JULY/AUGUST 2010 | VOL 1 | NO 3 by Value-Based Cancer Care

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JULY/AUgUst 2010 VOL 1 NO 3

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Consumer Genetics: Paradigm Shift or Flash in the Pan?

Do End-of-Life Products Deserve Special Treatment?

Conference touts promise, but real-world regulation intrudes

More issues than answers at lively session

By Cherie Dewar Boston, MA—“An insurance provider with 1 million members spends $11,000,000 annually on 15 drugs that patients either do not respond to, or are likely to have an adverse reaction with,” declared Rick Schatzberg, president and CEO of Generation Health, at the 2nd Annual Consumer Genetics Conference held June 2-4. To mitigate these costs and improve healthcare, conference participants discussed how the power of an unlocked genome can forecast a patient’s reaction to drug treatment,

optimize a medicinal cocktail, provide pinpoint diagnostics of a disease, and even foretell a patient’s propensity to develop a disease before symptoms occur. The burgeoning consumer genetics industry presents the possibility that genetic testing will streamline the decision process for disease treatments. Mara Aspinall, president and CEO of On-Q-ity, forecasted that Continued on page 27

Individualizing Colorectal Cancer Care through Genetics

By Daniel Vollaro Atlanta, GA—Echoes of the recent contentious American debate over healthcare could be clearly heard in a session at the meeting of the International Society for Pharmacoeconomics and Outcomes Research that addressed issues surrounding the funding of new treatments, technologies, and drugs for patients nearing the end of the life, covering everything from standards for economic evaluations of new drugs to the philosophical questions surrounding treatments near the end of life. In a wide-ranging discussion, a 3speaker panel comprised of Nicole Mittmann, PhD, Marc Berger, MD, and Mark Sculpher, PhD, generally agreed that significant tradeoffs occur when healthcare systems fund new

treatments, but in a spirited Q&A session that followed, some audience members challenged these basic assumptions. One audience member took pointed aim at the British healthcare system’s denial of coverage for some new cancer drugs, asking Dr Sculpher, a University of York professor of Health Economics and director of the Program on Economic Evaluation and Health Technology Assessment for the school’s Center for Health Economics, “Would you feel any different about the societal perspective if you yourself were diagnosed with metastatic colon cancer knowing that there are drugs Continued on page 17

By Jennifer Erickstad San Diego, CA—Three nurse researchers from the Oncology Nursing Society (ONS) Cancer Genetics Special Interest Group shared how the results of genetic testing conducted within the care setting are individualizing— and improving—care for colorectal cancer (CRC) at a session at the Annual ONS Congress. Beginning with an overview of the carcinogenesis of CRC, Carol Viele, RN, MS, a clinical nurse specialist at the University of California San Francisco (UCSF) Medical Center, detailed both its modifiable and nonmodifiable risk factors. She stated that

even though keeping good health habits, such as exercising regularly, avoiding tobacco, and minimizing alcohol use, can greatly reduce one’s CRC risk, other risk factors, such as advancing age, family history, and genetics, cannot be controlled. By accepting this latter fact, however, and learning more about patients’ genetic make-up, Ms Viele and the other presenters illustrated that healthcare professionals are improving patients’ prognosis, reducing treatment toxicity, and saving cost. Karen Roesser, RN, MSN, oncology clinical nurse specialist at CIW Medical Center in Richmond, VA, detailed that by determining whether Continued on page 15

Cost Considerations Change Dialogue Physicians, patients must navigate shifting conversational landscape By Wayne Kuznar

lthough financial concerns are increasingly influencing choices in cancer therapy, barriers to cost discussions between physicians and patients often limit the scope of such discussions. Incentives for oncologists to use high-cost interventions and patients’ perceptions that cost consideration equates to second-class care are but 2 barriers to meaningful cost discussion. The issue of addressing the cost of cancer care with patients was examined in an educational session at the

2010 American Society of Clinical Oncology (ASCO) annual meeting. Traditionally, physicians were warned to avoid limiting treatment based on cost considerations, with the belief that all patients should be treated the same regardless of their ability to pay, said Lidia Schapira, MD, assistant professor, department of medicine, Harvard Medical School, Boston, MA. But an ethical detour has emerged in the past few years— physicians are now expected to provide advice to patients regarding the treatments that best meet the patients’ interests and values. Continued on page 5

IN THIS ISSUE Reasons for breast cancer care disparities.............................................

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

Oncology-related updates from the FDA................................................. 23 Focus on hematopoietic growth factors.................................................. 24 Meetings calendar..................................................................................... 25 ©2010 Engage Healthcare Communications, LLC

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

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

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TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Directors, Client Services John Hennessy john@greenhillhc.com 732-992-1886 Phil Pawelko phil@greenhillhc.com 732-992-1887 Cristopher Pires cris@greenhillhc.com 732-992-1896 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Managing Editor Colin Gittens colin@engagehc.com 732-992-1536 Senior Production Manager Robyn Jacobs Business Manager Blanche Marchitto Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. BPA Worldwide membership applied for August 2010. Contact Information: For subscription and reprint information please contact: circulation@valuebasedcare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881. Address all editorial correspondence to: editor@valuebasedcare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

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July/August 2010

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ISPOR Conference

4 Value Propositions

18 Evolution Continues for AMCP Formulary

ASCO Annual Meeting

Submission Guidelines

5 The New Face of the Community Oncology Practice 6 Pathway Compliance Reduces Drug, Nondrug Expenses Comparative Effectiveness Research Will Help Guide Health Policy

7 Reasons for Breast Cancer Care Disparities Remain Unclear Adherence to Colon Cancer Chemotherapy Guidelines Depends on Treatment Setting

8 How Will Costs Be Contained in the New Healthcare Environment? Annual ONS Congress

13 Clinical Trials: Understanding Cost, Coverage

19 Moving Targets: Personalized Medicine and Targeted Therapy

21 Communications About CER in a Charged Environment

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

Implications Direct-to-Consumer Genetics/Genomics: A “New Paradigm” in Providing Healthcare Information

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

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

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

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

Craig Deligdish, MD Florida Comprehensive Cancer Network Melbourne, FL

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Jayson Slotnik, JD, MPH Foley Hoag Washington, DC

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

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

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

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Naimish Pandya, MD University of Maryland Baltimore, MD

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

David Hom, MBA Solucia Farmington, CT

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

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

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VALUE PROPOSITIONS Reducing X-ray Use Starts at the Top After noting a large number of requested routine trauma x-rays of the cervical spine after a computed tomography scan had demonstrated no significant findings, the management at University of Rochester Medical Center in NY instituted an imaging algorithm produced by the radiology department and distributed through the medical director’s office. One year after implementing the policy, the number of unnecessary x-ray exams performed was reduced by 83%. Mark J. Adams, MD, MBA, the lead author of the study (J Am Coll Radiol. 2010;7[7]:531-532), pointed out that “not only are these x-ray exams unwarranted, they consume valuable resources, add an additional burden to emergency department and radiology staff, and subject patients to unnecessary radiation.”

Cancer Diagnosis: Off the Shelf to on the Chart Credit: D. Shin/Rice University

Rice University biomedical engineers and researchers from the University of Texas M.D. Anderson Cancer Center have created an inexpensive device that combines an off-the-shelf digital camera with a small bundle of fiber-optic cables that can, when used with a common fluorescent dye, allow doctors to easily distinguish cancerous cells from healthy cells simply by viewing the LCD monitor on the back of the cam- Researchers can easily cancer cells from era (PLoS One. 2010;5[6]:e11218). Study lead distinguish healthy cells in photos of tissue author Rebecca Richards-Kortum said that “a samples taken with a $400 Olympus E-330 camera. portable, battery-powered device like this could be 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 Cancer A retrospective claims analysis looking at the overall costs of care associated with taxane use for metastatic breast cancer (American Health & Drug Benefits. 2010;3[4]:276-284) has found that generic paclitaxel was the least costly option ($3203 adjusted median per patient per month cost), followed by nab-paclitaxel ($3997) and docetaxel ($4042). Use of nabpaclitaxel was associated with lower utilization and costs for colonystimulating factors compared with the other 2 drugs, but patients in the nab-paclitaxel group did receive more doses of that drug.

For Cancer Survivors, Care Costs Too Much Two million cancer survivors did Type of care % not get needed medical services in Medical 7.8 the previous year because of conPrescription medications 9.9 cerns about cost, according to Dental 11.3 research published in Cancer (pub2.7 lished online: June 14, 2010; doi: Mental health 10.1002/cncr.25209). Researchers an alyzed data from the annual US National Health Interview Survey, which included data on 6602 adult cancer survivors and 104,364 individuals with 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 than hoped, according to a new study (BMJ. 2010 June 16;340:c3111. doi: 10.1136/bmj.c3111). The Summary Care Record (SCR) is an electronic summary of patient medical records accessible over a secure internet connection by authorized National Health Service staff. By early 2010, 1.5

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July/August 2010

million SCRs had been created, but the researchers found that creating SCRs and supporting their adoption and use was a complex, technically challenging, and labor-intensive process. Individual clinicians accessed available SCRs between 0 and 84% of the time, a figure that varied considerably depending on setting, the type of clinician, and their level of experience. When accessed, SCRs seemed to support better quality care and increase clinician confidence in some encounters.

Boosting Colon Cancer Screening—Automatically A study involving nearly 6000 Kaiser Permanente members in Washington and Oregon who were overdue for colon cancer screening found that automated telephone reminders increased screening rates by 30%. The automated calls in English and Spanish lasted about 1 minute. Members were told about the importance of screening, and were asked to press a number on their phone if they wanted to order a free at-home fecal occult blood test kit, which requires people to place stool samples on cards and then send the cards to a lab. If the person did not order and complete the test within 6 weeks they received a second call, and if they didn’t respond in another 6 weeks, they received a third call.

Screening Model Finds Good Value A probabilistic Markov model estimating the incremental cost-effectiveness of 10 strategies for colorectal cancer screening in Canada focused on 3 tests currently in use in some Canadian provinces: low-sensitivity guaiac fecal occult blood test, performed annually; fecal immunochemical 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, compared with no screening. These strategies generated incremental cost-effectiveness ratios of $9159, $611, and $6133 (Canadian) per quality-adjusted lifeyear, respectively. The authors conclude that either an annual high-sensitivity fecal test or colonoscopy every 10 years offers good value for the money 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, this practice also carries considerable monetary and resource costs as well as the 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 directed only to those at highest risk for colorectal cancer. A strategy of screening both high- and low-risk patients with colonoscopy every 3 years may be attractive to gastroenterologists with medico-legal concerns over missed neoplasia, the authors say, but this is cost-ineffective and potentially harmful in comparison to less intensive surveillance.

Recession Sapping Hospital Quality Unlike past recessions, the current economic malaise may be negatively impacting hospital quality and the ability of these institutions to grow in the postrecession environment. “Hospitals seem to be dealing with the economic crisis by reducing staff, scaling back or completely stopping new construction projects, and implementing various efforts to improve efficiencies of care,” said lead author Jeremy Syussman, MD, MS, a physician and clinical scholar at the University of Michigan Health System. Three quarters of hospitals surveyed reported receiving less reimbursement from insurers per discharge and more than half reported a decrease in patient admissions. In addition, more than half of hospitals reported difficulty obtaining bonds—an important means of paying for new construction or big-ticket equipment purchases (J Hosp Med. 2010;5[5]:302-305).

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ASCO ANNUAL MEETING

Cost Considerations Change Dialogue However, the value attached to a treatment is not always easy to quantify, said Dr Schapira, and may depend on the expectations of the patient and the clarity of the information that he or she has received. “Patients come with ideas, and perceptions of gain…based on a concept that is not clearly shaped in their minds,” she said. Further barriers to cost discussions include the mixed loyalties of physicians as both drivers of medical costs and advocates to patients. In addition, there is the embarrassment that patients may feel about discussing finances with their doctor and that “they may not want us to modify a recommendation if we have a suspicion that perhaps they’re not able to pay,” she said. Also, too little time is allotted during appointments to have cost discussions, and patients are often unwilling to mention cost concerns to avoid influencing the doctor’s recommendation. Surveys have shown that doctors are indeed willing to have cost discussions with their patients. Oncologists, however, believe that “there are not enough data to guide them in these conversations and that makes these conversations difficult,” said Dr Schapira. One such survey of 787 ASCO members1 found that 84% strongly or somewhat agreed that patient out-of-pocket costs influence their treatment recommendations. Less than half (43%) responded that they frequently or occasionally discussed the cost of new cancer treatments with their patients. Eighty percent of patients expressed a desire for more use of costeffectiveness data in coverage and payment decisions for cancer drugs. Only 42% agreed that they were wellprepared to interpret and use costeffectiveness information in their treatment decisions. Seventy-nine percent favored more comparative effectiveness research. What Physicians Are Doing Very little is known about how patients prefer cost issues be discussed, said Deborah Schrag, MD, MPH, attending physician/oncologist, 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 decisions, but “we ourselves are pulled in quite a few different directions,” she said. Physicians hold the belief that care should be equitable and do not view their roles as economic advisors

even as they recognize that many interventions have limited value. Dr Schrag’s survey of medical oncologists found that 30% discussed the cost of cancer treatment most of the time, 30% discussed it some of the time, and 16% refused to discuss cost at all.2 Approximately 80% either strongly agreed or agreed that oncol-

Continued from cover

ments, new benefit design plans, and patent expirations emerge, she said. Ill-aligned incentives may also be preventing the use of cost considerations in patient management. Physicians have strong incentive to use high-cost interventions, although evidence exists that they can be motivated by economic incentives, such as

Physicianshavestrongincentivetousehigh-cost interventions,althoughevidenceexiststhattheycanbe motivatedbyeconomicincentives. ogists have a responsibility to consider the impact that treatment decisions may have on the patients’ financial well-being. The quality-adjusted life-year (QALY) is a standard measure by which cost can be compared across interventions and compared side by side, said Dr Schrag. Currently, an intervention with a QALY less than $100,000 is regarded as meeting the cost-effectiveness threshold for US healthcare interventions. Translating cost into value is a constantly shifting landscape, however, as new treat-

Lidia Schapira, MD

off-label use of expensive treatments and a preference for on-patent versus off-patent agents. In addition, “treating with therapies of marginal utility is often the path of least resistance,” said Dr Schrag. The forecast is for change in cancer care delivery, she said, with realignment of incentives. A greater emphasis on the cognitive/compassionate component of care is in the offing, along with streamlined, coordinated guideline-driven care, and less reliance on delivery of expensive chemotherapy and a shift away from the predisposi-

tion to think that “more is better.” Moving forward, the solution may lie in more comparative effectiveness research, believes Dr Schrag. However, “it requires large-scale data collection and greater investment in intraoperable systems to track outcomes and figure out what’s valuable and thereby take a back-door approach to the cost issue.” ■ References 1. Neumann P, Palmer JA, Nadler E, et al. Cancer therapy costs influence treatment: a national survey of oncologists. Health Aff (Millwood). 2010;29:196-202. 2. Schrag D, Hanger M. Medical oncologists’ views on communicating with patients about chemotherapy costs: a pilot survey. J Clin Oncol. 2007;25:233-237.

