july/august 2010 | vol 1 | no 3

Cost Considerations Change DialoguePhysicians, patients must navigate shifting conversational landscape

Consumer Genetics: Paradigm Shiftor Flash in the Pan?Conference touts promise, but real-world regulation intrudes

Do End-of-Life Products DeserveSpecial Treatment?More issues than answers at lively session

©2010 Engage Healthcare Communications, LLC

Continued on page 27



Individualizing Colorectal CancerCare through Genetics

San Diego, CA—Three nurse re -searchers from the Oncology NursingSociety (ONS) Cancer Genetics SpecialInterest Group shared how the resultsof genetic testing conducted withinthe care setting are individualizing—and improving—care for colorectalcancer (CRC) at a session at theAnnual ONS Congress. Beginning with an overview of the

carcinogenesis of CRC, Carol Viele,RN, MS, a clinical nurse specialist atthe University of California SanFrancisco (UCSF) Medical Center,detailed both its modifiable and non-modifiable risk factors. She stated that

even though keeping good healthhabits, such as exercising regularly,avoiding tobacco, and minimizingalcohol use, can greatly reduce one’sCRC risk, other risk factors, such asadvancing age, family history, andgenetics, cannot be controlled. Byaccepting this latter fact, however, andlearning more about patients’ geneticmake-up, Ms Viele and the other pre-senters illustrated that healthcare pro-fessionals are improving patients’prognosis, reducing treatment toxici-ty, and saving cost. Karen Roesser, RN, MSN, oncology

clinical nurse specialist at CIWMedical Center in Richmond, VA,detailed that by determining whether

Atlanta, GA—Echoes of the recentcontentious American debate overhealthcare could be clearly heard in asession at the meeting of theInternational Society for Pharma -coeconomics and Outcomes Researchthat addressed issues surrounding thefunding of new treatments, technolo-gies, and drugs for patients nearingthe end of the life, covering every-thing from standards for economicevaluations of new drugs to the philo-sophical questions surrounding treat-ments near the end of life. In a wide-ranging discussion, a 3-

speaker panel comprised of NicoleMittmann, PhD, Marc Berger, MD,and Mark Sculpher, PhD, generallyagreed that significant tradeoffs occurwhen healthcare systems fund new

treatments, but ina spirited Q&Asession that fol-lowed, some au -di ence memberschallenged thesebasic assumptions.One audience

member tookpointed aim atthe British healthcare system’s denialof coverage for some new cancerdrugs, asking Dr Sculpher, aUniversity of York professor of HealthEconomics and director of theProgram on Economic Evaluation andHealth Technology Assessment for theschool’s Center for Health Economics,“Would you feel any different aboutthe societal perspective if you yourselfwere diagnosed with metastatic coloncancer knowing that there are drugs

www.ValueBasedCancer.com

IN THIS ISSUE

JULY/AUgUst 2010 VOL 1 NO 3

By Jennifer Erickstad

Boston, MA—“An insurance providerwith 1 million members spends $11,000,000 annually on 15 drugs thatpatients either do not respond to, orare likely to have an adverse reactionwith,” declared Rick Schatzberg,president and CEO of GenerationHealth, at the 2nd Annual ConsumerGenetics Conference held June 2-4. Tomitigate these costs and improvehealthcare, conference participantsdiscussed how the power of anunlocked genome can forecast apatient’s reaction to drug treatment,

optimize a me -dicinal cocktail,provide pinpointdiagnostics of adisease, and evenforetell a pa -tient’s propensi-ty to develop adisease beforesymptoms occur. The burgeoning consumer genetics

industry presents the possibility thatgenetic testing will streamline thedecision process for disease treat-ments. Mara Aspinall, president andCEO of On-Q-ity, forecasted that

By Cherie Dewar

Although financial concerns are increasingly influencingchoices in cancer therapy, bar-

riers to cost discussions betweenphysicians and patients often limit thescope of such discussions. Incentivesfor oncologists to use high-cost inter-ventions and patients’ perceptionsthat cost consideration equates to sec-ond-class care are but 2 barriers tomeaningful cost discussion.The issue of addressing the cost of

cancer care with patients was exam-ined in an educational session at the

2010 American Society of ClinicalOncology (ASCO) annual meeting. Traditionally, physicians were

warn ed to avoid limiting treatmentbased on cost considerations, with thebelief that all patients should be treat-ed the same regardless of their abilityto pay, said Lidia Schapira, MD, assistant professor, department ofmedicine, Harvard Medical School,Boston, MA. But an ethical detour hasemerged in the past few years—physicians are now expected to pro-vide advice to patients regarding thetreatments that best meet the patients’interests and values.

Continued on page 5

By Daniel Vollaro

By Wayne Kuznar

Reasons for breast cancer care disparities............................................. 7

How will costs be contained in the new environment? .......................... 8

Oncology-related updates from the FDA................................................. 23

Focus on hematopoietic growth factors.................................................. 24

Meetings calendar..................................................................................... 25

VBCC_August 081110_ASCO Highlights Tabloid 8/13/10 4:49 PM

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


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

TABLE OF CONTENTS

PublisherNicholas [email protected]

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Directors, Client ServicesJohn [email protected]

Phil [email protected]

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Managing EditorColin [email protected]

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Business ManagerBlanche Marchitto

July/August 2010 Vol. 1 No. 3

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.

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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

4 Value Propositions

ASCO Annual Meeting

5 The New Face of the Community Oncology Practice

6 Pathway Compliance Reduces Drug, NondrugExpenses

Comparative Effectiveness Research Will HelpGuide Health Policy

7 Reasons for Breast Cancer Care Disparities Remain Unclear

Adherence to Colon Cancer ChemotherapyGuidelines Depends on Treatment Setting

8 How Will Costs Be Contained in the NewHealthcare Environment?

Annual ONS Congress

13 Clinical Trials: Understanding Cost, CoverageImplications

Direct-to-Consumer Genetics/Genomics: A “NewParadigm” in Providing Healthcare Information

ISPOR Conference

18 Evolution Continues for AMCP FormularySubmission Guidelines

19 Moving Targets: Personalized Medicine and Targeted Therapy

21 Communications About CER in a ChargedEnvironment

23 Oncology-related Updates from the FDA

Focus On

24 Hematopoietic Growth Factors: What’s New in 2010?

VBCC Perspective

25 What’s a PBM to Do with CSFs?

27 Meetings Calendar

Value-Based Cancer Care is the official publication of the Association for Value-Based Cancer Care

Save the date for our first annual meeting, Tuesday, October 12, 2010, in St. Louis, Missouri

Coverage of the ASCO Annual Meeting and the ISPOR conference will continue in next month’s issue.

VBCC_August 081110_ASCO Highlights Tabloid 8/16/10 9:34 AM

4 I VALUE-BASED CANCER CARE I July/August 2010 VOL. 1 I NO. 3

VALUE PROPOSITIONS

Reducing X-ray Use Starts at the TopAfter noting a large number of requested routine trauma x-rays of the

cervical spine after a computed tomography scan had demonstrated nosignificant findings, the management at University of Rochester MedicalCenter in NY instituted an imaging algorithm produced by the radiologydepartment and distributed through the medical director’s office. Oneyear after implementing the policy, the number of unnecessary x-rayexams performed was reduced by 83%. Mark J. Adams, MD, MBA, thelead author of the study (J Am Coll Radiol. 2010;7[7]:531-532), pointed outthat “not only are these x-ray exams unwarranted, they consume valu-able resources, add an additional burden to emergency department andradiology staff, and subject patients to unnecessary radiation.”

Cancer Diagnosis: Off the Shelf to on the Chart Rice University biomedical engineers and

researchers from the University of Texas M.D.Anderson Cancer Center have created an inex-pensive device that combines an off-the-shelfdigital camera with a small bundle of fiber-opticcables that can, when used with a common fluo-rescent dye, allow doctors to easily distinguishcancerous cells from healthy cells simply byviewing the LCD monitor on the back of the cam-era (PLoS One. 2010;5[6]:e11218). Study leadauthor Rebecca Richards-Kortum said that “aportable, battery-powered device like this couldbe particularly useful for global health. This could save many lives in countries where conventional diagnostic technology is simply too expensive.”

Overall Costs of Taxane Use in Breast CancerA retrospective claims analysis looking at the overall costs of care asso-

ciated with taxane use for metastatic breast cancer (American Health &Drug Benefits. 2010;3[4]:276-284) has found that generic paclitaxel was theleast costly option ($3203 adjusted median per patient per month cost),followed by nab-paclitaxel ($3997) and docetaxel ($4042). Use of nab-paclitaxel was associated with lower utilization and costs for colony- stimulating factors compared with the other 2 drugs, but patients in thenab-paclitaxel group did receive more doses of that drug.

For Cancer Survivors, Care Costs Too Much Two million cancer survivors did

not get needed medical services inthe previous year because of con-cerns about cost, according toresearch published in Cancer (pub-lished online: June 14, 2010; doi:10.1002/cncr.25209). Researchers an -a lyzed data from the annual US National Health Interview Survey, whichincluded data on 6602 adult cancer survivors and 104,364 individualswith no history of cancer who were surveyed between 2003 and 2006. The table shows the proportion of cancer survivors foregoing different

types of care due to cost.

Electronic Records Face Implementation Hurdles The adoption of shared electronic patient records in the United

Kingdom has taken longer and demonstrated more modest benefits thanhoped, according to a new study (BMJ. 2010 June 16;340:c3111. doi:10.1136/bmj.c3111). The Summary Care Record (SCR) is an electronicsummary of patient medical records accessible over a secure internet con-nection by authorized National Health Service staff. By early 2010, 1.5

million SCRs had been created, but the researchers found that creatingSCRs and supporting their adoption and use was a complex, technicallychallenging, and labor-intensive process. Individual clinicians accessedavailable SCRs between 0 and 84% of the time, a figure that varied con-siderably depending on setting, the type of clinician, and their level ofexperience. When accessed, SCRs seemed to support better quality careand increase clinician confidence in some encounters.

Boosting Colon Cancer Screening—AutomaticallyA study involving nearly 6000 Kaiser Permanente members in

Washington and Oregon who were overdue for colon cancer screeningfound that automated telephone reminders increased screening rates by30%. The automated calls in English and Spanish lasted about 1 minute.Members were told about the importance of screening, and were asked topress a number on their phone if they wanted to order a free at-homefecal occult blood test kit, which requires people to place stool samples oncards and then send the cards to a lab. If the person did not order andcomplete the test within 6 weeks they received a second call, and if theydidn’t respond in another 6 weeks, they received a third call.

Screening Model Finds Good Value A probabilistic Markov model estimating the incremental cost-effec-

tiveness of 10 strategies for colorectal cancer screening in Canada focusedon 3 tests currently in use in some Canadian provinces: low-sensitivityguaiac fecal occult blood test, performed annually; fecal immunochemi-cal test, performed annually; and colonoscopy, performed every 10 years.These strategies reduced the incidence of colorectal cancer by 44%, 65%,and 81%, and mortality by 55%, 74%, and 83%, respectively, comparedwith no screening. These strategies generated incremental cost-effective-ness ratios of $9159, $611, and $6133 (Canadian) per quality-adjusted life-year, respectively. The authors conclude that either an annual high-sensi-tivity fecal test or colonoscopy every 10 years offers good value for themoney in Canada (CMAJ. 2010 Jul 12 [Epub ahead of print]).

Looking Less May Yield More“Surveillance colonoscopy is a widely accepted and utilized practice

that has the potential to decrease the burden of colorectal cancer. Yet, thispractice also carries considerable monetary and resource costs as well asthe risk of procedure-related complications.”

Sameer Dev Saini, MD, MS, lead author of a study (Gastroenterology.2010;138[7]:2292-2299) arguing that surveillance colonoscopy should be direct-ed only to those at highest risk for colorectal cancer. A strategy of screening bothhigh- and low-risk patients with colonoscopy every 3 years may be attractive togastroenterologists with medico-legal concerns over missed neoplasia, theauthors say, but this is cost-ineffective and potentially harmful in comparison toless intensive surveillance.

Recession Sapping Hospital Quality Unlike past recessions, the current economic malaise may be negative-

ly impacting hospital quality and the ability of these institutions to growin the postrecession environment. “Hospitals seem to be dealing with theeconomic crisis by reducing staff, scaling back or completely stoppingnew construction projects, and implementing various efforts to improveefficiencies of care,” said lead author Jeremy Syussman, MD, MS, a physi-cian and clinical scholar at the University of Michigan Health System.Three quarters of hospitals surveyed reported receiving less reimburse-ment from insurers per discharge and more than half reported a decreasein patient admissions. In addition, more than half of hospitals reporteddifficulty obtaining bonds—an important means of paying for new con-struction or big-ticket equipment purchases (J Hosp Med. 2010;5[5]:302-305).

Type of care %

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ASCO ANNUAL MEETING

Continued on page 6

Cost Considerations Change Dialogue Continued from cover

However, the value attached to atreatment is not always easy to quantify, said Dr Schapira, and maydepend on the expectations of thepatient and the clarity of the informa-tion that he or she has received.“Patients come with ideas, and per-ceptions of gain…based on a conceptthat is not clearly shaped in theirminds,” she said.Further barriers to cost discussions

include the mixed loyalties of physi-cians as both drivers of medical costsand advocates to patients. In addi-tion, there is the embarrassment thatpatients may feel about discussingfinances with their doctor and that“they may not want us to modify arecommendation if we have a suspi-cion that perhaps they’re not able topay,” she said. Also, too little time isallotted during appointments to havecost discussions, and patients areoften unwilling to mention cost con-cerns to avoid influencing the doc-tor’s recommendation.Surveys have shown that doctors are

indeed willing to have cost discussionswith their patients. Oncologists, how-ever, believe that “there are not enoughdata to guide them in these conversa-tions and that makes these conversa-tions difficult,” said Dr Schapira.One such survey of 787 ASCO mem-

bers1 found that 84% strongly or some-what agreed that patient out-of-pocketcosts influence their treatment recom-mendations. Less than half (43%)responded that they frequently oroccasionally discussed the cost of newcancer treatments with their patients.Eighty percent of patients ex -

pressed a desire for more use of cost-effectiveness data in coverage andpayment decisions for cancer drugs.Only 42% agreed that they were well-prepared to interpret and use cost-effectiveness information in theirtreatment decisions. Seventy-ninepercent favored more comparativeeffectiveness research.

