-ed. “The surgeon is the one who selectsthe patients and produces the results.”

Jonathan D. Moreno, MD, David andLyn Silfen University Professor ofMedical Ethics, University of Penn -sylvania School of Medicine, secondedthis conclusion. “Perhaps it’s better tothink of this as device-assisted surgery,an extension of the kinds of tools sur-geons have used for a long time,” hesaid. “A true robot is autonomous.”

Despite the state of the US economy,Dr Moreno said he expects that plentyof money will be invested in new med-ical technology, including enhance-ments to the da Vinci robot and thedevelopment of new robotic systems.“In 25 years, we’ll have a device thatwill be able to interact with [the sur-geon],” he said.

Other panelists were enthusiasticabout robot-assisted surgery. “The robotcan work in places you can’t get yourhands in. This technology is really in itsinfancy,” said William Welch, MD, pro-fessor of neurosurgery at the Universityof Pennsylvania School of Medicine.

Use Ahead of the Evidence

Despite the generally positive reac-tion to the technology at PennsylvaniaHospital, at least one cautionary notewas struck. John Y.K. Lee, MD, assistantprofessor of neurosurgery at theUniversity of Pennsylvania School of

Medicine and medical director of theGamma Knife Center at PennsylvaniaHospital, remarked on the difficultiesof performing comparative effective-ness studies. “How do we get random-ized studies? It’s very difficult,” he said,pointing out that this is particularly thecase for the rare tumors seen in neurol-ogy. “The patient doesn’t want to berandomized to open or endoscopic[surgery]. They want the least invasiveor maximally effective [procedure].We’ll never have comparative effective-ness studies for these types of tumors.”

Outside of the institution, studies ofthe merits of robot-assisted surgery haveemerged, and although some have beeninconclusive, some researchers havetaken definite stands on the comparativeeffectiveness of the technology. Hu andcolleagues performed a population-based observational cohort study usinginformation from a national cancer data-base.5 They determined that patientswho underwent minimally invasiveradical prostatectomy (standard androbot-assisted) experienced shorterlength of stay and fewer miscellaneoussurgical complications and strictures

than patients in the open prostatectomygroup, but experienced more genitouri-nary complications, incontinence, anderectile dysfunction. The researchersconcluded that patients “had beenenamored of new technology” in choos-ing minimally invasive surgery insteadof the established gold standard of openradical prostatectomy.4

When Breitenstein and colleaguesconducted a case-matched study ofrobot-assisted versus standard laparo-scopic cholecystectomy, they found sim-ilar outcomes, but hospital costs were28% higher for the robot-assisted chole-cystectomies.6 “Costs of robots…arehigh and do not justify the use of thistechnology considering the lack of bene-fits for patients,” the authors concluded.

The debate will certainly continue.When more experience is gained withrobotic technology, outcomes shouldimprove and costs should drop as thetechnology improves and competitorsenter the field. In the meantime, the daVinci robot should not be seen as amiraculous device that can overcomethe limitations of an inexperienced sur-geon, according to Vipul Patel, MD,medical director of the Global RoboticsInstitute at Florida Hospital, Orlando.Dr Patel, who did not attend the meet-ing, commented in a separate interviewthat “the robot is an enabling technolo-gy. It makes a good surgeon better; itdoesn’t make a bad surgeon good.” �

References1. Bräutigam WM, Engl T, Bentas W, et al. Robotic-assisted laparoscopic radical prostatectomy: theFrankfurt technique. World J Urol. 2003;21(3):128-132.2. Bentas W, Wolfram M, Jones J, et al. Robotic technol-ogy and the translation of open radical prostatectomyto laparoscopy: the early Frankfurt experience withrobotic radical prostatectomy and 1-year follow-up.Eur Urol. 2003;44(2):175-181.3. Rassweiler J, Binder J, Frede I. Robotic andtelesurgery: will they change our future? Curr OpinUrol. 2001;11(3):309-320.4. Kolata G. Results unproven, robotic surgery winsconverts. New York Times. February 14, 2010;A1.5. Hu JC, Gu X, Lipsitz SR, et al. Comparative effec-tiveness of minimally invasive vs open radical prosta-tectomy. JAMA. 2009;302(14):1557-1564.6. Breitenstein S, Nocito A, Puhan M, et al. Robotic-assisted versus laparoscopic cholecystectomy: out-come and cost analyses of a case-matched controlstudy. Ann Surg. 2008;247(6):987-993.

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

“The robot is a tool. The surgeon is the one who selects the patients and producesthe results.” —Daniel Eun, MD

A study examining the effective-ness of robotic versus standardprostatectomy for prostate cancer ispresently under way. Principalinvestigator Martin G. Sanda, MD,the director of the Beth IsraelDeaconess Medical Center ProstateCancer Care Center, will examinehealth-related quality of life beforeand after surgery, and will look at

how surgeon experience relates tooutcomes, and whether robotic assis-tance reduces variance. Finally, thestudy will compare costs and costeffectiveness between standard androbot-assisted prostatectomy usingquality adjusted life-year models.Preliminary results will be submittedto a peer reviewed publication thisfall, Dr Sanda said.

Economic and Outcome Answers on the Way


Cost-Effectiveness in the New Comparative... Continued from cover

If that is the case, does cost-effective-ness analysis (CEA) have a future?“We’re on a precipice…a policy win-dow of sorts, and while that window isopen, lots of creative activities can takeplace,” said Jean Slutsky, director of theCenters for Outcomes and Evidence,Agency for Healthcare Research andQuality, Rockville, MD.

Given this new reality, Dr Pearsonsuggested that “impact on service” isone way that patients would findCEA helpful. “Certain prostate can-cer therapies involve 1 overnight hos-pital stay and a few doctor visits

down the road; others involve a dailydoctor’s visit for up to 6 to 8 weeks,”he noted. “Just putting that down canbe powerful.” Assessing the cost toreduce side effects is another exam-ple. “If you’ve got 2 different agents[for] the same thing and one has alower rate of side effects but is moreexpensive, how much are we spend-ing to reduce that risk of a sideeffect?” he wondered.

Ms Slutsky asserted that CEA des-perately needs to overhaul its publicimage. “We’ve allowed all these tags tobe associated with it, and it’s nowbecome a public relations game, notan information game,” she said. Ac -knowledging that “it’s the terminologythat gets a little tricky,” she said that“transparency is needed so the publicknows how we come to cost conclu-sions. I really can’t emphasize enoughhow much we need effective commu-nication so it comes across in a non-threatening way.”

Putting Cost-Effectiveness in

the Equation

Lewis Sandy, MD, senior vice presi-dent of clinical advancement at Uni -tedHealth Group, Minneapolis, MN,described how separating clinical

value from cost-effectiveness is used todetermine the benefits his companyprovides. UnitedHealth Group’s differ-ent committees research the clinicalvalue of a procedure, device, or drugby asking questions including:• Does it work?• How strong is the evidence?• What are the outcomes?• How does it work in the real world?