The New Face of the Community Oncology Practice Those not throwing in the towel urged to “get over it,” embrace change By Caroline Helwick

ommunity oncologists are facing big changes to the way they have traditionally practiced, and they would be wise to accept, adapt, and move on, speakers said at a session at the 2010 ASCO annual meeting titled “The Challenge of Financial Survival.” Economic pressures are essentially killing many community practices, according to Elaine L. Towle, CMPE, director of oncology services at Oncology Metrics, a division of Altos Solutions, Los Altos, CA, who drew on data from the National Practice Benchmark, an annual survey of nearly 200 US practices that her company conducts. “Total collected revenue in these practices increased 6% from 2007 to 2008, and at first glance this is good news. However, total practice expense increased 16% over the same period, resulting in fewer dollars available to support practice operations,” Ms Towle said. “When oncology practice expenses rise more rapidly than revenue, the result is lower physician incomes.”

In the most recent (2009) survey of 190 oncologists, 73% of respondents were still independent physicianowned practices but changes were occurring. Eleven percent practiced oncology within a multispecialty group, 6% were hospital-affiliated physicians or hospital employees, 5% were physician-owned but had a hospital or corporate affiliation, 2% were affiliated with US Oncology, 1% were academic-affiliated, and 2% described their practice setting as “other.” Perhaps more telling were their predictions: only 20% envisioned their practices and business structure remaining “unchanged and viable” for at least 5 years, 20% said they are “changing now,” and 60% predicted they will be stable for only “the foreseeable future.” What is pressuring oncologists to think about different business models? Declining physician compensation was the main reason (54%), according to the survey. Also cited were loss of referrals as a result of local competition (19%) and the need to reduce practice overhead expenses (15%). Interestingly, only 4% cited reduced reimbursements as a reason,

and just 3% listed lower drug-cost margins. But oncologists have seen drug margin as a percentage of total revenue increasingly fall, from 45% in 2002 to just 9% today, according to Ms Towle. She noted that the lost revenue contributes to the “dramatic decline in the funds available to run a medical oncology practice.” Still, profit related to drugs is more important than ever, she added, telling the physicians, “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.” The “new normal,” with regard to drug revenue, she said, is now “low margin, high volume.” More Problems and Pressures Oncologists face other problems as well: greater regulatory exposure, information overload, scarcity of resources, increased practice size, and changes in patient profiles, Ms Towle said. The patient base, for example, now includes more Medicare patients lacking secondary insurance. More than Continued on page 6

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Pathway Compliance Reduces Drug, Nondrug Expenses By Caroline Helwick

valuation of a regional payerbased pay-for-quality (P4Q) oncology program showed that Pathways programs can greatly reduce the cost of cancer care by slowing the growth rate of both drug and nondrug expenses. Although oncology clinical Pathways are common in current practice, there has been little evaluation of how costs can be reduced when Pathways are enacted. This study evaluated the potential cost-savings of a payerbased P4Q program employing clinical pathways, said Jeffrey A. Scott, MD, and colleagues from P4 Healthcare in Ellicott City and CareFirst BlueCross BlueShield, Baltimore, MD. P4 Healthcare is a privately held healthcare company that helps oncology practices increase efficiency and enhance the quality of patient care. Dr Scott described a P4Q program enacted in 3 northeastern states on

August 1, 2008, that had 57 participating practices (176 physicians; 10,432 patients). Participating practices were compared with 43 nonparticipating practices (194 physicians; 4137 patients). The Pathways, developed by a 15-oncologist steering commit-

Estimated savings for antineoplastic drugs between Pathways participants and nonparticipating centers were calculated at $6,766,500; total savings were $12,232,967. tee, consisted of physician-generated treatments (breast, lung, and colorectal cancers) and supportive care pathways (colony-stimulating factors, erythropoiesis-stimulating agents, and antiemetics) based on medical literature and national guidelines. Participants received feedback regarding compliance. Fee schedules in year 1 of the program were adjusted in year 2 contingent on compliance in year 1. Savings analysis used the dif-

model and are incorporating new entities such as specialty pharmacy and centralized infusion services. Ms Towle advised physicians to do “strategic planning,” and become involved in aspects of healthcare reform that would serve their practices, such as demonstration projects and clinical process measurements. “Pay-for-service is going away; new

“If drug management is not a core competency in your practice, you are losing revenue.…Practices that are still in the buyand-bill model are greatly impacted.” —Elaine L. Towle, CMPE An additional drain on resources comes from handling insurance and payer issues, with the average practice employing 1.2 billing staff for every physician and 0.4 patient financial advocates. How Practices Are Coping One increasingly common means of coping with the changing environment is to consolidate: to sell one’s practice to a hospital or otherwise join a hospital physician network, to merge to form a larger organization, or to join a university system or insurance “preferred” network of physicians. In addition, more practices are moving away from the “buy and bill”

Table Summary of Cost-Savings Results 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 a

Fee schedule impact

(3,647,818)

Adjusted for fee schedule increase

8,585,149

The New Face of... Continued from page 5 half the survey respondents said at least 10% of their Medicare patients have no secondary insurance, leading more physicians to refer patients for chemotherapy visits outside of their practices. Although about half the respondents refer patients for 40 chemotherapy visits at most per year, 33% refer for up to 400 visits and 9% refer for more than 1000 visits.

ference between the participating and nonparticipating practice growth rates from the year before the program (pre) to year 1 to estimate yearly savings for the participating practices. The study found that 96% of the participating practices were able to

systems will pay for quality and outcomes,” she said. Oncologists can also partner with others in the community to increase efficiency, especially in areas that require capital or specialized, highly paid staff, such as radiation, imaging, and infusion therapy. Most importantly, practices must be able to adapt, she emphasized. “The good old days are gone,” Ms Towle said. “New practice models are developing. Investi gate and embrace them.” ■

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July/August 2010

meet the 65% treatment compliance threshold and the 80% supportive care compliance threshold. Across all participating practices, 86% and 95% of patients complied with treatment and supportive care pathways, respectively. Pathways-Compliant Practices Reduced Costs The study found the pre-year 1 to year-1 growth rate in cost was 7.7% for antineoplastic drugs, –3.0% for supportive care drugs, and 2.8% for nondrug services in the participating practices. In contrast, costs in the nonparticipating practices were 15.4%, 2.4%, and 19.0%, respectively, Dr Scott reported. Estimated savings between Path ways participants and nonparticipating centers (Table) were calculated

Fee schedule impact represents the expenditure attributable to the increase in fee schedule during the first year of the program for the participating practices. Fee schedule was treated as a cost of the program and factored directly out of estimated savings.

for antineoplastic drugs ($6,766,500), supportive care drugs ($1,427,108), nondrug services ($4,039,359), and total costs ($12,232,967). When the costs of the year-1 fee schedule increase for participating practices were factored out, the total savings were estimated at $8,585,149. “Our further evaluations will explore the indications of how these costs were reduced, for instance, by drug selection, and consider clinical outcomes and compliance in relation to cost-savings,” Dr Scott said. “Although the majority of the estimated cost-savings were drug-related (77%), the amount of savings due to nondrug services was substantial,” he added. ■

Comparative Effectiveness Research Will Help Guide Health Policy

he cost of caring for cancer rose from $27 billion in 2009 to $90 billion in 2008, yet unwarranted variation in that care persists across centers, providers, and patients. As yet, there is little evidence on comparative effectiveness of the different management options and on the value provided by different healthcare services, but this is expected to change, said Elena B. Elkin, PhD, assistant attending outcomes research scientist at Memorial Sloan-Kettering Cancer Center, an invited discussant of several cost-effectiveness studies at ASCO. More than $1 billion in the stimulus package is earmarked for comparative effectiveness research (CER), and these findings will be used to inform clinical guidelines, provider reimbursement, coverage decisions, and cost-sharing. Healthcare reform and the mandated expansion of insurance coverage

provide “demand and opportunity” for investigating the impact of insurance on cost and value of care. But in the interpretation of CER, she cautioned that “correlation does not equal causation,” and said that although there are “promises” inherent in the move toward CER there are pitfalls as well. In analyses of treatment options, for example, it can be hard to adjust accurately for comorbidity and other inevitable confounders, she pointed out. The hope is that studies funded through the stimulus package and healthcare reform legislation will have rigorous methodology and be based on “sound assumptions,” she said. In addition, the study process should be transparent, should allow for updates to incorporate new evidence and options, and should encourage the dissemination of information to all stakeholders. —CH ■

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ASCO ANNUAL MEETING

Reasons for Breast Cancer Care Disparities Remain Unclear By Wayne Kuznar Chicago, IL—Insurance status and socioeconomic status (SES) explain little of the racial and ethnic variation in the receipt of recommended therapy for breast cancer, found Rachel Freedman, MD, MPH, in her examination of a national cancer registry. She sought to determine the variables that might explain differences in care between 662,117 white (86% of the cohort), black (10%), and Hispanic (4%) women diagnosed with a first invasive breast cancer during 19982005 at hospitals included in the National Cancer Database, a hospitalbased cancer registry run by the American College of Surgeons and the American Cancer Society. Fiftyone percent had private insurance and 40% had Medicare. For this analysis, 4 variables were assessed: • Receipt of the locoregional therapy • Receipt of hormonal therapy in the adjuvant setting • Receipt of chemotherapy in the adjuvant setting • Hormone receptor testing at diagnosis. At about 98%, “hormone receptor testing was very high for all groups, which is reassuring, but there were subtle differences for all of the other measures by race, particularly the black patients versus the white patients,” said Dr Freedman, a medical oncologist at Dana-Farber Cancer Institute, and instructor in medicine at Harvard Medical School, Boston. Definitive locoregional therapy was instituted for 74.3% of Hispanic women, 75.5% of black women, and 80.6% of white women. Receipt of adjuvant hormonal therapy was 40.2%, 45.4%, and 54.4% for Hispanic, black, and white women, respectively; and receipt of adjuvant chemotherapy was 59.5%, 58.4%, and 48.7% for Hispanic, black, and white women, respectively. “Accounting for insurance barely attenuated any of the differences, so although there were insurance differences, race is definitely more important than insurance in this data set,” Dr Freedman emphasized. Socioeconomic status was also not associated with outcome but “the SES data we had were area level and not individualized SES,” she said. Large Data Set, Big Limitations “These big data set projects have tons of limitations because we don’t have any information about reason-

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ing for omission of treatment, provider information, or patient stresses. Although we controlled for some prognostic variables, we didn’t have

Other studies have shown that minorities are more likely to mistrust their doctors and less likely to enroll in clinical trials, and whether such differ-

“What this study shows is that fixing insurance and expansion of insurance in the United States may not fix everything.” —Rachel Freedman, MD, MPH information on HER-2 positivity and other things that can be a part of why people receive care. There were also comorbidities that we couldn’t account for.”

ences in behavior are responsible for differences in receipt of treatment by race is not known, said Dr Freedman. “What this study shows is that fixing insurance and expansion of insur-

ance in the United States may not fix everything, and that there are other things that we have to tackle,” she concluded. She added that examination of the receipt of treatment by patient age is forthcoming. “We really can’t look much further unless we want to look at hospital characteristics such as volume and quality, which is one of the things I’m trying to do,” she said. An assessment of other large databases, such as the National Comprehensive Cancer Network, may provide more clues about factors that explain disparities in receipt of recommended breast cancer care, she said. ■