What Physicians Are Doing

Very little is known about howpatients prefer cost issues be dis-cussed, said Deborah Schrag, MD,MPH, attending physician/oncolo-gist, Dana-Farber Cancer Institute,and associate professor of medicine,Harvard Medical School, Boston.The vantage point of physicians is

that they have a big influence on deci-sions, but “we ourselves are pulled inquite a few different directions,” shesaid. Physicians hold the belief thatcare should be equitable and do notview their roles as economic advisors

even as they recognize that manyinterventions have limited value.Dr Schrag’s survey of medical

oncologists found that 30% discussedthe cost of cancer treatment most ofthe time, 30% discussed it some of thetime, and 16% refused to discuss costat all.2 Approximately 80% eitherstrongly agreed or agreed that oncol-

ogists have a responsibility to consid-er the impact that treatment decisionsmay have on the patients’ financialwell-being.The quality-adjusted life-year

(QALY) is a standard measure bywhich cost can be compared acrossinterventions and compared side byside, said Dr Schrag. Currently, anintervention with a QALY less than$100,000 is regarded as meeting thecost-effectiveness threshold for UShealthcare interventions. Translatingcost into value is a constantly shiftinglandscape, however, as new treat-

ments, new benefit design plans, andpatent expirations emerge, she said.Ill-aligned incentives may also be

preventing the use of cost considera-tions in patient management. Physi -cians have strong incentive to usehigh-cost interventions, although evi-dence exists that they can be motivat-ed by economic incentives, such as

off-label use of expensive treatmentsand a preference for on-patent versusoff-patent agents. In addition, “treat-ing with therapies of marginal utilityis often the path of least resistance,”said Dr Schrag. The forecast is for change in cancer

care delivery, she said, with realign-ment of incentives. A greater emphasison the cognitive/compassionate com-ponent of care is in the offing, alongwith streamlined, coordinated guide-line-driven care, and less reliance ondelivery of expensive chemotherapyand a shift away from the predisposi-

tion to think that “more is better.”Moving forward, the solution

may lie in more comparative effec-tiveness research, believes Dr Schrag.However, “it requires large-scale datacollection and greater investment inintraoperable systems to track out-comes and figure out what’s valuableand thereby take a back-door approachto the cost issue.” �

References1. Neumann P, Palmer JA, Nadler E, et al. Cancer therapy costs influence treatment: a national survey ofoncologists. Health Aff (Millwood). 2010;29:196-202.2. Schrag D, Hanger M. Medical oncologists’ views oncommunicating with patients about chemotherapycosts: a pilot survey. J Clin Oncol. 2007;25:233-237.

Community oncologists are fac-ing big changes to the waythey have traditionally prac-

ticed, and they would be wise toaccept, adapt, and move on, speakerssaid at a session at the 2010 ASCOannual meeting titled “The Challengeof Financial Survival.” Economic pressures are essentially

killing many community practices,according to Elaine L. Towle, CMPE,director of oncology services atOncology Metrics, a division of AltosSolutions, Los Altos, CA, who drewon data from the National PracticeBenchmark, an annual survey of near-ly 200 US practices that her companyconducts.“Total collected revenue in these

practices increased 6% from 2007 to 2008, and at first glance this is good news. However, total practiceexpense increased 16% over the sameperiod, resulting in fewer dollarsavailable to support practice opera-tions,” Ms Towle said. “When oncolo-gy practice expenses rise more rapid-ly than revenue, the result is lowerphysician incomes.”

In the most recent (2009) survey of190 oncologists, 73% of respondentswere still independent physician-owned practices but changes wereoccurring. Eleven percent practicedoncology within a multispecialtygroup, 6% were hospital-affiliatedphysicians or hospital employees, 5%were physician-owned but had a hos-pital or corporate affiliation, 2% wereaffiliated with US Oncology, 1% wereacademic-affiliated, and 2% describedtheir practice setting as “other.”Perhaps more telling were their

predictions: only 20% envisionedtheir practices and business structureremaining “unchanged and viable”for at least 5 years, 20% said they are“changing now,” and 60% predictedthey will be stable for only “the fore-seeable future.”What is pressuring oncologists to

think about different business mod-els? Declining physician compensa-tion was the main reason (54%),according to the survey. Also citedwere loss of referrals as a result oflocal competition (19%) and the needto reduce practice overhead expenses(15%). Interestingly, only 4% citedreduced reimbursements as a reason,

and just 3% listed lower drug-costmargins. But oncologists have seen drug

margin as a percentage of total rev-enue increasingly fall, from 45% in2002 to just 9% today, according to MsTowle. She noted that the lost revenuecontributes to the “dramatic declinein the funds available to run a med-ical oncology practice.”Still, profit related to drugs is more

important than ever, she added,telling the physicians, “If drug man-agement is not a core competency inyour practice, you are losing rev-enue….Practices that are still in thebuy-and-bill model are greatlyimpacted.” The “new normal,” withregard to drug revenue, she said, isnow “low margin, high volume.”

More Problems and Pressures

Oncologists face other problems aswell: greater regulatory exposure,information overload, scarcity ofresources, increased practice size, andchanges in patient profiles, Ms Towlesaid.The patient base, for example, now

includes more Medicare patients lack-ing secondary insurance. More than

The New Face of the Community Oncology PracticeThose not throwing in the towel urged to “get over it,” embrace changeBy Caroline Helwick

Physicianshavestrongincentivetousehigh-cost

interventions,althoughevidenceexiststhattheycanbe

motivatedbyeconomicincentives.

Lidia Schapira, MD



Evaluation of a regional payer-based pay-for-quality (P4Q)oncology program showed that

Pathways programs can greatly re -duce the cost of cancer care by slow-ing the growth rate of both drug andnondrug expenses.Although oncology clinical Path -

ways are common in current practice,there has been little evaluation of howcosts can be reduced when Pathwaysare enacted. This study evaluated thepotential cost-savings of a payer-based P4Q program employing clini-cal pathways, said Jeffrey A. Scott,MD, and colleagues from P4 Health -care in Ellicott City and CareFirstBlueCross BlueShield, Baltimore, MD.P4 Healthcare is a privately held

healthcare company that helps oncol-ogy practices increase efficiency andenhance the quality of patient care.Dr Scott described a P4Q program

enacted in 3 northeastern states on

August 1, 2008, that had 57 participat-ing practices (176 physicians; 10,432patients). Participating practices werecompared with 43 nonparticipatingpractices (194 physicians; 4137patients). The Pathways, developedby a 15-oncologist steering commit-

tee, consisted of physician-generatedtreatments (breast, lung, and colorec-tal cancers) and supportive care path-ways (colony-stimulating factors, ery-thropoiesis-stimulating agents, andantiemetics) based on medical litera-ture and national guidelines.Participants received feedback

regarding compliance. Fee schedulesin year 1 of the program were adjustedin year 2 contingent on compliance inyear 1. Savings analysis used the dif-

ference between the participating andnonparticipating practice growth ratesfrom the year before the program (pre)to year 1 to estimate yearly savings forthe participating practices.The study found that 96% of the

participating practices were able to

meet the 65% treatment compliancethreshold and the 80% supportivecare compliance threshold. Across all participating practices, 86% and95% of patients complied with treat-ment and supportive care pathways,respectively.

Pathways-Compliant Practices

Reduced Costs

The study found the pre-year 1 toyear-1 growth rate in cost was 7.7%for antineoplastic drugs, –3.0% forsupportive care drugs, and 2.8% fornondrug services in the participatingpractices. In contrast, costs in the non-participating practices were 15.4%,2.4%, and 19.0%, respectively, DrScott reported.Estimated savings between Path -

ways participants and nonparticipat-ing centers (Table) were calculated

for antineoplastic drugs ($6,766,500),supportive care drugs ($1,427,108),nondrug services ($4,039,359), andtotal costs ($12,232,967). When thecosts of the year-1 fee scheduleincrease for participating practiceswere factored out, the total savingswere estimated at $8,585,149. “Our further evaluations will

explore the indications of how thesecosts were reduced, for instance, bydrug selection, and consider clinicaloutcomes and compliance in relationto cost-savings,” Dr Scott said. “Al -though the majority of the estimatedcost-savings were drug-related (77%),the amount of savings due to nondrugservices was substantial,” he added. �

ASCO ANNUAL MEETING

Pathway Compliance Reduces Drug, Nondrug Expenses

Estimated savings for antineoplastic drugs between

Pathways participants and nonparticipating centers were

calculated at $6,766,500; total savings were $12,232,967.

half the survey respondents said atleast 10% of their Medicare patientshave no secondary insurance, leadingmore physicians to refer patients forchemotherapy visits outside of theirpractices. Although about half therespondents refer patients for 40chemotherapy visits at most per year,33% refer for up to 400 visits and 9%refer for more than 1000 visits.

An additional drain on resourcescomes from handling insurance andpayer issues, with the average prac-tice employing 1.2 billing staff forevery physician and 0.4 patient finan-cial advocates.

How Practices Are Coping

One increasingly common meansof coping with the changing environ-ment is to consolidate: to sell one’spractice to a hospital or otherwise joina hospital physician network, tomerge to form a larger organization,or to join a university system or insur-ance “preferred” network of physi-cians. In addition, more practices aremoving away from the “buy and bill”

model and are incorporating newentities such as specialty pharmacyand centralized infusion services. Ms Towle advised physicians to do

“strategic planning,” and becomeinvolved in aspects of healthcarereform that would serve their prac-tices, such as demonstration projectsand clinical process measurements.“Pay-for-service is going away; new

systems will pay for quality and out-comes,” she said. Oncologists can also partner with

others in the community to increaseefficiency, especially in areas thatrequire capital or specialized, highlypaid staff, such as radiation, imaging,and infusion therapy. Most impor-tantly, practices must be able to adapt,she emphasized. “The good old daysare gone,” Ms Towle said. “New prac-tice models are developing. Inves ti -gate and embrace them.” �

The New Face of... Continued from page 5

The cost of caring for cancer rosefrom $27 billion in 2009 to $90billion in 2008, yet unwarranted

variation in that care persists acrosscenters, providers, and patients. Asyet, there is little evidence on compar-ative effectiveness of the differentmanagement options and on the valueprovided by different healthcare serv-ices, but this is expected to change,said Elena B. Elkin, PhD, assistantattending outcomes research scientistat Memorial Sloan-Kettering CancerCenter, an invited discussant of sever-al cost-effectiveness studies at ASCO. More than $1 billion in the stimulus

package is earmarked for compara-tive effectiveness research (CER), andthese findings will be used to informclinical guidelines, provider reim-bursement, coverage decisions, andcost-sharing.Healthcare reform and the mandat-

ed expansion of insurance coverage

provide “demand and opportunity”for investigating the impact of insur-ance on cost and value of care. But inthe interpretation of CER, she cau-tioned that “correlation does notequal causation,” and said thatalthough there are “promises” inher-ent in the move toward CER there arepitfalls as well. In analyses of treat-ment options, for example, it can behard to adjust accurately for comor-bidity and other inevitable con-founders, she pointed out. The hope is that studies funded

through the stimulus package andhealthcare reform legislation willhave rigorous methodology and bebased on “sound assumptions,” shesaid. In addition, the study processshould be transparent, should allowfor updates to incorporate new evi-dence and options, and shouldencourage the dissemination of infor-mation to all stakeholders. —CH �

Comparative Effectiveness ResearchWill Help Guide Health Policy

Table Summary of Cost-SavingsResults by Expenditure Type

Expenditure Savings, $

Antineoplastic drugs 6,766,500

Supportive care drugs 1,427,108

Nondrug services 4,039,359

Program impact 12,232,967

Fee schedule impacta (3,647,818)

Adjusted for fee schedule 8,585,149increaseaFee schedule impact represents the expenditureattributable to the increase in fee schedule duringthe first year of the program for the participatingpractices. Fee schedule was treated as a cost ofthe program and factored directly out of estimat-ed savings.

By Caroline Helwick

“If drug management is not a core

competency in your practice, you are losing

revenue.…Practices that are still in the buy-

and-bill model are greatly impacted.”

—Elaine L. Towle, CMPE

For more information on

Oncology Metrics visit

http://oncomet.wordpress.com



Chicago, IL—Insurance status andsocio economic status (SES) explainlittle of the racial and ethnic variationin the receipt of recommended thera-py for breast cancer, found RachelFreedman, MD, MPH, in her exami-nation of a national cancer registry.She sought to determine the vari-

ables that might explain differences incare between 662,117 white (86% ofthe cohort), black (10%), and Hispanic(4%) women diagnosed with a firstinvasive breast cancer during 1998-2005 at hospitals included in theNational Cancer Database, a hospital-based cancer registry run by theAmerican College of Surgeons andthe American Cancer Society. Fifty-one percent had private insuranceand 40% had Medicare.For this analysis, 4 variables were

assessed:• Receipt of the locoregional therapy• Receipt of hormonal therapy in theadjuvant setting

• Receipt of chemotherapy in theadjuvant setting

• Hormone receptor testing at diag-nosis.At about 98%, “hormone receptor

testing was very high for all groups,which is reassuring, but there weresubtle differences for all of the othermeasures by race, particularly theblack patients versus the whitepatients,” said Dr Freedman, a med-ical oncologist at Dana-Farber CancerInstitute, and instructor in medicineat Harvard Medical School, Boston. Definitive locoregional therapy was

instituted for 74.3% of Hispanicwomen, 75.5% of black women, and80.6% of white women. Receipt ofadjuvant hormonal therapy was40.2%, 45.4%, and 54.4% for Hispanic,black, and white women, respective-ly; and receipt of adjuvant chemother-apy was 59.5%, 58.4%, and 48.7% forHispanic, black, and white women,respectively.“Accounting for insurance barely

attenuated any of the differences, soalthough there were insurance differ-ences, race is definitely more impor-tant than insurance in this data set,”Dr Freedman emphasized.Socioeconomic status was also not

associated with outcome but “the SESdata we had were area level and notindividualized SES,” she said.

Large Data Set, Big Limitations

“These big data set projects havetons of limitations because we don’thave any information about reason-

ing for omission of treatment, pro -vider information, or patient stresses.Although we controlled for someprognostic variables, we didn’t have

information on HER-2 positivity andother things that can be a part of whypeople receive care. There were alsocomorbidities that we couldn’taccount for.”

Other studies have shown thatminorities are more likely to mistrusttheir doctors and less likely to enroll inclinical trials, and whether such differ-

ences in behavior are responsible fordifferences in receipt of treatment byrace is not known, said Dr Freedman.“What this study shows is that fix-

ing insurance and expansion of insur-

ance in the United States may not fixeverything, and that there are otherthings that we have to tackle,” sheconcluded.She added that examination of the

receipt of treatment by patient age isforthcoming. “We really can’t look much further

unless we want to look at hospitalcharacteristics such as volume andquality, which is one of the things I’mtrying to do,” she said.

An assessment of other large databases, such as the National Com -pre hensive Cancer Network, may pro-vide more clues about factors thatexplain disparities in receipt of recom-mended breast cancer care, she said. �

ASCO ANNUAL MEETING

“What this study shows is that fixing

insurance and expansion of insurance in

the United States may not fix everything.”