“This clinical value calculus affectscoverage decisions,” he said. “Is the pro -duct included in the envelope for bene-fit coverage? Cost-effectiveness canaffect how it is covered—what is the

benefit level and structure?” Dr Sandyexpressed hope that CEA will be in theexamination room in the future, whenthe patient needs to make a high-stakeschoice. “Comparative effectivenessneeds to support optimal decision-making between doctors and patients,”he argued, adding that it should foster“a dialogue about evidence and an elic-itation of preferences.”

Hemal Shah, PharmD, executivedirector of health economics and out-comes research at Boehringer Ingel -heim, Ridgefield, CT, concurred withDr Sandy that cost and value should be

evaluated only after clinical outcomesare assessed. Using CEA to determine aone-size-fits-all measure of value isimpractical, she argued, and insteadshould be done at regional or local lev-els. “Depending on the region andpractice patterns, you’ll see very differ-ent ways cost and utilization areobserved,” Dr Shah noted.

Dr Pearson summed up the futureof cost-effectiveness. “The UnitedStates has largely ignored how it usesits re sources for healthcare,” he said.“If we feel we’re on an unsustainablepath, what are the ways we can en -gage the public in a dialogue aboutsome of those issues? Cost-effective-ness is not thought of as a method, it’sthought of as a form of decision-making. We may want to rename itand think of it in new terms.” �

By Cherie Dewar

Boston, MA—The work of 3 HarvardMedical School researchers presentedat June’s AcademyHealth Conferenceprovided a snapshot of how cancercare outcomes compare between theVeterans Health Administration (VHA)and the fee-for-service Medicare com-munity. In this case, the notion of “youget what you pay for” may not neces-sarily be true.

As the largest integrated deliverysystem in the world, the VHA provid-ed free or low-cost healthcare to 5.5million veterans in 2007. The paperspresented at this session focused onmale patients aged >65 years with can-cer diagnosed or their first course oftreatment received at the VHA be -tween 2001 and 2004. This cohort wascompared with a similar populationidentified from the Surveillance,Epidemiology, and End Results (SEER)Medicare database, whose regionscover about 25% of the United States.The researchers’ analytic strategy andsensitivity analysis accounted forobserved differences seen between the2 populations (eg, the higher percent-age of blacks in the veteran populationand a lower median income amongveterans’ ZIP codes).

After coinvestigator ElizabethLamont, MD, MS, established statisti-cally that the VHA’s data were accu-rate, Nancy Keating, MD, MPH, pre-sented findings on the quality of cancercare in the VHA versus the private sec-tor. Showing a graph depicting a high-er rate of stage I colon cancer diagnosisat the VHA compared with SEER(29.6% and 24.5%, respectively), DrKeating noted, “this is consistent withother studies that demonstrate the

VHA has higher rates of early screen-ing than the private sector.”

Dr Keating then compared the VHAand SEER’s propensity scores for stan-dard treatments, including chemother-apy, surgery, radiation, and bisphos-phonates for 6 cancer types: colon,small-cell lung, non–small-cell lung, pros -tate, non-Hodgkin lymphoma (NHL),and myeloma. The results showed theVHA and SEER exchanging the leadposition of higher propensity scores forthe different procedures. For example,the VHA’s tendency to perform cura-tive surgery for non–small-cell lungcancer was 60.2% versus 65.6% forSEER. Conversely, the propensity scoreof CHOP (cyclophosphamide, hydrox-ydaunorubicin [doxorubicin], Oncovin[vincristine], and prednisone/pred-nisolone) treatments to diffuse large B-

cell NHL at the VHA was 71.2% versus60.7% for SEER. Taking a closer look atinstances when the VHA did notappear to perform as well as the pri-vate sector, Dr Keating’s team adjustedfor unobserved factors, such as thehigher smoking rate, lower educationlevel, and more severe comorbiditiesthat veterans are known to have. “If weaccount for the severity of comorbid ill-ness within the VA population, particu-larly with chronic obstructive pul-monary disease, we see the differencesin treatment erased, or even reversed,”she said.

Is Aggressive End-of-Life Care

Better?

Treatment of older patients with can-cer at the end of life has becomeincreasingly aggressive over time,despite the absence of evidence thataggressive care at the end of life is asso-ciated with better outcomes, accordingto a second paper presented by DrKeating, entitled “Cancer Care at theEnd of Life in the VHA Versus thePrivate Sector.” Dr Keating’s teamlooked at 3 measures of end-of-life carefor stage IV colorectal and lung cancer:chemotherapy within 14 days of death,admission to the intensive care unit inthe last month of life, and >1 emer-gency department visit in the lastmonth of life. The VHA had a lowerpropensity score for all 3 measures, butDr Keating postulated that this maynot necessarily be a bad thing. “Theseare indicators for care that are not

Comparing VHA with Fee-for-Service Cancer CareImplications for cancer care outside the VHA

at a glanceCost 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

Although complex, comparative

effectiveness analysis could

provide value for patient-level

decision-making

“Comparative effectiveness needs to support optimaldecision-making between doctors and patients.”

—Lewis Sandy, MD

“The VHA’s less aggressive care for advanced cancershould be considered for healthcare reform.”

—Mary Beth Landrum, PhD


ACADEMYHEALTH CONFERENCE

ACADEMYHEALTH CONFERENCE


potentially useful,” she said. “Theselower rates are probably better,although there are some that mightargue that.” Dr Keating surmised thatthe VHA is less aggressive with end-of-life care perhaps “due to the absence offinancial incentives for end-of-lifemeasures, or the integrated deliverysystem may be better structured tolimit potentially futile medical care.”

These end-of-life care statistics do notappear to jeopardize survival at theVHA. Mary Beth Landrum, PhD, pre-sented research indicating that survivalfor older men with colorectal or lungcancer was comparable or better at theVHA when weighed against the privatesector.1 However, Dr Landrum ack nowl -edged, “We don’t really understand therelationship between aggressive end-of-life care and patients’ preferences.Ongoing work is looking at that.”

When asked how their studies’results may impact the larger world ofcancer care, Dr Landrum suggestedthat “the VHA’s less-aggressive care foradvanced cancer should be consideredfor healthcare reform.” Citing theVHA’s quick uptake of expensivemedicinal options (eg, rituximab-CHOPchemotherapy) versus its slower imple-mentation of complex equipment thatrequires highly trained workers (eg, 3-dimensional conformal radiotherapyand intensity-modulated radio therapy),

Dr Keating proposed that “large capitaloutlay may not translate to better sur-vivability. Comparative effectivenesscan provide some good data to deter-mine the better route.” �

Reference1. Keating NL, Landrum MB, Lamont EB, et al. End-of-life care for older cancer patients in the VeteransHealth Administration versus the private sector.Cancer. 2010;116(15):3732-3739.

Comparing VHA with Fee-for-Service... Continued from page 20

“Large capital outlay maynot translate to bettersurvivability. Comparativeeffectiveness can providesome good data todetermine the betterroute.”