Adherence to Colon Cancer Chemotherapy Guidelines Depends on Treatment Setting

hen treating patients with colon cancer in the community oncology setting, adherence to evidence-centered guidelines for the use of chemotherapy regimens varies by setting, with adherence rates higher in the adjuvant setting and somewhat lower in the metastatic setting, said McKesson Specialty Care Solutions’ Zhaohui Wang, MD, PhD, at the 2010 ASCO meeting. The cost of guideline-based therapy also varies widely, ranging from $6590 to more than $40,000 (Medicare cost) in the adjuvant setting, and from $2930 to more than $50,000 in the first-line metastatic setting. These findings came from examination of a large, US medical oncology clinical database containing data for calendar year 2009. Treatment regimen cost information was derived from Regimen Profiler, which is a web-based program that evaluates regimen-associated costs for payers, including Medicare. (For more on Regimen Profiler, see the story “New Tools Arriving to Measure and Manage Chemotherapy Care,” in the May issue of VBCC.) The database included 2976 treatment regimens (≥1 chemotherapeutic/ biologic agents administered in a repeating pattern) for patients with colon cancer who were treated in 383 community oncology practices across 45 states. A total of 1380 adjuvant regimens and 1596 first-line metastatic regimens were analyzed. The rate of guideline adherence was 80.9% in the

adjuvant setting and 76.6% in the metastatic setting. The top 5 regimens used in the adjuvant setting were given to 80% of patients, whereas the top 5 regimens used in the first-line metastatic setting were given to only 60% of patients, said Dr Wang. The most often used “off guideline” regimen was a combination of FOLFOX-4 (oxaliplatin, leucovorin, fluorouracil) with bevacizumab given at 10 mg/kg. The guideline recommendation is 5 mg/kg for the bevacizu-

rouracil, leucovorin) to $39,683 for CAPOX with bevacizumab on day 1, based on 3 months of therapy. Adherence Falling Short “Guideline adherence rates for cancer treatment should approach 80% to 90%, taking into account various patient-specific comorbid conditions that preclude guideline adherence,” Dr Wang told meeting attendees. Guideline adherence in the adjuvant setting, at 80.9%, approached this level but fell short in the first-line

“Guideline adherence rates for cancer treatment should approach 80% to 90%, taking into account various patientspecific comorbid conditions.” —Zhaohui Wang, MD, PhD mab component of this combination. When bevacizumab was first approved by the US Food and Drug Administration (FDA), it was at the 10-mg/kg dose level, he noted, “but subsequent studies have failed to find a dose-response relationship between 5 and 10 mg/kg, so the guidelines recommend 5 mg/kg. Physicians who are not aware of these data may be continuing to give the FDA-approved dose even though it is considered ‘off guideline.’” 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 for modified FOLFIRI (irinotecan, 5-fluo-

metastatic setting. “With the plethora of new agents now available in the marketplace, and phase 3 randomized trial data showing good outcomes with the use of many regimens and the widespread use of guidelines, compliance should seemingly be higher,” he said. “One possible reason that treatment guideline adherence rates for the metastatic treatment setting are lower than the adjuvant group could be that the metastatic group is likely to have more comorbidities than the adjuvant group due to previous exposure to drugs, radiation, or surgery,” Dr Wang explained. Few resources have been devoted to the cost of cancer care, even though programs such as Regimen Profiler are available, said Dr Wang. —WK ■

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ASCO ANNUAL MEETING

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

rospective payment and bundling of payments offer the most promising means to contain healthcare costs, said David O. Meltzer, MD, PhD, who gave a rundown of the weaknesses and strengths of some of the proposed remedies to reel in healthcare costs in the postreform United States. He made these remarks during a special session on healthcare reform. Economists believe that the single reason that healthcare costs are rising is the use of more technologies, and that the real price of quality-adjusted healthcare is actually falling, said Dr Meltzer, associate professor, department of medicine, Harris School, and department of economics, University of Chicago, IL. Cost-effectiveness analysis could ensure that technologies are used appropriately. However, “the politics of rationing remain as toxic as they have always been.”

sons, we don’t want to give sick people a tremendous dependency on costs so that they are making life-ordeath decisions based simply on the availability of capital in their family,” Dr Meltzer argued.

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.

Rising healthcare costs are due largely to increased technology use Prospective payments and bundling may offer the best chance for cost containment Bundled payments may reduce financial “turf wars” among caregiver groups Other cost-control measures also are likely to be insufficient, he said. Savings from malpractice reform would amount to 2% to 5% at most. And although prevention is a valuable way to promote health, it usually does not reduce costs, Dr Meltzer indicated. “You know people aren’t really serious about cost control when they say that prevention is going to reduce costs.” Health information technology might eventually reduce costs, by decreasing practice variations and encouraging use of more effective technologies. “But in the short run, there is really no good evidence that it will do this.” Taxing high-benefit health plans could affect costs, but probably not substantially. Costs could be reduced if copayments are increased. However, the vast majority of expense is incurred when people are very sick. “For very good social rea-

VALUE-BASED CANCER CARE

prospective payment at a fixed amount for hospitalizations, lengths of stay and expenditures fell dramatically. Bundling has several advantages: “it not only gives you a single number to target, it changes the poli-

Indication

at a glance

Solutions from the Payer Side The only true engine for containing costs that has worked in the past, according to Dr Meltzer, is the combination of prospective payment and bundling. When Medicare instituted

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

July/August 2010

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ASCO ANNUAL MEETING tics of reimbursement. Once you bundle, you don’t have every group arguing for their own payment. They are all in it together.” It is likely that hospital stays will be bundled with ambulatory care, and physician fees will be combined with hospital care, Dr Meltzer said.

With more Americans having access to healthcare, the system will no longer be able to justify cross-subsidies from the insured to finance the uninsured’s costs. The healthcare system will have to move to a system of prospective costs and bundling, and the 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 there will be no one able to argue for themselves; we will have to fight among ourselves.” This may not sound ideal from a reimbursement perspective, but Dr

Meltzer says that from the standpoint of the healthcare system, this may not be bad. “There are wonderful examples of integrated organizations that provide wonderful care for their patients and of physicians and other providers who thrive within these organizations,” he said. ■

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

Metastatic breast cancer

Metastatic hormone-refractory prostate cancer

Multiple myeloma

Metastatic lung cancer and other solid tumors

Metastatic renal cell carcinoma

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

More than

April 2010

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YEARS of real-world experience C-ZOM-100050

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

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

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

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

(2%) (1%) (51%) —

n/N

(%)

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

(3%) (2%) (33%) —

VBCC_August 081110_ASCO Highlights Tabloid 8/13/10 4:49 PM Page 11

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

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

Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Grade 3

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

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

— — (1%) —

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

(1%) — (5%) (1%)

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

1Grade

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

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

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

Zometa 4 mg

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

Placebo

1031 (100) 1015 (98)

556 (100) 548 (99)

455 (100) 445 (98)

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

175 83 53

(32) (15) (10)

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

476 333 320 249 143 105 86 82

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

266 183 162 162 81 74 65 61

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

171 122 174 83 48 31 14 17

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

398 328 252 215 112

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

240 172 108 126 62

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

130 89 114 84 28

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

n (%)

(%)

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

(9) (15)

41 30

(9) (7)

231 164 145 130

81 50 60 48

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

105 61 59 45

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

569 239 216 156 143

(22) (16) (14) (13) (55) (23) (21) (15) (14)

316 143 131 106 84

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

205 (20)

(17)

284 74 73 40 52

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

89 (20)

Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia

191 180 166 149 127

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

149 91 111 85 65

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

50 58 73 35 43

Psychiatric Depression Anxiety Confusion

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

95 73 39

(17) (13) (7)

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

Respiratory Dyspnea Cough

282 (27) 224 (22)

155 129

(28) (23)

107 (24) 65 (14)

Skin Alopecia Dermatitis

125 (12) 114 (11)

80 74

(14) (13)

36 38

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

(8) (8)

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

Placebo

(%)

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

(2%) (<1%) (7%) (<1%) —

n/N

(%)

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

(2%) — (3%) (2%) (<1%)

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

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

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

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

(<1%) (<1%) (<1%) — (<1%)

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

(<1%) (<1%) — — (<1%)

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

— (<1%) (<1%) (<1%) —

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

50 82

n/N

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

Multiple Myeloma and Breast Cancer

124 (12) 101 (10)

Pamidronate 90 mg

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

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

(%)

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

(%)

12/82 4/10 16/92

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

Pamidronate 90 mg n/N

(%)

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

(%)

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

(%)

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

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

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

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

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

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

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Clinical Trials: Understanding Cost, Coverage Implications By Jennifer Erickstad San Diego, CA—Emphasizing the costs and financial reimbursement issues associated with the “everchanging, ever-complex environment” of clinical trial research, a session at the 35th Annual Oncology Nursing Society (ONS) Congress addressed a crowd of both current clinical trial nurses and attendees who may take on this role, discussing how the team responsible for the hours of logistical work and research coordination supporting these trials can work more effectively. Clinical trials have the obvious benefits of developing new therapies and treatment standards, said Rose Ermete, RN, BSN, a clinical trials nurse at St. Mary Mercy Hospital, Livonia, MI. Another benefit, according to copresenter Denise Friesema, MS, RN, director of clinical research operations at the University of Chicago Medical Center, is that they allow nurses to “leave our fingerprint on science.” Both presenters, however, took care to outline potential pitfalls when conducting clinical research. According to Ms Ermete, it is extremely important to be in compliance with all billing rules, as the costs of noncompliance range from adverse publicity to Medicare exclusion to criminal penalties. The practices that most commonly lead to noncompliance, she explained, are “double dipping” (when a hospital bills for a service or drug already provided by the sponsor), billing for services that were provided free as part of the trial, and billing for services that would not ordinarily be covered if they were not part of the clinical trial. Illustrating the dangers of noncompliance, Ms Ermete highlighted the situations of several large institutions—such as Johns Hopkins, the Mayo Clinic, and Rush University Medical Center— that have been fined by the US Attorney General’s Office and the Office of Inspector General because of noncompliance issues. Yet the story of Rush University Medical Center can also be seen as a helpful example for nurses looking to either begin or improve their clinical trial programs, Ms Ermete explained. After being fined $1 million, Rush launched a comprehensive compliance assurance program, which started with—and is centered around— moving from a “siloed” system to a centralized billing process. With one research office handling all paperwork, providing oversight across the

organization, and conducting monthly reconciliations, Rush has “set the standard for what the government is looking for when it comes to compliance,” Ms Ermete said. The idea of centralization or “harmonization,” as the pre-

fying the patient before they receive care and then using study-specific charts) or a back-end one (pulling out all bills before they are sent to determine which costs are paid by the study organization). Bringing the rel-

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. senters explained, was a key theme of the presentation, one to which both Ms Ermete and Ms Friesema repeatedly returned. They stressed that by aligning the multiple departments that work together during a clinical trial under one centralized office, a facility can ensure they are remaining compliant, avoiding fraudulent billing, and conducting research in a consistent manner throughout the institution. Establish Standard Processes To establish this centralized system, Ms Ermete noted that institutions can either use a front-end process (identi-

evant departmental teams together is key—especially those people who will be registering patients and billing payers—as is drawing up a flowchart to show how bills should be accurately routed. Regardless of how the system is developed, however, Ms Ermete concluded “there has to be some type of evaluation taking place.” This process should include both active and past accounts, with auditors reviewing invoice details to confirm appropriate billing. Ms Friesema instructed session participants on the “budget basics” of clinical trial research. Noting that “it’s

just not worth the effort” to open a clinical trial that includes only a few patients, she instructed that the first and most important question nurses should ask is whether the facility cares for an adequate patient population. Next, 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. Finally, clinical trial nurses should examine all 4 components of the study budget: the start-up fees, research-related clinical care expenses, the cost of study implementation and oversight, and indirect costs that go to the facility (such as institutional overhead). Although burnout is common and high turnover rates among clinical trial nurses have been well documented, Ms Friesema concluded that by considering the strategies outlined in the session and avoiding the pitfalls illustrated by other facilities, clinical trial nurses can help create a successful research program at their institution. ■

Direct-to-Consumer Genetics/Genomics: A “New Paradigm” in Providing Healthcare Information San Diego, CA—A session at the 35th Annual ONS Congress happening the same week that Walgreens decided to postpone selling a direct-to-consumer (DTC) genetic test kit raised more questions than provided answers when it framed the discussion by asking whether these tests were “good, bad, or benign.” Even for an advanced audience such as this, the question may be premature: only one audience member had ever helped a patient decipher DTC genetic test results. Presenters Patricia Kelly, RN, DNP, MS, a clinical education specialist/ genomic consultant at Texas Health

at a glance Consumer 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

Resources in Dallas, and Jennifer Loud, RN, CRNP, DNP, assistant branch chief at the National Cancer Institute in Rockville, MD, analyzed a range of issues. Noting that DTC genetic testing represents “a new paradigm of how healthcare information is communicated to the public,” Dr Loud acknowledged that DTC testing may make many healthcare professionals uncomfortable because of the shift in power that it causes. “We are used to being in control and having patients come to us for advice and guidance,” she said, “this has the potential of flipping that on its head.” Despite nurses’ potential discomfort, however, the two advocated that the participants should develop the relevant genetic nursing competencies— such as providing patients with accurate genetic information, resources, and services to guide their decision making and to identify the myriad ethical, religious, cultural, and legal issues related to genetic testing. Acing the Genetic Info Exam Another question tackled by the team was how to determine the value of the information derived through

“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

DTC genetic testing. To aid nurses in this pursuit, Dr Kelly shared the ACCE model, which consists of criteria developed by the Centers for Disease Control and Prevention’s (CDC) Office of Public Health Genomics to help evaluate the roughly 1600 genetic tests currently in use (approximately 500 of Continued on page 14

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Direct-to-Consumer Genetics/Genomics... these are DTC). The ACCE model’s 4 areas of investigation include examining the test’s: 1. Analytic validity: how sensitive and specific the test is for picking up on the specific genetic mutation 2. Clinical validity: how consistently and accurately the test predicts the disease or question of interest 3. Clinical utility: how does the genetic test impact care and how significantly can it improve outcomes 4. Ethical, legal, and social issues: how is privacy maintained with the test, how are the test results communicated, what happens to the sample after testing, etc. In addition to nurses’ own test evaluations, Dr Kelly discussed DTC genetic testing’s formal process of quality assurance. Although the Federal Trade Commission oversees advertising, it has “played a fairly minor role” in looking at the promotion of DTC genetic testing to date, Dr Kelly noted, aside from publishing a 2006 consumer alert that advocated a “healthy dose of skepticism.” Three federal agencies—the CDC, the Centers for Medicare & Medicaid Services, and the US Food and Drug Administration—currently oversee the testing, and “states regulate [it] a great deal” (25 allow its use, 12 permit limited use, and 13 ban it). Providing possibly another safeguard, the National Institutes of Health in March announced the establishment of a voluntary genetic testing registry. The registry—which will include ACCE information—is expected to be up and running in 2011. The session concluded with a critical thinking exercise on the potential benefits and risks of DTC genetic testing and how test information may impact patients. For example, they noted that for a young man who receives confirmation of harboring the prostate cancer mutation, this information may lead to unjustified anxiety and unnecessary screening— especially in light of the fact that studies have shown a thorough family history to be a better predictor of prostate cancer risk than the existence of the mutation. On the other hand, an older man who tests negative may feel a false reassurance and forego screening. According to both presenters, potential benefits of DTC genetic testing may be increased access to the tests, reduced risk of privacy violations, lowered costs due to competitive pricing, and empowered consumers 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 a strategy for approaching the issues. Quoting from a 2009 paper,1 Dr Kelly noted that healthcare professionals must find a balance—avoiding exces-

Continued from page 13

sive paternalism and fear of change while stressing that genetic information not be used inappropriately or prematurely—in order to help patients “explore their genome with marvelous and exciting new

tools at hand in a way that values medical experience and technological innovation.”—JE ■ Reference 1. Evans JP, Green RC. Direct to consumer genetic testing: avoiding a culture war. Genet Med. 2009;11: 568-569.

