JUNE 2010 | VOL 1 | NO 2 by Value-Based Cancer Care

june 2010 VOL 1 nO 2

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Breast and Ovarian Cancer Testing After the Myriad Genetics Decision By Rosemary Frei, MSc

here’s no question that when, on March 29, a federal district court judge ruled the patents held by Myriad Genetics to the BRCA1 and 2 gene mutation sequences are invalid, a shock went through the healthcare and genetics communities. What’s also not in doubt is that the case will continue—Myriad immediately indicated it will appeal the decision to the Court of Appeals for the Federal Circuit, which has been the appeal court for all patent cases since 1982. To read the VBCC Perspective on this story, please turn to page 10.

What remains an open question, however, is whether the court will uphold this first ruling—and, if it does, whether and to what extent the justices of the Supreme Court will do the same. “There was a lot of hand-wringing before the ruling that if the case went the way the ACLU [American Civil Liberties Union] wanted it to, biotech would be dead,” observed Robert Cook-Deegan, MD, director of the Continued on page 7

Two Steps Forward in the War Against Cancer By Scott Gottlieb, MD

ews from this week’s gathering of the American Society of Clinical Oncology in Chicago, the world’s largest annual cancer meeting, underscores how good we have become at turning new scientific principles into superior medicines. For those who gripe that progress from our huge investments in cancer research is too little or too slow, stunning results from 2 experimental drugs tell a different story. Bristol Myers’s drug Ipilimumab, the first treatment to extend the lives of patients with advanced melanoma skin cancer, is based on science that is

30 years in the making. Pfizer’s drug Crizotinib, which shrank some of the most resistant and fatal forms of lung cancer, was developed as a result of science done over the last decade. Developing drugs will always be a lengthy, iterative process. Ipilimumab’s origins are a prime example. The drug springs from a modern understanding of how our immunity works that was first developed in academic labs in the 1980s. Private industry used this knowledge to make copies of antibodies—immune molecules that our bodies produce to fight disease—and turn them into medicines. The first antibody drugs, developed in the mid 1980s, were made from Continued on page 28

From Dollars to Sense Comparative effectiveness research funded, now comes the hard part—implementation By Colin Gittens

ith the inclusion of $1.1 billion in the American Recovery and Reinvestment Act of 2009 for comparative effectiveness research (CER), this topic has suddenly become a matter of great importance in the clinical and research communities. The idea of directly comparing tests, treatments, and drugs in a head-to-head fashion to determine which are most effective makes intuitive sense, but the process will require fundamental changes in how research is conducted. Moreover, the financial implications associated with CER ensure that all stakeholders (including health services researchers, government payers, and drug and device manufacturers) will need to To read the VBCC Perspective on this story, please turn to page 18.

have careful deliberations about putting these techniques into effect. Even as the monies for CER have already begun to flow out to individual institutions and organizations, questions remain as to how the technique can best be implemented, where it can be applied, and how this new research paradigm might impact patient care. A New Way to Approval A fundamental way of instituting CER, one that would signal a seismic shift in the drug evaluation process, has been put forth by Alec B. O’Connor, MD, MPH,1 among others. In a recent commentary, he argues that the current US Food and Drug Administration (FDA) standards for new drug approval do not allow determination of whether a new treatment is less efficacious or less well tolContinued on page 15

Linked Databases, Health IT, and Informatics Essential for CER and Personalized Medicine By Patricia Williams Washington, DC—Health information technology (IT) and informatics are fundamental to all comparative effectiveness research (CER), Amy Abernethy, MD, associate director of the Duke Comprehensive Medical Center and founder and director of the Duke Cancer Care Research Program, told attendees at a session of the American Association of Cancer Research (AACR) 101st Annual Meeting. In particular, patient registries— with their structured inventories of patient data—are a critical platform for CER, assessment of the quality of cancer care, and rapid learning. The use of information from linked databases can provide real-time information about the benefits and harms of alternative methods to prevent,

diagnose, treat, and monitor cancer or improve the delivery of cancer care, Dr Abernethy said at the session, titled Healthcare Reform: The Confluence Continued on page 24

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

Proven chemotherapy-induced nausea and vomiting (CINV) prevention in a single IV dose. • Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 • Powerful acute CINV prevention following highly emetogenic chemotherapy3 • Can be used in multiple-day chemotherapy regimens4* * The restriction on repeated dosing of ALOXI within a 7-day interval was removed from the label.5

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of Full Prescribing Information. References: 1. Gralla R, et al. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, et al. Cancer. 2003;98:2473-2482. 3. Aapro MS, et al. Ann Oncol. 2006;17:1441-1449. 4. ALOXI® (palonosetron HCl) injection full prescribing information. 5. Data on file. Eisai Inc., Woodcliff Lake, NJ.

STARTS STRONG. LASTS LONG.

FDA UPDATES

Oncology-related updates from the US Food and Drug Administration IV Ondansetron May Be Contaminated The FDA has alerted healthcare professionals not to use certain intravenous (IV) bags of ondansetron (an ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

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antiemetic) and metronidazole and ciprofloxacin (both antibiotics) because of potential contamination. IV bags manufactured by Claris Lifesciences Limited, Ahmedabad, India, General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

have generated reports of floating matter in the bags. Potentially affected products are sold under the Claris, Sagent Pharmaceuticals, Pfizer, and West-Ward Pharmaceuticals labels. Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

Healthcare professionals should not use and should immediately remove from their pharmacy inventories IV bags manufactured by Claris and sold under any of these labels. (May 29, 2010) Tramadol Warning Strengthened The FDA advised healthcare professionals of label changes to 2 tramadol products (tramadol hydrochloride, Ultram; and tramadol hydrochloride/acetaminophen, Ultracet). The opioid, indicated for the management of moderate- to moderately severe–chronic pain, now contains a stronger warning regarding the risk of suicide for patients who are addiction-prone and/or taking tranquilizers or antidepressant drugs, and also warns about the risk of overdose. (May 25, 2010) Thyrogen Supply Limited Due to manufacturing difficulties at one of Genzyme’s plants, the supply of Thyrogen will be temporarily limited. Thyrogen is a recombinant thyroid-stimulating hormone that is used in the treatment and follow-up diagnosis of thyroid cancer. Genzyme has entered into a consent degree with the FDA that restricts distribution of the drug to only those for whom it is medically necessary. The shortfall will last until the manufacturing issues are resolved, or operations are transferred to another facility. (May 24, 2010) GnRH Agonists Undergoing Safety Review The FDA has notified healthcare professionals and patients of their preliminary and ongoing review that suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with gonadotropin-releasing hormone (GnRH) agonists. These drugs, among them Lupron, Zoladex, Trelstar, Viadur, Vantas, Eligard, Synarel, and other generics, suppress the production of testosterone, a hormone that is involved in the growth of prostate cancer. Most of the studies reviewed by the FDA reported small, but statistically significant increased risk. The FDA’s review is ongoing and the agency has not yet made any conclusions about risks associated with GnRH agonists. (May 3, 2010) In related news, the FDA is also conducting a safety review of Stalevo. Data from a single trial suggest that patients taking the drug may be at an increased risk for developing prostate cancer. (March 31, 2010)

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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

June 2010 3 6 8

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. 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.

Oncology-related updates from the FDA Value Propositions Cervical Cancer Screening Only Marginally Improved VBCC Perspective Reaching for Consistency with Genetic Testing/ Winston Wong, PharmD CER “Cyberinfrastructure” May Boost Cancer Research VBCC Perspective CER: Use, Controversy Both Growing/ Denise K. Pierce

Coverage from the Academy of Managed Care Pharmacy’s Annual Meeting & Showcase 19 Variant Methodology Impedes Cost-effectiveness Research Managed Care Pharmacist Boosts Drug Replacement, Reimbursement Patients More Likely to Abandon Drug Therapy When Paying More Out of Pocket 20 Survey Provides a Window Into Payer’s Decisionmaking Process Researchers Analyze Relationship Between Pharmacogenomics and Appropriate Oncology Care Pemetrexed as Maintenance Therapy Likely to Have ‘Minimal Impact’ on Health Plan Budget

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Coverage from IMPAKT Breast Cancer Conference 21 Better Targeting for Targeted Therapy Genetic Testing as Simple as 1-2-3 Circulating Tumor Cells Signal Worse Survival Coverage from the 101st Annual Meeting of the American Association for Cancer Research 25 $3 Million to Toss a Life Ring? 26 An Early Look at New Drugs on the Horizon With Loss of Tumor Supressor, Herceptin Resistance Increases Coverage from the 2nd European Lung Cancer Conference 27 Radiation with Pemetrexed a Possibility 28 Accelerated Radiotherapy Brings Survival Benefit Keep a Close Eye on Heart and Liver Transplant Patients 30 VBCC Perspective Premarket Policies May Generate the Best Value/ Jayson Slotnik, JD, MPH 31 Meetings Calendar

Complete coverage of the ASCO Annual Meeting will appear beginning in the July/August issue of Value-Based Cancer Care.