—Rachel Freedman, MD, MPH

When treating patients withcolon cancer in the com -munity oncology setting,

adherence to evidence-centeredguidelines for the use of chemothera-py regimens varies by setting, withadherence rates higher in the adju-vant setting and somewhat lower inthe metastatic setting, said McKessonSpecialty Care Solutions’ ZhaohuiWang, MD, PhD, at the 2010 ASCOmeeting.The cost of guideline-based therapy

also varies widely, ranging from$6590 to more than $40,000 (Medicarecost) in the adjuvant setting, and from$2930 to more than $50,000 in thefirst-line metastatic setting.These findings came from examina-

tion of a large, US medical oncologyclinical database containing data forcalendar year 2009. Treatment regi-men cost information was derivedfrom Regimen Profiler, which is aweb-based program that evaluatesregimen-associated costs for payers,including Medicare. (For more onRegimen Profiler, see the story “NewTools Arriving to Measure andManage Chemotherapy Care,” in theMay issue of VBCC.)The database included 2976 treat-

ment regimens (≥1 chemothera peutic/biologic agents administered in arepeating pattern) for patients withcolon cancer who were treated in 383community oncology practices across45 states.A total of 1380 adjuvant regimens

and 1596 first-line metastatic regi-mens were analyzed. The rate ofguideline adherence was 80.9% in the

adjuvant setting and 76.6% in themetastatic setting.The top 5 regimens used in the

adjuvant setting were given to 80% ofpatients, whereas the top 5 regimensused in the first-line metastatic settingwere given to only 60% of patients,said Dr Wang.The most often used “off guideline”

regimen was a combination of FOL-FOX-4 (oxaliplatin, leucovorin, fluo-rouracil) with bevacizumab given at10 mg/kg. The guideline recommen-dation is 5 mg/kg for the bevacizu -

mab component of this combination.When bevacizumab was first ap -proved by the US Food and DrugAdministration (FDA), it was at the10-mg/kg dose level, he noted, “butsubsequent studies have failed to finda dose-response relationship between5 and 10 mg/kg, so the guidelines rec-ommend 5 mg/kg. Physicians whoare not aware of these data may becontinuing to give the FDA-approveddose even though it is considered ‘offguideline.’”A standard course of therapy in

the adjuvant setting ranged from$8124 for 5-flourouracil-leucovorin to $51,242 for CAPOX (cetuximab, oxaliplatin, capecitabine). In the first-line metastatic setting,

regimen costs ranged from $5286 formodified FOLFIRI (irinotecan, 5-fluo-

rouracil, leucovorin) to $39,683 forCAPOX with bevacizumab on day 1,based on 3 months of therapy.

Adherence Falling Short

“Guideline adherence rates for can-cer treatment should approach 80% to90%, taking into account variouspatient-specific comorbid conditionsthat preclude guideline adherence,”Dr Wang told meeting attendees.Guideline adherence in the adjuvantsetting, at 80.9%, approached thislevel but fell short in the first-line

metastatic setting. “With the plethoraof new agents now available in themarketplace, and phase 3 random-ized trial data showing good out-comes with the use of many regimensand the widespread use of guidelines,compliance should seemingly behigher,” he said.“One possible reason that treat-

ment guideline adherence rates forthe metastatic treatment setting arelower than the adjuvant group couldbe that the metastatic group is likelyto have more comorbidities than theadjuvant group due to previous expo-sure to drugs, radiation, or surgery,”Dr Wang explained.Few resources have been devoted

to the cost of cancer care, even thoughprograms such as Regimen Profilerare available, said Dr Wang. —WK �

Adherence to Colon Cancer ChemotherapyGuidelines Depends on Treatment Setting

“Guideline adherence rates for cancer treatment should

approach 80% to 90%, taking into account various patient-

specific comorbid conditions.” —Zhaohui Wang, MD, PhD

Reasons for Breast Cancer Care Disparities Remain UnclearBy Wayne Kuznar



ASCO ANNUAL MEETING

Prospective payment and bun -dling of payments offer themost promising means to con-

tain healthcare costs, said David O.Meltzer, MD, PhD, who gave a rundown of the weaknesses andstrengths of some of the proposedremedies to reel in healthcare costs inthe postreform United States. Hemade these remarks during a specialsession on healthcare reform.Economists believe that the single

reason that healthcare costs are risingis the use of more technologies, andthat the real price of quality-adjustedhealthcare is actually falling, said DrMeltzer, associate professor, depart-ment of medicine, Harris School, anddepartment of economics, Universityof Chicago, IL.Cost-effectiveness analysis could

ensure that technologies are usedappropriately. However, “the politicsof rationing remain as toxic as theyhave always been.”

Other cost-control measures alsoare likely to be insufficient, he said.Savings from malpractice reformwould amount to 2% to 5% at most.And although prevention is a valu-able way to promote health, it usuallydoes not reduce costs, Dr Meltzerindicated. “You know people aren’treally serious about cost control whenthey say that prevention is going toreduce costs.” Health information technology

might eventually reduce costs, bydecreasing practice variations andencouraging use of more effectivetechnologies. “But in the short run,there is really no good evidence that itwill do this.” Taxing high-benefit health plans

could affect costs, but probably notsubstantially. Costs could be re -duced if copayments are increas ed.However, the vast majority ofexpense is incurred when people arevery sick. “For very good social rea-

sons, we don’t want to give sick peo-ple a tremendous dependency oncosts so that they are making life-or-death decisions based simply on theavailability of capital in their family,”Dr Meltzer argued.

Solutions from the Payer Side

The only true engine for containingcosts that has worked in the past,according to Dr Meltzer, is the combi-nation of prospective payment andbundling. When Medicare instituted

prospective payment at a fixedamount for hospitalizations, lengthsof stay and expenditures fell dramati-cally. Bundling has several advan-tages: “it not only gives you a singlenumber to target, it changes the poli-

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.

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 Novartis

3:22 PM

How Will Costs Be Contained in the New Healthcare Environment?By Wayne Kuznar

at a glanceRising healthcare costs

are due largely to increased

technology use

Pro spective payments and

bundling may offer the best

chance for cost containment

Bundled payments may reduce

financial “turf wars” among

caregiver groups



ASCO ANNUAL MEETING

tics of reimbursement. Once you bun-dle, you don’t have every group argu-ing for their own payment. They areall in it together.” It is likely that hos-pital stays will be bundled withambulatory care, and physician feeswill be combined with hospital care,Dr Meltzer said.

With more Americans havingaccess to healthcare, the system willno longer be able to justify cross-sub-sidies from the insured to finance theuninsured’s costs. The healthcare sys-tem will have to move to a system ofprospective costs and bundling, andthe type of capitated care that was

more prevalent 15 to 20 years ago.“Following that, costs will be cut.These will be large bundles, and therewill be no one able to argue for them-selves; we will have to fight amongourselves.”This may not sound ideal from a

reimbursement perspective, but Dr

Meltzer says that from the standpointof the healthcare system, this may notbe bad. “There are wonderful exam-ples of integrated organizations thatprovide wonderful care for theirpatients and of physicians and otherproviders who thrive within theseorganizations,” he said. �

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

3:22 PM


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 —

2 6 4:10 PM


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



3 6

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San Diego, CA—Emphasizing thecosts and financial reimbursementissues associated with the “ever-chang ing, ever-complex environ-ment” of clinical trial research, a ses-sion at the 35th Annual OncologyNursing Society (ONS) Congressaddressed a crowd of both currentclinical trial nurses and attendees whomay take on this role, discussing howthe team responsible for the hours oflogistical work and research coordina-tion supporting these trials can workmore effectively.Clinical trials have the obvious ben-

efits of developing new therapies and treatment standards, said RoseErmete, RN, BSN, a clinical trials nurseat St. Mary Mercy Hospital, Livonia,MI. Another benefit, according to cop-resenter Denise Friesema, MS, RN,director of clinical research operationsat the University of Chicago MedicalCenter, is that they allow nurses to“leave our fingerprint on science.”Both presenters, however, took care tooutline potential pitfalls when con-ducting clinical research.According to Ms Ermete, it is

extremely important to be in compli-ance with all billing rules, as the costsof noncompliance range from adversepublicity to Medicare exclusion tocriminal penalties. The practices thatmost commonly lead to noncompli-ance, she explained, are “double dip-ping” (when a hospital bills for aservice or drug already provided bythe sponsor), billing for services thatwere provided free as part of the trial,and billing for services that would notordinarily be covered if they were notpart of the clinical trial. Illustratingthe dangers of noncompliance, MsErmete highlighted the situations ofseveral large institutions—such asJohns Hopkins, the Mayo Clinic, andRush University Medical Center—that have been fined by the USAttorney General’s Office and theOffice of Inspector General because ofnoncompliance issues. Yet the story of Rush University

Medical Center can also be seen as ahelpful example for nurses looking toeither begin or improve their clinicaltrial programs, Ms Ermete explained.After being fined $1 million, Rushlaunched a comprehensive compli-ance assurance program, which start-ed with—and is centered around—moving from a “siloed” system to acentralized billing process. With oneresearch office handling all paper-work, providing oversight across the

organization, and conducting monthlyreconciliations, Rush has “set the stan-dard for what the government is look-ing for when it comes to compliance,”Ms Ermete said. The idea of centraliza-tion or “harmonization,” as the pre-

senters explained, was a key theme ofthe presentation, one to which both MsErmete and Ms Friesema repeatedlyreturned. They stressed that by align-ing the multiple departments thatwork together during a clinical trialunder one centralized office, a facilitycan ensure they are remaining compli-ant, avoiding fraudulent billing, andconducting research in a consistentmanner throughout the institution.

Establish Standard Processes

To establish this centralized system,Ms Ermete noted that institutions caneither use a front-end process (identi-

fying the patient before they receivecare and then using study-specificcharts) or a back-end one (pulling outall bills before they are sent to deter-mine which costs are paid by thestudy organization). Bringing the rel-

evant departmental teams together iskey—especially those people whowill be registering patients and billingpayers—as is drawing up a flowchartto show how bills should be accurate-ly routed. Regardless of how the sys-tem is developed, however, MsErmete concluded “there has to besome type of evaluation takingplace.” This process should includeboth active and past accounts, withauditors reviewing invoice details toconfirm appropriate billing. Ms Friesema instructed session par-

ticipants on the “budget basics” ofclinical trial research. Noting that “it’s

just not worth the effort” to open aclinical trial that includes only a fewpatients, she instructed that the firstand most important question nursesshould ask is whether the facilitycares for an adequate patient popula-tion. Next, clinical trial nurses shouldcollaborate with the trial physician todetermine which parts of the trialwould be provided to patients any-way as standard care and what servic-es would be considered additionalinvestigational expense. Finally, clini-cal trial nurses should examine all 4components of the study budget: thestart-up fees, research-related clinicalcare expenses, the cost of studyimplementation and oversight, andindirect costs that go to the facility(such as institutional overhead).Although burnout is common and

high turnover rates among clinicaltrial nurses have been well docu-mented, Ms Friesema concluded thatby considering the strategies outlinedin the session and avoiding the pit-falls illustrated by other facilities,clinical trial nurses can help create asuccessful research program at theirinstitution. �

Clinical Trials: Understanding Cost, Coverage ImplicationsBy Jennifer Erickstad

Clinical trial nurses should collaborate with the trial physician

to determine which parts of the trial would be provided to

patients anyway as standard care and what services would

be considered additional investigational expense.

San Diego, CA—A session at the 35thAnnual ONS Congress happening thesame week that Walgreens decided topostpone selling a direct-to-consumer(DTC) genetic test kit raised morequestions than provided answerswhen it framed the discussion by asking whether these tests were“good, bad, or benign.” Even for anadvanced audience such as this, thequestion may be premature: only oneaudience member had ever helped apatient decipher DTC genetic testresults.Presenters Patricia Kelly, RN, DNP,

MS, a clinical education specialist/genomic consultant at Texas Health

Resources in Dallas, and JenniferLoud, RN, CRNP, DNP, assistantbranch chief at the National CancerInstitute in Rockville, MD, analyzed arange of issues. Noting that DTCgenetic testing represents “a new par-adigm of how healthcare informationis communicated to the public,” DrLoud acknowledged that DTC testingmay make many healthcare profes-sionals uncomfortable because of theshift in power that it causes. “We areused to being in control and havingpatients come to us for advice andguidance,” she said, “this has thepotential of flipping that on its head.”Despite nurses’ potential discomfort,however, the two advocated that theparticipants should develop the rele-vant genetic nursing competencies—such as providing patients with accu-rate genetic information, resources,and services to guide their decisionmaking and to identify the myriadethical, religious, cultural, and legalissues related to genetic testing.

Acing the Genetic Info Exam

Another question tackled by theteam was how to determine the valueof the information derived through

DTC genetic testing. To aid nurses inthis pursuit, Dr Kelly shared the ACCEmodel, which consists of criteria devel-oped by the Centers for DiseaseControl and Prevention’s (CDC) Officeof Public Health Genomics to helpevaluate the roughly 1600 genetic testscurrently in use (approximately 500 of

Direct-to-Consumer Genetics/Genomics: A “NewParadigm” in Providing Healthcare Information

“We are used to being in

control and having patients

come to us for advice and

guidance. This has the potential

of flipping that on its head.”

—Jennifer Loud, RN, CRNP, DNP


at a glanceConsumer genetic tests have

been more discussed than used

There are roughly 1600 genetic

tests in use, 500 of which are

direct to consumer

Genetic testing is overseen by a

patchwork of state and Federal

agencies


ANNUAL ONS CONGRESS


these are DTC). The ACCE model’s 4areas of investigation include examin-ing the test’s:1. Analytic validity: how sensitiveand specific the test is for pickingup on the specific genetic mutation

2. Clinical validity: how consistentlyand accurately the test predicts thedisease or question of interest

3. Clinical utility: how does the genet-ic test impact care and how signifi-cantly can it improve outcomes

4. Ethical, legal, and social issues:how is privacy maintained with thetest, how are the test results com-municated, what happens to thesample after testing, etc. In addition to nurses’ own test eval-

uations, Dr Kelly discussed DTCgenetic testing’s formal process ofquality assurance. Although theFederal Trade Commission overseesadvertising, it has “played a fairlyminor role” in looking at the promo-tion of DTC genetic testing to date, DrKelly noted, aside from publishing a2006 consumer alert that advocated a “healthy dose of skepticism.” Three federal agencies—the CDC, theCenters for Medicare & MedicaidServices, and the US Food and DrugAdministration—currently overseethe testing, and “states regulate [it] agreat deal” (25 allow its use, 12 permitlimited use, and 13 ban it). Providingpossibly another safeguard, theNational Institutes of Health in Marchannounced the establishment of a vol-untary genetic testing registry. Theregistry—which will include ACCEinformation—is expected to be upand running in 2011. The session concluded with a criti-

cal thinking exercise on the potentialbenefits and risks of DTC genetic test-ing and how test information mayimpact patients. For example, theynoted that for a young man whoreceives confirmation of harboringthe prostate cancer mutation, thisinformation may lead to unjustifiedanxiety and unnecessary screening—especially in light of the fact that stud-ies have shown a thorough family his-tory to be a better predictor ofprostate cancer risk than the existenceof the mutation. On the other hand,an older man who tests negative mayfeel a false reassurance and foregoscreening. According to both presen-ters, potential benefits of DTC genetictesting may be increased access to thetests, reduced risk of privacy viola-tions, lowered costs due to competi-tive pricing, and empowered consu m -ers who can change their lifestyles.Although the presenters discussed

many questions surrounding genetic

testing that have yet to be answered,they did provide attendees with astrategy for approaching the issues.Quoting from a 2009 paper,1 Dr Kellynoted that healthcare professionalsmust find a balance—avoiding exces-

sive paternalism and fear of changewhile stressing that genetic infor -mation not be used inappropriately or prematurely—in order to helppatients “explore their genome with marvelous and exciting new

tools at hand in a way that values medical experience and technologicalinnovation.”—JE �

Reference1. Evans JP, Green RC. Direct to consumer genetic testing:avoiding a culture war. Genet Med. 2009;11: 568-569.