—Nancy Keating, MD, MPH

at a glanceThe 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

TM

CONTINUING EDUCATION


By Michael Jacobs, RPh

Value in healthcare is defined ashealth outcome/dollar of costexpended.1 From a payer’s per-

spective, this simply means that ifmore resources are expended,improved health outcomes should fol-low within a reasonable time period.Likewise, if consistently good healthoutcomes can be achieved by investinga predictable amount of resources (ie,by following a narrow clinical pathwayto treat a given disease or condition),payers will attempt to establish a bene-fit design and cost-sharing philosophythat provides those outcomes with asfew barriers as possible to patients andcaregivers.

Several steps must be taken in thehealthcare system to provide value-basedbenefits in oncology. These include:

• Designing benefits that arrange cost-sharing based on the weight of scien-tific evidence

• Selecting networks and providersbased on historic performance anddelivery of desired health outcomesat financially acceptable levels

• Providing recognition (ie, compensa-tion) for high-performing compo-nents of the healthcare system.2

Designing benefits that align theinterests and incentives of all parties inoncology care is no simple task. This ispartly because a number of payers donot know where, or how much, they arespending for many of these therapies.3

Some payers cover oncology therapiesin the medical benefit, some cover themin the pharmacy benefit, and still othersare paying for them through a codingsystem (J codes) that does not identifythe specific therapies administered to

the patients, instead listing only thecharges for these therapies.

Along with these billing options,today’s patients have more choices ofwhere to receive oncology therapies.These drugs can be provided through ahospital setting, a physician’s office, aninfusion center, a specialty pharmacyprovider, or a local pharmacy provider,just to name a few.

Managing Complex Care

With more than 800 new oncologypharmaceutical drug entities in devel-opment, and many of these classifiedas specialty medications,4 cost isbecoming an increasing concern forpayers. It is estimated that as many as400 of these new therapies could cost inexcess of $50,000 per course of therapy,which raises the following question formany payers: will the health outcomesproduced by these expensive medica-

tions justify the added investment?Payer concerns regarding health out-

comes and healthcare costs have ledmany to accept the concept that follow-ing evidence-based, consensus-driventreatment protocols and pathways maybe the most appropriate way to go, espe-cially in oncology. This approach allowspayers and clinicians to collect data,compare results, and identify potentialcare improvements as physicians beginprescribing new agents, as well as tobegin achieving therapeutic predictabili-ty. With this collected information, pay-ers can better plan benefits and sharecosts; identify the highest qualityproviders, provider networks, and dis-tribution channels; and reward thesehigh-quality providers for their efforts.

But payers, physicians, and patientsalso need to move beyond these efforts.Concerns have been raised about howto determine, with a reasonable certain-ty, that a given therapy will produce apositive result in a particular patient.The opposite is also true—how do weidentify the patients in whom a giventherapy will not produce the desiredresults? In some cases, pharmacoge-nomics can play a role. For example,women with certain breast cancertumors possessing a genetic variant thatcauses overexpression of the HER2 pro-tein will benefit if trastuzumab is part oftheir therapeutic regimen.5 On the otherhand, women with estrogen receptor-negative/progesterone receptor-nega-tive (ER-/PgR-) tumors will not benefitfrom endocrine therapy, such as tamox-ifen.6 Another example of the benefit ofpharmacogenetics has recently beenevidenced in multiple myeloma. Evenas the ability of bortezomib therapy toovercome the high-prognostic risk asso-ciated with a deletion of chromosome13 has been relatively well documented,several studies suggest that patientswho have this deletion do not benefitfrom thalidomide.7-10 As more informa-tion is gained regarding the molecular

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

PROGRAM P10024Initial Release Date: September 15, 2010 • Expiration Date: September 15, 2011.Estimated time to complete activity: 1 hour.

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

TARGET AUDIENCEThis activity was developed for oncology pharmacists and other healthcare professionals.

LEARNING OBjECTIVESUpon 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

Designing benefits that align the interests and incentivesof all parties in oncology care is no simple task.

Michael Jacobs, RPh, is national clinical practiceleader for Buck Consultants, LLC, A Xerox Company,Atlanta, GA.

Value-Based Oncology Benefits


COMMERCIAL SUPPORTACKNOWLEDGMENT

This activity is supported by an educationalgrant from Millennium Pharmaceuticals, Inc.

INSTRUCTIONS FOR CREDIT

There is no fee for this activity. After readingthis CE activity in its entirety, participants mustcomplete the posttest and evaluation. Theposttest and evaluation can be completedonline at www.mlicme.org/10024.html. Uponcompletion of the evaluation and scoring 70%or better on the posttest, you will immediatelyreceive your certificate online. If you do notachieve a score of 70% or better on theposttest, you will be asked to take it again.Please retain a copy of the certificate for yourrecords.

PHARMACISTS’ DESIGNATION

Medical Learning Institute, Inc, isaccredited by the AccreditationCouncil for Pharmacy Education

(ACPE) as a provider of continuing pharmacyeducation. Completion of this activity provides

for 1.0 contact hour (0.1 CEU) of continuingeducation credit. The universal activity numberfor this activity is 0468-9999-10-027-HO1-P.

For questions regarding the accreditation ofthis activity, please contact Medical LearningInsti tute, Inc, at 609-333-1693 or [email protected].

DISCLOSURES

Before the activity, all faculty will disclose theexistence of any financial interest and/or rela-tionship(s) they might have with the manufac-turer(s) of any commercial product(s) to be dis-cussed during their presentation(s): honoraria,expenses, grants, consulting roles, speaker’sbureau membership, stock ownership, or otherspecial relationships. Presenters will informparticipants of any off-label discussions.

• Michael Jacobs, RPh, has nothing to dis-close.

• Bruce A. Cutter, MD, MMM, is on the speak-er’s bureau for Pfizer.

• Kavita V. Nair, PhD, is a consultant andresearcher for Centocor and a researcher forAmgen, Novartis, and Daiichi Sankyo.

The associates of Medical Learning Institute,Inc., the accredited provider for this activity,and Center of Excellence Media, LLC, do nothave any financial relationships or relationshipsto products or devices with any commercialinterest related to the content of this CME/CEactivity for any amount during the past 12months.

DISCLAIMER

The information provided in this CE activity isfor continuing education purposes only and isnot meant to substitute for the independentmedical judgment of a healthcare provider rel-ative to diagnostic and treatment options of aspecific patient’s medical condition. Tradenames used in this supplement are for thelearner’s reference only. No promotion of orbias toward any product should be inferred.



By Kavita V. Nair, PhD

Avariety of strategies—includingvalue-based benefit design,payment reform, and compara-

tive effectiveness research (CER)—arebeing used by payers, providers, andemployers to address the central issueof value in healthcare. In general,healthcare value can be defined as“improving the net ratio of benefitsobtained per dollar spent on health-care”1; when attempting to define valuefor specific disease states, oncology hasbeen largely ignored. Under healthcarereform, however, the provision ofhealthcare is now a mandate, withemployers required to provide healthinsurance, payers required to cover allindividuals, and consumers required topurchase health insurance or face finan-cial penalties.