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

Jayson Slotnik, JD, MPH Foley Hoag Washington, DC

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

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

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

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

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

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

David Hom, MBA Solucia Farmington, CT

VALUE-BASED CANCER CARE

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

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

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

June 2010

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

One focus: 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.

VALUE PROPOSITIONS The Shifting Burden of Cancer Care Costs Between 1987 and 2005, the total medical cost of cancer (in 2007 US dollars) has roughly doubled, increasing to $48.1 billion from $24.7 billion. This is likely due to the aging US population, the authors posit, and a greater number of people being diagnosed with the disease. Who paid for this care, then and now? Payers of cancer care Private payers Medicare Out of pocket Other public Medicaid

1987 42% 33% 17% 7% 1%

2001-2005 50% 34% 8% 5% 3%

In addition, the share of total cancer costs that resulted from inpatient admissions fell from 64.4% in 1987-27.5% in 2001-2005, meaning the greater portion of care was provided in the outpatient setting. These findings are presented in Cancer (2010;doi:10.1002/cncr.25150).

Informed Patients Lower Costs of Care Knowing how much a healthcare visit will cost can have a blunting effect on utilization, say researchers who surveyed approximately 1500 employees of the Commonwealth of Massachusetts over a time of increasing copayments. Amy Lischko, DSc, of Tufts University School of Medicine, and James Burgess, PhD, of Boston University School of Public Health assessed the effect of knowledge and perceptions of cost-sharing levels, and found that more informed individuals made more office visits, while less informed individuals used the emergency department more frequently. The study appeared in The American Journal of Managed Care (2010; 16[4]:298-304).

Making Patients Price Savvy The North Shore-LIJ Health System in New York has launched an online service to allow consumers to learn the cost of medical services in advance, learn about eligibility for financial assistance, and to get help in paying bills. The web site, www.northshorelij.com/FinancialHelp, is intended to help patients better understand their bills, estimate out-ofpocket costs, and to establish interest-free payment plans and online payment arrangements.

Cost an Obstacle to Seeking Coronary Care Patients experiencing a heart attack put off care by more than 6 hours due to lack of health insurance and financial worries about the cost of care, according to a study published in JAMA (2010;303[14]:1392-1400). Even more striking was that some patients with health insurance put off care due to financial concerns. The study used a registry of 3721 patients from 24 US hospitals, of whom 40% were uninsured or were insured but reported financial concerns. Forty-nine percent of uninsured patients and 45% of insured patients with financial concerns delayed seeking care by more than 6 hours during a heart attack, compared with only 39% of insured patients without financial concerns.

Halving Colonoscopy Prep Does Not Lessen Clinical Effectiveness A randomized, single-blind study of 116 colonoscopy patients has found that reducing colonoscopy preparation from 2 days to 1 (where the same amount of drugs are given the morning of the procedure rather than split between then and the night before) results in less abdominal pain, sleep loss, and workday interference. What is more, the resulting images of the colon were adequate in both groups, and polyp detection was actually greater in the morning colon prep group. The findings were presented in the online edition of the American Journal of Gastroenterology (2010 Apr 20. [Epub ahead of print]).

Are Enhanced Pharmacy Services Really That Enhanced? “Value for money is also difficult to determine because the true costs of providing pharmaceutical services are obscure, especially in relation to premises and staff.” From the authors of a paper examining whether the move toward privatizing services once done by physicians into pharmacies (also known as enhanced pharmacy services) in the United Kingdom truly does save money and increase access and patient choice. The jury is still out, Elizabeth Richardson and Allyson Pollock find. (BMJ. 2010; May 11;340:c2298.doi:10.1136/bmj.c2298).

Vaccine Use Hamstrung by Financial Issues Widespread use of the herpes zoster vaccine has been hampered by financial and other issues, and greater access to the drug may be fostered through changes to how the drug is reimbursed under Medicare. The vaccine, with an average wholesale cost of $194, is one of the most expensive adult vaccines, and is covered under Medicare Part D (which pays for pharmacy benefits) rather than Medicare Part B (which covers medical treatments). Changing to this latter coverage arrangement may provide the biggest boost in vaccinations, say the authors. The findings were published in a study in the Annals of Internal Medicine (2010;152:555-560).

There’s No Place Like a Home Full of Doctors Creating a “medical home”—an environment in which an old-fashioned family doctor know patients individually, has access to electronic records and communications, is linked to a team of professionals, and that has more time for visits with fewer patients—can provide dramatically better patient outcomes. A 2-year evaluation at Seattle’s Group Health Cooperative to transform primary care resulted in 29% fewer emergency department visits and 6% fewer hospitalizations among patients, and less burnout among clinicians. After 2 years, for every dollar spent by Group Health, it recouped $1.50. The study appeared in Health Affairs (2010; 29[5]:844-851).

No Matter the User, Radiology Use Rising Adding Computerized Order Entry, Subtracting Mortality Introducing a computerized physician order entry (CPOE) system at Lucile Packard Children's Hospital was correlated with a 20% decrease in mortality rates at the hospital over an 18-month period. “What we found is that CPOE implementation was statistically correlated with fewer patient deaths,” said lead author Christopher Longhurst, MD. “As you can imagine, this is very meaningful.” The study was published online May 3 in Pediatrics.

VALUE-BASED CANCER CARE

June 2010

259% Percent increase between 2002 and 2007 in amount of Medicare positron emission tomography scans done by radiologist-owned facilities. 737% Percent increase in these scans during the same time period among nonradiologist-owned or leased facilities. Source: Agarwal R, Levin DC, Parker L, Rao VM. Trends in PET scanner ownership and leasing by nonradiologist physicians. J Am Coll Radiol. 2010;7(3):187-191.

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GENETIC TESTING

Breast- and Ovarian-cancer Testing... Institute for Genome Sciences & Policy’s Center for Genome Ethics, Law & Policy at Duke University in Durham, NC. “That of course is garbage. It’s very unlikely that courts are going to invalidate all gene patents retroactively.” Value-Based Cancer Care has waded into the fray to understand Judge Robert W. Sweet’s decision, and how Myriad and its tests may fare in the court and the marketplace. The Judgment The ACLU Foundation and the Public Patent Foundation, together with the Association for Molecular Pathology (AMP), filed a lawsuit on May 12, 2009, in the US District Court for the Southern District of New York against the United States Patent and Trademark Office (USPTO) and Myriad Genetics and the University of Utah Research Office. The latter 2 organizations hold 7 patents relating to the BRCA genes, and the ACLU Foundation and the AMP were plaintiffs together with other groups such as the American Society of Human Genetics and the American College of Medical Genetics. The lawsuit contended that the BRCA1 and 2 DNA sequences are products of nature and hence cannot be patented. The plaintiffs asked for a summary judgment from Judge Sweet; in other words, they asked that there not be a trial by jury but rather that the judge make his own decision. This was because they believed that it was the interpretation of the facts rather than the facts themselves that were contended by themselves and the defense. In his March 29, 2010, decision, Judge Sweet agreed to provide a summary judgment. In his judgment, Judge Sweet did not weigh in on the plaintiffs’ contentions that patenting gene-based material is unconstitutional, and that patents stifle research and impede patient access to testing and treatment. He agreed with the plaintiffs, however, that the BRCA1 and 2 gene sequences are not markedly different from wild-type or native DNA and hence cannot be patented. He also agreed that Myriad’s patents for its methods of isolating, sequencing, and comparing DNA segments from patients to those with BRCA1 and 2 mutations are invalid. His reasoning was that the isolated segments are products of nature that don’t have significantly different characteristics from those in their native state, and

that isolating and sequencing segments is a set of simple data-gathering steps that do not involve any new technologies or processes. Thus the judge concludes that “the patents issued by USPTO are directed to a law of nature and were therefore improperly granted.”