Direct-to-Consumer Genetics/Genomics... Continued from page 13

8

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.

S

MC49047-B 04-10 www.neulasta.com

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ANNUAL ONS CONGRESS


CRC patients have a genetic mutationleading to Lynch syndrome, clinicianscan more actively screen for othercancers that are associated with thecondition (including endometrial,ovarian, and stomach). Clinicians

have been using certain tests, includ-ing microsatellite instability testingand immunohistochemistry testing,to better determine which patientsmay have the syndrome and shouldundergo further genetic testing.

The session’s third presenter mostdirectly addressed how clinicians areindividualizing CRC care in clinicalpractice. Pamela Viale, RN, MS, CS,ANP, an oncology nurse practitioneralso practicing at UCSF, discussed

several genetic mutations and howthey impact decisions made in CRCcare. Beginning with perhaps themost well known, Ms Viale explainedthat approximately 40% of CRC

Individualizing Colorectal Cancer Care... Continued from cover

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


� 80% reduction in febrile neutropenia–related IV anti-infective use


N

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-B 04-10 www.neulasta.com

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ANNUAL ONS CONGRESS


Individualizing Colorectal Cancer Care... Continued from page 15

patients have a mutated KRAS genethat makes treatment with certainmonoclonal antibodies unsuccessful.Specifically, the mutated KRAS genemeans that 2 important drugs—pani-tumumab and cetuximab—used to

target the epidermal growth factorreceptor (EGFR) are ineffective inturning off the cell signaling systemand limiting tumor growth. As aresult, Ms Viale noted that practition-ers must determine early on if a

patient has the KRAS mutation toavoid treating the patient with inef-fective drugs. She added that both theNational Comprehensive CancerNetwork (NCCN) guidelines and theAmerican Society of Clinical On -

cology professional opinion state-ment call for KRAS testing beforebeginning therapy with monoclonalantibodies. Similarly, Ms Viale notedthat patients with the BRAF mutationhave also shown to be unresponsiveto anti-EGFR monoclonal antibodiesand that the NCCN now recognizestesting for this mutation as a prudenttreatment decision.

Ms Viale also covered findings per-taining to TP 53, a tumor suppressorgene that plays an important role inthe growth and differentiation ofCRC. Between 40% and 60% of CRCpatients have the mutation, and itsexistence may help practitioners provide a more accurate prognosis.According to Ms Viale, one studyfound that patients with a mutated TP53 have a poorer prognosis than thosewithout in both stage II and stage IIICRC when treated with surgeryalone. Additionally, data have shownthat TP 53 inhibits the body’sresponse to 5-fluorouracil therapy,although conflicting data have alsosurfaced.

In addition, Ms Viale also detailedhow genetic information can reducetoxicity. The UGT1A1 enzyme inacti-vates the metabolite of the chemo -therapy agent irinotecan. Patientswith Gilbert syndrome, however, havedecreased efficiency of UGT1A1, mak-ing them unable to adequately metab-olize the drug and leading to in -creased neutropenia and diarrhea.

Ms Viale provided statistics from asurvey conducted at the NCCN 2010meeting on the prevalence of genetictesting in the treatment of CRC.Responses revealed that 51% ofrespondents test for the KRAS muta-tion before therapy is initiated,whereas 37% test for the mutationonly when considering treatmentwith an anti-EGFR monoclonal anti-body. Ten percent tested for an alter-ation of UGT1A1, 16% tested forUGT1A1 only after already treatingthe patient with irinotecan and expe-riencing problems, and 63% conduct-ed no UGT1A1 testing. Thus,although the data showed that it is“standard practice now to test for theKRAS mutation,” the numbersrevealed fewer clinicians are utilizinginformation from UGT1A1 tests. �

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

By determining before

treatment which patients have

diminished efficacy of

UGT1A1, patients can avoid

unnecessary toxicity.


ISPOR CONFERENCE


Do End-of-Life Products Deserve... Continued from cover

available that could treat you thatNICE [National Institute for Healthand Clinical Excellence] has deniedbecause of cost?” “I don’t know what I would think if

I were in that position,” Dr Sculpherreplied, after dismissing as “unreli-able” recent research suggesting thatmore patients die of cancer in theUnited Kingdom (UK) because somedrugs are not funded, “but ultimately,as a citizen, I believe in a healthcaresystem which has the purpose ofimproving health across all patientgroups. Every time we say yes to adrug that generates relatively smallimprovements for high cost, some-body else in that system suffers.” This exchange highlighted the

tension between those who explicit-ly acknowledge limitations withinhealth care systems and those who donot. Dr Sculpher was eager to illumi-nate the gulf separating these posi-tions. “Some healthcare systems pre-tend that there are no opportunitycosts, that people don’t suffer whenyou agree to reimburse new drugs,but in the UK that has become moretransparent.”

Frameworks and Tradeoffs

Honestly discussing this tradeoffwithin healthcare systems and how to

manage it equitably was a main themeof the panel discussion. The first pan-elist, Dr Mittmann, discussed the stan-dards used in Canada to prioritizedecisions about funding new cancer

treatments. An associate scientist at theSunnybrook Health Sciences Centre inToronto, Dr Mittmann walked theaudience through the process followedby a 15-member team of investigatorsas it “cancerized” the CanadianAgency for Drugs and Technologies inHeath’s (CADTH) guidelines for theconduct of economic evaluations.They examined the CADTH guide-lines carefully, looking for ways tomake the specific cancer guidelineswithin them more explicit and clear.Working for 3 years and producing 29different iterations of the document,the team was able to create a soundmethodological framework for mak-ing funding decisions for new cancertreatments. The challenges were significant,

admits Dr Mittmann. Their initial sur-vey of the problem uncovered a lackof adherence to guidelines used to doeconomic evaluation, a lack of stan-dardization in economic evaluations,and differential levels of evidence toevaluate cancer products. “Sometimes you just don’t have a

phase 3 trial that is available to you,”observed Dr Mittmann. “So you needto consider phase 2 studies. How doyou methodologically deal with this?” Panelist Marc Berger also grappled

with the “framework” for decision-making in a talk that raised important

philosophical questions about howhealthcare systems evaluate the valueof new cancer therapies used for can-cer treatment at the end of life. DrBerger, a vice president of Global

Health Outcomes at Eli Lilly,observed that the “number of oncolo-gy drugs is about the explode” with a10-fold increase in number of newcancer products on the horizon, andthis plethora of new treatments willforce a number of philosophical ques-tions. For example, what is the valueof life extension and is it the same forall diseases and medical conditions? “Human beings are not pure utili-

tarian creatures,” Dr Berger remindedthe audience, “and we do find a lot ofpeople who believe that there is agreater need to intervene there [in thearea of life extension].”

Uncomfortable Questions,

Expensive Solutions

Berger posed other potentiallyuncomfortable questions as well:“What value do we assign to apatient’s life beyond direct medicalcosts and workplace productivity?”Many people getting cancer after theyretire will not be adding to the grossdomestic product, he observed. Is apurely utilitarian metric appropriatehere? What is the value of life exten-sion and is it the same as for othermedical conditions? How does apatient benefit from slowing diseaseprogression if he/she still does notlive any longer? There is value to hav-ing a better quality of life…how do

symptoms and disease progressionimpact a patient’s independence? Dr Berger was realistic about the

necessary tradeoffs implied by askingthese questions. “The way that decisions have been

made is in the context of a handful ofbiologics or new cancer therapies,” heobserved. “If you imagine a future 10years from now where you have 50, 75,a 100 of these, I don’t think we’regoing to be paying $20,000 a month or$100,000 a year for a 100 new cancertherapies; that’s just not going to hap-pen. So how that conversation is goingto happen is going to be a really inter-esting evolution in the marketplace.” In the lively Q&A that followed the

session, Dr Berger joined Dr Sculpherin defending NICE as pragmatic andrealistic in ways that the Americansystem is not.

“The UK has determined what it’sgoing to cap its total healthcare expen-ditures at,” he observed. “Could it bemore? Sure. On the other hand, in thiscountry, medical care expenditures aregoing up and we’re frightened todeath by what that means.” Dr Berger also argued that there is

no “Pareto optimal” when makingdecisions about how to allocateresources in a healthcare system. “Wemake choices all the time. What wewant to have at bottom is a fair andjust society in which the process bywhich those decisions are made,everyone feels like they have a fairshake. I think that NICE has madegreat strides over its 11 years of existence.” �

Medicare, a Major P(l)ayer, Not Ready for New Payment Policy Evidence

Atlanta, GA—A session at the 2010meeting of the International Society forPharmacoeconomics and Out comesResearch discussing how Medicare’sevidence requirements for coveringnew technologies might change underthe new healthcare reform bill painteda portrait of an agency that has recent-ly raised the evidentiary standards for evaluating new technologies but is slow to change, especially in the

arena of advanced technology.Panelist Steve E. Phurrough, MD,

MPA, chief operating officer and sen-ior clinical director at the Center forMedical Technology Policy and a for-mer coverage director at the Centersfor Medicare & Medicaid Services(CMS), observed that Medicare hasnever clearly expressed its standardsfor covering new medical technolo-gies. “Medicare has a mantra, ‘reason-able and necessary’; it does not payfor things that are not reasonable and

necessary,” said Dr Phurrough. “Since1965, Medicare has never definedwhat that means.” Dr Phurroughacknowledged that the agency hasrecently said that it will considersomething to be “reasonable and nec-essary if it improves net health bene-fits. Dr Phurrough further explainedthat although a “conditional” ap -proach to coverage has the potentialto speed coverage and develop addi-tional evidence, the current agencyposition of making clear-cut decisions

about coverage is incompatible withthat concept.In presenting a quick history of

Medicare’s coverage policy thatemphasized the agency’s inability toclearly define its research require-ments, Dr Phurrough quipped,“Medicare pays for stuff, and pays forstuff in unusual ways.”Dr Phurrough also observed that

Medicare has traditionally appliedlow, medium, and high standards ofevidence. For the approval of kypho-

“Ultimately, as a citizen, I believe in a

healthcare system which has the purpose

of improving health across all patient

groups.” —Mark Sculpher, PhD

“I don’t think we’re going to be

paying $20,000 a month or

$100,000 a year for a 100 new

cancer therapies; that’s just

not going to happen.”

—Marc Berger, MD

at a glanceMaking healthcare therapies

available to the broadest

population will involve tradeoffs

in costs and access

Economic evaluations of cancer

therapies are hampered by a lack

of guidelines and standards

Utilitarian economic analyses of

cancer products are hampered

by emotional and values-based

confounders

By Daniel Vollaro




Atlanta, GA—The history, purpose,and impact of the Academy ofManaged Care Pharmacy (AMCP)Format for Formulary Submissions—as well as their future in a changingworld of drug and regulatory devel-opment—was detailed by a panel ofinsiders at a session at the 15thAnnual Meeting of the ISPOR.For the past 10 years, these guide-

lines have evolved as an industrystandard for increasing the flow ofproduct information between phar-maceutical companies and healthcaresystems, particularly pharmacy andtherapeutics (P&T) committees. Firstdrafted in 1999 as a response to thepoor quality of submissions by phar-maceutical companies to health plans,

these guidelines have subsequentlypassed through 3 major revisions. Thelatest round of revisions reduced the

size of the document, focused it, andclarified sections.

Promotion, Rather than Evidence

According to panelist Sean Sullivan,PhD, professor and director of thePharmaceutical Outcomes Research &Policy Program at the University ofWashington’s Depart ment of Pharma -

cy, the guidelines were necessarybecause much of the documentationsubmitted in the 1990s was “promo-

tional and insufficient to inform evi-dence-based decision-making.”Dr Sullivan explained that the Divi -

sion of Drug Marketing, Adver tising,and Communications, which regu-lates the content of information sentfrom manufacturer to healthcare pro-fessionals and health plans, does notsupport the dissemination of data

beyond what is included in the prod-uct label. “A lot of research done tosupport a product never found itsway to the ultimate decisionmaker,”Dr Sullivan said. “That was, ofcourse, a problem.” A response to these concerns, the

new AMCP format was created as avoluntary reporting system that urgeshealth systems to formally request astandardized “dossier” from drugcompanies containing detailed infor-mation about the drug’s safety, effica-cy, and overall clinical and economicvalue relative to alternative therapies. Dr Sullivan, who served on the

original committee formed in 1999and has remained engaged in therevision process ever since, expressedcontinued concern over the quality ofevidence provided by pharmaceuticalcompanies to healthcare systems.Acknowledging that many people

have asked him why health plans donot use the information provided bypharmaceutical companies, he said“part of the answer lies in the fact thatthe dossier process is in some caseshijacked by commercial interests in thepharmaceutical industry. The healthplans want and desire a scientific com-munication, and if vendors are drivinga promotional focus, I guarantee youthat those documents won’t be read orused in the P&T process.”The audience, which contained

many representatives from drug man-ufacturers, indicated a desire to betterunderstand the guideline’s use. RobinTurpin, senior director at BaxterHealthcare, asked the panel if theyknew how often the AMCP dossierformat has been used by organiza-tions other than health plans. Richard Fry, RPh, the panel moder-

ator and director of programs for the Foundation for Managed CarePharmacy, admitted that they didn’thave good intelligence on this issue. Citing the ongoing debate about

changing evidence requirements fornew drugs and treatments, JenniferGraff, PharmD, research director ofMethods, Evidence & Coverage at theNational Pharmaceutical Council,asked, “What recommendations doyou have that would allow payers tofeel more comfortable in the non-RCT[randomized controlled trial] world?” Dr Sullivan acknowledged that the

“hierarchy of evidence we’ve grownup to [use] may not be reasonable for certain circumstances and for certain clinical questions” but empha-sized that the committee took a conservative path when consideringthese issues. �

Evolution Continues for AMCP Formulary Submission GuidelinesBy Daniel Vollaro

plasty, for example, Medicare deter-mined that there was not enough evi-dence to support its benefit but con-tinued to fund it anyway. On theother hand, Medicare has 6 timesasked for new evidence to support theuse of carotid stents. According to DrPhurrough, the round of decisionsaround carotid stents suggests agrowing tendency for CMS to requiremore evidence for new technologies.He explained why: In 2008, CMSreleased a proposed decision thatchanged the payment practices atMedicare. “Because the legislationsays, ‘don’t pay for things that are notreasonable and necessary,’ if in factyou have paid for something, youhave determined it reasonable andnecessary.” Dr Phurrough continued,saying, “Once you’ve paid for it, youhave met the evidentiary bar, most ofthe time, having never looked at the

evidence.” Once Medicare agrees topays for something, he detailed, itwill only deny coverage with clearpositive evidence of harm or posi -tive evidence of lack of benefit.Consequently, CMS has recentlyfocused on coverage decisions fornew drugs and technologies that havenot had local coverage decisions, andin those cases, it is applying relativelyhigh evidentiary standards.