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions.

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Individualizing Colorectal Cancer Care... CRC patients have a genetic mutation leading to Lynch syndrome, clinicians can more actively screen for other cancers that are associated with the condition (including endometrial, ovarian, and stomach). Clinicians

have been using certain tests, including microsatellite instability testing and immunohistochemistry testing, to better determine which patients may have the syndrome and should undergo further genetic testing.

Continued from cover

The session’s third presenter most directly addressed how clinicians are individualizing CRC care in clinical practice. Pamela Viale, RN, MS, CS, ANP, an oncology nurse practitioner also practicing at UCSF, discussed

several genetic mutations and how they impact decisions made in CRC care. Beginning with perhaps the most well known, Ms Viale explained that approximately 40% of CRC Continued on page 16

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

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: ■ 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 93% reduction in febrile neutropenia–related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 80% reduction in febrile neutropenia–related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

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 placebotreated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

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

target the epidermal growth factor receptor (EGFR) are ineffective in turning off the cell signaling system and limiting tumor growth. As a result, Ms Viale noted that practitioners must determine early on if a receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

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

Musculoskeletal and connective tissue disorders Bone pain

26%

31%

Pain in extremity

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

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

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

cology professional opinion statement call for KRAS testing before beginning therapy with monoclonal antibodies. Similarly, Ms Viale noted that patients with the BRAF mutation have also shown to be unresponsive to anti-EGFR monoclonal antibodies and that the NCCN now recognizes testing for this mutation as a prudent treatment decision.

By determining before treatment which patients have diminished efficacy of UGT1A1, patients can avoid unnecessary toxicity. Ms Viale also covered findings pertaining to TP 53, a tumor suppressor gene that plays an important role in the growth and differentiation of CRC. Between 40% and 60% of CRC patients have the mutation, and its existence may help practitioners provide a more accurate prognosis. According to Ms Viale, one study found that patients with a mutated TP 53 have a poorer prognosis than those without in both stage II and stage III CRC when treated with surgery alone. Additionally, data have shown that TP 53 inhibits the body’s response to 5-fluorouracil therapy, although conflicting data have also surfaced. In addition, Ms Viale also detailed how genetic information can reduce toxicity. The UGT1A1 enzyme inactivates the metabolite of the chemotherapy agent irinotecan. Patients with Gilbert syndrome, however, have decreased efficiency of UGT1A1, making them unable to adequately metabolize the drug and leading to increased neutropenia and diarrhea. Ms Viale provided statistics from a survey conducted at the NCCN 2010 meeting on the prevalence of genetic testing in the treatment of CRC. Responses revealed that 51% of respondents test for the KRAS mutation before therapy is initiated, whereas 37% test for the mutation only when considering treatment with an anti-EGFR monoclonal antibody. Ten percent tested for an alteration of UGT1A1, 16% tested for UGT1A1 only after already treating the patient with irinotecan and experiencing problems, and 63% conducted no UGT1A1 testing. Thus, although the data showed that it is “standard practice now to test for the KRAS mutation,” the numbers revealed fewer clinicians are utilizing information from UGT1A1 tests. ■

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Do End-of-Life Products Deserve... available that could treat you that NICE [National Institute for Health and Clinical Excellence] has denied because of cost?” “I don’t know what I would think if I were in that position,” Dr Sculpher replied, after dismissing as “unreliable” recent research suggesting that more patients die of cancer in the United Kingdom (UK) because some drugs are not funded, “but ultimately, as a citizen, I believe in a healthcare system which has the purpose of improving health across all patient groups. Every time we say yes to a drug that generates relatively small improvements for high cost, somebody else in that system suffers.” This exchange highlighted the tension between those who explicitly acknowledge limitations within healthcare systems and those who do not. Dr Sculpher was eager to illuminate the gulf separating these positions. “Some healthcare systems pretend that there are no opportunity costs, that people don’t suffer when you agree to reimburse new drugs, but in the UK that has become more transparent.” Frameworks and Tradeoffs Honestly discussing this tradeoff within healthcare systems and how to

at a glance Making 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

manage it equitably was a main theme of the panel discussion. The first panelist, Dr Mittmann, discussed the standards used in Canada to prioritize decisions about funding new cancer

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philosophical questions about how healthcare systems evaluate the value of new cancer therapies used for cancer treatment at the end of life. Dr Berger, a vice president of Global

“Ultimately, as a citizen, I believe in a healthcare system which has the purpose of improving health across all patient groups.” —Mark Sculpher, PhD

treatments. An associate scientist at the Sunnybrook Health Sciences Centre in Toronto, Dr Mittmann walked the audience through the process followed by a 15-member team of investigators as it “cancerized” the Canadian Agency for Drugs and Technologies in Heath’s (CADTH) guidelines for the conduct of economic evaluations. They examined the CADTH guidelines carefully, looking for ways to make the specific cancer guidelines within them more explicit and clear. Working for 3 years and producing 29 different iterations of the document, the team was able to create a sound methodological framework for making funding decisions for new cancer treatments. The challenges were significant, admits Dr Mittmann. Their initial survey of the problem uncovered a lack of adherence to guidelines used to do economic evaluation, a lack of standardization in economic evaluations, and differential levels of evidence to evaluate cancer products. “Sometimes you just don’t have a phase 3 trial that is available to you,” observed Dr Mittmann. “So you need to consider phase 2 studies. How do you methodologically deal with this?” Panelist Marc Berger also grappled with the “framework” for decisionmaking in a talk that raised important

Health Outcomes at Eli Lilly, observed that the “number of oncology drugs is about the explode” with a 10-fold increase in number of new cancer products on the horizon, and this plethora of new treatments will force a number of philosophical questions. For example, what is the value of life extension and is it the same for all diseases and medical conditions? “Human beings are not pure utilitarian creatures,” Dr Berger reminded the audience, “and we do find a lot of people who believe that there is a greater need to intervene there [in the area of life extension].” Uncomfortable Questions, Expensive Solutions Berger posed other potentially uncomfortable questions as well: “What value do we assign to a patient’s life beyond direct medical costs and workplace productivity?” Many people getting cancer after they retire will not be adding to the gross domestic product, he observed. Is a purely utilitarian metric appropriate here? What is the value of life extension and is it the same as for other medical conditions? How does a patient benefit from slowing disease progression if he/she still does not live any longer? There is value to having a better quality of life…how do

symptoms and disease progression impact a patient’s independence? Dr Berger was realistic about the necessary tradeoffs implied by asking these questions. “The way that decisions have been made is in the context of a handful of biologics or new cancer therapies,” he observed. “If you imagine a future 10 years from now where you have 50, 75, a 100 of these, 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. So how that conversation is going to happen is going to be a really interesting evolution in the marketplace.” In the lively Q&A that followed the session, Dr Berger joined Dr Sculpher in defending NICE as pragmatic and realistic in ways that the American system is not.

“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 “The UK has determined what it’s going to cap its total healthcare expenditures at,” he observed. “Could it be more? Sure. On the other hand, in this country, medical care expenditures are going up and we’re frightened to death by what that means.” Dr Berger also argued that there is no “Pareto optimal” when making decisions about how to allocate resources in a healthcare system. “We make choices all the time. What we want to have at bottom is a fair and just society in which the process by which those decisions are made, everyone feels like they have a fair shake. I think that NICE has made great strides over its 11 years of existence.” ■

Medicare, a Major P(l)ayer, Not Ready for New Payment Policy Evidence By Daniel Vollaro Atlanta, GA—A session at the 2010 meeting of the International Society for Pharmacoeconomics and Outcomes Research discussing how Medicare’s evidence requirements for covering new technologies might change under the new healthcare reform bill painted a portrait of an agency that has recently 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 senior clinical director at the Center for Medical Technology Policy and a former coverage director at the Centers for Medicare & Medicaid Services (CMS), observed that Medicare has never clearly expressed its standards for covering new medical technologies. “Medicare has a mantra, ‘reasonable and necessary’; it does not pay for things that are not reasonable and

necessary,” said Dr Phurrough. “Since 1965, Medicare has never defined what that means.” Dr Phurrough acknowledged that the agency has recently said that it will consider something to be “reasonable and necessary if it improves net health benefits. Dr Phurrough further explained that although a “conditional” approach to coverage has the potential to speed coverage and develop additional evidence, the current agency position of making clear-cut decisions

about coverage is incompatible with that concept. In presenting a quick history of Medicare’s coverage policy that emphasized the agency’s inability to clearly define its research requirements, Dr Phurrough quipped, “Medicare pays for stuff, and pays for stuff in unusual ways.” Dr Phurrough also observed that Medicare has traditionally applied low, medium, and high standards of evidence. For the approval of kyphoContinued on page 18

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Evolution Continues for AMCP Formulary Submission Guidelines By Daniel Vollaro Atlanta, GA—The history, purpose, and impact of the Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions— as well as their future in a changing world of drug and regulatory development—was detailed by a panel of insiders at a session at the 15th Annual Meeting of the ISPOR. For the past 10 years, these guidelines have evolved as an industry standard for increasing the flow of product information between pharmaceutical companies and healthcare systems, particularly pharmacy and therapeutics (P&T) committees. First drafted in 1999 as a response to the poor quality of submissions by pharmaceutical companies to health plans,

these guidelines have subsequently passed through 3 major revisions. The latest round of revisions reduced the

“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 size of the document, focused it, and clarified sections. Promotion, Rather than Evidence According to panelist Sean Sullivan, PhD, professor and director of the Pharmaceutical Outcomes Research & Policy Program at the University of Washington’s Department of Pharma-

Medicare, a Major P(l)ayer... plasty, for example, Medicare determined that there was not enough evidence to support its benefit but continued to fund it anyway. On the other hand, Medicare has 6 times asked for new evidence to support the use of carotid stents. According to Dr Phurrough, the round of decisions around carotid stents suggests a growing tendency for CMS to require more evidence for new technologies. He explained why: In 2008, CMS released a proposed decision that changed the payment practices at Medicare. “Because the legislation says, ‘don’t pay for things that are not reasonable and necessary,’ if in fact you have paid for something, you have determined it reasonable and necessary.” Dr Phurrough continued, saying, “Once you’ve paid for it, you have met the evidentiary bar, most of the time, having never looked at the

at a glance Medicare’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

cy, the guidelines were necessary because much of the documentation submitted in the 1990s was “promo-

tional and insufficient to inform evidence-based decision-making.” Dr Sullivan explained that the Division of Drug Marketing, Advertising, and Communications, which regulates the content of information sent from manufacturer to healthcare professionals and health plans, does not support the dissemination of data

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evidence.” Once Medicare agrees to pays for something, he detailed, it will only deny coverage with clear positive evidence of harm or positive evidence of lack of benefit. Consequently, CMS has recently focused on coverage decisions for new drugs and technologies that have not had local coverage decisions, and in those cases, it is applying relatively high evidentiary standards. Shifting Landscape, Static Organization Panelist James Chambers, MPharm, MSc, project director at Tufts Medical Center, supported many of Dr Phurrough’s claims about Medicare. Mr Chambers discussed how CMS is more likely to cover a new technology if good quality clinical evidence exists to support its efficacy. Coverage is less likely, said Mr Chambers, if an alternative therapy is available, a coverage decision has been made in recent years, or if there is no estimate of cost effectiveness available. His research, which was conducted by surveying National Coverage Determinations between 1999 and 2007, also shows a broad trend in CMS covering costeffective technologies. In the question session, Bryan Luce, senior vice president, Science Policy for United BioSource Corporation, asked if the health reform bill’s suggested investment in health information technology (HIT) will change the way Medicare evaluates evidence and makes coverage decisions by providing a “feedback loop” and “rapid learning system” for continually pre-