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mentally different from anything that occurs in nature.” For their part, the AMP cheered the judgment. A release sent to the media on March 31 used unequivocal language. “This is a landmark decision that has the potential to dramatically

“We’re not claiming that Myriad is doing bad testing. But if you have more people [and laboratories] doing the same test with different methods, that can help resolve indeterminant results.” —Karen Mann, PhD

The Reactions The day after Judge Sweet made his ruling, the next phase of the battle began. In a news release indicating Myriad will appeal the decision, the company’s president and CEO struck back. “While we are disappointed that Judge Sweet did not follow prior judicial precedent or Congress’s intent that the Patent Act be broadly construed and applied, we are very confident that the Court of Appeals for the Federal Circuit will reverse this decision and uphold the patent claims being challenged in this litigation,” said Peter Meldrum. “More importantly, we do not believe that the final outcome of this litigation will have a material impact on Myriad’s operations due to the patent protection afforded Myriad by its remaining patents.” BIO—the Biotechnology Industry Organization—also released a statement that day defending Myriad. BIO is one of the groups that had filed briefs before Judge Sweet in support of Myriad Genetics and the USPTO. “The invalidation of the diagnostic method claims was done under a Federal Circuit opinion…which will soon be clarified further by the Supreme Court,” BIO president and CEO Jim Greenwood said in the statement. “From the mass production of life-saving medicines by cell cultures to the screening of our blood supply for life-threatening viruses, patented DNA molecules have been put to countless uses that have benefited society. Preparations of isolated and purified DNA molecules, which alone can be put to use in these ways, are patentable because they are funda-

improve patient access to genetic testing. It is a boon to personalized medicine in the purest sense, as nothing is more personal than one’s genetic makeup,” AMP president Karen Mann, PhD, said in the release. “… DNA patents have delayed, limited, or even shut down clinical testing and scientific research, and in the case of BRCA genes, Myriad’s lab is the only place in the country that performs full sequencing of the genes for diagnostic purposes. Patients can’t get a second opinion before they make major, irreversible health decisions.” When asked by Value-Based Cancer Care to further clarify this statement, Dr Mann opined that bringing more competition into BRCA testing would broaden access and potentially improve accuracy. “We’re not claiming that Myriad is doing bad testing. But if you have more people [and laboratories] doing the same test with different methods, that can help resolve indeterminant results. And also, if there were multiple people offering the test, I have no doubt it would be cheaper.” The Context Two sets of case studies that happened to be published just 2 weeks after Judge Sweet made his ruling provide a wealth of material on whether gene patents and licensing practices hinder access to genetic testing for cancer. Both papers took years to complete, and both were published in the journal Genetics in Medicine. In one of the analyses, E. Richard Gold, BSc, and Julia Carbone, LLB, outline the formation of Myriad Genetics in 1991 by University of Utah researcher Marc Skolnick, and

how the tension built up between Myriad and the clinical research community, the public, and healthcare administrators.1 After Myriad secured patents that covered the entire BRCA1 gene and the tools to sequence and compare patients’ gene sequences, it introduced a test for BRCA1 and 2 in the late 1990s. It has the exclusive license to use these tests in the United States. Shortly thereafter, Myriad sought to ensure the exclusivity of testing by issuing cease-and-desist letters to the Genetics and IVF Institute (GIVF) and the University of Pennsylvania’s Genetic Diagnostic Laboratory (GDL) in 1998. GIVF immediately stopped BRCA testing, but GDL did so only after Myriad signed an agreement with the National Cancer Institute (NCI) that stipulates the company has to provide, at cost or below cost, testing to the NCI and any researcher working on an NCI-funded project. The fact that Myriad was willing to quickly jump into the enforcement track against any group performing testing created enmity not only within the research community, but also, eventually, with patients and large swaths of the healthcare sector. Indeed, the Secretary’s Advisory Committee on Genetics, Health, and Society, which advises the Secretary of Health and Human Services on a range of issues relating to the intersection between genetics and medicine, issued a report on February 10, 2010, that determined gene patents are not an important incentive to develop and make available genetic tests. The committee recommended, among other things, that any group or individual with the appropriate equipment and expertise should be able to conduct diagnostic testing, even if there are patents covering parts of that testing. This was part of the crack in the gene-patenting superstructure that may well have helped lead to Judge Sweet’s decision. Gold and Carbone in fact make a convincing case that it was because of Myriad’s aggressive and nonconciliatory practices that the company and indeed the whole biotechnology community have found themselves defending the very right to patent genetic sequences. Dr Cook-Deegan is the first author of a paper in the same issue of Genetics in Medicine comparing the impact of gene patents and licensing practices in breast, ovarian, and colon cancers.2 He told Value-Based Cancer Care that in the diagnostics fields Continued on page 8

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Breast- and Ovarian-cancer Testing... there are few companies like Myriad with exclusive patent rights, and that use their exclusivity and patent protection to reduce competition only after other companies’ products have reached the market first. “This is very unusual—that wouldn’t be the case for Lipitor or other drugs, or even for gene-based biologics like erythropoietin,” he said. In their analysis—in which Dr Cook-Deegan and his team compare the development of, and access to, testing for BRCA1 and 2 to that for hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP)—they find that the price Myriad charges for analyzing a small unit of DNA known as an amplicon is lower for BRCA1/2 than for the colorectal-cancer genes. Myriad charges $38.05/BRCA1 and 2 amplicon, compared to $40.80/FAP amplicon and $49.17/HNPCC amplicon. Its FAP price is at the high end of what other groups charge, and its HNPCC price is in the middle of the range, Dr Cook-Deegan and his coinvestigators found. The patents for the genes associated with HNPCC are held by the Oregon Health Sciences University and the Dana-Farber Cancer Institute in Seattle, and Johns Hopkins University. The patent for the FAP-associated gene is held by Johns Hopkins. The licenses for testing for the genes are held by 7 academic institutions and by Myriad and Quest Diagnostics. Additional findings from the team include: • Despite the company’s maintaining it has never enforced its patents on the BRCA1 and 2 genes and tests for them against basic-science researchers, “Myriad cannot fully elude responsibility for any chilling effect on research, because the company could fully anticipate that others would refrain from research for fear of being sued for infringement,” in light of Myriad’s earlier actions against GIVF and GDL; • Myriad has only developed bloodbased testing and has decided not to test paraffin-embedded tissue even though there are instances in which the latter might be clinically useful; in contrast, in the area of colorectal-cancer forms of testing are proliferating and, for example, 8 different tests are available for detection, compared to zero for breast cancer. • Myriad has conducted extensive direct-to-consumer advertising which, studies indicate, significant-

ly increased women’s interest in being tested for BRCA1 and 2, particularly among those at high risk for breast and ovarian cancer. “Based on these latter points, it is, therefore, difficult to attribute reduced access to BRCA testing to patents. We cannot exclude the possibility that patent holders’ investments in education about hereditary breast and ovarian cancer and testing have actually had the opposite effect, of increasing access to testing,” conclude Dr Cook-Deegan and his co-authors.

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ods claims, and uphold his judgment on that. But I don’t think they’ll agree with him in ruling that you can’t patent DNA at all. That, at least on the surface, looks to be incompatible with decisions that the court of appeals has made over the years.” James Evans, MD, PhD, is the Bryson Distinguished Chair of Human Genetics at the University of North Carolina-Chapel Hill and a member of the board of the American College of Medical Genetics. He wrote an editorial in Genetics in

“I don’t think they’ll agree with him in ruling that you can’t patent DNA at all. That, at least on the surface, looks to be incompatible with decisions that the court of appeals has —Robert Cook-Deegan, MD made over the years.”

The Next Round Whatever the actual effect of patents on patient access, the die is cast and the court of public opinion must now give way to judges’ deliberations. That hasn’t of course stopped everyone from speculating about what will happen. “I don’t think either side will be fully satisfied with the ruling that comes out of the court of appeals,” said Dr Cook-Deegan. “I think the court of appeals will decide that Judge Sweet got it right on the meth-

Medicine praising the analyses by Dr Cook-Deegan’s team and by Gold and Carbone, and pointing to a number of harms from diagnostic gene patents.3 “Patient access to testing can suffer, most clearly when exclusive providers fail to contract with insurers such as state Medicaid programs, leaving patients without the option of a given genetic test should it be recommended by their provider,” he wrote. Dr Evans told Value-Based Cancer Care that the process unfolding in the

courts may in fact fit with Myriad’s own business plan. “On one hand, Myriad says that this is a broad decision, and that it has serious and problematic implications for genetic testing and diagnosis,” he said. “But on the other hand, they’re telling their shareholders—and I agree with them—that this isn’t the end of the world, that it’s not going to destroy their core business. My understanding of Myriad’s business plan is that it is based ultimately on therapeutics, which would have many downstream patents protecting it.” Dr Cook-Deegan has a slightly different take on the future for Myriad. “Their diagnostics patent protection will begin to expire in 4 years anyway, and so they will have to develop a less patent-dependent business model, and they appear to be positioned to do so with their current services,” he said. “They have long since been rewarded for having won the BRCA1 race by a couple months. As of March 29 they’ve had to compete on terms other than intellectual property-protected technology. Now let them compete.” ■ References 1. Gold ER, Carbone J. Myriad Genetics: in the eye of the policy storm. Genet Med. 2010;12(4):S39-S70. 2. Cook-Deegan R, DeRienzo C, Carbone J, et al. Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer: comparing breast and ovarian cancers with colon cancers. Genet Med. 2010;12(4):S15-S38. 3. Evans JP. Putting patients before patents. Genet Med. 2010;12(4):S3-S4.