Shifting Landscape, Static

Organization

Panelist James Chambers, MPharm,MSc, project director at Tufts MedicalCenter, supported many of DrPhurrough’s claims about Medicare.Mr Chambers discussed how CMS ismore likely to cover a new technologyif good quality clinical evidence existsto support its efficacy. Coverage is lesslikely, said Mr Chambers, if an alter-native therapy is available, a coveragedecision has been made in recentyears, or if there is no estimate of costeffectiveness available. His research,which was conducted by surveyingNational Coverage Determinationsbetween 1999 and 2007, also shows abroad trend in CMS covering cost-effective technologies.In the question session, Bryan Luce,

senior vice president, Science Policyfor United BioSource Corporation,asked if the health reform bill’s sug-gested investment in health informa-tion technology (HIT) will change theway Medicare evaluates evidence andmakes coverage decisions by provid-ing a “feedback loop” and “rapidlearning system” for continually pre-

senting and evaluating evidence. Acknowledging that CMS possess-

es great data resources, panelist PennyMohr, MA, vice president of Programsfor the Center for Medical TechnologyPolicy in Baltimore, was less than opti-mistic about implementing HIT atCMS. “While I think it’s a good oppor-tunity,” she said, “we have a long wayto go to get to that point.”Dr Phurrough was more blunt in his

assessment of the potential for HITreforms in CMS. “Briefly, no,” he pro-nounced. “CMS has this process, fairlywell defined now, and that processdoesn’t include using those kinds ofdatabases. If clinical research deter-mines ways to use those kinds of data-bases in fairly formal trials to come upwith good quality evidence; then theywill use that evidence, but for HIT tomake a difference in coverage deci-sions, the coverage process needs afairly significant transformation.” �

ISPOR CONFERENCE

“If vendors are driving a promotional focus,

I guarantee you that those documents won’t

be read or used in the P&T process.”

—Sean Sullivan, PhD

Medicare, a Major P(l)ayer... Continued from page 17

at a glanceMedicare’s “reasonable and

necessary” standard for

covering new technologies is not

necessarily clear and convincing

Evidentiary requirements for

Medicare reimbursement have

grown tighter since a shift in

payment standards in 2008

A growing use of health

information technology may

not translate into changed

evidence-evaluation procedures

by Medicare

“The coverage process needs

a fairly significant

transformation.”

—Steve E. Phurrough, MD, MPA


ISPOR CONFERENCE


Atlanta, GA—Even as the developmentof targeted therapies has advanced rap-idly in the past several years, the evi-dence base, evaluation, and reimburse-ment structures surrounding the use ofthese products in the real world havelagged behind. A panel presentingresearch, governmental, and privatepayer perspectives discussed theseissues, and some potential solutions, atthe first plenary session of the 15thAnnual Meeting of the InternationalSociety for Pharma coeconomics andOutcomes Research (ISPOR). Fully realizing pharmacogenomics

and personalized medicine will allowphysicians to “identify diseases at an earlier, more curable stage,” sug-gested Scott D. Ramsey, MD, PhD, of the Fred Hutchinson CancerResearch Center and the University ofWashington, Seattle. “If we can dothat, we can afford our patients muchgreater survival and at the same timelower the cost of care for individuals.”

This is especially important, hepointed out, when cancer products arebeing introduced that commonly cost$10,000 per month. “The proportion ofpatients that respond to these cancertherapies has remained fairly con-stant,” which means, of course, “we’respending ever more money for a flatresponse in terms of improvement.”Targeted therapies may improve

those response rates, but their useraises other clinical and cost concerns,as Dr Ramsey indicated. “We expect a huge number of these

biomarkers to be introduced over thenext 5 to 10 years, and there are sever-al key questions,” Dr Ramsey out-lined. “Who will drive their use? Will patients be asking for these testsor will clinicians? When cliniciansreview the evidence, when will they

know that there is sufficient evidenceto use in practice?” Payers will alsoneed information to determine pay-ment policies and encourage the useof these products.

Process Costly, Often Flawed

The current situation regardingpaying for genomic tests may give ahelpful perspective on where costsare headed. According to Dr Ramsey,

data from a medium-sized healthplan in Washington State (theRegence Group) indicated that in a12-month period “there were almost

Moving Targets: Personalized Medicine and Targeted Therapies

By Colin Gittens

©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.

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at a glanceGenomic tests have resulted

more from researcher interest

than identified clinical need

The Evaluation of Genomic

Applications in Practice and

Prevention (EGAPP) process

may bring structure to test

development

Payers are now actively

collaborating with researchers

to assess targeted therapies in

real-world situations


ISPOR CONFERENCE


Moving Targets: Personalized Medicine... Continued from page 19

100,000 claims for genomic tests and$85 million billed, just for the testsalone.” That figure does not includeall the counseling and other costs. “If you do the math, we’re looking

at about $1000/test,” he concluded.“So there’s a lot of testing going on,but not a lot of certainty about whatwe’re getting for that money.” When evaluating genomic tests, Dr

Ramsey emphasized the need to keyin on 4 elements—does the test meas-ure what is intended (analytic validi-ty); does it measure that item con- sistently and accurately (clinicalvalidity); and is the test likely toimprove patient outcomes (clinicalutility). The fourth quality—value, orevaluating whether the test influencescare and represents good value com-pared with not using the test—isincreasingly gaining in importance. The current model of cancer geno -

mic test development is lacking, Dr

Ramsey suggested, with gene candi-dates selected through the idiosyn-crasies of individual researchers whoare “not necessarily motivated byclinical priorities, [but] are motivatedby the area of expertise.” Later on, the difference between the

population used to validate the drugand that in the real world throws offtest results. Finally, limited funding isalso a factor for evaluating new testsonce they are released. “Ninety-sevenpercent of genomics publications arein that very early phase” of the discov-ery process, said Dr Ramsey, com-pared with almost no publicationslater on, when the population healthimpact might be assessed.Evaluating genomic tests ideally

would involve understanding theclinical context for that test earlier on, followed by a cost-effectivenessanalysis and professional assessmentand incorporation into clinical prac-tice guidelines if deemed worthwhile.Currently, a rigorous test evaluationdoes not happen or happens haphaz-ardly, and tests are moving directlyfrom development into clinical prac-tice, Dr Ramsey outlined.This process echoes what happened

with prostate-specific antigen (PSA)testing, and that is “a lesson we don’t

want to repeat,” emphasized DrRamsey. Since being approved by theUS Food and Drug Administration(FDA) in 1994, 30 million men arescreened annually with PSA testing ata cost of $3 billion. Only in 2009 were2 studies published evaluating theefficacy of this testing; one showed“no impact of testing on prostate can-cer deaths,” Dr Ramsey reported,while the other indicated that forevery man helped by PSA testing, 48received unnecessary testing.

How to Move Forward

According to Dr Ramsey, there areseveral ways that personalized medi-cine can be advanced. First is to con-sider genomic testing as a partnershipbetween test developers and researchgroups on the one hand, and thehealth system on the other. “I thinkwe need the health system involved,”said Dr Ramsey.

Lawrence J. Lesko, PhD, FCP, direc-tor of the Office of Clinical Pharma -cology at the FDA, emphasized thispoint, saying, “It’s important to designthese studies with the right questionsin mind. It’s amazing to me how oftenstudies are conducted that simplydon’t ask the right questions.”Dr Lesko discussed some other

obstacles to the development andwidespread adoption of personalizedmedicine, the first of which is too muchinformation. “Many of the predictedfindings of the technology involvehundreds of genes that technologydevelopers have to boil down to some-thing that they can make useful for cli-nicians,” he pointed out. Second, theFDA and other regulatory agencies thatinfluence the direction of research havenot been clear about what re searchneeds to be done for approvals.Another tool that may advance

genomic testing is the Evaluation ofGenomic Applications in Practice andPrevention (EGAPP) process. Ralph J.Coates, PhD, associate director for sci-ence for the Office of Public HealthGenomics at the Centers for DiseaseControl and Prevention, discussedhow this effort attempts to establish asystematic, evidence-based processfor evaluating genetic tests, and move

them from research to practice. Thecriteria look at factors includinghealth outcomes and utility in deci-sion-making, and in many of theexamples given by Dr Coates—depression, breast cancer, warfarindosing—there was insufficient evi-dence, uncertainty, or a lack of trial-based data available to allow a recom-mendation about the use of genetictests. The Centers for Medicare &Medicaid Services has employed theEGAPP process when making a cov-erage decision regarding genetic test-ing for response to warfarin.

Payers Ahead of the Pack

Despite the imperfections of the cur-rent evaluative system, payers areeager to expand the use of targetedtherapies and realize their benefits, saidRobert S. Epstein, MD, MS, chief med-ical officer and president of MedcoResearch Institute, Medco HealthSolutions, Inc. According to a Medcosurvey of payers from 2008, pharma-cogenomics was tied with consumer-ism as the second most im portant topic on their radar screens. “Payersfind this topic fascinating—they loveit,” remarked Dr Epstein, elaboratingthat pharmacogenomics allows target-ing of therapy, reduced adverse out-comes, and improved efficacy—“allthings payers would like to see.” Payersare now paying Medco to identifypatients on certain drugs to ensure thatthe right patient is receiving that drugat the proper dose, Dr Epstein noted.Payers are now offering their mem-

bership to do prospective studies,“and I wouldn’t have thought thatwould happen.” Dr Epstein discusseda collaborative study of this typelooking at warfarin and hospitaliza-tions. It was not randomized, but waslarge, and was “powered to look atthe real question on a payer’s mind—

not a surrogate end point, but ‘cangenotyping reduce a hard end pointlike hospitalizations?’” With personalized medicine, Dr

Epstein continued, payers are lookingfor the same thing as with drugs—value for money. They want real-world comparative data with real out-comes of interest, and evaluation ofconsequential, matters. For the privatesector, however, determining return oninvestment is difficult, and this may bethe key factor holding back a wideradoption of pharmacogenomics. An audience member wondered

what would happen if the genomicsand personalized medicine achievedthe hoped-for result—what if all thebest candidates for a drug were suc-cessfully identified? What happens topricing if the market for drugs is cutby two thirds? Dr Ramsey acknowl-edged the disconnect between drugdevelopment and this testing, saying“it’s putting companies in a bind.”Using the example of cetuximab, andhow its marketing strategy had tochange once KRAS informationbecame part of the labeling, DrRamsey offered a guess “that compa-nies are going to have to get on top ofit.” Nevertheless, narrowing the pop-ulation “might not be a bad thing ifthe efficacy is there,” he suggested. “We are definitely moving from

blockbuster to nichebuster,” said DrEpstein. He pointed out that Gleevec,which has a small population, is amultibillion-dollar drug. Also, in1998, there was only one billion-dol-lar cancer drug; there are now 20 “andthey’re all targeted.” Payers might pay a higher price on

a smaller subset of people for a morepredictable response, he concluded.“As long as you have better efficacy,or better safety, payers are not upsetabout that.” �

The experience of OncoType DXillustrates some of the issues associ-ated with introducing a new genet-ic test. Dr Lesko cited this as anexample of how a product wascarefully researched and intro-duced into the market through adeliberate, scientific process. Thetest “cost $400 million to develop,”he said, “but that may be what it takes.”Dr Ramsey focused on the poten-

tial for confusion from conflictingrecommendations for using this

product from the National Compre -hen sive Cancer Network (whichsays clinicians should considerusing this test for women withearly-stage breast cancer) andEGAPP (which says that there isuncertainty that the evidence is suf-ficient to make a recommendationfor or against).These mixed recommendations

“reflect the uncertainty of the field,”said Dr Ramsey. Even so, 134,000 ofthe tests have been ordered since itwas introduced in 1994. �

OncoType DX: Diagnostic Dilemma

“It’s amazing to me how often studies are

conducted that simply don’t ask the right

questions.”

—Lawrence J. Lesko, PhD, FCP


ISPOR CONFERENCE


Atlanta, GA—A session intended tooutline how communications regard-ing the coming wave of comparativeeffectiveness research (CER) studieswill need to done carefully in a polar-ized environment also pointed outthat although the methodology ofthese studies may be new, the com-munications process is in many waysthe same as for traditional research. With the huge increase in federal

funding for CER, there are “going tobe numerous projects with reports—100, 200, 300—who knows how manya year?” said Robert Dubois, PhD,MD, chief medical officer of CernerLife Sciences, Beverly Hills, CA, inopening the workshop at the 15thAnnual Meeting of the InternationalSociety for Pharmacoeconomics andOutcomes Research (ISPOR). BecauseCER will be so common and influen-tial, it possesses the ability to improveor worsen care depending upon howit is interpreted and disseminated, he argued.

Interpreting the New Science

Dr Dubois outlined some key, guid-ing principles for those needing tointerpret CER, which were first pre-sented in a 2009 white paper preparedby Cerner LifeSciences and sponsoredby the National Pharmaceutical Coun -cil. Unlike the process when examin-ing “traditional” studies, Dr Duboisrecommended that for CER studies,the evaluation be turned on its head.Readers of these studies should firstconsider for whom the findings areapplicable. “If you’re a primary caredoctor, and this deals with reallysevere specialty patients, you may noteven need to read the report,” he sug-gested. If the study passes this initialtest, only then is an evaluation of themethodology warranted. Lastly, thesereports must be evaluated in regard to evolving evidence, because this

research has a “half-life,” he noted. “Atsome point, it’s no longer going to bethe right answer.”For each step in the process, he rec-

ommended that checklists be used toaid evaluation of the studies. The var-ious study designs—randomized con-trolled trials, meta-analyses, andobservational studies—demand ques-tions specific to each type, and check-lists can help a study reader evaluatea study quickly and accurately. (Thosechecklists were developed and includ -ed in the publications.)