This legislation has therefore trig-gered an urgent need to find ways todefine value in oncology for several keyreasons. First, there are substantial costsassociated with treating an oncologypatient. A recent study of multiplemyeloma costs showed that the directmedical costs for 1 therapeutic courseof bortezomib, bortezomib plus dox-orubicin, thalidomide plus low-dosedexamethasone, and lenalidomideplus low-dose dexamethasone rangedfrom $33,966 to $47,002.2 In addition,the management of complications such

as hypercalcemia, anemia, bone lesionsand fractures, and renal failure canthemselves be quite high.3

Second, there is an urgency associat-ed with treating oncology patients. Theindividualized and emotional nature ofthis disease has resulted in a “one-size-does-not-fit-all” approach to how it iscurrently managed. Oncologists mayfeel the need to treat patients with thenewest (and most expensive) agents

that may extend survival for only a fewmonths. The sheer complexity of oncol-ogy management has deterred manyinnovators from pursuing efforts todemonstrate value. The goal of thisarticle is to provide a broad overviewon how value can be defined in oncol-ogy management.

Many Means of Establishing Value

One of the first steps in defining valueis to conduct CER for drug therapies,technologies, and surgical options. CERcompares the benefits, risks, and costs ofstrategies for the treatment of a specificdisease. The Comparative EffectivenessResearch Act of 2009 allocated $1.1 bil-lion in preliminary funding, andlaunches plans for more formal CER.4

Although the high cost of cancer drugtherapies and treatment options makethis disease area ripe for CER studies,conducting these within oncology poseschallenges. The multifaceted therapyoptions used to treat cancer make CER

complicated—it is not enough to deter-mine if one drug is better than another;evaluations must consider whether adrug regimen may be superior to analternative regimen or surgical option.In addition, it is unclear who will bearthe cost of these evaluations. Are payersor pharmaceutical manufacturers will-ing to develop randomized clinical trialsto gather evidence of comparative effec-tiveness or do oncology practices have

to do so within their own individualpractices? Related to the issue of gather-ing CER data is the adoption of practiceguidelines for the cost-effective utiliza-tion of oncology drugs.

The manner in which drug therapiesare made available to oncology pa tientsis another defining value issue. Oncol -ogy drugs are unique in that both oncol-ogists and pharmacy directors canacquire and dispense the drug. Oncol -ogists employ a “buy-and-bill” ap -proach, whereas pharmacy payers dis-pense oncology drugs through specialtypharmacies and tiered formularies.Therefore, the 2 common ap proachesfor accessing oncology drugs arethrough the medical benefit (typicallythrough oncology practices) andthrough the pharmacy benefit. Eachapproach has downsides, includingincreased patient cost-sharing if drugsare purchased through the pharmacybenefit, and possible de layed access totherapy if patients have to wait for their

physicians to acquire their medications.The unique nature of oncology drugmanagement and the dichotomy of thisdistribution has prompted discussionsabout newer value-based benefit designoptions and integrated care models foroncology medication management.

Another means of establishing valuein oncology management is outcomesmeasurement. In oncology clinical tri-als, the primary goal typically is toobtain evidence regarding the benefit-to-risk profile of the experimental inter-vention relative to an existing standardof care. Although the efficacy of oncolo-gy drugs has historically been meas-ured by overall survival, surrogate end-points, such as time-to-progression(TTP) and progression-free-survivalhave been more frequently utilizedover the last decade.5 Other end points,such as tolerability of side effects,patient quality of life, cost effectivenessof drug therapies (ie, quality-adjustedlife-years and incremental rate ratioscan be utilized before starting treatmentto determine the utility of using a newand expensive drug therapy. For exam-ple, the VISTA trial compared borte-zomib plus melphalan/prednisone(VMP) with melphalan/prednisone(MP) in newly-diagnosed multiplemyeloma patients ineligible for stem-cell transplant.6 VMP was found to besuperior to MP for TTP, the primaryendpoint for the trial. VMP also provid-ed a substantial survival benefit. Anincremental cost analysis was conduct-ed to compare lifetime health outcomesand cost effectiveness of VMP com-

Defining Value in Oncology

The sheer complexity of oncology management has deterredmany innovators from pursuing efforts to demonstrate value.

Kavita V. Nair, PhD is associate professor and direc-tor, graduate studies (pharmaceutical outcomesresearch track) at the School of Pharmacy,University of Colorado, Denver.

path o genesis of cancer and more target-ed therapies are developed, the pharma-cogenomics industry will continue todevelop tests to identify patients thatwill benefit (or not benefit) from theseagents.

Pharmacogenomic tests promise bet-ter targeting of care, but are also indica-tive of how complex cancer care hasbecome. Aside from complicating thepractices of pharmacy and medicine,pharmacogenomics raises questionsregarding how best to manage thesetherapies, given the involved laboratorytesting, physician input, and specialtypharmacy distribution of the drug com-ponent of therapy. In addition, ancillaryservices, such as support for caregivers,emotional support, and financial consid-erations, may be beyond the primaryinsurance coverage.

One patient care management model

being discussed (and in some cases, putinto practice) by payers is the medicalhome. With this approach, pharmaco-logic therapy is provided by the lowest-cost provider, the oncologist providesthe medical component of therapy, and acase management firm coordinatesbetween these providers while alsoinvolving home caregivers to ensureemotional support for those who need it.For this approach to be successful, how-ever, the healthcare system will have toevolve and will require an integratedhealth record, among other resources.

A Vision of the Future

For payers to provide these newoncology technologies and therapieseffectively and appropriately, they willhave to make increased demands onproviders that will impact all aspects ofoncology treatment. Payers may insist

that newly introduced therapies havesolid outcomes data and predictableresults for specific disease and tumortypes before they will be fully reim-bursed. This requirement may beaccompanied by required pharmacoge-nomic tests (with the accompanyingexpense of these tests). Total patientmanagement will be in greater demand,and a leveling of the playing field fordistribution channels is expected, sothat “gaming” of the system will beeliminated. Benefit designs that foster apatient’s preventive activities willbecome more common, with barriers toprevention and wellness being re movedfrom healthcare benefits. Lastly, the useand acceptance of clinical pathways willbecome a standard component of onco-logic therapies. �

References1. 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%2FsecureDocument%2Ecfm&destinationParms=docID%3D825.(password protected site). Accessed August 18, 2010.3. Buck Consultants. Second Annual Prescription DrugBenefit Survey. San Francisco, CA; 2009:33.4. Pharmaceutical Research and Manufacturers ofAmerica. 2009 Report Medicines in Development forCancer. www.phrma.org/files/attachments/09-046PhRMACancer09_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 fromadjuvant tamoxifen therapy in primary breast cancerpatients according oestrogen receptor, progesteronereceptor, 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 prognosisconferred by chromosome 13 deletion in phase 2 and 3trials. Leukemia. 2007;21:151-157.8. Sagaster V, Ludwig H, Kaufmann H, et al.Bortezomib in relapsed multiple myeloma: responserates and duration are independent of a chromosome13q-deletion. Leukemia. 2007; 21:164-168.9. Attal M, Harousseau J-L, Leyvraz S, et al.Maintenance therapy with thalidomide improves sur-vival in patients with multiple myeloma. Blood.2006;108:3289-3294.10. Sahebi F, Speilberger R, Kogut NM, et al.Maintenance thalidomide following single cycleautologous peripheral blood stem cell transplant inpatients with multiple myeloma. Bone Mar Transpl.2006;37:825-829.