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“The coverage process needs a fairly significant transformation.” —Steve E. Phurrough, MD, MPA senting and evaluating evidence. Acknowledging that CMS possesses great data resources, panelist Penny Mohr, MA, vice president of Programs for the Center for Medical Technology Policy in Baltimore, was less than optimistic about implementing HIT at CMS. “While I think it’s a good opportunity,” she said, “we have a long way to go to get to that point.” Dr Phurrough was more blunt in his assessment of the potential for HIT reforms in CMS. “Briefly, no,” he pronounced. “CMS has this process, fairly well defined now, and that process doesn’t include using those kinds of databases. If clinical research determines ways to use those kinds of databases in fairly formal trials to come up with good quality evidence; then they will use that evidence, but for HIT to make a difference in coverage decisions, the coverage process needs a fairly significant transformation.” ■

beyond what is included in the product label. “A lot of research done to support a product never found its way to the ultimate decisionmaker,” Dr Sullivan said. “That was, of course, a problem.” A response to these concerns, the new AMCP format was created as a voluntary reporting system that urges health systems to formally request a standardized “dossier” from drug companies containing detailed information about the drug’s safety, efficacy, and overall clinical and economic value relative to alternative therapies. Dr Sullivan, who served on the original committee formed in 1999 and has remained engaged in the revision process ever since, expressed continued concern over the quality of evidence provided by pharmaceutical companies to healthcare systems. Acknowledging that many people have asked him why health plans do not use the information provided by pharmaceutical companies, he said “part of the answer lies in the fact that the dossier process is in some cases hijacked by commercial interests in the pharmaceutical industry. The health plans want and desire a scientific communication, and if vendors are driving a promotional focus, I guarantee you that those documents won’t be read or used in the P&T process.” The audience, which contained many representatives from drug manufacturers, indicated a desire to better understand the guideline’s use. Robin Turpin, senior director at Baxter Healthcare, asked the panel if they knew how often the AMCP dossier format has been used by organizations other than health plans. Richard Fry, RPh, the panel moderator and director of programs for the Foundation for Managed Care Pharmacy, admitted that they didn’t have good intelligence on this issue. Citing the ongoing debate about changing evidence requirements for new drugs and treatments, Jennifer Graff, PharmD, research director of Methods, Evidence & Coverage at the National Pharmaceutical Council, asked, “What recommendations do you have that would allow payers to feel more comfortable in the non-RCT [randomized controlled trial] world?” Dr Sullivan acknowledged that the “hierarchy of evidence we’ve grown up to [use] may not be reasonable for certain circumstances and for certain clinical questions” but emphasized that the committee took a conservative path when considering these issues. ■

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Moving Targets: Personalized Medicine and Targeted Therapies By Colin Gittens Atlanta, GA—Even as the development of targeted therapies has advanced rapidly in the past several years, the evidence base, evaluation, and reimbursement structures surrounding the use of these products in the real world have lagged behind. A panel presenting research, governmental, and private payer perspectives discussed these issues, and some potential solutions, at the first plenary session of the 15th Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Fully realizing pharmacogenomics and personalized medicine will allow physicians to “identify diseases at an earlier, more curable stage,” suggested Scott D. Ramsey, MD, PhD, of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle. “If we can do that, we can afford our patients much greater survival and at the same time lower the cost of care for individuals.”

know that there is sufficient evidence to use in practice?” Payers will also need information to determine payment policies and encourage the use of these products.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) process may bring structure to test development

data from a medium-sized health plan in Washington State (the Regence Group) indicated that in a 12-month period “there were almost Continued on page 20

We are here, where you need us most

at a glance Genomic tests have resulted more from researcher interest than identified clinical need

Process Costly, Often Flawed The current situation regarding paying for genomic tests may give a helpful perspective on where costs are headed. According to Dr Ramsey,

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

Payers are now actively collaborating with researchers to assess targeted therapies in real-world situations This is especially important, he pointed out, when cancer products are being introduced that commonly cost $10,000 per month. “The proportion of patients that respond to these cancer therapies has remained fairly constant,” which means, of course, “we’re spending ever more money for a flat response in terms of improvement.” Targeted therapies may improve those response rates, but their use raises other clinical and cost concerns, as Dr Ramsey indicated. “We expect a huge number of these biomarkers to be introduced over the next 5 to 10 years, and there are several key questions,” Dr Ramsey outlined. “Who will drive their use? Will patients be asking for these tests or will clinicians? When clinicians review the evidence, when will they

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Moving Targets: Personalized Medicine... Continued from page 19 100,000 claims for genomic tests and $85 million billed, just for the tests alone.” That figure does not include all 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 what we’re getting for that money.” When evaluating genomic tests, Dr Ramsey emphasized the need to key in on 4 elements—does the test measure what is intended (analytic validity); does it measure that item consistently and accurately (clinical validity); and is the test likely to improve patient outcomes (clinical utility). The fourth quality—value, or evaluating whether the test influences care and represents good value compared with not using the test—is increasingly gaining in importance. The current model of cancer genomic test development is lacking, Dr

want to repeat,” emphasized Dr Ramsey. Since being approved by the US Food and Drug Administration (FDA) in 1994, 30 million men are screened annually with PSA testing at a cost of $3 billion. Only in 2009 were 2 studies published evaluating the efficacy of this testing; one showed “no impact of testing on prostate cancer deaths,” Dr Ramsey reported, while the other indicated that for every man helped by PSA testing, 48 received unnecessary testing. How to Move Forward According to Dr Ramsey, there are several ways that personalized medicine can be advanced. First is to consider genomic testing as a partnership between test developers and research groups on the one hand, and the health system on the other. “I think we need the health system involved,” said Dr Ramsey.

“It’s amazing to me how often studies are conducted that simply don’t ask the right questions.” —Lawrence J. Lesko, PhD, FCP

Ramsey suggested, with gene candidates selected through the idiosyncrasies of individual researchers who are “not necessarily motivated by clinical priorities, [but] are motivated by the area of expertise.” Later on, the difference between the population used to validate the drug and that in the real world throws off test results. Finally, limited funding is also a factor for evaluating new tests once they are released. “Ninety-seven percent of genomics publications are in that very early phase” of the discovery process, said Dr Ramsey, compared with almost no publications later on, when the population health impact might be assessed. Evaluating genomic tests ideally would involve understanding the clinical context for that test earlier on, followed by a cost-effectiveness analysis and professional assessment and incorporation into clinical practice guidelines if deemed worthwhile. Currently, a rigorous test evaluation does not happen or happens haphazardly, and tests are moving directly from development into clinical practice, Dr Ramsey outlined. This process echoes what happened with prostate-specific antigen (PSA) testing, and that is “a lesson we don’t

Lawrence J. Lesko, PhD, FCP, director of the Office of Clinical Pharmacology at the FDA, emphasized this point, saying, “It’s important to design these studies with the right questions in mind. It’s amazing to me how often studies are conducted that simply don’t ask the right questions.” Dr Lesko discussed some other obstacles to the development and widespread adoption of personalized medicine, the first of which is too much information. “Many of the predicted findings of the technology involve hundreds of genes that technology developers have to boil down to something that they can make useful for clinicians,” he pointed out. Second, the FDA and other regulatory agencies that influence the direction of research have not been clear about what research needs to be done for approvals. Another tool that may advance genomic testing is the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) process. Ralph J. Coates, PhD, associate director for science for the Office of Public Health Genomics at the Centers for Disease Control and Prevention, discussed how this effort attempts to establish a systematic, evidence-based process for evaluating genetic tests, and move

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them from research to practice. The criteria look at factors including health outcomes and utility in decision-making, and in many of the examples given by Dr Coates— depression, breast cancer, warfarin dosing—there was insufficient evidence, uncertainty, or a lack of trialbased data available to allow a recommendation about the use of genetic tests. The Centers for Medicare & Medicaid Services has employed the EGAPP process when making a coverage decision regarding genetic testing for response to warfarin. Payers Ahead of the Pack Despite the imperfections of the current evaluative system, payers are eager to expand the use of targeted therapies and realize their benefits, said Robert S. Epstein, MD, MS, chief medical officer and president of Medco Research Institute, Medco Health Solutions, Inc. According to a Medco survey of payers from 2008, pharmacogenomics was tied with consumerism as the second most important topic on their radar screens. “Payers find this topic fascinating—they love it,” remarked Dr Epstein, elaborating that pharmacogenomics allows targeting of therapy, reduced adverse outcomes, and improved efficacy—“all things payers would like to see.” Payers are now paying Medco to identify patients on certain drugs to ensure that the right patient is receiving that drug at the proper dose, Dr Epstein noted. Payers are now offering their membership to do prospective studies, “and I wouldn’t have thought that would happen.” Dr Epstein discussed a collaborative study of this type looking at warfarin and hospitalizations. It was not randomized, but was large, and was “powered to look at the real question on a payer’s mind—

not a surrogate end point, but ‘can genotyping reduce a hard end point like hospitalizations?’” With personalized medicine, Dr Epstein continued, payers are looking for the same thing as with drugs— value for money. They want realworld comparative data with real outcomes of interest, and evaluation of consequential, matters. For the private sector, however, determining return on investment is difficult, and this may be the key factor holding back a wider adoption of pharmacogenomics. An audience member wondered what would happen if the genomics and personalized medicine achieved the hoped-for result—what if all the best candidates for a drug were successfully identified? What happens to pricing if the market for drugs is cut by two thirds? Dr Ramsey acknowledged the disconnect between drug development and this testing, saying “it’s putting companies in a bind.” Using the example of cetuximab, and how its marketing strategy had to change once KRAS information became part of the labeling, Dr Ramsey offered a guess “that companies are going to have to get on top of it.” Nevertheless, narrowing the population “might not be a bad thing if the efficacy is there,” he suggested. “We are definitely moving from blockbuster to nichebuster,” said Dr Epstein. He pointed out that Gleevec, which has a small population, is a multibillion-dollar drug. Also, in 1998, there was only one billion-dollar cancer drug; there are now 20 “and they’re all targeted.” Payers might pay a higher price on a smaller subset of people for a more predictable response, he concluded. “As long as you have better efficacy, or better safety, payers are not upset about that.” ■

OncoType DX: Diagnostic Dilemma The experience of OncoType DX illustrates some of the issues associated with introducing a new genetic test. Dr Lesko cited this as an example of how a product was carefully researched and introduced into the market through a deliberate, scientific process. The test “cost $400 million to develop,” he said, “but that may be what it takes.” Dr Ramsey focused on the potential for confusion from conflicting recommendations for using this

product from the National Comprehensive Cancer Network (which says clinicians should consider using this test for women with early-stage breast cancer) and EGAPP (which says that there is uncertainty that the evidence is sufficient to make a recommendation for or against). These mixed recommendations “reflect the uncertainty of the field,” said Dr Ramsey. Even so, 134,000 of the tests have been ordered since it was introduced in 1994. ■

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Communications About CER in a Charged Environment Whether CER or “regular” studies, care needed to convey results effectively By Colin Gittens Atlanta, GA—A session intended to outline how communications regarding the coming wave of comparative effectiveness research (CER) studies will need to done carefully in a polarized environment also pointed out that although the methodology of these studies may be new, the communications process is in many ways the same as for traditional research. With the huge increase in federal funding for CER, there are “going to be numerous projects with reports— 100, 200, 300—who knows how many a year?” said Robert Dubois, PhD, MD, chief medical officer of Cerner Life Sciences, Beverly Hills, CA, in opening the workshop at the 15th Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Because CER will be so common and influential, it possesses the ability to improve or worsen care depending upon how it is interpreted and disseminated, he argued.

at a glance Increased 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 Interpreting the New Science Dr Dubois outlined some key, guiding principles for those needing to interpret CER, which were first presented in a 2009 white paper prepared by Cerner LifeSciences and sponsored by the National Pharmaceutical Council. Unlike the process when examining “traditional” studies, Dr Dubois recommended that for CER studies, the evaluation be turned on its head. Readers of these studies should first consider for whom the findings are applicable. “If you’re a primary care doctor, and this deals with really severe specialty patients, you may not even need to read the report,” he suggested. If the study passes this initial test, only then is an evaluation of the methodology warranted. Lastly, these reports must be evaluated in regard to evolving evidence, because this

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research has a “half-life,” he noted. “At some point, it’s no longer going to be the right answer.” For each step in the process, he recommended that checklists be used to aid evaluation of the studies. The various study designs—randomized controlled trials, meta-analyses, and observational studies—demand questions specific to each type, and checklists can help a study reader evaluate a study quickly and accurately. (Those checklists were developed and included in the publications.) CER and Formularies According to Brian Sweet, RPh, MBA, chief pharmacy officer, Well Point, Grand Island, NY, CER is important to the firm as an important source of decision-making information, one that can help develop coverage and cost-sharing policies. According to Mr Sweet, CER does not make care decisions, he emphasized, but enables dialog and better-informed decision-making. A key tool used by the company is its outcomes-based formulary, which is intended to improve drug therapy, even if that means using a more expensive drug (the thinking being that with a patient’s health improved, less healthcare resources are used overall). So the company begins by carefully evaluating clinical trial data to ensure that studies are of sufficient quality to be used for decision-making, and then uses integrated pharmacy, medical, and laboratory data from the real world to determine drug outcomes in those environs. The process for the pharmacy and therapeutics committee has a “traditional” clinical review, but also incorporates a valueassessment component, which helps in assigning drugs to their final tiering level. Mr Sweet says that the firm has been working with CER-style data since 1998, so “this is not new to us.” But with the expected flood of CER studies, and because of guidelines that WellPoint had put in place in 2002, the firm realized that they would not be able to use CER studies to support decision-making. These studies are “very useful in filling the gaps of what randomized trials don’t tell us,” he noted. Like Cerner, WellPoint has published a set of CER evaluation criteria, which have been posted as a public document on their website (https://www.wellpointnextrx .com/shared/noapplication/f1/s0/ t0/pw_b145032.pdf).