CER and Formularies

According to Brian Sweet, RPh,MBA, chief pharmacy officer, Well -Point, Grand Island, NY, CER isimportant to the firm as an importantsource of decision-making informa-tion, one that can help develop coverage and cost-sharing policies.According to Mr Sweet, CER does notmake care decisions, he emphasized,but enables dialog and better-inform -ed decision-making. A key tool used by the company is

its outcomes-based formulary, whichis intended to improve drug therapy,even if that means using a moreexpensive drug (the thinking beingthat with a patient’s health improved,less healthcare resources are usedoverall). So the company begins bycarefully evaluating clinical trial datato ensure that studies are of sufficientquality to be used for decision-mak-ing, and then uses integrated pharma-cy, medical, and laboratory data fromthe real world to determine drug out-comes in those environs. The processfor the pharmacy and therapeuticscommittee has a “traditional” clinicalreview, but also incorporates a value-assessment component, which helpsin assigning drugs to their final tier-ing level. Mr Sweet says that the firm has

been working with CER-style datasince 1998, so “this is not new to us.”But with the expected flood of CERstudies, and because of guidelinesthat WellPoint had put in place in2002, the firm realized that theywould not be able to use CER studiesto support decision-making. Thesestudies are “very useful in filling thegaps of what randomized trials don’ttell us,” he noted. Like Cerner,WellPoint has published a set of CERevaluation criteria, which have beenposted as a public document on theirwebsite (https://www.wellpointnextrx.com/shared/noapplication/f1/s0/t0/pw_b145032.pdf).

A third panelist, Jean Slutsky, PA,MSPH, director of the Center forOutcomes and Evidence at theAgency for Healthcare Research andQuality, Rockville, MD, also empha-sized the importance of using a sys-tematic process for setting clinical

policy, suggesting that questions suchas “How good is the evidence that theinterventions can improve those out-comes?” and “What constitutes ‘goodenough’ evidence?” be kept in mindwhen evaluating these studies. Heragency has worked to improve com-munications generally, translatingevidence-based information into con-sumer guides written at an 8th-gradelevel and created with input fromend-users. These consumer guides arepaired with concise, actionable physi-cian education guides that help con-vey the level of certainty or uncertain-ty in the findings. In discussing the soundness of evi-

dence used to back CER, Les Paul,MD, MS, vice president of Clinicaland Scientific Affairs, NationalPharmaceutical Council, Reston, VA,emphasized that it needs to be consid-ered within the context of the bestjudgment of the provider and thepreferences of the patient, which“tend to be lost in the current conver-sation that we are having.” Thesepreferences “are going to become thatmuch more important as more CER findings become available,” heventured.When communicating CER find-

ings, Dr Paul emphasized the needfor an approach that did not soundout of place for “regular” research—high-quality methods, and balancedand timely findings that describestrengths, limitations, generalizabili-ty, and “actionability” in the realworld.

Same as the Old Science

The real world, and the matter of acharged environment, was coveredmost directly during the Q&A ses-sion. A questioner wondered whowill determine whether CER studiesare well-conducted and whether their

results should be used in decision-making; Ms Slutsky pointed out that“that situation exists now. We haveprivate health plans, industry, andother groups writing consumer docu-ments.” This flood of informationconfuses the consumer, she empha-

sized, saying “there are many sectorsthat create documents that are sec-ondary to research.”Dr Paul noted that because some

methods in CER are relatively new incomparison to randomized clinicaltrials, there will be a learning curveassociated with the science. “We’venow had decades of experience inhow to communicate the results of tri-als. There’s an iterative process for the development of more advancedmethods that we are only now devel-oping in what I would characterize asthe young science of CER. How do wereconcile this long history of well-controlled trials that often take placein a regulatory environment withCER that will employ newer andoften nonexperimental study designsin a nonregulatory environment?”Mr Sweet lamented the press pick-

ing up the results of poor studies,which then makes them big news.Firms such as his are then left tocounter the demand from patientsand providers for new therapies.Although this already occurs, he feelsthat this will occur “at a much highermagnitude,” once the higher volumeof these new studies is seen.CER may be new, but at its core,

“this is science,” argued Ms Slutsky.It’s not science as usual, asking ques-tions for the sake of intellectualcuriosity, she suggested, but becauseanswers are truly needed. “The samescientific principles should apply,whether it’s CER or any other sort ofclinical study.” It’s important “not to politicize the

findings that are coming out of thesepublicly sponsored studies,” warnedDr Paul. The responsibility is “on thescientific and medical community notto let it become politicized. At the endof the day, this is about improvingpatient care.” �

Communications About CER in a Charged EnvironmentWhether CER or “regular” studies, care needed to convey results effectively

By Colin Gittens

“How do we reconcile this long history of

well-controlled trials that often take place in

a regulatory environment with CER?”

—Les Paul, MD, MS

at a glanceIncreased funding for comparative

effectiveness research (CER) will

lead to a flood of new studies

These studies employ some new

methodologies and will require

new interpretive perspectives

As with “traditional” studies, CER

studies will become outdated as

new evidence develops



As oncologists and hematolo-gists face a multitude of simul-taneous paradigm shifts relat-

ed to their ability to deliver newbiotechnology cancer-fighting medica-tions, more pro viders are turning toNew York–based OncoMed, TheOncology Pharmacy, a leading phar-maceutical services company that spe-cializes solely in oncology pharmaceu-ticals.In response to this surge in demand,

OncoMed recently opened its newestfacility in New England to providehigh-level oncology pharmacy servic-es in that region, and the company hasannounced plans to open 4 additionalnew facilities this year in Boca Raton,Florida; Buffalo, New York; Chicago,Illinois; and Phoenix, Arizona. Thecompany, founded in 2004, is licensedto provide oral, injected, and infusedpatient-specific oncology prescrip-tions in all 50 states to patients cov-ered by Medicare, Medicaid, and pri-vate health plans.“We have established

ourselves as a trustedmem ber of the cancer carecommunity for de livering‘just in time treatment day’oncology pharmaceuticalsand care managementservices,” said Chief Exec- u tive Officer Burt Zweig -en haft. “We’ve done thisby studying the market-place, listening to physi-cian practices, and providing market-proven solutions to the challenges thatour 600 current oncology practiceproviders face in the cancer care envi-ronment today.”“We are recognized for our rigorous

clinical standards in preparing anddelivering complex pharmaceuticalregimens,” Zweigenhaft said. “Theevolving role of the oncology pharma-cist is to be a cohort of the doctor’soffice. This is done by assisting withcritical clinical thinking during theregimen selection process. We alsomaximize the clinical yield of theseexpensive drugs through eliminatingdrug waste by compounding thepatient-specific orders and then deliv-ering them in treatment day doses.”

Adding Oncology Pharmacists to

the Mix

The OncoMed service modeldeploys specially trained oncologypharmacy technicians and expertoncology pharmacists to reduce ad -min istrative pressures on physicianpractices related to the complex andtime-consuming tasks of investigatinga patient’s insurance benefits, con-firming therapy reimbursement, andnavigating managed care priorauthorization processes. Additionally,the company has a staff of speciallytrained Insurance ReimbursementAdvocates who help patients gainaccess to the numerous patient finan-cial assistance programs as the tradi-tional $20 to $50 copayments now typ-ically rise into the thousands ofdollars, as is the case with MedicareParts B and D. Industry experts expectdramatically increasing copays to bethe trend, as noted recently duringspeeches and panels conducted at the

National ComprehensiveCancer Network (NCCN)and the Hematology/On -cology Pharmacy Associ -ation conferences.Having an oncology

pharmacist review andprocess each order ensuresthat all prescription regi-mens are routinely evalu-ated against the rapidlyemerging standards incare, such as the NCCN

Guidelines. This enables OncoMed’spharmacists to alert physician prac-tices to contraindicated drugs or treat-ment complications in advance oftherapy. Events like this do happen,and one such event occurred recentlywhen OncoMed pharmacists receiveda prescription for bevacizumab(Avastin) and cetuximab (Erbitux) totreat the same patient with previouslyuntreated metastatic colorectal cancer.In this instance, the oncology pharma-cist called the physician and alertedhim to the very recent study thatfound the combination of bevacizum-ab and cetuximab, when administeredalongside chemotherapy, worsens col-orectal cancer outcomes amongpatients with previously untreated,

metastatic colorectal cancer andresults in shorter progression-free sur-vival and worse quality of life. Thephysician was grateful for the clinicalinformation and then changed thetreatment order.

Change Is the Constant

“It’s a field that’s constantly evolv-ing, with research driving changes inoncology day by day,” added KevinAskari, RPh, president and chief clini-cal pharmacist of Onco Med. “Our goalis to act as a virtual oncology pharma-cy within the practice, and also beused as a pharmacological re sourceand experienced knowledge center inthe oncologist’s office.”Among the challenges they are fac-

ing today, oncology providers point to:• Reduced margins on drug reim-bursement;

• Additional administrative burdensto verify complex patient benefitprograms;

• Evolving new studies and standardsin care, with more drug combina-tions and protocols from which tochoose;

• More patients who see dramatic in -creases in copays, a financial respon-sibility that many can’t handle;

• More prior authorization require-ments for approved treatments; and

• An explosion in inventory “carrycosts” and the risks of bad debt withlow drug margins.OncoMed gives providers a new

option for dealing with these prob-lems and the economic challenges ofmanaging and dispensing oncologymedicine.“Working with OncoMed has been a

win-win situation for our practice,”said Jeff Gaspar, practice admin -

istrator for North Shore Hematology/Oncology, a 6-physician practice onLong Island, New York. “We can getmedication on the same day that it isprescribed, which is very importantbecause of the rapidly changing dis-

ease status seen in oncology patients.”Gaspar went on to say that, “theoncology pharmacy model is superiorin knowledge, execution, and servicesdelivered when compared with themail-order specialty pharmacies ordrug replacement programs that somemanaged care plans now require ourpractice to use.“Having to treat patients with

chemotherapy regimens that rangefrom weekly to every 21 days in a dis-ease that is continuously morphing,while dealing with the multiple sideeffects and reimbursement challenges,is a lot for us to manage in the currenteconomic environment,” Gaspar said.“So when we outsource the drugs andend up with an inexperiencedprovider on the other side of thephone or fax machine who does notunderstand the therapy or treatmentcycle time sensitivity, as we have expe-rienced from the specialty mail-orderpharmacies, it places a huge burdenon my staff and puts our practice in avery difficult position.”OncoMed’s pharmacy model en -

ables physician practices to budgetinternal resources more appropriately,thereby reducing staff time spentinvestigating benefits with insurancecarriers as well as the procurementsourcing tasks of accessing limiteddistribution drugs from manufactur-ers and wholesalers as well as FDA-imposed special processes. The resultfor practices is reduced capital expens-

Sea Change in Oncology Creates Demand For OncoMed

Evolution inOncology Practice Management

PART3OF A SERIES

OncoMed providedfunding and

editorial support for this article

www.OncoMed.net

ADVERTORIAL

™

Burt Zweigenhaft, CEO

“The oncology pharmacy model is superior inknowledge, execution, and services delivered whencompared with the mail-order specialty pharmacies drug replacement programs that some managedcare plans now require our practice to use.”

—Jeff GasparPractice Administrator

North Shore Hematology/Oncology



To learn more about OncoMed or to request a presentation, contact OncoMed at 1-877-662-6633, extension 1298 or [email protected], or go to www.oncomed.net.

EVOLUTION IN ONCOLOGY PRACTICE MANAGEMENT™

es and risks associated with copay-ment collection and bad debt.OncoMed also facilitates the priorauthorization process with insurancecarriers.

Expertise Needed for New

Complexities

At the heart of the prescriptionintake process and supervising all dis-pensing activities are OncoMed’soncology pharmacists. All compound-ing and mixing is conducted in a USP<797>–compliant clean room environ-ment. Each dose and measure goesthrough a 6-point quality-check pro -cess done by oncology pharmacists orpharmacy technicians to ensure safetyand accuracy. OncoMed goes an extrastep to ensure that all of its pharma-ceuticals are purchased under a pub-licly disclosed “Drug PedigreeProgram” that specifically allows onlydirect documented purchases from theprime manufacturers to ensure 100%drug efficacy and inventory safety.

“I can’t stress the human factorenough,” said Askari, the chief clinicalpharmacist. “Our facilities are top-notch, but we know they are only asgood as the people who work withinthem. That is why we have formalizedan ongoing oncology pharmacy train-ing program for everyone regardlessof their role in our organization and

we have a Professional PracticesReview and Oversight Committee thatreviews our performance quarterly.”

The arsenal of oncology pharmaceu-ticals and biotechnology targeteddrugs has grown dramatically inrecent years. As recently as the 1970s,there were no biologics and few drugchoices, and cancer frontline treat-ments were mainly surgery and radia-tion. Many of the firstchemotherapy drugs, novelat the time, are obsoletetoday as stand-alone drugs(some remain effective incombination with the newtargeted biotechnologydrugs used in protocols).

“Given the expandingcomplexity of therapiesand protocols, I saw therewas a need for an oncologypharmacy,” said Askari. “Iwanted to be involved inan evolving, dynamic field. Every day,even now, you get bombarded withnew information. The treatment thatwas the best thing yesterday may notwork today.”

Amid this complexity, Askari saidhis emphasis remains on safety andquality. As an example, he said, “wehire only pharmacists who meet ourown rigorous oncology pharmacyexperience standards, who are then

shadowed under close supervision for6 months before they work on the dis-pensing front.”

Focus on Patients,

Not Dollars

Historically, oncology providershave purchased and dispensed oncol-ogy medicines under a “buy and bill”system where they buy the drugs from

the manufacturer/whole-saler, keep them in theiroffice, and prepare thedrugs and dispense themto patients when needed.Medicare and other man-aged care payers havechanged the drug reim-bursement methodologiesand moved to market-based reimbursementschedules, reducing theamount they reimbursethe physician practices.

Today, most payers have moved todiscounting the AWP (average whole-sale price) to AWP minus 15% to 18%and/or some have replaced the AWPstandard with the Medicare standardof ASP (average sales price) plus 6%.This reimbursement compression, aswell as the more administrativelycomplex process for acquiring themedications, has made the downsideeconomics of “buy and bill” more

apparent to physician practices. Notall physician practices have the neces-sary scale, professional resources, andcapitalization required to providethese drugs and services profitablyand that is exactly the market nichethat OncoMed is positioned to service.

“Physicians should be focused oncaring for their patients and their com-plex disease,” said Zweigenhaft.“They should not have to worry aboutrunning a pharmacy and the tasks ofacquiring and maintaining an invento-ry of medications, the drug authoriza-tion burdens, collection of copaymentsand drug reim bursement, and the riskof bad debt.” Zweigenhaft went on tosay that, “we see new challengesappearing as more state pharmacyboards seek to control enforcement ofthe drug preparation sites using USP<797> and PCAB [PharmaceuticalCompounding Accreditation Board]certifications.”