Value-Based Oncology... Continued from page 22



By Bruce Cutter, MD, MMM

Treatment of multiple myeloma(MM) has evolved rapidly inrecent years, from a relatively

simple, cheap, and somewhat effectiveregimen (melphalan hydrochlorideand prednisone), to high-dose chemo -therapy with autologous stem celltransplantation, to new and more effec-tive agents.1 Although we are now see-ing impressive responses and signifi-cantly improved survival times, thisprogress has not come without cost.The newer agents (eg, thalidomide,lenalidomide, and bortezomib) havetheir own toxicities, and considerableprice tags have accompanied treatmentadvances. In addition, some of theseagents are delivered orally, which rais-es unique issues regarding cost, acces-sibility, and system that are beyond thescope of this article.

Looking ahead, we need to under-stand how best to combine these newagents, among themselves and witholder medications, and to determine therole autotransplantation will continue toplay. As our understanding of MM’s cel-lular pathways and molecular geneticscontinues to improve, additional effec-tive treatments will likely be developed.

Along with the clinical challenge pre-sented by MM, today’s clinician alsomust deal with matters of value andsustainability. Value (defined as qualityand outcomes divided by costs) is cen-tral to the availability and success of

cancer treatments; at its core, the issue is“bang for the buck.” Clinical pathwaysare an important means of addressingthe large value deficit in oncology.

Clinical Pathways: Components

and Processes

At the most fundamental level, clini-cal pathways represent an agreementby oncologists to treat a patient with acertain disease in a certain way; theyare a tool to standardize care andreduce unexplained variation. Clinicalpathways hold the promise of helpingto drive fundamental change in thecurrent system of oncology care andremedy the existing value deficit. Theypossess a number of beneficial quali-ties, including: • Being physician (provider) devel-

oped and owned• Being narrowly structured (ie, they

are a pathway, not a menu)

• Being supportive of clinical researchand knowledge advancement (eg, clin-ical trials are always “on pathway”)

• Being based on Institute of Medicinequality principles, including beingeffective (evidence-based), safe,patient-centered, timely, efficient,and equitable

• Having physician accountability as acentral component

• Having an opt-out (“off pathway”)mechanism to allow for appropriatevariation based on clinical needs

• Containing an ongoing review pro -cess to assist with accountability andto modify treatment as needed

• Being transparent and auditable• Addressing both the numerator and

denominator of the value equation.A clinical pathway for MM (or any

other cancer) would be formulatedand implemented by a group of oncol-ogists, preferably in collaboration witha health plan, who would look at theevidence for MM treatment anddecide, based on clinical outcomes andother patient-centered factors (ie, toxi-city and convenience), the most appro-priate treat ment(s) for the disease.Cost would be considered next, to helpdetermine what treatment(s) are to be“on pathway”; cost, however, nevertrumps clinical criteria. The pathwaywould then be adopted by a practiceand operationally “rolled out,” with aprospective review mechanism byphysician peers to assure complianceand accountability, and to allow for thepatient to be treated “off pathway” ifclinical circumstances warrant (asreviewed and agreed upon by physi-cian peers). Pathway compliance andthe reasons for treating a patient “off-pathway” are documented, and retro-spective data monitoring takes placeto assess pathway appropriatenessand accountability. A thorough path-way review is undertaken at leastyearly, or more frequently if necessary,to adjust for changes in clinical prac-tice and the literature.

The Cancer Care Northwest

Pathway Experience

In our practice, Cancer Care North -west, a pharmacy and therapeuticscommittee is charged with pathwaydevelopment and physician account-ability. The Cancer Care Northwestpathways are part of a larger qualityinitiative called Foundations of Qual -ity, developed in close collaborationwith Premera Blue Cross, a regional

health plan, beginning in 2002. Thisclinical quality program has beenpaired with a pay-for-quality con-tract that created physician incen-tives and rewards for the value webring to the table. Explicit in this pro-gram’s development was the beliefthat this model of standardizing careand reducing unexplained variationwill enhance the value of care provid-ed to our patients.

Although this belief is yet unproved,data in support of this value hypothe-sis are beginning to appear in the liter-ature. So far, we have developed a“proof of concept,” in which providersand health plans collaborate in a team-based fashion to develop delivery sys-tem innovation that promises toenhance patient quality of care,address value, and promote sustain-ability for the system, the providers,and health plans.

Although clinical pathways can helpto standardize care and reduce unex-plained variation, changes necessary toaddress the value deficit in oncologywill require fundamental culturechange for providers and health plans.The major barriers to adoption of path-ways and other tools to address thevalue deficit involve culture, leader-ship, and change management, notoperations. Because pathways are evi-dence-based, quality-driven, and value-focused—in addition to being opera-tionally viable and scalable—theyspeak to the needs and values of bothproviders and health plans. Moreimportantly they speak to the realneeds of patients. �

Reference1. Jagannath S, Kyle RA, Palumbo A, et al. The currentstatus and future of multiple myeloma in the clinic.Clin Lymphoma Myeloma Leuk. 2010;10(1):28-43.

Putting Multiple Myeloma on the Clinical Pathway

Clinical pathways hold the promise of helping to drive fundamental change in oncology care.

Bruce Cutter, MD, MMM, is a consultant inSpokane, WA.

pared with MP. Although the total life-time direct medical costs for VMP maybe more than twice those for MP, thecost per life-year was approximately18% less while providing more quality-adjusted-life-years.7

Payment reform in primary care hasalso been investigated. Pay-for-perfor-mance (P4P) models, in which physi-cians are provided financial incentivesfor improving outcomes of care, haveemerged across the nation. Althoughthese P4P models have traditionallybeen used in primary care to rewardphysicians for improving such clinicalmeasures as glycemic control in dia-betes, for example, they can also start tobe utilized in oncology management.One option under discussion is pre-

ferred tiered provider networks, where-in providers are rewarded for achievinglower-cost care with better clinical out-comes. P4P options, however, can onlybe developed in oncology managementwhen there is better evidence aboutwhich drug therapy or surgical optionsprovide the best outcomes.