A third panelist, Jean Slutsky, PA, MSPH, director of the Center for Outcomes and Evidence at the Agency for Healthcare Research and Quality, Rockville, MD, also emphasized the importance of using a systematic process for setting clinical

results should be used in decisionmaking; Ms Slutsky pointed out that “that situation exists now. We have private health plans, industry, and other groups writing consumer documents.” This flood of information confuses the consumer, she empha-

“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

policy, suggesting that questions such as “How good is the evidence that the interventions can improve those outcomes?” and “What constitutes ‘good enough’ evidence?” be kept in mind when evaluating these studies. Her agency has worked to improve communications generally, translating evidence-based information into consumer guides written at an 8th-grade level and created with input from end-users. These consumer guides are paired with concise, actionable physician education guides that help convey the level of certainty or uncertainty in the findings. In discussing the soundness of evidence used to back CER, Les Paul, MD, MS, vice president of Clinical and Scientific Affairs, National Pharmaceutical Council, Reston, VA, emphasized that it needs to be considered within the context of the best judgment of the provider and the preferences of the patient, which “tend to be lost in the current conversation that we are having.” These preferences “are going to become that much more important as more CER findings become available,” he ventured. When communicating CER findings, Dr Paul emphasized the need for an approach that did not sound out of place for “regular” research— high-quality methods, and balanced and timely findings that describe strengths, limitations, generalizability, and “actionability” in the real world. Same as the Old Science The real world, and the matter of a charged environment, was covered most directly during the Q&A session. A questioner wondered who will determine whether CER studies are well-conducted and whether their

sized, saying “there are many sectors that create documents that are secondary to research.” Dr Paul noted that because some methods in CER are relatively new in comparison to randomized clinical trials, there will be a learning curve associated with the science. “We’ve now had decades of experience in how to communicate the results of trials. There’s an iterative process for the development of more advanced methods that we are only now developing in what I would characterize as the young science of CER. How do we reconcile this long history of wellcontrolled trials that often take place in a regulatory environment with CER that will employ newer and often nonexperimental study designs in a nonregulatory environment?” Mr Sweet lamented the press picking up the results of poor studies, which then makes them big news. Firms such as his are then left to counter the demand from patients and providers for new therapies. Although this already occurs, he feels that this will occur “at a much higher magnitude,” once the higher volume of 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 questions for the sake of intellectual curiosity, she suggested, but because answers are truly needed. “The same scientific principles should apply, whether it’s CER or any other sort of clinical study.” It’s important “not to politicize the findings that are coming out of these publicly sponsored studies,” warned Dr Paul. The responsibility is “on the scientific and medical community not to let it become politicized. At the end of the day, this is about improving patient care.” ■

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ADVERTORIAL

OncoMed provided funding and editorial support for this article www.OncoMed.net

3 OF A SERIES

Evolution in

PART

Oncology Practice Management

™

Sea Change in Oncology Creates Demand For OncoMed s oncologists and hematolo- Adding Oncology Pharmacists to gists face a multitude of simul- the Mix taneous paradigm shifts relatThe OncoMed service model ed to their ability to deliver new deploys specially trained oncology biotechnology cancer-fighting medica- pharmacy technicians and expert tions, more providers are turning to oncology pharmacists to reduce ad New York–based OncoMed, The ministrative pressures on physician Oncology Pharmacy, a leading phar- practices related to the complex and maceutical services company that spe- time-consuming tasks of investigating cializes solely in oncology pharmaceu- a patient’s insurance benefits, conticals. firming therapy reimbursement, and In response to this surge in demand, navigating managed care prior OncoMed recently opened its newest authorization processes. Additionally, facility in New England to provide the company has a staff of specially high-level oncology pharmacy servic- trained Insurance Reimbursement es in that region, and the company has Advocates who help patients gain announced plans to open 4 additional access to the numerous patient finannew facilities this year in Boca Raton, cial assistance programs as the tradiFlorida; Buffalo, New York; Chicago, tional $20 to $50 copayments now typIllinois; and Phoenix, Arizona. The ically rise into the thousands of company, founded in 2004, is licensed dollars, as is the case with Medicare to provide oral, injected, and infused Parts B and D. Industry experts expect patient-specific oncology prescrip- dramatically increasing copays to be tions in all 50 states to patients cov- the trend, as noted recently during ered by Medicare, Medicaid, and pri- speeches and panels conducted at the vate health plans. National Comprehensive “We have established Cancer Network (NCCN) ourselves as a trusted and the Hematology/Onmember of the cancer care cology Pharmacy Associcommunity for delivering ation conferences. ‘just in time treatment day’ Having an oncology oncology pharmaceuticals pharmacist review and and care management process each order ensures services,” said Chief Execthat all prescription regiutive Officer Burt Zweigmens are routinely evaluenhaft. “We’ve done this ated against the rapidly by studying the market- Burt Zweigenhaft, CEO emerging standards in place, listening to physicare, such as the NCCN cian practices, and providing market- Guidelines. This enables OncoMed’s proven solutions to the challenges that pharmacists to alert physician pracour 600 current oncology practice tices to contraindicated drugs or treatproviders face in the cancer care envi- ment complications in advance of ronment today.” therapy. Events like this do happen, “We are recognized for our rigorous and one such event occurred recently clinical standards in preparing and when OncoMed pharmacists received delivering complex pharmaceutical a prescription for bevacizumab regimens,” Zweigenhaft said. “The (Avastin) and cetuximab (Erbitux) to evolving role of the oncology pharma- treat the same patient with previously cist is to be a cohort of the doctor’s untreated metastatic colorectal cancer. office. This is done by assisting with In this instance, the oncology pharmacritical clinical thinking during the cist called the physician and alerted regimen selection process. We also him to the very recent study that maximize the clinical yield of these found the combination of bevacizumexpensive drugs through eliminating ab and cetuximab, when administered drug waste by compounding the alongside chemotherapy, worsens colpatient-specific orders and then deliv- orectal cancer outcomes among ering them in treatment day doses.” patients with previously untreated,

VALUE-BASED CANCER CARE

July/August 2010

metastatic colorectal cancer and results in shorter progression-free survival and worse quality of life. The physician was grateful for the clinical information and then changed the treatment order.

istrator for North Shore Hematology/ Oncology, a 6-physician practice on Long Island, New York. “We can get medication on the same day that it is prescribed, which is very important because of the rapidly changing dis-

“The oncology pharmacy model is superior in knowledge, execution, and services delivered when compared with the mail-order specialty pharmacies drug replacement programs that some managed care plans now require our practice to use.” —Jeff Gaspar Practice Administrator North Shore Hematology/Oncology Change Is the Constant “It’s a field that’s constantly evolving, with research driving changes in oncology day by day,” added Kevin Askari, RPh, president and chief clinical pharmacist of OncoMed. “Our goal is to act as a virtual oncology pharmacy within the practice, and also be used as a pharmacological resource and experienced knowledge center in the oncologist’s office.” Among the challenges they are facing today, oncology providers point to: • Reduced margins on drug reimbursement; • Additional administrative burdens to verify complex patient benefit programs; • Evolving new studies and standards in care, with more drug combinations and protocols from which to choose; • More patients who see dramatic increases in copays, a financial responsibility that many can’t handle; • More prior authorization requirements for approved treatments; and • An explosion in inventory “carry costs” and the risks of bad debt with low drug margins. OncoMed gives providers a new option for dealing with these problems and the economic challenges of managing and dispensing oncology medicine. “Working with OncoMed has been a win-win situation for our practice,” said Jeff Gaspar, practice admin-

ease status seen in oncology patients.” Gaspar went on to say that, “the oncology pharmacy model is superior in knowledge, execution, and services delivered when compared with the mail-order specialty pharmacies or drug replacement programs that some managed care plans now require our practice to use. “Having to treat patients with chemotherapy regimens that range from weekly to every 21 days in a disease that is continuously morphing, while dealing with the multiple side effects and reimbursement challenges, is a lot for us to manage in the current economic environment,” Gaspar said. “So when we outsource the drugs and end up with an inexperienced provider on the other side of the phone or fax machine who does not understand the therapy or treatment cycle time sensitivity, as we have experienced from the specialty mail-order pharmacies, it places a huge burden on my staff and puts our practice in a very difficult position.” OncoMed’s pharmacy model enables physician practices to budget internal resources more appropriately, thereby reducing staff time spent investigating benefits with insurance carriers as well as the procurement sourcing tasks of accessing limited distribution drugs from manufacturers and wholesalers as well as FDAimposed special processes. The result for practices is reduced capital expens-

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EVOLUTION IN ONCOLOGY PRACTICE MANAGEMENT™

es and risks associated with copayment collection and bad debt. OncoMed also facilitates the prior authorization process with insurance carriers.

we have a Professional Practices shadowed under close supervision for Review and Oversight Committee that 6 months before they work on the disreviews our performance quarterly.” pensing front.” The arsenal of oncology pharmaceuticals and biotechnology targeted Focus on Patients, drugs has grown dramatically in Not Dollars Expertise Needed for New recent years. As recently as the 1970s, Historically, oncology providers Complexities there were no biologics and few drug have purchased and dispensed oncolAt the heart of the prescription choices, and cancer frontline treat- ogy medicines under a “buy and bill” intake process and supervising all dis- ments were mainly surgery and radia- system where they buy the drugs from pensing activities are OncoMed’s tion. Many of the first the manufacturer/wholeoncology pharmacists. All compound- chemotherapy drugs, novel saler, keep them in their ing and mixing is conducted in a USP at the time, are obsolete office, and prepare the <797>–compliant clean room environ- today as stand-alone drugs drugs and dispense them ment. Each dose and measure goes (some remain effective in to patients when needed. through a 6-point quality-check pro - combination with the new Medicare and other mancess done by oncology pharmacists or targeted biotechnology aged care payers have pharmacy technicians to ensure safety drugs used in protocols). changed the drug reimand accuracy. OncoMed goes an extra “Given the expanding bursement methodologies step to ensure that all of its pharma- complexity of therapies and moved to marketceuticals are purchased under a pub- and protocols, I saw there based reimbursement Kevin Askari, RPh licly disclosed “Drug Pedigree was a need for an oncology President and Chief schedules, reducing the Program” that specifically allows only pharmacy,” said Askari. “I Clinical Pharmacist amount they reimburse direct documented purchases from the wanted to be involved in the physician practices. prime manufacturers to ensure 100% an evolving, dynamic field. Every day, Today, most payers have moved to drug efficacy and inventory safety. even now, you get bombarded with discounting the AWP (average whole“I can’t stress the human factor new information. The treatment that sale price) to AWP minus 15% to 18% enough,” said Askari, the chief clinical was the best thing yesterday may not and/or some have replaced the AWP pharmacist. “Our facilities are top- work today.” standard with the Medicare standard notch, but we know they are only as Amid this complexity, Askari said of ASP (average sales price) plus 6%. good as the people who work within his emphasis remains on safety and This reimbursement compression, as them. That is why we have formalized quality. As an example, he said, “we well as the more administratively an ongoing oncology pharmacy train- hire only pharmacists who meet our complex process for acquiring the ing program for everyone regardless own rigorous oncology pharmacy medications, has made the downside of their role in our organization and experience standards, who are then economics of “buy and bill” more

apparent to physician practices. Not all physician practices have the necessary scale, professional resources, and capitalization required to provide these drugs and services profitably and that is exactly the market niche that OncoMed is positioned to service. “Physicians should be focused on caring for their patients and their complex disease,” said Zweigenhaft. “They should not have to worry about running a pharmacy and the tasks of acquiring and maintaining an inventory of medications, the drug authorization burdens, collection of copayments and drug reimbursement, and the risk of bad debt.” Zweigenhaft went on to say that, “we see new challenges appearing as more state pharmacy boards seek to control enforcement of the drug preparation sites using USP <797> and PCAB [Pharmaceutical Compounding Accreditation Board] certifications.” The validation of the OncoMed Oncology Pharmacy model is evidenced by the hundreds of physicians who have chosen the company as their preferred partner to navigate the sea change in oncology pharmaceuticals. Perhaps the greatest value, however, is the support the oncology pharmacy model can provide for the patients, who face the supreme challenge of defeating their cancer. ◆