Cervical Cancer Screening Only Marginally Improved Study of 35 centers in California adds to mixed results with financial incentives By Rosemary Frei, MSc

new study suggests that removing financial incentives for screening for cervical cancer, diabetic retinopathy, and hypertension and diabetes control reduces performance, including screening rates. The study was published online in May in the British Medical Journal (2010;340:c1898). The lead investigator acknowledges, however, that the study is far from the last word on whether paying physicians to perform tests increases the fraction of the population that receives them. “Our study adds more evidence to the incentives debate, but does not in any way conclusively show that incentives have a direct effect on screening rates,” said Helen Lester, MD, professor, NIHR School for

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June 2010

Primary Care Research, Manchester, United Kingdom. “There are important caveats to this study, such as the difficulty of separating the impact of financial incentives from that of other regional efforts directed towards the same quality measures.

The incentives were relatively large: in 2006, for example, the 35 facilities were awarded $42 million. So the most we can say is that there may be some change in doctor behavior once financial incentives are removed.” Indeed, the Centers for Disease Control and Prevention’s Task Force on Community Preventive Services has found insufficient evidence to

show financial incentives increase cancer screening (Am J Prev Med. 2008; 35[1S]:S21-S25), and that provider reminder and recall systems produce more significant increases in screening rates (Am J Prev Med. 2010;38[1]: 110-117). Dr Lester and 6 other researchers from the United Kingdom and California examined the effects of adding or removing incentives for various screening tests and process measures. They focused on 35 outpatient facilities owned and operated by Kaiser Permanente Northern California that serve more than 2.5 million adults. The facilities as a whole (rather than individual physicians) were given the incentives by Kaiser Permanente. The incentives were relatively large: in 2006, for example, the 35 facilities were awarded $42 million. The decision to add incen-

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tives was largely based on whether Kaiser officials believed the incentives were likely to significantly increase screening rates. The decision to remove incentives was based on whether the rates were projected to continue to increase without them because of the screening behavior or behaviors had become routine. During the study period of 1999-2007, Kaiser Permanente first removed incentives paid to facilities for screening for diabetic retinopathy and cervical cancer, and then reinstated the cervical cancer screening incentives.

effect if the incentive were to be taken away in other centers or countries at other times.” The study was conducted to determine what the effect might be of the

planned removal of incentives for 8 clinical indicators in generalphysician offices across the United Kingdom in April 2011. Dr Shekelle said the results in the United

Kingdom will depend on what substitutes are used for financial incentives, and whether these substitutes “are ingrained into the normal workflow” or not. ■

Adding incentives for cervical cancer screening led to an increase of patients being screened from 77.4% to 78.0%. Dr Lester and her colleagues found that having incentives in place for diabetic retinopathy screening resulted in an increase from 84.9% of patients screened in 1999 to 88.1% screened in 2003. The incentives were then removed, and by 2007, the proportion had dropped to 80.5%. Similarly, adding incentives for cervical cancer screening led to an increase of patients being screened from 77.4% to 78.0%. Removing the incentives was followed by a drop in rates to 74.3%, and adding the incentives again saw rates increase to 75.3%. Value-Based Cancer Care asked Paul Shekelle, PhD, director, Southern California Evidence-Based Practice Center, RAND Corporation, and director, Quality Assessment and Quality Improvement Program, RAND Health, Los Angeles, for a comment. He noted that the increases and decreases in screening rates were relatively small, and thus he “wouldn’t expect there to be a very great

Complete coverage of the ASCO Annual Meeting will appear beginning in the July/August issue of Value-Based Cancer Care.

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

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VBCC PERSPECTIVE

Reaching for Consistency with Genetic Testing By Winston Wong, PharmD itive outcome) and reduces risk (ie, of exposing a patient to the adverse effects of a treatment that has little potential clinical benefit). Genetic and

ecent articles in the New England Journal of Medicine1 and the Journal of the American Medical Association2 note the tremendous increase in the cost of cancer care, which has at least doubled since 1990. The reasons for this steep increase have been attributed to the release and utilization of new medications, in tandem with more sophisticated surgery and radiation techniques. This, combined with an increasing number of patients who are candidates for these new treatment modalities, has resulted in an unsustainable cost trend. As a result, payers—including private insurers, the public sector, and governmental programs—have been forced to consider various options to “blunt” this trend. The usual first course of action is to reduce reimbursement, which does not address the topic of utilization.

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

From the clinician’s perspective, these new, more sophisticated, and specific medications represent new treatment alternatives for the appropriate population. Identifying that appropriate population involves 2 specific, but necessary, concerns: (1) the appropriate utilization of a specific treatment regimen; and (2) the ability to project the best possible outcome from a treatment regimen for a specific patient in his or her clinical situation. Identifying the appropriate treatment population minimizes unnecessary wasted cost (eg, by identifying patients for whom the regimens will have little chance of resulting in a pos-

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.

Winston Wong is an editorial board member of Value-Based Cancer Care and the associate vice president of pharmacy management at CareFirst BlueCross BlueShield, Baltimore, MD.

VALUE-BASED CANCER CARE

market today, only a select few have been able to withstand the extensive review needed to determine that the results are consistent, and to consistently correlate to predictions of outcome. The review criteria of the

Indication

We soon expect the endorsement of the BRAF mutation marker, as well as the absence of the P-TEN marker, to identify an additional 30% of the potential Erbitux/Vectibix treatment population where these agents will not be effective.

biomarker identification can help identify these appropriate populations, and will play an increasingly significant role in these efforts. Although there are many genetic and biomarker tests and assays on the

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BlueCross BlueShield Association Technology Evaluation Center (TEC) are rigorous, and as a “Blues” plan, TEC serves as the basis of our own evaluations. As a result, the human epidermal growth factor receptor 2

(HER2), OncotypeDx, and KRAS testing are considered as “standard of therapy” today. These tests allow us to determine and identify the most appropriate populations for treatment. The HER2

test, for example, allows us to predict the effectiveness of Herceptin (trastuzumab) therapy in women with breast cancer; the OncotypeDx test allows us to predict the longterm clinical benefit of adjuvant

chemotherapy. It is estimated that nearly 50% of women with breast cancer who are candidates for adjuvant chemotherapy following surgery will show no reduction in the risk for Continued on page 26

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

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www.ValueBasedCancer.com

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

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

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

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

(2%) (1%) (51%) —

n/N

(%)

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

(3%) (2%) (33%) —

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

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

Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Grade 3

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

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

— — (1%) —

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

(1%) — (5%) (1%)

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

1Grade

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

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

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

Zometa 4 mg

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

Placebo

1031 (100) 1015 (98)

556 (100) 548 (99)

455 (100) 445 (98)

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

175 83 53

(32) (15) (10)

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

476 333 320 249 143 105 86 82

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

266 183 162 162 81 74 65 61

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

171 122 174 83 48 31 14 17

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

398 328 252 215 112

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

240 172 108 126 62

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

130 89 114 84 28

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

124 (12) 101 (10)

50 82

(9) (15)

41 30

(9) (7)

231 164 145 130

81 50 60 48

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

105 61 59 45

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

n (%)

(%)

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

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

205 (20)

316 143 131 106 84 97

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

284 74 73 40 52

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

89 (20)

Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia

191 180 166 149 127

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

149 91 111 85 65

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

50 58 73 35 43

Psychiatric Depression Anxiety Confusion

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

95 73 39

(17) (13) (7)

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

Respiratory Dyspnea Cough

282 (27) 224 (22)

155 129

(28) (23)

107 (24) 65 (14)

Skin Alopecia Dermatitis

125 (12) 114 (11)

80 74

(14) (13)

36 38

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

(8) (8)

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

Placebo

(%)

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

(2%) (<1%) (7%) (<1%) —

n/N

(%)

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

(2%) — (3%) (2%) (<1%)

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

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

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

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

(<1%) (<1%) (<1%) — (<1%)