Another way of defining value is inthe area of cancer prevention. Screen -ing rates for prostate and colon can-cer are between 50% and 60% nation-wide, well below expected levels.In creasing screening compliance rateshas the potential to demonstratevalue for employers in terms of earlydetection, lower direct medical costs,and fewer losses in productivity.Although cancer screening has not

traditionally been a focus for employ-er prevention efforts (because of thesmall prevalence of disease), focusingon increasing screening rates forhigh-risk populations can result insignificant medical cost savings andlimit productivity losses for employ-ers and payers.

Finally, in the oncology value equa-tion, awareness and communication ofthe true cost of a drug therapy or a pro-cedure and its expected benefits (with-in the context of costs) for both thepracticing oncologist and the patientcan help facilitate informed decision-making. Understanding the cost-shar-ing levels a patient may face with aparticular drug or procedure, and mak-ing that part of the physician–patientdiscussion, will provide more value inchoosing the right option. �

References1. Schickedanz A, rapporteur. Assessing and ImprovingValue in Cancer Care. Workshop Summary. Washing -ton, DC: The National Academies Press; 2009. http://www.nap.edu/catalog/12644.html.2. Fullerton DSP, Trautman H, Huang H, et al. A budgetimpact model comparing resource utilization of fourapproved therapies for multiple myeloma (MM) in theUS. Blood. 2007;110(suppl):abstract 3324.3. Cook R. Economic and clinical impact of multiplemyeloma 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 accel-erated approval process. Health Aff (Millwood). 2005;24(1):67-78.6. San Miguel JF, Schlag R, Khuageva NK, et al; VISTATrial Investigators. Bortezomib plus melphalan andprednisone 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-effective-ness of bortezomib for the initial treatment of multiplemyeloma in the United States. Blood (ASH AnnualMeeting Abstracts). 2009;114(22):561. Abstract 1379.8. Centers for Disease Control and Prevention.Behavioral Risk Factor Surveillance System SurveyData. Atlanta, Georgia: US Department of Health andHuman Services, Centers for Disease Control andPrevention, 2007.

Defining Value in... Continued from page 23

FOCUS ON


By Caroline Helwick

Virtually all patients that succumbto prostate cancer die of metasta-tic castration-resistant disease

(CRPC). Doce taxel, the standard of carefor these patients, provides a modestprolongation of survival, but there is anurgent need for novel treatment strate-gies. Recently, the biological and molec-ular mechanisms driving prostate can-cer growth and progression havebecome better understood, and this hasresulted in widespread clinical testing ofnumerous new targeted therapies. Atleast some of these may extend and ide-ally even save the lives of the 218,000men who develop this disease annually,some 32,000 of whom will die of prostatecancer under current therapies.1

September is National Prostate Can -cer Awareness Month, a time in whichcancer organizations emphasize pre-vention and symptom recognition inthe hopes of saving lives. In 2010, themessage is also one of therapeutic opti-mism, as agents capitalizing on uniquemechanisms of action begin to enterthe marketplace.

Immunotherapy

Several forms of immunotherapymade news in 2010, most strikingly theantigen-specific product sipuleucel-T(Provenge; Dendreon Corporation),which became US Food and DrugAdministration (FDA)-approved onApril 29, 2010, for metastatic CRPCbased on survival benefits shown inphase 3 trials. Sipuleucel-T is an activecellular immunotherapy, ie, a type oftherapeutic cancer vaccine. It is derivedfrom autologous peripheral blood cellsthat are collected during leukapheresisto contain only antigen-presenting cells.This product is cultured ex vivo with arecombinant fusion protein containingprostatic acid phosphatase (a prostateantigen) and granulocyte-macrophagecolony-stimulating factor to producethe vaccine that is infused into thepatient to boost T-cell response againstprostate cancer cells.

In the phase 3 IMPACT trial, patientsreceiving the vaccine had a median sur-vival time of 25.8 months and 3-yearsurvival of 32.1%, compared with 21.7months and 23%, respectively, forpatients receiving placebo.2 While thisamounted to a 22% relative reduction inrisk of death, the vaccine did not delaydisease progression, which occurred inapproximately 14 weeks in each arm.

Treating men with an immunothera-py when they have metastatic and cas-tration-resistant disease is “an uphill

battle that probably involves barriersthat have not yet been defined,” accord-ing to Dan Longo, MD, of the NationalInstitute on Aging, who wrote anaccompanying editorial to the publica-tion of the IMPACT results. He notedthat a 22% reduction in mortality in thischallenging group may bode well foruse of the drug earlier in the disease,although he felt the lack of an effect onprogression is concerning. Benefits tobe gained from this drug may becomeclearer with the final results of theongoing phase 2 ProACT trial.

Androgen Receptor Targeting

Prostate cancer is a hormonally sen-sitive disease that can be controlled forlong periods with androgen-depriva-tion therapy. The androgen receptorplays a critical role in maintaining theproliferation of prostate cancer cells,not only before androgen ablation butalso after hormonal treatments fail.Novel therapeutic strategies aim toinhibit and destabilize the function ofthis receptor and its interaction withkey proteins. Early success with theseoral compounds is being observed.

Abiraterone acetate (Cougar Biotech/Johnson & Johnson) is an orally admin-istered small molecule that irreversiblyand specifically inhibits cytochromeP17, a key enzyme in the generation ofandrogens and thus the production oftestosterone. Testosterone levels in thetestes and adrenals are thought to stim-ulate the growth of prostate cancercells. Therefore, by selectively inhibit-ing the target enzyme, abiraterone con-sequently blocks testosterone produc-tion in both the adrenals and testes andsuppresses cancer cell growth. Abira -terone has proven highly active in somemen, with responses ranging from 45%in heavily pretreated patients to 75% inpatients without extensive secondaryhormonal therapy or chemotherapy.3

In a phase 2 trial reported this year byinvestigators from the United King -dom, half of the 47 docetaxel-treatedpatients had ≥50% declines in prostate-specific antigen (PSA), and mediantime to PSA progression was 169 days.4

One fourth of the patients were stillbenefiting from the treatment afteralmost 1 year.

Additional studies recently reportedat the 2010 meeting of the AmericanSociety of Clinical Oncology showed

durable responses (ie, median time toPSA progression of 71 weeks) in 58%of chemo-naive CRPC patients receiv-ing abiraterone5 and prolonged remis-sions in patients with <5 circulatingtumor cells after 1 month of abi-raterone treatment.6

Also showing promise in this class ofagents is MDV3100 (Medivation/Astellas). MDV3100 is a small-mole-cule androgen receptor antagonist thatinhibits androgen receptor function byblocking nuclear translocation of thereceptor and DNA binding. The drug’s

researchers claim that MDV3100 differsfrom other antiandrogens in its robustaffinity for the androgen receptor andits multifaceted approach to stiflingandrogen production and activity. Itworks by 3 complementary actions:blocking testosterone binding to theandrogen receptor, impeding move-ment of the androgen receptor to thenucleus of prostate cancer cells, andinhibiting the binding to DNA.