The validation of the OncoMedOncology Pharmacy model is evi-denced by the hundreds of physicianswho have chosen the company as theirpreferred partner to navigate the seachange in oncology pharmaceuticals.Perhaps the greatest value, however, isthe support the oncology pharmacymodel can provide for the patients,who face the supreme challenge ofdefeating their cancer. �

FDA UPDATES

Review for ARBs Following

Cancer Connection

The FDA is investigating a connec-tion between angiotensin receptorblockers (ARBs) and cancer followingpublication of a meta-analysis (LancetOncol. 2010;11[7]:627-636) suggestingthe drug’s use may slightly increasethe risk of cancer. The FDA empha-sized that review is ongoing and thatthey have not concluded that ARBsincrease the risk of cancer. The FDAalso presently believes that the bene-fits of these agents continue to out-weigh their potential risks and thatthese drugs should continue to beused as recommended in theirapproved labels. (July 15, 2010)

Blood Thinner Recalled

After determining that isopropanollevels in some Coumadin 1-mg tabletblister packs could impact theamount of Coumadin delivered topatients over time, Bristol-MyersSquibb voluntarily recalled the fol-

lowing lots: Physician Sample BlisterPacks—lot numbers 9A48931A,9A48931B, 9A48931C, expirationJanuary 2012; HUD Blister Pack—lot numbers 8F34006B, 8K44272A,8K46168A, 9F44437A, and 9K58012Bwith expiry dates between June 2011and November 2012. (July 12, 2010)

Mylotarg Pulled After

Disappointing Follow-up

On the heels of results from a recentclinical trial that raised new concernsabout gemtuzumab ozogamicin(Mylotarg)’s safety and the drug’sfailure to demonstrate clinical benefitto acute myeloid leukemia (AML)patients enrolled in trials, the drug’smanufacturer, Pfizer, Inc, withdrewthe drug at the request of the FDA.Mylotarg was approved in May 2000under the FDA’s accelerated approvalprogram, which used a surrogate endpoint of response rate (ie, the percent-age of patients whose leukemiadecreased or disappeared in laborato-

ry tests) observed in 142 patients withAML across 3 clinical trials. A confir-matory, postapproval clinical trialwas begun in 2004, but the trial wasstopped early when no improvementin clinical benefit was observed, andafter a greater number of deathsoccurred in the group of patients whoreceived Mylotarg compared withthose receiving chemotherapy alone.(June 21, 2010)

Rapid Approval for Nilotinib

Following a single randomized,active-control, open-label, multina-tional clinical trial comparing theresponse of 846 patients with newly diagnosed Philadelphia chro-mosome–positive chronic myeloidleukemia (Ph+ CML) in chronic phase(CP-CML) to either nilotinib (TasignaCapsules, Novartis PharmaceuticalsCorporation) or imatinib, the FDAgranted accelerated approval to nilo-tinib. The drug was originallyapproved in October 2007 for the

treatment of adult patients with CP-CML and accelerated phase resistantor intolerant to prior therapy thatincluded imatinib. (June 17, 2010)

Cabazitaxel Gains Combined Use

Indication

The FDA approved cabazitaxel(Jevtana Injection, sanofi-aventis) foruse in combination with prednisonefor treatment of patients with metasta-tic hormone-refractory pros tate cancer(mHRPC) previously treated with adocetaxel-containing regimen. Theapproval is based primarily on theresults of a randomized, open-label,international trial of 755 patients withmHRPC previously treated with doc-etaxel-containing regimens. Mediansurvival was 15.1 months for cabazi-taxel-treated pa tients (compared with12.7 months for those treated withmitoxantrone). The most commongrade 3-4 adverse reactions includedneutropenia, leukopenia, anemia, andfebrile neutropenia; growth colony-

Kevin Askari, RPhPresident and ChiefClinical Pharmacist



FOCUS ON


Hematopoietic Growth Factors: What’s New in 2010?

Chemotherapy-induced neutro -penia is a risk associated withmany common chemo therapy

regimens. Especially when associatedwith fever—ie, febrile neutropenia(FN)—it is dose-limiting and some-times life-threatening. Certainly, itincreases resource utilization—including hospitalization—and cost.Myeloid growth factors can reducethe incidence, duration, and severityof neutropenic events and thereforeare recommended for prophylaxis insome situations. It is important forpayers to remain up to date on thisimportant component of supportivecare. To this end, this report describesrecent recommendations and researchfindings that affect the optimum useof growth factors.

ESMO Updates Guidelines

In July, the European Society forMedical Oncology (ESMO) releasedan enhanced and revised set of clinicalrecommendations for cancer care, the 2010 ESMO Clinical PracticeGuidelines, which contains a sectionon hematopoietic growth factors.1 Theguidelines recommend hemato poieticgrowth factors for patients with a riskof FN ≥20% (listing chemotherapyregimens that pose this risk), or underspecial circumstances.

Primary prophylaxis is deemed justified for patients with reducedmarrow reserve due to radiotherapyof >20% of the marrow, humanimmunodeficiency virus, or aged ≥65years and receiving curative regi-mens. Secondary prophylaxis isadvised for patients at risk for furtherinfections considered life-threatening,patients with dose reductions of con-cern and treatment delays, andpatients for whom lack of protocol

adherence would compromise clinicaloutcomes. Other high-risk situationsin which growth factors are indicatedinclude autologous marrow trans-plant, allogeneic marrow transplant,and graft failure, the report states.

Treatment with growth factors isadvised for patients with protractedFN (>7 days), hypotension, sepsis,pneumonia or fungal infection, andfor patients at risk for death fromradiation injury. Growth factors withor without chemotherapy are aneffective component of peripheralblood stem cell mobilization prior totransplant, the guidelines note.

The new guidelines are the firststage in the development of guide-lines addressing 55 different clinicalsituations, including the therapeuticuse of growth factors.

NCCN 2010 Guidelines

The selective use of colony-stimu-lating factors (CSFs) in patients atincreased risk for neutropenic compli-cations may enhance the cost-effec-tiveness of these agents, according tothe 2010 guidelines of the NationalComprehensive Cancer Network(NCCN).2 The indication for prophy-lactic CSF use depends on the risk ofFN or other neutropenic events thatcan potentially compromise treat-ment. Based on chemotherapy regi-men and patient-related risk factors,the patient is assigned to a high-riskgroup (>20% risk of FN) intermedi-ate-risk group (10%-20% risk), or low-risk group (<10% risk). For the high-risk group, NCCN has a category 1recommendation for using CSF whenthe treatment intent is curative or toprolong survival and improve qualityof life. For intermediate-risk patientswith this intent, CSF should be con-sidered. Prophylaxis is not recom-mended for low-risk patients.

There remains no consensus nomo-gram for risk assessment, but severalrisk factors are well established. Newto the 2010 guidelines is the notationthat a “prior episode of FN is a riskfactor for poor clinical outcome or fordeveloping infection-associated com-plications.”3 Also new is the additionof several regimens to those associat-ed with high risk: hyperCVAD(cyclophosphamide, vincristine, dox-orubicin, dexamethasone) for the

treatment of multiple myeloma; anti -thymocyte globulin, rabbit/cyclo -sporine for the treatment of myelo dy -splastic syndrome; and do x o ru bicin/gemcitabine for the treatment of kidney cancer.4

Publications of Note

Aapro et al evaluated 254 elderlybreast cancer patients receiving chemo -therapy supported by pegfilgrastim(Neulasta) primary prophylaxis orcurrent practice neutropenia manage-ment.5 FN incidence was 6% with peg-filgrastim prophylaxis, compared with24% under current neutropenia prac-

tice; FN-related hospitalization inci-dence was 5% and 15%, respectively;and dose reductions were needed for15% and 29%, respectively.

Gerds et al conducted a phase 3randomized, double-blind, placebo-controlled trial comparing efficacy,costs, and safety of single-dose peg-filgrastim versus daily filgrastim(Neupogen) after autologous periph-eral stem cell transplantation in 78patients.6 They found the 2 regimensto be equally effective in time to neu-trophil engraftment, with no differ-ence in clinical sequelae; however,pegfilgrastim achieved a cost-savingsof $961 per patient over filgrastim.

Similarly, several other studiesfound pegfilgrastim cost-effective over6 days of filgrastim. In a study byLyman et al, in patients with non-Hodgkin’s lymphoma receiving myelo -suppressive chemotherapy, the incre-mental cost-effectiveness ratio (ICER)for pegfilgrastim was $2167/FNepisode avoided.7 Adding a survivalbenefit derived from avoiding FNmortality yielded an ICER of $5532/life-year (LY) gained or $6190/quality-adjusted life-year (QALY) gained.When the potential benefit of opti-mized chemotherapy was included,the ICER was $1494/LY gained or$1677/QALY gained.

Italian investigators also conclud-ed that primary prophylaxis withpegfilgrastim improved health out-comes with a “very limited costincrease” for the National HealthService payer. “Even when very lowprices of filgrastim and high prices ofpegfilgrastim were considered in themodel, the resulting ICER remainedwell within the acceptable cost-effec-

tiveness limit of €50,000/QALY,”Danova et al noted.8

Columbia University investigatorsreported that the sequential adminis-tration of sargramostim (Leukine) andfilgrastim in 31 children undergoingmyeloablative conditioning was safeand cost-effective and resulted inprompt myeloid engraftment.9 Sar gra -mostim 250 mcg/m2 once daily wasbegun on the day of stem cell infusion,switching to filgrastim 10 mcg/kgonce daily when white blood cellswere ≥300/mm3, for 2 days. Filgrastimwas continued until the absolute neu-trophil count (ANC) was ≥2500/mm3

for 2 days, then tapered to maintainANC ≥1000/mm3. The sequentialapproach, versus filgrastim alone, wasestimated to save $1311 per patient.

Naproxen was effective in reducingpegfilgrastim-induced bone pain in arandomized, double-blind, placebo-controlled trial of 510 cancer patientspresented at the American Society ofClinical Oncology annual meeting.10

Mean AUC for pain was 7.71 forpatients receiving placebo and 6.04for those receiving naproxen 500 mgtwice daily (P = .037). Naproxen re -duced the overall pain incidence from76% to 66% (P = .0085) and durationfrom 2.40 to 1.92 days (P = .009). �

References1. Crawford J, Caserta C, Roila F. Hematopoieticgrowth factors: ESMO Clinical Practice Guidelines forthe applications. Ann Oncol. 2010;21(suppl 5):v248-v251.2. National Comprehensive Cancer Network: NCCNPractice Guidelines in Oncology—v.1.2010. Availableat: www.nccn.org/professionals/physicians_gls/PDF/myeloid_growth.pdf.3. National Comprehensive Cancer Network: NCCNPractice Guidelines in Oncology—v.1.2010. MGF-E.Available at: www.nccn.org/professionals/physicians_gls/PDF/myeloid_growth.pdf.4. National Comprehensive Cancer Network: NCCNPractice Guidelines in Oncology—v.1.2010. MGF-A.Available at: www.nccn.org/professionals/physicians_gls/PDF/myeloid_growth.pdf.5. Aapro M, Schwenkglenks M, Lyman GH, et al.Pegfilgrastim primary prophylaxis vs current practiceneutropenia management in elderly breast cancerpatients receiving chemotherapy. Crit Rev OncolHematol. 2010;74:203-210. 6. Gerds A, Fox-Geiman M, Dawravoo K, et al.Randomized phase 3 trial of pegfilgrastim versus fil-grastim after autologous peripheral blood stem celltransplantation. Biol Blood Marrow Transplant. 2010;16:678-685. 7. Lyman G, Lalla A, Barron R, Dubois RW. Cost effec-tiveness of pegfilgrastim versus 6-day filgrastim pri-mary prophylaxis in patients with non-Hodgkin’slymphoma receiving CHOP-21 in the United States.Curr Med Res Opin. 2009;25:401-411. 8. Danova M, Chiroli S, Rosti G, Doan QV. Cost effec-tiveness of pegfilgrastim versus 6 days of filgrastimfor preventing febrile neutropenia in breast cancerpatients. Tumori. 2009;95:219-226. 9. Waxman IM, Militano O, Baldinger L, et al.Sequential administration of sargramostim and fil-grastim in pediatric allogeneic stem cell transplanta-tion recipients undergoing myeloablative condition-ing. Pediatr Transplant. 2009;13:464-474. 10. Kirshner JJ, Heckler CE, Dakhil SR, et al.Prevention of pegfilgrastim-induced bone pain: aURCC CCOP randomized, double-blind, placebo- controlled trial of 510 cancer patients. Presented at:American Society of Clinical Oncology annual meet-ing; June 4-8; 2010. Chicago, IL. Abstract 9104.

By Caroline Helwick

The selective use of colony-stimulating factors (CSFs) in

patients at increased risk for neutropenic complications may

enhance the cost-effectiveness of these agents.

at a glanceThe European Society for Medical

Oncology has just released

updated information on

hematopoietic growth factors

2010 NCCN guidelines

emphasized that selective use of

colony stimulating factors (CSF)

may enhance the cost

effectiveness of these agents

A number of recent studies have

looked at the costs and clinical

effectiveness of CSF treatments

for febrile neutropenia


VBCC PERSPECTIVE


FDA UPDATES Continued from page 23

stimulating factors may be adminis-tered to reduce the risks of neu-tropenic complications associatedwith cabazitaxel use. (June 17, 2010)

Safety Concerns for Pediatric

Taxotere Use

The FDA announced changes to theTaxotere (docetaxel) label, notingadverse reactions including scleroder-ma-like cutaneous changes usuallypreceded by peripheral lymphedemaand instances of renal failure, themajority of which were associatedwith concomitant nephrotoxic drugs.(May 2010)

Warnings Strengthened for

Camptosar

The FDA announced changes to theCamptosar (irinotecan HCl) label,adding warnings concerning pul-monary toxicity and dangers inpatients with reduced UGT1A1 activ-ity. Patients with this allele had higherincidences of grade 4 neutropenia. Inaddition, a notation regarding inter-

stitial pulmonary disease was addedunder the adverse reactions. (May2010)

Better Bladder Imaging

The FDA granted approval forhexaminolevulinate hydrochloride(Cysview for Intravesical Solution,Photocure ASA), as an optical imag-ing agent for use in combination withthe Karl Storz Photodynamic Diag -nostic D-Light C (PDD) System. Thedevice plus imaging agent allows forcystoscopic detection of nonmuscleinvasive papillary cancer of the blad-der in patients suspected or known tohave lesion(s) on the basis of a priorcystoscopy (using the blue light set-ting [Mode 2] as an adjunct to thewhite light setting [Mode 1]). Theapproval was based on a prospective,multicenter, controlled clinical trial of779 adult patients, who were giventhe drug and evaluated in white andblue light mode or were not given thedrug and evaluated using white lightonly. (May 28, 2010)

The Prescription Solution guide-lines are based on both US Food and Drug Administration (FDA)-approved uses and nonapproveduses, provided there is an evidencebase for the nonapproved uses, DrSolow described. His firm begins by looking at the FDA-approved indications—febrile neutropenia pro-phylaxis, for example—and ensuringthat this condition is listed in theproduct insert. For this condition,there are separate guidelines for fil-grastim (Neupogen) and pegfilgras-

tim (Neulasta). In the case of patientswith acute myelogenous leukemiareceiving induction or consolidationtherapy there are indications for sargramostim (Leukine) and filgras-tim. So the recommended drugs areswitched around “depending onwhat’s FDA indicated,” Dr Solowsaid. The firm offers guidelines for neu-

tropenia associated with cancerchemotherapy, including criteria forsecondary prophylaxis of febrile neu-tropenia as well as its off-label use.These criteria also include the dura-tion of therapy. As described by DrSolow, the Prescription Solutionsguidelines offer a fairly granularbreakdown of when the drugs can beused, but because this breakdown isevidence based, it is “pretty well rec-ognized…if you don’t meet the crite-ria, you’re going to have to tell uswhy the patient gets it.“You can’t just say ‘my patient is

neutropenic’—it’s not good enough,”Dr Solow argued. In the case of off-label use, Prescription Solutions willcover drugs listed in one of the accept-ed compendia or if the physician cansupply enough reference materials tosupport the use of these drugs. “We recognize that if there is litera-

ture to support it as opposed to anec-dotes, then there’s a good chance it’s

going to be approved,” Dr Solowexplained. “We’re in the business ofdoing the best thing for the patient,”he said. Although there are some who say

that PBMs are about withholdingdrugs, he pointed out that “patientsafety and quality care come first.Unfortunately, not just with this classbut with a lot of these specialty class-es, there’s people who don’t knowhow to use these drugs.”Dr Solow’s role as a medical director

is to create these medically soundguidelines. PBMs have to look at thetotal picture—the literature, the indi-cations concerning off- and on-labeluse, and all evidence—and painstak-ingly design guidelines that work with

the oncologists and transplant physi-cians who are prescribing these drugs.Although the granular breakdown ofacceptable uses in these authorizationprograms may frustrate physicians,their intent goes back to the patient,helping ensure the right medicationfor the right patient at the right dose. But he acknowledged hearing anec-

dotally that physicians say, “I don’twant to go with these guidelines. Mypatient just needs this drug.” Or thephysician may fall back on experienceor current practice, saying, “all mypatients are on Neupogen.” That maybe, said Dr Solow, but “the physicianneeds to provide us with soundrationale for its use before its authori-zation is approved.” �

What’s a PBM to Do with CSFs?