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

(<1%) (<1%) — — (<1%)

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

— (<1%) (<1%) (<1%) —

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

569 239 216 156 143

n/N

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

Multiple Myeloma and Breast Cancer

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

Pamidronate 90 mg

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

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

(%)

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

(%)

12/82 4/10 16/92

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

Pamidronate 90 mg n/N

(%)

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

(%)

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

(%)

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

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

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

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

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

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

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COMPARATIVE EFFECTIVENESS

From Dollars to Sense Continued from cover erated than existing alternatives. The solution, he proposes, is active comparator trials designed and powered to demonstrate superiority, equivalence, or noninferiority that are run under strict oversight by the FDA. An FDA-assembled panel could recommend the best active comparator, dosing schemes, and calculation powering. Doing this “would yield highly relevant comparative efficacy and tolerability information at the time the drugs…reach the market,” Dr O’Connor argues, and that information could be included on labeling, which would be very clinically relevant.1

coverage decisions) be considered. This last matter is perhaps the most controversial among various stakeholders, but it gets to the heart of the matter. As the authors ask, “What good is comparative effectiveness if it cannot be used to discern anything about value to clinicians, insurers, patients, and society?”2 The need to get beyond the “pharmacentric” approach of most CER studies was brought forth in another recent study. Michael Hochman, MD, of the University of Southern California, Los Angeles, and Danny McCormick, MD, MPH, of Harvard

More comparative effectiveness research should evaluate nonpharmacologic treatments and strategies. The clinical benefits of this approach could be tempered by the business impact, Dr O’Connor acknowledges, saying that such trials “could conceivably reduce new drug and device development due to the increased costs of trials including active comparators and the increased risk of discovering late in the development process that a new treatment is inferior to existing treatments.”1 But he points out that new treatments for which placebo-controlled trials are unethical (ie, antibiotics, anticoagulants, and chemotherapeutic agents) are continuing to be developed. In addition, an approach similar to that recommended in Europe, which would incorporate both active comparator and placebo-controlled groups simultaneously, may also be helpful, Dr O’Connor suggests. Randall Stafford, MD, PhD, of Stanford University School of Medicine, and Caleb Alexander, MD, at the University of Chicago, also emphasized the need for changes in the FDA drug approval process in a commentary released last year, arguing that the process of placebo comparison be modified.2 They also offered additional ideas for maximizing the impact of CER, ideas that have gained traction in the research community as CER has come closer to widespread implementation. The two suggest that it is imperative to obtain comparative effectiveness information earlier in the life of a drug or device; that evidence be linked to strategies proven to modify physician behavior; that the focus of CER go beyond drugs and devices to consider lifestyle modifications and alternative therapies; and finally, that the cost implications (eg, including cost-effectiveness in

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Medical School, Boston, took stock of CER studies concerning medications published between June 2008 and

September 2009 in 6 leading medical journals.3 They found that just 11% of CER studies compared medications with nonpharmacologic interventions. Hochman and McCormick believe more CER should evaluate non-pharmacologic treatments and strategies. For example, is surgery, radiation, or watchful waiting the best approach for managing earlystage prostate cancer? Does early involvement of palliative care consultants in the care of patients with cancer lead to improved patient satisfaction and outcomes? Are lifestyle changes or medications better for treating patients with mildly elevated cholesterol levels? Hochman’s and McCormick’s study also indicated that CER studies were less likely than non-CER studies to have been exclusively commercially funded (13% vs 45%), and that noncommercial entities jointly or exclusively funded 87% of the CER studies.

In addition to changed regulations and a wider-view approach, greater coordination and communication among researchers must also occur if CER is to become an everyday and essential part of clinical and health services research. A June 2009 report prepared by AcademyHealth reported a large volume of ongoing CER, but with little coordination among funders and researchers to track the type of work being done, and therefore the potential for duplication.4 Better communication would also foster awareness of the most cost-efficient study designs. Publication Processes Also in Flux Given the growing interest in CER, it is not surprising that medical journals are gearing up for the changes that the new approach will bring. In April, a team of authors led by Harold C. Sox, MD, the editor emeritus of the Continued on page 16

CER “Cyberinfrastructure” May Boost Cancer Research Researchers from the University of California and the University of California San Diego (UCSD) have begun working on a prototype “cyberinfrastructure” that would allow cancer researchers to collect and interpret data from multiple sources to compare the effectiveness of preventive measures, drugs, treatments, and interventions during the course of clinical trials. The project, known as CYCORE (Cyberinfrastructure for Comparative Effectiveness Research), will aggregate data from clinical trials, patient medical records, self-reported and objectively monitored social and behavioral data, data on cancer outcomes from regional cancer registries, and cost-benefit analyses. The goal is to allow scientists to better collate ever-increasing amounts of data, and to use that both to impact the design of future trials and to positively affect patient outcomes in the present. Collecting Real-world Data A key part of the project will involve home and mobile phone– based sensing devices that will allow real-time capture of pertinent patient data. Kevin Patrick, MD, a professor in UCSD’s Department of Family and Preventive Medicine and a principal investigator in the project, emphasized the novelty of the approach in a press release dis-

cussing the effort. “A primary focus will be on tackling the problem of obtaining, in patients’ homes, objective person-level data on behaviors such as adherence to cancer medications, diet, physical activity, sleep, environmental exposures, and quality of life,” he said. These factors are wide ranging, encompassing everything from physiological matters (eg, cardiac function, blood pressure, sleep-related EEG data, etc), to

ly expand our understanding of who does well on what treatment, when, why, and for how long.” Laura Wolszon, PhD, a program director on the project, elaborated, saying “one of the reasons that cancer treatments haven’t progressed further is because researchers don’t typically evaluate the impact of a patient’s behavior and personal environment when deciding whether one treatment works better than

“A primary focus will be on obtaining objective, person-level data on behaviors such as adherence to cancer medications.” —Kevin Patrick, MD behavior-related issues (eg, do they take their medication as prescribed, do they exercise, do they seem lethargic, are they still smoking, do they eat appropriate foods, etc), to environmental factors (eg, is there secondhand smoke in the home, is their neighborhood experiencing significant amounts of air pollution, is the patient always alone, etc). “These factors are enormously important in the course of medical treatment, but are almost always assessed through infrequent and after-the-fact self-reports,” Dr Patrick added. “To have these data in near-continuous form will great-

another. The more data we use, the more accurate and effective will be the treatment plan for that patient and, probably, others.” The researchers are constructing the prototype using data from their partner, M. D. Anderson Cancer Center, but the final goal is to include data from all cancer clinical trials. The research team emphasizes that the program will be open source, allowing others to modify it for their own purposes, and will be adaptive to changes in policy along the way—say, if changes in privacy laws occur that suddenly restrict access to certain data. ■

www.ValueBasedCancer.com

COMPARATIVE EFFECTIVENESS

From Dollars to Sense Continued from page 15 Annals of Internal Medicine and cochair of the Institute of Medicine’s Committee on Comparative Effectiveness Research Prioritization, published a statement of principles for how medical journals should specifically address CER-focused studies submitted for peer review and publication.5 Because CER will use evidence outside of what is customarily seen in randomized clinical trials, including data obtained in the course of regular practice, the authors emphasize, journal editors and their peer review processes must account for the limitations inherent in such research, including “missing data, incomplete follow-up, unmeasured biases, the potential role of chance, competing interests, and selective reporting of results.”5

introduced to the cost of tests they order,6 and the American College of Physicians (ACP) recently announcing plans to provide physicians and patients with evidence-based recommendations for specific interventions

for a variety of clinical problems. The program, titled the High-Value, CostConscious Care Initiative, will assess benefits, harms, and costs of diagnostic tests and treatments for various diseases to determine whether they

provide good value. “Shared decision making between physicians and patients is an integral part of highvalue, cost-conscious care,” said Steven Weinberger, MD, deputy executive vice president and senior vice

“Shared decision making between physicians and patients is an integral part of high-value, cost-conscious care.” —Steven Weinberger, MD The authors emphasize that CER trials should be as much like “regular” trials as possible, with publicly accessible protocols written in advance, a high degree of transparency, public accessibility, and scrupulous reporting of potential conflicts of interest by researchers. By doing so, the authors argue, the principles of CER will be more effectively achieved. The statement is notable for its conclusion, which suggests a role for editors beyond the usual conductor and arbiter of peer review. “Medical journals are the primary evaluators and disseminators of peer-reviewed health research,” the authors state. “As such, they must ready themselves to play a crucial role in advocating for CER, advancing CER methods, and facilitating the translation of CER results into practice.”5 What is also noteworthy is that the statement appeared simultaneously in 6 other medical journals, and was endorsed by the editors of several others.