In a recent phase 1/2 trial, more thanhalf the patients with CRPC had ≥50%reduction in PSA, and median time toprogression was 47 weeks.7 In addi-tion, 22% of patients had soft-tissueresponses and 56% had stabilized bonedisease. “We were encouraged to seeantitumor activity in men whose dis-ease had spread after either becomingresistant to previous hormone treat-ments or progressing following chemo -therapy,” said the study’s lead authorHoward Scher, MD, of MemorialSloan-Kettering Cancer Center, in apress release. “These findings strength-en the drug’s potential to change theoutlook for a group of patients whocurrently have limited effective treat-ment options.” MDV3100 is being fur-ther evaluated in the 1200-patientAFFIRM trial.

Histone deacetylase inhibitors alsotarget androgen receptor activity, andclinical trials are evaluating vorinostat(Zolinza; Merck) and panobinostat(LBH589; Novartis) within this class.

New Taxane

The FDA recently granted approvalto a promising new taxane, cabazitaxel

(Jevtana; sanofi-aventis), for the treat-ment of metastatic CRPC after docetax-el fails. Cabazitaxel works by disrupt-ing the microtubular network that is

essential for mitotic and interphase cel-lular functions and causes inhibition ofcell division and cell death. Cabazitaxelshowed a highly significant 30% reduc-tion in mortality over mitoxantrone inthe phase 3 TROPIC trial.8 In the finalanalysis of the study, median overallsurvival was improved from 12.7months with mitoxantrone to 15.1months with cabazitaxel.9

In a press statement, Richard Pazdur,MD, Director of the Office of OncologyDrug Products at the FDA, commentedon the potential value of cabazitaxel bystating, “The FDA was able to reviewand approve the application for Jevtanain 11 weeks, expediting the availabilityof this drug to men with prostate can-cer.” Future studies will evaluate thedrug in less-advanced disease.

Endothelial Receptor Antagonists

Endothelins have been implicated innumerous physiologic and pathologicconditions. In prostate cancer, levels ofendothelin-1 are increased, heighten-ing the peptide’s ability to modulatemitogenesis and apoptosis upon bind-ing to the endothelin-A receptor.Endothelin antagonism, therefore, maybe useful in that it blocks the activationof endothelin-A and thereby inhibitstumor growth.

The investigational oral endothelinreceptor antagonists have shown somebiologic activity but have not yetimproved clinical outcomes in CRPC.In phase 3 trials of atrasentan (Xinlay;Abbott), clinical efficacy was minimalalthough responses in PSA and otherbiomarkers were observed.10-11 Thephase 3 SWOG S0421 trial is currentlyinvestigating docetaxel plus atrasentan.Similarly, zibotentan (AstraZeneca) hasbeen shown safe when coupled withdocetaxel in preliminary studies, butclinical efficacy of zibotentan has notyet been established.12 Treatment withzibotentan plus docetaxel is being fur-ther evaluated in an ongoing phase 3program that includes patients withnonmetastatic disease (ENTHUSEM0), asymptomatic meta static CRPC(ENTHUSE M1), and symp tomaticmetastatic CRPC (ENTHUSE M1C). �

References1. 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-Timmunotherapy for castration-resistant prostate can -cer. N Engl J Med. 2010;363:411-422.3. Ryan CJ, Rosenberg J, Lin A, et al. Phase I evaluationof abiraterone acetate (CB7630), a 17-alpha hydroxy-lase C17,20-lyase inhibitor in androgen-independentprostate cancer. Presented at the 2007 AmericanSociety of Clinical Oncology Prostate Cancer Sym po -sium. Abstract 278.

New Compounds Hold Promise for Prostate CancerSeveral options arriving, with some unique mechanisms of action

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

In 2010, the message is one of therapeutic optimism, asagents capitalizing on unique mechanisms of actionbegin to enter the marketplace.


VBCC PERSPECTIVES


By Yu-Ning Wong, MD, MSCE

Sipuleucel-T (Provenge) and cabaz-itaxel (Jevtana) have drawn muchattention both for being the first

new treatments for advanced prostatecancer since docetaxel (Taxotere) wasapproved in 2004, and for their highcosts. As described in Dr Newcomer’saccompanying piece, they will add sig-nificantly to the cost of care for prostatecancer patients. Ironically, although$93,000 for a course of sipuleucel-T and$8000 per dose of cabazitaxel seem high,these figures aren’t completely surpris-ing when placed in the context of newtherapies that have been approved inrecent years for other disease sites.

In many ways, we are victims of ourown success. We now talk about canceras a “chronic disease,” where patientsare sequenced through multiple differ-ent therapies. With each FDA approval,there is a new “line” of therapy. Forexample, there have been 6 new agentsapproved for advanced renal cell can-cer since late 2005, of which several cost$8000 to $10,000 per month. This doesnot include surveillance blood work,supportive care medications, or othertreatment-related costs. Therefore, eventhough we don’t spend the whole

$93,000 price tag up front, we can easilyapproach that with several months.

The survival benefit for each indi-vidual treatment is often modest (gen-erally between 2-4 months), but theadditive benefits resulting from this“daisy chain” fashion has lead to thesignificant improvement in survival formany advanced cancers. For examplethe life expectancy of patients treatedwith sequential new therapies foradvanced colorectal cancer now ex -ceeds 2 years; prior to 1996 there wasonly 1 active agent and life expectancyfor these patients was only about 12

months. As a practicing physician, Iknow of many patients who have ben-efited from these treatments; althoughmany have died, I believe that theylived longer than they would havewithout these new drugs. Many con-tinue to work and care for their fami-lies. These are the successes that keepme and other oncologists motivated tocontinue to take care of patients withincurable diseases.

However, is making available everypossible treatment for every patient“worth it?” It was easy when the econ-omy was doing well. However, it’s the$93,000 question that has drawn a greatdeal more attention as the economyworsens. The current system is terriblybroken. It allows well-insured patientsaccess to the most expensive therapiesbut implicitly rations care to patientswho are uninsured or underinsured.Many patients are facing increasedcost-sharing for anticancer medica-

tions, supportive care drugs, imagingstudies, and doctors’ visits. It placespatients in the impossible position ofhaving to make complex financial deci-sions alongside medical ones. Oncol -ogists are trained to counsel patientsabout risks and benefits, includingtreatment-associated survival im -prove ments and toxicities. However,even as we are encouraged to promote“shared decision-making,” physiciansare ill prepared to add the “cost andvalue” dimension to these discussions.Framing these issues in the context ofmedian- and long-term survival rates

is nearly impossible. (Im agine asking“Would you spend your child’s collegesavings for a 15% chance that you’ll bealive in 2 years to see him graduatefrom high school?”)

As a society, we need to have anuncomfortable discussion about howwe will address these issues. Althoughinsured patients rarely face the full costof care, we all pay for these treatmentsthrough taxes and premiums. As longas we have publicly funded insuranceand share risk with our colleaguesthrough employer-sponsored commer-cial insurance plans, these should beshared discussions as well.