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

FDA UPDATES Review for ARBs Following Cancer Connection The FDA is investigating a connection between angiotensin receptor blockers (ARBs) and cancer following publication of a meta-analysis (Lancet Oncol. 2010;11[7]:627-636) suggesting the drug’s use may slightly increase the risk of cancer. The FDA emphasized that review is ongoing and that they have not concluded that ARBs increase the risk of cancer. The FDA also presently believes that the benefits of these agents continue to outweigh their potential risks and that these drugs should continue to be used as recommended in their approved labels. (July 15, 2010) Blood Thinner Recalled After determining that isopropanol levels in some Coumadin 1-mg tablet blister packs could impact the amount of Coumadin delivered to patients over time, Bristol-Myers Squibb voluntarily recalled the fol-

lowing lots: Physician Sample Blister Packs—lot numbers 9A48931A, 9A48931B, 9A48931C, expiration January 2012; HUD Blister Pack— lot numbers 8F34006B, 8K44272A, 8K46168A, 9F44437A, and 9K58012B with expiry dates between June 2011 and November 2012. (July 12, 2010) Mylotarg Pulled After Disappointing Follow-up On the heels of results from a recent clinical trial that raised new concerns about gemtuzumab ozogamicin (Mylotarg)’s safety and the drug’s failure to demonstrate clinical benefit to acute myeloid leukemia (AML) patients enrolled in trials, the drug’s manufacturer, Pfizer, Inc, withdrew the drug at the request of the FDA. Mylotarg was approved in May 2000 under the FDA’s accelerated approval program, which used a surrogate end point of response rate (ie, the percentage of patients whose leukemia decreased or disappeared in laborato-

ry tests) observed in 142 patients with AML across 3 clinical trials. A confirmatory, postapproval clinical trial was begun in 2004, but the trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone. (June 21, 2010) Rapid Approval for Nilotinib Following a single randomized, active-control, open-label, multinational clinical trial comparing the response of 846 patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP-CML) to either nilotinib (Tasigna Capsules, Novartis Pharmaceuticals Corporation) or imatinib, the FDA granted accelerated approval to nilotinib. The drug was originally approved in October 2007 for the

treatment of adult patients with CPCML and accelerated phase resistant or intolerant to prior therapy that included imatinib. (June 17, 2010) Cabazitaxel Gains Combined Use Indication The FDA approved cabazitaxel (Jevtana Injection, sanofi-aventis) for use in combination with prednisone for treatment of patients with metastatic hormone-refractory prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The approval is based primarily on the results of a randomized, open-label, international trial of 755 patients with mHRPC previously treated with docetaxel-containing regimens. Median survival was 15.1 months for cabazitaxel-treated patients (compared with 12.7 months for those treated with mitoxantrone). The most common grade 3-4 adverse reactions included neutropenia, leukopenia, anemia, and febrile neutropenia; growth colonyContinued on page 25

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FOCUS ON

Hematopoietic Growth Factors: What’s New in 2010? By Caroline Helwick

hemotherapy-induced neutropenia is a risk associated with many common chemotherapy regimens. Especially when associated with fever—ie, febrile neutropenia (FN)—it is dose-limiting and sometimes life-threatening. Certainly, it increases resource utilization— including hospitalization—and cost. Myeloid growth factors can reduce the incidence, duration, and severity of neutropenic events and therefore are recommended for prophylaxis in some situations. It is important for payers to remain up to date on this important component of supportive care. To this end, this report describes recent recommendations and research findings that affect the optimum use of growth factors. ESMO Updates Guidelines In July, the European Society for Medical Oncology (ESMO) released an enhanced and revised set of clinical recommendations for cancer care, the 2010 ESMO Clinical Practice Guidelines, which contains a section on hematopoietic growth factors.1 The guidelines recommend hematopoietic growth factors for patients with a risk of FN ≥20% (listing chemotherapy regimens that pose this risk), or under special circumstances. Primary prophylaxis is deemed justified for patients with reduced marrow reserve due to radiotherapy of >20% of the marrow, human immunodeficiency virus, or aged ≥65 years and receiving curative regimens. Secondary prophylaxis is advised for patients at risk for further infections considered life-threatening, patients with dose reductions of concern and treatment delays, and patients for whom lack of protocol

at a glance The 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

adherence would compromise clinical outcomes. Other high-risk situations in which growth factors are indicated include autologous marrow transplant, allogeneic marrow transplant, and graft failure, the report states. Treatment with growth factors is advised for patients with protracted FN (>7 days), hypotension, sepsis, pneumonia or fungal infection, and for patients at risk for death from radiation injury. Growth factors with or without chemotherapy are an effective component of peripheral blood stem cell mobilization prior to transplant, the guidelines note.

treatment of multiple myeloma; anti thymocyte globulin, rabbit/cyclosporine for the treatment of myelodysplastic syndrome; and doxorubicin/ gemcitabine for the treatment of kidney cancer.4 Publications of Note Aapro et al evaluated 254 elderly breast cancer patients receiving chemotherapy supported by pegfilgrastim (Neulasta) primary prophylaxis or current practice neutropenia management.5 FN incidence was 6% with pegfilgrastim prophylaxis, compared with 24% under current neutropenia prac-

The selective use of colony-stimulating factors (CSFs) in patients at increased risk for neutropenic complications may enhance the cost-effectiveness of these agents. The new guidelines are the first stage in the development of guidelines addressing 55 different clinical situations, including the therapeutic use of growth factors. NCCN 2010 Guidelines The selective use of colony-stimulating factors (CSFs) in patients at increased risk for neutropenic complications may enhance the cost-effectiveness of these agents, according to the 2010 guidelines of the National Comprehensive Cancer Network (NCCN).2 The indication for prophylactic CSF use depends on the risk of FN or other neutropenic events that can potentially compromise treatment. Based on chemotherapy regimen and patient-related risk factors, the patient is assigned to a high-risk group (>20% risk of FN) intermediate-risk group (10%-20% risk), or lowrisk group (<10% risk). For the highrisk group, NCCN has a category 1 recommendation for using CSF when the treatment intent is curative or to prolong survival and improve quality of life. For intermediate-risk patients with this intent, CSF should be considered. Prophylaxis is not recommended for low-risk patients. There remains no consensus nomogram for risk assessment, but several risk factors are well established. New to the 2010 guidelines is the notation that a “prior episode of FN is a risk factor for poor clinical outcome or for developing infection-associated complications.”3 Also new is the addition of several regimens to those associated with high risk: hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) for the

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tice; FN-related hospitalization incidence was 5% and 15%, respectively; and dose reductions were needed for 15% and 29%, respectively. Gerds et al conducted a phase 3 randomized, double-blind, placebocontrolled trial comparing efficacy, costs, and safety of single-dose pegfilgrastim versus daily filgrastim (Neupogen) after autologous peripheral stem cell transplantation in 78 patients.6 They found the 2 regimens to be equally effective in time to neutrophil engraftment, with no difference in clinical sequelae; however, pegfilgrastim achieved a cost-savings of $961 per patient over filgrastim. Similarly, several other studies found pegfilgrastim cost-effective over 6 days of filgrastim. In a study by Lyman et al, in patients with nonHodgkin’s lymphoma receiving myelosuppressive chemotherapy, the incremental cost-effectiveness ratio (ICER) for pegfilgrastim was $2167/FN episode avoided.7 Adding a survival benefit derived from avoiding FN mortality yielded an ICER of $5532/ life-year (LY) gained or $6190/qualityadjusted life-year (QALY) gained. When the potential benefit of optimized chemotherapy was included, the ICER was $1494/LY gained or $1677/QALY gained. Italian investigators also concluded that primary prophylaxis with pegfilgrastim improved health outcomes with a “very limited cost increase” for the National Health Service payer. “Even when very low prices of filgrastim and high prices of pegfilgrastim were considered in the model, the resulting ICER remained well within the acceptable cost-effec-

tiveness limit of €50,000/QALY,” Danova et al noted.8 Columbia University investigators reported that the sequential administration of sargramostim (Leukine) and filgrastim in 31 children undergoing myeloablative conditioning was safe and cost-effective and resulted in prompt myeloid engraftment.9 Sargra mostim 250 mcg/m2 once daily was begun on the day of stem cell infusion, switching to filgrastim 10 mcg/kg once daily when white blood cells were ≥300/mm3, for 2 days. Filgrastim was continued until the absolute neutrophil count (ANC) was ≥2500/mm3 for 2 days, then tapered to maintain ANC ≥1000/mm3. The sequential approach, versus filgrastim alone, was estimated to save $1311 per patient. Naproxen was effective in reducing pegfilgrastim-induced bone pain in a randomized, double-blind, placebocontrolled trial of 510 cancer patients presented at the American Society of Clinical Oncology annual meeting.10 Mean AUC for pain was 7.71 for patients receiving placebo and 6.04 for those receiving naproxen 500 mg twice daily (P = .037). Naproxen re duced the overall pain incidence from 76% to 66% (P = .0085) and duration from 2.40 to 1.92 days (P = .009). ■ References 1. Crawford J, Caserta C, Roila F. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 2010;21(suppl 5):v248-v251. 2. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology—v.1.2010. Available at: www.nccn.org/professionals/physicians_gls/PDF/ myeloid_growth.pdf. 3. National Comprehensive Cancer Network: NCCN Practice 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: NCCN Practice 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 practice neutropenia management in elderly breast cancer patients receiving chemotherapy. Crit Rev Oncol Hematol. 2010;74:203-210. 6. Gerds A, Fox-Geiman M, Dawravoo K, et al. Randomized phase 3 trial of pegfilgrastim versus filgrastim after autologous peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2010;16: 678-685. 7. Lyman G, Lalla A, Barron R, Dubois RW. Cost effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin’s lymphoma 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 effectiveness of pegfilgrastim versus 6 days of filgrastim for preventing febrile neutropenia in breast cancer patients. Tumori. 2009;95:219-226. 9. Waxman IM, Militano O, Baldinger L, et al. Sequential administration of sargramostim and filgrastim in pediatric allogeneic stem cell transplantation recipients undergoing myeloablative conditioning. Pediatr Transplant. 2009;13:464-474. 10. Kirshner JJ, Heckler CE, Dakhil SR, et al. Prevention of pegfilgrastim-induced bone pain: a URCC CCOP randomized, double-blind, placebocontrolled trial of 510 cancer patients. Presented at: American Society of Clinical Oncology annual meeting; June 4-8; 2010. Chicago, IL. Abstract 9104.

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VBCC PERSPECTIVE

What’s a PBM to Do with CSFs?

Brian K. Solow, MD, vice president and senior medical director of clinical services at the pharmacy benefit management (PBM) firm Prescription Solutions in Irvine, CA, explained the process of what goes into the prior authorization guidelines concerning the use of colony-stimulating factors (CSFs). As with all clinical guidelines, it is essential to have an evidence base supporting their appropriate use.

The Prescription Solution guidelines are based on both US Food and Drug Administration (FDA)approved uses and nonapproved uses, provided there is an evidence base for the nonapproved uses, Dr Solow described. His firm begins by looking at the FDA-approved indications—febrile neutropenia prophylaxis, for example—and ensuring that this condition is listed in the product insert. For this condition, there are separate guidelines for filgrastim (Neupogen) and pegfilgras-

tim (Neulasta). In the case of patients with acute myelogenous leukemia receiving induction or consolidation therapy there are indications for sargramostim (Leukine) and filgrastim. So the recommended drugs are switched around “depending on what’s FDA indicated,” Dr Solow said. The firm offers guidelines for neutropenia associated with cancer chemotherapy, including criteria for secondary prophylaxis of febrile neutropenia as well as its off-label use. These criteria also include the duration of therapy. As described by Dr Solow, the Prescription Solutions guidelines offer a fairly granular breakdown of when the drugs can be used, but because this breakdown is evidence based, it is “pretty well recognized…if you don’t meet the criteria, you’re going to have to tell us why 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 offlabel use, Prescription Solutions will cover drugs listed in one of the accepted compendia or if the physician can supply enough reference materials to support the use of these drugs. “We recognize that if there is literature to support it as opposed to anecdotes, then there’s a good chance it’s

FDA UPDATES Continued from page 23 stimulating factors may be administered to reduce the risks of neutropenic complications associated with cabazitaxel use. (June 17, 2010) Safety Concerns for Pediatric Taxotere Use The FDA announced changes to the Taxotere (docetaxel) label, noting adverse reactions including scleroderma-like cutaneous changes usually preceded by peripheral lymphedema and instances of renal failure, the majority of which were associated with concomitant nephrotoxic drugs. (May 2010) Warnings Strengthened for Camptosar The FDA announced changes to the Camptosar (irinotecan HCl) label, adding warnings concerning pulmonary toxicity and dangers in patients with reduced UGT1A1 activity. Patients with this allele had higher incidences of grade 4 neutropenia. In addition, a notation regarding inter-

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stitial pulmonary disease was added under the adverse reactions. (May 2010) Better Bladder Imaging The FDA granted approval for hexaminolevulinate hydrochloride (Cysview for Intravesical Solution, Photocure ASA), as an optical imaging agent for use in combination with the Karl Storz Photodynamic Diagnostic D-Light C (PDD) System. The device plus imaging agent allows for cystoscopic detection of nonmuscle invasive papillary cancer of the bladder in patients suspected or known to have lesion(s) on the basis of a prior cystoscopy (using the blue light setting [Mode 2] as an adjunct to the white light setting [Mode 1]). The approval was based on a prospective, multicenter, controlled clinical trial of 779 adult patients, who were given the drug and evaluated in white and blue light mode or were not given the drug and evaluated using white light only. (May 28, 2010)

going to be approved,” Dr Solow explained. “We’re in the business of doing the best thing for the patient,” he said. Although there are some who say that PBMs are about withholding drugs, he pointed out that “patient safety and quality care come first. Unfortunately, not just with this class but with a lot of these specialty classes, there’s people who don’t know how to use these drugs.” Dr Solow’s role as a medical director is to create these medically sound guidelines. PBMs have to look at the total picture—the literature, the indications concerning off- and on-label use, and all evidence—and painstakingly design guidelines that work with

the oncologists and transplant physicians who are prescribing these drugs. Although the granular breakdown of acceptable uses in these authorization programs may frustrate physicians, their intent goes back to the patient, helping ensure the right medication for the right patient at the right dose. But he acknowledged hearing anecdotally that physicians say, “I don’t want to go with these guidelines. My patient just needs this drug.” Or the physician may fall back on experience or current practice, saying, “all my patients are on Neupogen.” That may be, said Dr Solow, but “the physician needs to provide us with sound rationale for its use before its authorization is approved.” ■

MEETINGS CALENDAR August 14-17 Personalized Interdisciplinary Cancer Treatment: The Importance of Timing, Houston Contact: The University of Texas M. D. Anderson Cancer Center CME/Conference Services, Unit 1381, PO Box 301439, Houston, TX 77230. 713-792-2223 or register@ mdanderson.org. August 20-22 9th International Congress on Targeted Therapies in Cancer, Washington, DC Contact: Physicians' Education Resource, 3500 Maple Avenue, Suite 700, Dallas, TX 75219. 888-949-0045 or info@cancerlearning.com. August 28 16th Annual Perspectives in Breast Cancer, New York City Contact: Imedex, 4325 Alexander Drive, Alpharetta, GA 30022. 770-751-7332 or meetings@imedex.com. September 12-15 Joint Metastasis Research SocietyAACR Conference, Philadelphia Contact: AACR, 615 Chestnut St., 17th Floor, Philadelphia, PA 19106. 215-4409300 or meetings@aacr.org. September 25 The Management of Women with Chronic Immune Disorders in the Era of Biologics, New York City Contact: Imedex, 4325 Alexander Drive, Alpharetta, GA 30022. 770-751-7332 or meetings@imedex.com. September 26-29 Scripps Cancer Center’s 30th Annual Oncology Nurses Symposium, San Diego Contact: Scripps Conference Services & CME, 11025 North Torrey Pines Rd., Suite 200, Mail Stop SCRC 200, La Jolla, CA 92037. 858-652-5400 or med.edu@scrippshealth.org.