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED. IF PATIENTS REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN, THEY SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute respiratory distress syndrome (ARDS) has been reported. Evaluate patients who develop fever, lung infiltrates, or respiratory distress for ARDS. If patient is diagnosed with ARDS, discontinue and/or withhold Neulasta® until resolution.

Changing Mindsets, Changing Care Again and again, researchers writing about CER emphasize that changing the focus to this type of research is not simply an academic exercise, but a serious effort to improve patient care. And that perspective seems to be taking root in wider ways, with physicians in training now being

VALUE-BASED CANCER CARE

Allergic reactions to Neulasta®, manifesting as anaphylaxis, angioedema, or urticaria have been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment. Severe sickle cell crises have been associated with the use of Neulasta® in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta® for such patients.

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COMPARATIVE EFFECTIVENESS president, Medical Education and Publishing, ACP, in a press release announcing the program. Efforts like these—at the physician, patient, and system levels—may be the best way to improve the healthcare system so that it offers quality, value-based care. But such improve-

ments will likely cost a great deal of money. Although it is sometimes said that “you can’t solve a problem by throwing money at it,” in this instance, the roughly $1 billion— along with thoughtful, innovative leadership—may engender some significant problem solving. ■

References 1. O’Connor AB. Building comparative efficacy and tolerability into the FDA approval process. JAMA. 2010;303(10):979-980. 2. Alexander GC, Stafford RS. Does comparative effectiveness have a comparative edge? JAMA. 2009;301 (23):2488-2490. 3. Hochman M, McCormick D. Characteristics of published comparative effectiveness studies of medications. JAMA. 2010;303(10):951-958. 4. Holve E, Pittman P. A First Look at the Volume

and Cost of Comparative Effectiveness Research in the United States. Washington, DC: AcademyHealth; June 2009. 5. Sox HC, Helfand M, Grimshaw J, Dickersin K, the PLoS Medicine Editors, et al. Comparative effectiveness research: challenges for medical journals. PLoS Med. 2010;7(4):e1000269. doi:10.1371/journal.pmed. 1000269. 6. Okie S. Teaching physicians the price of care. The New York Times. May 4, 2010:D5.

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

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

Neulasta® should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. The use of Neulasta® has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C). In a placebo-controlled trial, bone pain occurred at a higher incidence in patients treated with Neulasta®, as compared to placebo-treated patients. The most common adverse events reported in either placebo- or active-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia.

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VBCC PERSPECTIVE

CER: Use, Controversy Both Growing By Denise K. Pierce

tiveness research (CER) was well under way, even if it was not specifically called comparative effectiveness. Humana’s recent Medical Coverage Policy for taxanes, for example, is an organizational-level initiative based

ven before enactment of national healthcare reform initiatives, development and implementation of a variety of comparative effec-

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. CONTRAINDICATIONS Neulasta is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ pegfilgrastim‚ Filgrastim, or any other component of the product. WARNINGS General The safety and efficacy of Neulasta for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Neulasta should not be used for PBPC mobilization. Splenic Rupture SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA AND ITS PARENT COMPOUND, FILGRASTIM. PATIENTS RECEIVING NEULASTA WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Neulasta, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Neulasta who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition. Allergic Reactions Allergic reactions to Neulasta, including anaphylaxis, skin rash, urticaria, and erythema/flushing have been reported in postmarketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta should be permanently discontinued in patients with serious allergic reactions. Sickle Cell Disorders Severe sickle cell crises have been associated with the use of Neulasta in patients with sickle cell disorders. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta for such patients, and only after careful consideration of the potential risks and benefits. PRECAUTIONS General Use With Chemotherapy and/or Radiation Therapy Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. The use of Neulasta has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C). The administration of Neulasta concomitantly with 5-fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did not adversely affect survival. The use of Neulasta has not been studied in patients receiving radiation therapy. Potential Effect on Malignant Cells Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.* Information for Patients Patients should be informed of the possible side effects of Neulasta and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta treatment, including regular monitoring of blood counts. If it is determined that a patient or caregiver can safely and effectively administer Neulasta (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta (pegfilgrastim) should be provided for patients and their caregivers, including careful review of the “Information for Patients and Caregivers” insert. Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes and needles should be available. Laboratory Monitoring To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended. Drug Interaction No formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils;

patients receiving lithium and Neulasta should have more frequent monitoring of neutrophil counts. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted. When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected. Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day. Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation. Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon assessment of fertility indices. There are no adequate and well-controlled studies in pregnant women. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised when Neulasta is administered to a nursing woman. Pediatric Use The safety and pharmacokinetics of Neulasta were studied in 37 pediatric patients with sarcoma. The mean (± Standard Deviation) systemic exposure (AUC0-inf) of Neulasta after subcutaneous administration at 100 mcg/kg was 22.0 (±13.1) mcg·hr/mL in the 6–11 years age group (n = 10), 29.3 (±23.2) mcg·hr/mL in the 12–21 years age group (n = 13) and 47.9 (±22.5) mcg·hr/mL in the youngest age group (0–5 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. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. 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. ADVERSE REACTIONS (See WARNINGS, Splenic Rupture, Acute Respiratory Distress Syndrome (ARDS), Allergic Reactions, and Sickle Cell Disorders.) Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Neulasta cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to Neulasta use and for approximating rates. The data described below reflect exposure to Neulasta in 932 patients. Neulasta was studied in placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The ethnicity of the patients was as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53]) or 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. In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta-treated patients as compared to placebo-treated patients. The incidence of other commonly reported adverse events were similar in the Neulasta- and placebo-treated patients, and were consistent with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflect those adverse events occurring in at least 10% of patients treated with Neulasta in the placebo-controlled study. Table 1. Adverse Events Occurring in ≥ 10%a of Patients in the Placebo-Controlled Study Event Alopecia Bone Painb Diarrhea Pyrexia (not including febrile neutropenia) Myalgia Headache Arthralgia Vomiting Asthenia Peripheral Edema Constipation

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Neulasta (n = 467) 48% 31% 29%

Placebo (n = 461) 47% 26% 28%

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Events occurring in ≥ 10% of Neulasta-treated patients and at a higher incidence as compared to placebo-treated patients Bone pain is limited to the specified adverse event term “bone pain”

In the active controlled studies, common adverse events occurred at similar rates and severities in both treatment arms (Neulasta, n = 465; Filgrastim, n = 331). These adverse experiences occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. Bone Pain The analysis of bone pain described below is based on a composite analysis using multiple, related, adverse event terms. In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta-treated patients compared to 50% in placebo-treated patients. Bone pain was generally reported to be of mild-to-moderate severity. Among patients experiencing bone pain, approximately 37% of Neulasta- and 31% of placebo-treated patients utilized non-narcotic analgesics and 10% of Neulasta- and 9% of placebo-treated patients utilized narcotic analgesics. In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with bone pain was similar between Neulasta- and Filgrastim treated patients. No patient withdrew from study due to bone pain. Laboratory Abnormalities In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. Leukocytosis was not associated with any adverse effects. 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 sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Cytopenias resulting from a neutralizing antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia. This has not been observed in clinical studies of Neulasta. Postmarketing Experience The following adverse reactions have been identified during postapproval 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. • splenic rupture (see WARNINGS: Splenic Rupture) • acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory Distress Syndrome) • allergic reactions (including anaphylaxis, skin rash, urticaria, erythema/flushing) (see WARNINGS: Allergic Reactions) • sickle cell crisis (see WARNINGS: Sickle Cell Disorders) • injection site pain • Sweet’s syndrome (acute febrile dermatosis) OVERDOSAGE The maximum amount of Neulasta that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum ANC of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 109/L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS). The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. No dosing adjustment is necessary for renal dysfunction. Neulasta should be visually inspected for discoloration and particulate matter before administration. Neulasta should not be administered if discoloration or particulates are observed. Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755, as well as other patents or patents pending. REFERENCE *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710-4718. v.10 Issue Date: 11/2008

on a comprehensive comparative clinical and cost review. The payer prefers documented failure to meet treatment goals or intolerance of conventional, generic paclitaxel (Taxol) prior to the use of other branded taxanes in most indications where taxanes are used.1 Regence BlueCross BlueShield, covering beneficiaries in Idaho, Oregon, Utah, and Washington, provides another example of a CER model with its Medication Cost Integration formulary, which premiered in February of this year. The innovation of this formulary is that it formally integrates medical and pharmacy benefits, assessing oral and injectable cancer drugs together. The resulting patient cost share levels are not established by whether the drug/biologic is accessed at the retail pharmacy or physician office, but rather by internal comparative research across a drug’s clinical, safety, and cost aspects. This VBCC Perspective refers to the article “From Dollars to Sense,” beginning on the cover.