Instead of asking an individual whatshe is willing to pay for care, we shouldbe asking as a society what we are will-ing to sacrifice to make the newesttreatment available. Are we willing topay more in taxes and premiums? Arewe willing to cut coverage for otherservices? Are we willing to ask

investors to accept lower profits as aresult of lower prices? Are we willingto ask doctors and patients to gothrough more bureaucratic hurdles toensure that these resources are used forthose who are most likely to benefit?

I doubt that the United States will gothe way of the United Kingdom’sNational Health Service, which hasmade the difficult decision to refuse toadopt certain cancer treatments due totheir high cost and modest efficacy.However, there are other things we cando to better define the “value” of thetreatments we are prescribing. As dis-cussed in 2 recent editorials,1,2 we needto improve our clinical trial process toidentify which drugs have the bestchance of helping patients.

In addition, we must do a better jobin the postapproval setting of collectingdata about the efficacy and toxicity ofthese new drugs. Although most areapproved based on their first- or second-line data, many have broad indicationsand are often used in patients who havebeen heavily pretreated. Since only 5%of patients enroll in clinical trials, mostpatients receive costly and toxic thera-py of unknown benefit for which little,if any primary data are collected to fur-ther clarify the treatments’ risks andbenefits for future patients.

I am curious to see how Americaninsurers and policymakers will addressthe $93,000 question. While sipuleucel-T may be the most costly example todate, it should be seen as the treatmentthat has forced this conversation, not asan exception. �

References1. Young RC. Cancer clinical trials—a chronic but cur-able 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.

The $93,000 Question

By Lee Newcomer, MD

Prostate cancer patients have 2 newtherapeutic options this summerwith the approvals of sipuleucel-T

and cabazitaxel. The former drug is animportant scientific advance as one ofthe pioneering cancer vaccines to showa prolongation of survival. The latter isnot a new scientific breakthrough, but itdoes offer another option for patientswho have failed docetaxel.

Both drugs, however, spotlight theunsolved flaw in our national health-care policy. The nation has not decidedhow much it is willing to pay for anadditional year of life. Sipuleucel-T will

cost $93,000 for the 3 required infusionsand cabazitaxel is priced at $8000 perinfusion. To put this in perspective, the

average total cost of care for a prostatecancer patient at United Healthcarefrom diagnosis to death is $67,254.Treatment with just these 2 new drugswill increase the total cost of care by210%. For that increased expenditure,those few patients fortunate enough toget a response would gain an additional6.5 months of life.

Is that fair value? That decision isone for society to debate and decide. Inthe interim everyone will pay for the

indecision with higher taxes and ahigher premium for privately insuredpatients. Failing to address the issue issimply not sustainable.

In the interim, clinicians can help bybeing responsible stewards as they con-sider these therapies for patients.Sipuleucel-T was tested on a highly

New Prostate Cancer Therapies Raise New Issues

Yu-Ning Wong, MD, MSCE, is assistant professor,Fox Chase Cancer Center and adjunct senior fellow,Leonard Davis Institute of Health Economics,Univer sity of Pennsylvania, Philadelphia, PA andan editorial board member for Value-BasedCancer Care.

Lee Newcomer, MD, is business leader, oncol ogy servic-es, for United Healthcare, Edina, MN and an editorialboard member for Value-Based Cancer Care.

Even as we are encouraged to promote “shared decision-making,” physicians are ill prepared to add the “cost andvalue” dimension to these discussions.

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


selected group of patients with a hor-monally resistant disease, no visceralinvolvement, no opioid usage for 6months, no chemotherapy for 3months, opioid and an ECOG perform-ance status of 0 or 1. The current manu-facturing shortage will restrain off-labelusage this year. Next year will be morechallenging as the therapy becomeswidely available. Using the therapy forpatients who do not meet the preciseindications is simply conducting a$93,000 clinical trial with 1 subject. Itwould be a waste of precious resources.

Second, patients should be monitoredclosely for progression with cabazitaxeltherapy. It’s not often that insurers callfor more testing, but at $8000 per treat-

ment, a radiologic examination is aninexpensive way to ensure that the nexttreatment course is indicated.

Finally, these 2 drugs raise the ques-tion of regulation for pharmaceutical

pricing. There is no competition forthese products and the manufacturersare free to set any price they desire. Ina free market where the patient wasdeciding how to spend his own money,

this would be a fair practice. In today’ssystem, however, patients make thedecision with the public’s money.Perhaps the public should decide whatconstitutes a fair price. �

VBCC PERSPECTIVES

FOCUS ON


4. Reid AHM, Attard G, Danila DC, et al. Significantand sustained antitumor activity in post-docetaxel,castration-resistant prostate cancer with the CYP17inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489-1495. 5. Ryan CJ, Smith MR, Logothetis C, et al. Median timeto progression in chemotherapy-naïve patients withcastration-resistant prostate cancer treated with abi-raterone acetate and low-dose prednisone. Presentedat the 2010 American Society of Clinical Oncology.Abstract 4671. 6. Danila DC, Anand A, Sung CC, et al. Molecular pro-filing of circulating tumor cells in patients with cas-trate metastatic prostate cancer receiving abirateroneacetate after failure of docetaxel-based chemotherapy.Presented at the 2010 American Society of ClinicalOncology. Abstract 4635. 7. Sher HI, Beer TM, Higano CS, et al. Antitumor activ-ity 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. Caba -zitaxel or mitoxantrone with prednisone in patientswith metastatic castration-resistant prostate cancerpreviously treated with docetaxel: final results of amultinational phase 3 trial (TROPIC). Presented at the2010 Genitourinary Cancers Symposium. Abstract 9.9. De Bono JS, Oudard S, Ozguroglu M, et al.Cabazitaxel or mitoxantrone with prednisone inpatients with metastatic castration-resistant prostatecancer previously treated with docetaxel: final resultsof a multinational phase III trial (TROPIC). Presentedat the 2010 Annual Meeting of the American Society ofClinical Oncology. Abstract 4508. 10. Michaelson MD, Kaufman DS, Kantoff P, et al.Randomized phase II study of atrasentan alone or incombination with zoledronic acid in men withmetastatic prostate cancer. Cancer. 2006;107:530-535.11. Nelson JB, Love W, Chin JL, et al. for the Atrasen -tran Phase 3 Study Group Institutions. A phase 3 ran-domized controlled trial of the efficacy and safety ofatrasentan in men with metastatic hormone-refractoryprostate cancer. Cancer. 2007;110:1959-1966. 12. Trump DL, Payne H, Miller K, et al. Phase Istudy of the specific endothelin A receptor antago-nist zibotentan combined with docetaxel in patientswith metastatic castration-resistant prostate cancer:assessment of efficacy, pain, and safety. Presented atthe 2010 American Society of Clinical Oncology.Abstract 4664.

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