MEETINGS CALENDAR

August 14-17Personalized Interdisciplinary CancerTreatment: The Importance of Timing,HoustonContact: The University of Texas M. D.Anderson Cancer CenterCME/Conference Services,Unit 1381, PO Box 301439, Houston, TX77230. 713-792-2223 or [email protected].

August 20-229th International Congress onTargeted Therapies in Cancer,Washington, DCContact: Physicians' EducationResource, 3500 Maple Avenue, Suite 700,Dallas, TX 75219. 888-949-0045 [email protected].

August 2816th Annual Perspectives in Breast Cancer, New York CityContact: Imedex, 4325 Alexander Drive,Alpharetta, GA 30022. 770-751-7332 [email protected].

September 12-15Joint Metastasis Research Society-AACR Conference, PhiladelphiaContact: AACR, 615 Chestnut St., 17thFloor, Philadelphia, PA 19106. 215-440-9300 or [email protected].

September 25The Management of Women withChronic Immune Disorders in the Era of Biologics, New York CityContact: Imedex, 4325 Alexander Drive,Alpharetta, GA 30022. 770-751-7332 [email protected].

September 26-29Scripps Cancer Center’s 30th Annual Oncology Nurses Symposium,San DiegoContact: Scripps Conference Services &CME, 11025 North Torrey Pines Rd.,Suite 200, Mail Stop SCRC 200,La Jolla, CA 92037. 858-652-5400 [email protected].

September 27-30AACR International Conference onMolecular Diagnostics in CancerTherapeutic Development, DenverContact: AACR, 615 Chestnut St., 17thFloor, Philadelphia, PA 19106. 215-440-9300 or [email protected].

September 29-October 2 27th National Oncology EconomicsConference, St. LouisContact: Association of CommunityCancer Centers, 11600 Nebel Street, Suite 201, Rockville, MD 20852.301-984-9496, ext. 219 [email protected].

September 30-October 3Third AACR Conference on theScience of Cancer Health Disparitiesin Racial/Ethnic Minorities and theMedically Underserved, Miami, FLContact: AACR, 615 Chestnut Street,17th Floor, Philadelphia, PA 19106. 215-440-9300 or [email protected].

October 1-29th International Kidney CancerSymposium, ChicagoContact: Kidney Cancer Association, POBox 96503, Washington, DC 20090. 800-850-9132 or [email protected].

October 1-32010 Breast Cancer Symposium,National Harbor, MDContact: The American Society forClinical Oncology, 2318 Mill Road, Suite800, Alexandria, VA 22314. 571-483-1300or http://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].


Brian K. Solow, MD, vice presi-dent and senior medical director of clinical services at the pharmacy benefit management (PBM) firmPrescription Solutions in Irvine,CA, explained the process of whatgoes into the prior authorizationguidelines concerning the use ofcolony-stimulating factors (CSFs).As with all clinical guidelines, it isessential to have an evidence basesupporting their appropriate use.



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NCCN Roundtable: Clinical andEconomic Issues Impacting Cancer Care Delivery “Collision course” in sight

©2010 Engage Healthcare Communications, LLCContinued on page 24

Baltimore, MD—A long-held businesstruism is that “if you can’t measure it,you can’t manage it.” The application of this belief to the oncology setting was demonstrated at a session of theAssociation of Community Cancer Cen ters’ (ACCC) 36th Annual NationalMeeting. Kimberly Bergstrom, PharmD,chief clinical officer for McKessonSpecialty Care Solutions, told attendeesof the growing importance of developingand using standardized chemotherapytreatment regimens, and of the tools that

can benchmark performance and fostercompliance with treatment guidelines.Public and private payers are mov-

ing to control exploding healthcarecosts, Dr Bergstrom told attendees,and because increased cost controlwas inevitable, it is in providers’interest to get a seat at the table. “It is an important topic, because

this is one of those things, if we don’tget a handle on it, it’s going to happento us,” she said. “People and groupsand organizations are going to startdictating how we provide cancer care,and we can’t let that happen.”

Hollywood, FL—Clinical practiceguidelines issued by the NationalComprehensive Cancer Network(NCCN) are followed by conscien-tious oncologists in their everydaypractice, but they are developedbased on clinical efficacy and withoutregard to costs. At a roundtable heldduring the NCCN’s 15th AnnualConference, moderator CliffordGoodman, PhD, Senior Vice Presidentat The Lewin Group, predicted, “Theappropriate use of evidence-basedguidelines is on a collision coursewith the financial nonsustainability ofthe healthcare system.”

Dr Goodmanalluded to a levelof frustration thathas never beenhigher in cancercare. “Too manypatients are stilldying young. Weneed innovations and a cure,” he said.But the inadequacy of current treat-ments for cancer is no longer the mainproblem. Equally challenging, he sug-gested, is finding a means to pay forthe ever-costlier care that threatens tobankrupt the healthcare system. As society struggles to find solu-

tions, “the ground is shaking beneathus,” Dr Goodman commented.

Continued on page 8



By Audrey Andrews

SEER-Medicare Database AnalysisConfirms Expensive ProstateCancers Gaining SupremacyBut cost-effectiveness of this move remains to be determined

San Francisco, CA—The popularity ofminimally invasive radical prostatec-tomy (MIRP), intensity-modulatedradiation therapy (IMRT), and ofbrachytherapy combined with IMRTfor prostate cancer started to take offafter 2002, a new database analysishas confirmed.At the American Society of Clinical

Oncology’s 2010 Genitourinary Can -cers Symposium, Paul L. Nguyen,MD, presented the results of histeam’s analysis of data from theSurveillance, Epidemiology and EndResults (SEER)-Medicare database.Dr Nguyen, director of Prostate

Brachytherapy, Dana-Farber/Brigham

and Women’s Hospital, HarvardMedical School, Boston, and his co-investigators found MIRP jumpedfrom 1.5% of radical prostatectomies(RPs) in 2002 to 28.7% in 2005. Theyalso found that IMRT soared from8.7% of external radiation treatmentsfor prostate cancer to 81.7%. In addi-

By Rosemary Frei, MSc

New Tools Arriving to Measure andManage Chemotherapy CareBusiness, clinical concerns now connected in value-focused approach By Daniel Denvir

Breast Cancer Survival Improves,Thanks to New Therapies

The 2010 Genitourinary CancersSymposium: Progress in Multi -disciplinary Management was heldMarch 5-7 in San Francisco. All ses-sions emphasized a multidisciplinaryap proach to care; a number of thembrought out the cost and value issuesassociated with caring for genitouri-nary cancers.

Value-Based Cancer Carewill be at the ASCO Annual Meeting, June 4-8, in Chicago. Please visit us at booth 18121

Barcelona—Survival for patients withmetastatic breast cancer has improveddramatically in the last 20 years, espe-cially in the subgroup of patients withHER2-positive tumors, according toresearch presented at the 7th European

Breast Cancer Confer ence (EBCC7).This improvement, the researcherssuggest, is due to in creased use ofanthracyclines and the rise of targetedtherapies.“There is no doubt that trastuzu -

mab (Herceptin), which targets theHER2 gene, is the most important

By Colin Gittens


��

Photo by © ASCO/Todd Buchanan 2009

targeted therapies

VBCC_August 081110_ASCO Highlights Tabloid 8/16/10 9:38 AM

CONSUMER GENETICS


Consumer Genetics: Paradigm Shift or Flash... Continued from cover

genetic testing will create a funda-mental change in how oncologistscare for their patients, going from thetraditional, trial-and-error regimen ofobservation, action, and observableresults to a new process of observa-tion, test, action, and predictedresponse. “The new paradigm will

break the trial-and-error cycle,” shesaid, avoiding cytotoxicity and pre-venting lost therapy options should apatient relapse or experience refracto-ry cancer. Her company uses person-alized medical diagnostics to charac-terize a current diagnostic “blackhole,” assessing whether circulatingtumor cells in the bloodstream arestill a threat to the patient. Evenpatients’ drug compliance can in -crease when customized drugs anddosages are determined throughgenetic testing. Ms Aspinall cited anAmerican Heart Association studythat concluded, “If the patient be -lieves that the drug is personalizedfor them, compliance goes up.”

Moving Genetics from Theory to

Practice

The world—or at least the worldinhabited by meeting presenters—isvery much ready for genomic testing.Dietrich Stephan, PhD, of IgniteInstitute indicated the framework forpractical consumer genetics hasformed with the convergence of sev-eral components. “We now have accu-rate sequencing technology at a rea-sonable price for a one-shot moleculardiagnostic assay, and an increasingknowledge base to extract value fromthat genome. The delivery infrastruc-ture is in place, beginning with howto take a sample, where to send it,

secure delivery of the results, theirinterpretation, and finally genomiccounseling.” Speakers from these infrastructure

companies were well represented atthe conference. Mr Schatzberg’sGeneration Health has partnered withCVS Caremark to help them navigatewhich pharmacogenetic tests areappropriate. The 2 companies are cue-ing up a July pharmacogenetic-testingpilot program on 13 drugs. “We don’twant to increase testing or decreasetesting, we want to optimize it,” hesaid. Existence Genetics, a firm founded

by Brandon Colby, MD, performsgenetic tests and has developed aNext Generation Analysis Report toconvey the results in an easy-to-readformat so both patients and doctorscan understand them. To help cancer patients determine

their treatment options throughanalysis of their DNA, Life Tech -nologies Corporation announced at

the conference their Genomic CancerCare Alliance, a new partnership with Fox Chase Cancer Center,Scripps Genomic Medicine, and theTranslational Genomics ResearchInstitute. The US Food and Drug Adminis -

tration (FDA) is also readying itselffor the personalized care revolution.Paul Kim, JD, MPP, an attorney withFoley Hoag, advised the audience tobalance their day job with one eye on what the FDA will approve.“Consumer genetic devices have beenunder the radar, but the FDA is in theprocess of deciding their oversightpolicies for this industry, and will bereviewing their 501(k) processinggoals. Its new focus will be on trans-parency, consistency, and predictabili-

ty,” Mr Kim said. He also informedthe audience of 2 new organizations,the Centers for Medicare & MedicaidServices Innovation Center and theIndependent Payment AdvisoryBoard, that will research Medicarecost reform and where consumergenetic researchers can advance theirdevices. Although genetic testing is still in

its initial stages, Steve Murphy, MD,the founder of The PersonalizedMedicine Group, identified someareas where it needs to grow. DrMurphy called for widespread educa-tion about pharmacogenetic testingfor physicians and patients, and forinsurance companies to properlyreimburse physicians for the time ittakes to research genetic results.“There are 19,000 genes in thegenome, and it took me 6 hours toresearch 1 gene for a patient,” hereported. He also looks forward to aproliferation of the gene database todecrease the number of “unclassified

variant” or “novel mutation” analy-ses, and hopes more studies will leadto stronger data, increasing the accu-racy of risk estimates. When inconclu-sive or vague answers are reported topatients now, Dr Murphy noted,“they feel angst.” Speakers at the conference explored

the many possibilities for consumergenetics. Although genomic testing isperformed for particular newborns orfetuses, could this be expanded to allpregnancies? Dr Stephan postulatedhow perinatal screening could renderearly disease detection or susceptibili-ty, noting, “If every newborn gets asequencing test, can we spend thatmoney to save money later?” DrMurphy proposed an online HealthInsurance Portability and Account -

ability Act–compliant “Genetic Hub”that could be a connection pathwayfor doctors, patients, and laboratories.

The Personal Becomes Political

For many at the meeting, consumergenetics seemed on the cusp of abreakthrough, with Dr Stephan won-dering, “How will patients use theirgenetic information to develop per-sonalized combinatorial therapeuticsto allay their phenotype?” But justabout a week later (June 10), thepromise of consumer genetics took aserious hit with a series of letters fromthe FDA to makers of home genetictest kits, including 23andMe,deCODE Genetics, Knome, Illumina,and Navigenics. The letters statedthat the products sold by these companies are considered devices bythe FDA, and as such they fall underthe agency’s regulatory purview.Interestingly, the letters did not statethat the devices had to be removedfrom the market, but rather theyencouraged the firms to “meet withus to discuss whether there are testsyou are promoting that do not requirereview by the FDA and what informa-tion you would need to submit inorder for your product to be legallymarketed for the other uses.” Unlessthis issue is resolved, the future forconsumer genetics conferences seemsdecidedly less rosy. �

“There are 19,000 genes in

the genome, and it took me

6 hours to research 1 gene

for a patient.”

—Steve Murphy, MD Brandon Colby, MD

“Consumer genetic devices have been under the radar,

but the FDA is in the process of deciding their oversight

policies for this industry.” —Paul Kim, JD, MPP

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

October 18-20ASCO-NCI-EORTC Annual Meeting onMolecular Markers in Cancer,Hollywood, FLContact: ASCO, 2318 Mill Road, Suite800, Alexandria, VA 22314. 571-483-1351or www.molecularcameeting.org.

October 19-20ECRI Institute’s 17th Annual

Conference: Personalized Medicineand Comparative Effectiveness,Bethesda, MDContact: ECRI. 610-825-6000 orhttp://conferences.thehillgroup.com/CERandPMconference/registration.cfm.

October 20-23Southwest Oncology Group AnnualFall Meeting, 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: AICR. 800-843-8114 or [email protected].

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

MEETINGS CALENDAR Continued from page 25


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july/august 2010 | vol 1 | no 3

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