WellPoint recently announced its own formal organizational-specific CER process, establishing an outcomes-based formulary.2 WellPoint has published distinct criteria of how formulary decisions are made, with consideration of clinical data sources ranging from randomized controlled trials to observational studies. Once efficacy for a product is established based on what WellPoint determines to be a high-quality randomized controlled trial, observational studies may then be considered as part of an overall review when those studies are “scientifically credible” and their potential biases have been minimized. The final evaluation will result in a rating of the data as “useful,” “possibly useful,” or “not useful.”3 In its criteria, WellPoint states that “a more expensive medication can be less expensive overall if the member’s health is improved, resulting in use of fewer healthcare resources.” Another possible form of comparative effectiveness is that for oncology clinical pathways. Pathways for breast, colorectal, and lung cancers have been in place in individual oncology practices and at commercial payers for the past several years, with the trend increasing for development of more pathways across additional tumor types such as lymphomas and Continued on page 30 Denise K. Pierce is president, DK Pierce & Associates, Inc, Zionsville, IN, and a member of the editorial board of Value-Based Cancer Care.

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Variant Methodology Impedes Cost-effectiveness Research By Jennifer Erickstad San Diego—Despite increasing interest in cost-effectiveness (CE) research, the groups conducting these analyses continue to use models that are very different from each other, hampering a more precise understanding of drug comparability. This is what a team of researchers from PAREXEL Consulting (Waltham, MA) found when they examined CE studies on the world’s highest-selling drugs. The team analyzed CE studies published in peer-reviewed journals between 1999 and 2008, seeking to understand CE trends of the 20 bestselling medications. For each analysis, they collected data on the com-

parator drug used, the indication, the incremental cost-effectiveness ratio (ICER), the time duration, and the type of model, among other characteristics. The researchers found a large variability in CE for the same drugs for different indications, as well as in the methodology used by groups when determining CE for the same indications. Specifically, different groups selected various comparator drugs, used distinct overall treatment costs in the calculation, and projected the costs over dissimilar time frames, which made it difficult to compare outcomes. Primary care drugs had less variability than specialty drugs. The findings were presented at the

Academy of Managed Care Pharmacy (AMCP) 22nd Annual Meeting. Lead researcher Saurabh Aggarwal, PhD, notes that improvements should be made to the US healthcare system’s ICER methodology. “Unlike single payer systems, such as the United Kingdom—which has in-house experts to evaluate manufacturers’ CE models—the US system’s several hundred payers each evaluate CE differently; our system would benefit immensely if organizations such as AMCP or ISPOR [International Society for Pharmacoeconomics and Outcomes Research] would develop standards for building CE models,” he said. According to Jim Smeeding, RPh, MBA, president of the Jestarx Group and former

Saurabh Aggarwal, PhD ISPOR president, ISPOR “continues to examine ideas such as CE modeling and has begun to develop a task force to further investigate this issue.” ■

Managed Care Pharmacist Boosts Drug Replacement, Reimbursement By Jennifer Erickstad San Diego—Enlisting the services of a managed care pharmacist may help hospitals increase their reimbursement for chemotherapy agents, according to researchers from the University of Southern California’s Norris Cancer Hospital (NCH). Presenting the findings at the annual meeting of the AMCP, lead researcher Shetal Desai, PharmD, discussed how NCH decreased the number of disputed claims and recovered more than $1 million in drug replacement from manufacturer patient-assistance programs across 18 months after bringing a managed care pharmacist on board. Specifically, Dr Desai examined the hospital’s process and identified several problems that were leading to disputed claims and lower reimbursement, including: • Physician chemotherapy orders

were not always sent for prior authorization • The hospital lacked an authorization department that was staffed with clinical personnel who could best respond to payers’ queries and requests for clinical trial information • There was no centralized department that coordinated patient enrollment in manufacturer-sponsored assistance programs. In response to these findings, Dr Desai developed a clinically staffed chemotherapy authorization department which included a pharmacist, pharmacy techs, and nurses. In addition, she implemented PyxisConnect technology, which allows for realtime order scanning that is directly routed to authorization staff. Dr Desai also enrolled patients with indications not US Food and Drug Administration approved into patient-assistance programs.

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According to Michael Andreski, RPh, PhD, assistant professor of Clinical and Administrative Pharmacy at Drake University College of Pharmacy and Health Sciences, the findings “once again demonstrate the value of

timely pharmacist intervention in the medication use process.” He adds that the results “should stimulate similar efforts at other institutions that are greatly needed in our cost-conscious practice environment.” ■

Patients More Likely to Abandon Drug Therapy When Paying More Out of Pocket By Jennifer Erickstad San Diego—For health plans attempting to cut costs, instituting higher out-of-pocket (OOP) payments for patients taking oral oncology drugs may not be a prudent solution, according to research presented at the AMCP’s annual meeting. In a poster presentation at the meeting, researchers from Prime Therapeutics (Eagan, MN) revealed that when handed an OOP payment above a certain threshold, patients were 3 times as likely to abandon their initial drug therapy. The researchers examined a database of 7 million Blue Cross and Blue Shield members from the Midwest and South who were newly prescribed an oral oncology medication between July 2006 and June 2008. After reviewing members’ claims, the researchers placed them into 4 OOP expense groups—$0 to $100, $101 to $200, $201 to $500, and greater than $500. They then calculated the percentage in each group that abandoned therapy. The research team found that during the selected time frame, 1909 members began treatment with oral oncology drugs and 163 of them

(8.5%) abandoned therapy. Although most of the patients (1562 [81.8%]) had an OOP expense of $0 to $100, those with an OOP expense of $200 or more were 3 times more likely to abandon therapy than patients in the lower 2 groups. Neither age nor gender was associated with the likelihood of abandonment. According to lead researcher Catherine Starner, PharmD, BCPS, CGP, health plans should consider the study findings when determining their pharmacy benefits and should especially think about instituting a maximum OOP member expense per claim. “Patients who do not adhere to their medication regimen are at risk for serious medical and health complications, which could result in substantial medical or hospitalization expenses for both the patient and insurer,” Dr Starner said. Chyongchiou Jeng Lin, PhD, an associate professor of Health Economics in the Department of Family Medicine at the University of Pittsburgh who was not affiliated with the study, adds that the study is especially important given the large number of cancer patients prescribed oral oncology medications. ■

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AMCP ANNUAL MEETING

Survey Provides a Window Into Payers’ Decision-Making Process By Jennifer Erickstad San Diego—Payers believe that prescribing information, national guidelines, and prospective controlled randomized trials (PCRTs) are the most useful sources of information about oncology drugs, according to researchers from Genentech, Inc (South San Francisco). Presenting their findings at the Academy of Managed Care Pharmacy’s annual conference, lead researcher Ellen Yang, PharmD, noted that the study’s conclusions may help manufacturers more easily meet the evidentiary needs of payers while remaining within regulatory and legal boundaries. The study consisted of a 22-item electronic survey that questioned payers on their oncology drug review

process and the types of evidence they use when making formulary, coverage, and reimbursement decisions. The overall response rate was 15%. Of those who responded, 79% managed oral cancer drugs, and 52% managed intravenous therapies; 83% were pharmacists. Survey results showed that 83% said prescribing information was “useful” or “very useful,” followed by national treatment guidelines (80%), and PCRTs (76%). Economic models fell at the bottom of the list (13%), along with noncontrolled trials/retrospective studies (13%), and published pharmacoeconomic studies (17%). Approximately three-fourths of survey respondents noted that they value AMCP dossiers and reprints of study articles from peer-reviewed journals.