September 27-30 AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Denver Contact: AACR, 615 Chestnut St., 17th Floor, Philadelphia, PA 19106. 215-4409300 or meetings@aacr.org. September 29-October 2 27th National Oncology Economics Conference, St. Louis Contact: Association of Community Cancer Centers, 11600 Nebel Street, Suite 201, Rockville, MD 20852. 301-984-9496, ext. 219 or labankert@accc-cancer.org. September 30-October 3 Third AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, Miami, FL Contact: AACR, 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106. 215-440-9300 or meetings@aacr.org. October 1-2 9th International Kidney Cancer Symposium, Chicago Contact: Kidney Cancer Association, PO Box 96503, Washington, DC 20090. 800850-9132 or kidney.cancer@hotmail.com. October 1-3 2010 Breast Cancer Symposium, National Harbor, MD Contact: The American Society for Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 571-483-1300 or http://breastcasymposium.org/ Home.aspx. October 1-4 2010 iSBTc Annual Meeting, Washington, DC Contact: International Society for Biological Therapy of Cancer, 555 East Wells Street, Suite 1100, Milwaukee, WI 53202. 414-271-2456 or info@isbtc.org. Continued on page 27

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VBCC_August 081110_ASCO Highlights Tabloid 8/16/10 9:38 AM Page 26

value-focused www.ValueBasedCancer.com

New Tools Arriving to Measure and Manage Chemotherapy Care Business, clinical concerns now connected in value-focused approach By Daniel Denvir

payers

Baltimore, MD—A long-held business truism 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 the Association of Community Cancer Centers’ (ACCC) 36th Annual National Meeting. Kimberly Bergstrom, PharmD, chief clinical officer for McKesson Specialty Care Solutions, told attendees of the growing importance of developing and using standardized chemotherapy treatment regimens, and of the tools that

can benchmark performance and foster compliance with treatment guidelines. Public and private payers are moving to control exploding healthcare costs, Dr Bergstrom told attendees, and because increased cost control was 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’t get a handle on it, it’s going to happen to us,” she said. “People and groups and organizations are going to start dictating how we provide cancer care, and we can’t let that happen.” Continued on page 8

cost control

Value-Based Cancer Care will be at the ASCO Annual Meeting, June 4-8, in Chicago.

NCCN Roundtable: Clinical and Economic Issues Impacting Cancer Care Delivery “Collision course” in sight By Audrey Andrews Hollywood, FL—Clinical practice guidelines issued by the National Comprehensive Cancer Network (NCCN) are followed by conscientious oncologists in their everyday practice, but they are developed based on clinical efficacy and without regard to costs. At a roundtable held during the NCCN’s 15th Annual Conference, moderator Clifford Goodman, PhD, Senior Vice President at The Lewin Group, predicted, “The appropriate use of evidence-based guidelines is on a collision course with the financial nonsustainability of the healthcare system.”

Dr Goodman alluded to a level of frustration that has never been higher in cancer care. “Too many patients are still dying young. We need innovations and a cure,” he said. But the inadequacy of current treatments for cancer is no longer the main problem. Equally challenging, he suggested, is finding a means to pay for the ever-costlier care that threatens to bankrupt the healthcare system. As society struggles to find solutions, “the ground is shaking beneath us,” Dr Goodman commented.

SEER-Medicare Database Analysis Confirms Expensive Prostate Breast Cancer Survival Improves, Cancers Gaining Supremacy Photo by © ASCO/Todd Buchanan 2009

Thanks to New Therapies Barcelona—Survival for patients with metastatic breast cancer has improved dramatically in the last 20 years, especially in the subgroup of patients with HER2-positive tumors, according to research presented at the 7th European

Breast Cancer Conference (EBCC7). This improvement, the researchers suggest, is due to increased use of anthracyclines and the rise of targeted therapies. “There is no doubt that trastuzumab (Herceptin), which targets the HER2 gene, is the most important Continued on page 27

targeted therapies

efficacy

Continued on page 19

Please visit us at booth 18121

By Colin Gittens

clinical practice guidelines

cost effectiveness

But cost-effectiveness of this move remains to be determined By Rosemary Frei, MSc San Francisco, CA—The popularity of minimally invasive radical prostatectomy (MIRP), intensity-modulated radiation therapy (IMRT), and of brachytherapy combined with IMRT for prostate cancer started to take off after 2002, a new database analysis has confirmed. At the American Society of Clinical Oncology’s 2010 Genitourinary Cancers Symposium, Paul L. Nguyen, MD, presented the results of his team’s analysis of data from the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Dr Nguyen, director of Prostate Brachytherapy, Dana-Farber/Brigham

The 2010 Genitourinary Cancers Symposium: Progress in Multidisciplinary Management was held March 5-7 in San Francisco. All sessions emphasized a multidisciplinary approach to care; a number of them brought out the cost and value issues associated with caring for genitourinary cancers. and Women’s Hospital, Harvard Medical School, Boston, and his coinvestigators found MIRP jumped from 1.5% of radical prostatectomies (RPs) in 2002 to 28.7% in 2005. They also found that IMRT soared from 8.7% of external radiation treatments for prostate cancer to 81.7%. In addiContinued on page 24

A new publication for your new vocabulary The healthcare system is changing. Cancer care too. New products. New ideas. New business practices. A new regulatory environment. Don’t rely on outdated sources of information. Subscribe to Value-Based Cancer Care today.

www.ValueBasedCancer.com In print and online

VBCC_August 081110_ASCO Highlights Tabloid 8/13/10 4:51 PM Page 27

CONSUMER GENETICS

Consumer Genetics: Paradigm Shift or Flash... genetic testing will create a fundamental change in how oncologists care for their patients, going from the traditional, trial-and-error regimen of observation, action, and observable results to a new process of observation, test, action, and predicted response. “The new paradigm will

“There are 19,000 genes in the genome, and it took me 6 hours to research 1 gene for a patient.” —Steve Murphy, MD break the trial-and-error cycle,” she said, avoiding cytotoxicity and preventing lost therapy options should a patient relapse or experience refractory cancer. Her company uses personalized medical diagnostics to characterize a current diagnostic “black hole,” assessing whether circulating tumor cells in the bloodstream are still a threat to the patient. Even patients’ drug compliance can increase when customized drugs and dosages are determined through genetic testing. Ms Aspinall cited an American Heart Association study that concluded, “If the patient believes that the drug is personalized for them, compliance goes up.” Moving Genetics from Theory to Practice The world—or at least the world inhabited by meeting presenters—is very much ready for genomic testing. Dietrich Stephan, PhD, of Ignite Institute indicated the framework for practical consumer genetics has formed with the convergence of several components. “We now have accurate sequencing technology at a reasonable price for a one-shot molecular diagnostic assay, and an increasing knowledge base to extract value from that genome. The delivery infrastructure is in place, beginning with how to take a sample, where to send it,

secure delivery of the results, their interpretation, and finally genomic counseling.” Speakers from these infrastructure companies were well represented at the conference. Mr Schatzberg’s Generation Health has partnered with CVS Caremark to help them navigate which pharmacogenetic tests are appropriate. The 2 companies are cueing up a July pharmacogenetic-testing pilot program on 13 drugs. “We don’t want to increase testing or decrease testing, we want to optimize it,” he said. Existence Genetics, a firm founded by Brandon Colby, MD, performs genetic tests and has developed a Next Generation Analysis Report to convey the results in an easy-to-read format so both patients and doctors can understand them. To help cancer patients determine their treatment options through analysis of their DNA, Life Technologies Corporation announced at

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ty,” Mr Kim said. He also informed the audience of 2 new organizations, the Centers for Medicare & Medicaid Services Innovation Center and the Independent Payment Advisory Board, that will research Medicare cost reform and where consumer genetic researchers can advance their devices. Although genetic testing is still in its initial stages, Steve Murphy, MD, the founder of The Personalized Medicine Group, identified some areas where it needs to grow. Dr Murphy called for widespread education about pharmacogenetic testing for physicians and patients, and for insurance companies to properly reimburse physicians for the time it takes to research genetic results. “There are 19,000 genes in the genome, and it took me 6 hours to research 1 gene for a patient,” he reported. He also looks forward to a proliferation of the gene database to decrease the number of “unclassified

the conference their Genomic Cancer Care Alliance, a new partnership with Fox Chase Cancer Center, Scripps Genomic Medicine, and the Translational Genomics Research Institute. The US Food and Drug Administration (FDA) is also readying itself for the personalized care revolution. Paul Kim, JD, MPP, an attorney with Foley Hoag, advised the audience to balance their day job with one eye on what the FDA will approve. “Consumer genetic devices have been under the radar, but the FDA is in the process of deciding their oversight policies for this industry, and will be reviewing their 501(k) processing goals. Its new focus will be on transparency, consistency, and predictabili-

October 18-20 ASCO-NCI-EORTC Annual Meeting on Molecular Markers in Cancer, Hollywood, FL Contact: ASCO, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 571-483-1351 or www.molecularcameeting.org. October 19-20 ECRI Institute’s 17th Annual

Brandon Colby, MD ability Act–compliant “Genetic Hub” that could be a connection pathway for doctors, patients, and laboratories.

variant” or “novel mutation” analyses, and hopes more studies will lead to stronger data, increasing the accuracy of risk estimates. When inconclusive or vague answers are reported to patients now, Dr Murphy noted, “they feel angst.” Speakers at the conference explored the many possibilities for consumer genetics. Although genomic testing is performed for particular newborns or fetuses, could this be expanded to all pregnancies? Dr Stephan postulated how perinatal screening could render early disease detection or susceptibility, noting, “If every newborn gets a sequencing test, can we spend that money to save money later?” Dr Murphy proposed an online Health Insurance Portability and Account-

The Personal Becomes Political For many at the meeting, consumer genetics seemed on the cusp of a breakthrough, with Dr Stephan wondering, “How will patients use their genetic information to develop personalized combinatorial therapeutics to allay their phenotype?” But just about a week later (June 10), the promise of consumer genetics took a serious hit with a series of letters from the FDA to makers of home genetic test kits, including 23andMe, deCODE Genetics, Knome, Illumina, and Navigenics. The letters stated that the products sold by these companies are considered devices by the FDA, and as such they fall under the agency’s regulatory purview. Interestingly, the letters did not state that the devices had to be removed from the market, but rather they encouraged the firms to “meet with us to discuss whether there are tests you are promoting that do not require review by the FDA and what information you would need to submit in order for your product to be legally marketed for the other uses.” Unless this issue is resolved, the future for consumer genetics conferences seems decidedly less rosy. ■

Conference: Personalized Medicine and Comparative Effectiveness, Bethesda, MD Contact: ECRI. 610-825-6000 or http://conferences.thehillgroup.com/ CERandPMconference/registration.cfm.

October 21-22 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer, Washington, DC Contact: AICR. 800-843-8114 or researchconference@aicr.org.

October 20-23 Southwest Oncology Group Annual Fall Meeting, Chicago Contact: SWOG, 14980 Omicron Drive, San Antonio, TX 78245. 210-677-8808 or www.swog.org.

October 24-27 The 32nd Annual Meeting of the Society for Medical Decision Making, Toronto, Ontario, Canada Contact: The Society for Medical Decision Making, 390 Amwell Road, Suite 402, Hillsborough, NJ 08844. 908-359-1184 or info@smdm.org.

“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

MEETINGS CALENDAR Continued from page 25 October 8-9 Personalized Cancer Therapy and Prevention, Houston Contact: The University of Texas M. D. Anderson Cancer Center CME/Conference Services, Unit 1381, PO Box 301439, Houston, TX 77230. 713-792-2223 or register@ mdanderson.org.

Continued from cover

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VBCC_August 081110_ASCO Highlights Tabloid 8/13/10 4:51 PM Page 28

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

goal One goal: discovering and delivering breakthrough medicines to combat cancer. Now the innovative science of a leading American biopharmaceutical company joins the global assets of Takeda, Japan’s largest pharmaceutical company, for a global commitment to oncology. Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers. Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation. We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.