Researchers Analyze Relationship Between Pharmacogenomics and Appropriate Oncology Care By Jennifer Erickstad San Diego—Pharmacogenomic (PGx) testing seeks to optimize treatment by ensuring patients receive the bestsuited drug based on interindividual genetic variation. Currently, no published data exist on how this may influence the appropriateness of oncology treatment within a utilization management program. Seeking to remedy this, researchers from CVS Caremark (Northbrook, IL) analyzed data from their own utilization management program, within which PGx testing requirements are implemented for certain oncology therapies and specific indications. After gathering data on all of the patient assessments that required PGx testing between July 1, 2009, and December 31, 2009, the researchers categorized them into 3 groups: PGx performed and patient met criteria, PGx performed and patient did not meet criteria, and PGx not performed and patient did not meet criteria. They found that of the 801 total assessments, 424 required PGx; in 98% of these (417), the test was actually conducted. According to lead researcher Sherry Siegert, PharmD, the fact that such a “very high” percentage of patients received PGx testing when it was required “may indicate that most oncologists are prescribing in accordance with currently accepted guidelines for cancer care.” In addition,

Iris Tam, PharmD, and Ellen Yang, PharmD Although the sample size was small, Dr Yang believes the findings still provide valuable information for manufacturers looking to optimize their communication with payers. According to Peter Neumann, ScD, director of the Center for the Evaluation of Value and Risk in

Health at Tufts New England Medical Center, the survey “underscores that payers are looking at multiple sources for evidence on the clinical effectiveness of oncology drugs and that they value rigorous design and independently conducted or verified analyses.” ■

Pemetrexed as Maintenance Therapy Likely to Have ‘Minimal Impact’ on Health Plan Budget By Jennifer Erickstad

Sherry Siegert, PharmD although she acknowledges that the study’s small sample size and short duration impeded the team from developing a complete picture of agent utilization, she adds that payers can still use certain practices to support therapy appropriateness, including requesting copies of PGx test results and ensuring the laboratory quality of such tests meets standard requirements for clinical and analytical validity. Researcher M. Eileen Dolan, PhD, professor of medicine and chair of the Committee on Clinical Pharmacology and Pharmacogenomics at the University of Chicago, notes that utilizing pharmacogenomics is “particularly important to reduce the likelihood that patients will receive an ineffective drug while enduring side effects that can be severe, possibly even life-threatening.” ■

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San Diego—In the first study to estimate the budgetary impact of accepting pemetrexed as maintenance therapy for non–small-cell lung cancer (NSCLC), researchers found that adopting the drug did not significantly affect a health plan’s budget. Using a model designed to represent a 1 million–member health plan over a 1 year time frame, the research team—consisting of members from the consulting firm Medical Decision Modeling and Eli Lilly—input a series of variables, including: • the estimated market shares of several maintenance therapies before and after the introduction of pemetrexed • chemotherapy drug costs (obtained from Medicare reimbursement rates) • nondrug treatment costs (derived from a claims database of patients with lung cancer) • the number of NSCLC patients eligible for maintenance therapy (based on Surveillance, Epidemiology, and End Results data). The model showed that, assuming a 50% increase in the number of

patients receiving maintenance therapy as a result of the adoption of pemetrexed, the total annual cost increase would be $365 323. However, considering savings from patients who would switch to maintenance therapy from more expensive first-line therapy, the net budget impact would be $317 070. This translated to a cost of $679.22 per treated member per month and a per member per month cost (PMPM) of $0.026. The team concluded that only large increases in the number of maintenance patients would likely cause PMPM costs to rise by more than 3 cents. According to lead study author Robert Klein, the findings provide “valuable information to consider in evaluating treatment options available to plan members.” Outcomes researcher Bruce Hillner, a professor and associate chair of Information Sciences in the Department of Internal Medicine at Virginia Commonwealth University who was not affiliated with the study, notes that anchoring future research in data from health plan audits will improve the understanding of pemetrexed’s impact on health plan budgets. ■

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IMPAKT BREAST CANCER CONFERENCE

Better Targeting for Targeted Therapy By Colin Gittens Brussels—Researchers attempting to understand why some women with human epidermal growth factor receptor 2 (HER2)–positive breast cancer do not respond to drugs designed to target this molecule have found that inhibiting the PI3K/AKT molecular pathway instead may offer greater therapeutic benefit for this group. The findings were presented at the IMPAKT [Improving Care and Knowledge Through Translational Research] Breast Cancer Conference, held May 5-8. The overexpression of HER2 is an important marker in breast cancer, and it has been associated with a poor outcome for women. The advent of anti-HER2 targeted agents has im-

proved the prognosis for these women. Even so, oncologists have known for some time that some HER2+ breast cancers do not respond to trastuzumab (Herceptin, Genentech), currently the most commonly prescribed anti-HER2 agent. A United States/Belgian research team, led by Sherene Loi, MD, PhD, from the Institute Jules Bordet in Brussels, examined whether and how estrogen receptor (ER) status was involved in the biology of HER2+ breast cancer and response to anti-HER2 therapies. In a press release describing the study, Dr Loi detailed the approach, saying, “We looked at HER2+ breast cancer using gene expression data, array comparative genomic hybridization, cell lines, and clinical data

Genetic Testing as Simple as 1-2-3 By Colin Gittens Brussels—A simple genetic test using only 3 genes is among the most effective means of classifying breast cancer into the subtypes that indicate patients’ different prognoses and response or resistance to cancer therapies, say researchers, and this finding could allow greater use of personalized treatments in breast cancer. Breast cancer is not a single, biologically homogeneous disease but rather is composed of several molecular subtypes, each of which is characterized by distinct gene expression profiles. Several research groups have already developed a range of different genomic “fingerprints” they use to assign breast cancers into different subtypes, but questions have been raised about the reliability of these classifications.

“There is an urgent need for guidance for classifying breast cancer molecular subtypes.” Lead author Benjamin HaibeKains, PhD, a research fellow in the department of Biostatistics at the Dana-Farber Cancer Institute, described the statistical analysis comparing breast cancer subtypes, which analyzed 32 publicly available gene expression datasets, including more than 4600 breast cancer patients and 6 different classification models. He presented these findings at the IMPAKT Breast Cancer Conference.

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The research team compared 2 types of classification models—the single sample predictor (SSP) and subtype classification models (SCM) —each of which anaBenjamin lyzes different Haibe-Kains, PhD genes to assign breast cancer subtypes. In a press release, Dr Haibe-Kains described the research parameters: “We studied these models in terms of concordance and prognostic value and, for the first time, we estimated their robustness: that is, their capacity to assign the same tumors to the same molecular subtypes whatever the gene expression data used to fit this model. “Generally speaking, we found that SCMs yielded stronger concordance than SSPs,” Dr Haibe-Kains said, and his team observed that SCMGENE, an SCM that used only 3 genes—ESR1, ERBB2, and AURKA—was significantly more robust than SSPs. “The robustness of SCMs,” he concluded, “makes them promising candidates for an implementation into the clinic especially in the simplest form—that is, a model using only 3 genes.” There is an urgent need for such a tool “to provide clinicians with guidance for classifying breast cancer molecular subtypes, which could… aid in making therapeutic decisions.” This work has not yet been submitted to a peer-reveiwed journal. ■

from nearly 2000 patients.” What they found was that the “estrogen receptor status of HER2+ breast cancer seems to be correlated with different responses to anti-HER therapies. Currently, the biological differences in the group of breast cancers that overexpress HER2 are largely unknown.” The PI3K/AKT molecular pathway may be the dominant biological pathway for tumor growth and progression, say the authors, and so patients with ER+/HER2+ breast cancers (rather than ER-/HER2+ variety) may be better treated with drugs impacting this pathway. “Our data suggest that inhibition of estrogen receptor—alone and in combination with such an inhibitor— could actually result in a worse outcome for the patient,” Dr Loi added. ■

“Estrogen receptor status of HER2+ breast cancer seems to be correlated with different responses to anti-HER therapies.” —Sherene Loi, MD, PhD

Circulating Tumor Cells Signal Worse Survival By Colin Gittens Brussels—A retrospective study of patients with metastatic breast cancer shows that the number of circulating tumor cells in the patient’s bloodstream prognosticates the length of their survival, information that can be used to adjust treatment at the end of life. A team of researchers, including Antonio Giordano, MD, conducted this research using computer modeling known as an artificial neural network, which was developed at the University of Naples Federico II, Italy, and presented the findings at the IMPAKT Breast Cancer Conference. The team used the neural network to assess the relationship between increasing numbers of circulating tumor cells and survival for different subgroups of breast cancer. It has been known for the last several years that patients with 5 or more circulating tumor cells in 7.5 mL of blood survive on average for less time than those with fewer than 5 cells, and this current study attempted to refine this prognostic test. Dr Giordano and colleagues analyzed 516 consecutive metastatic breast cancer patients at M. D. Anderson Cancer Center, and he discussed the team’s findings in a press release. “We found that there was a linear

relationship between the number of circulating tumor cells and the risk of death in patients with metastatic breast cancer,” Dr Giordano said, and “most importantly, the risk of death after 1 year for patients with 40 circulating tumor cells in 7.5 mL of blood was about twice that for patients with none.

Monitoring of circulating tumor cell numbers should now be considered a standard test for patients with metastatic breast cancer. “These results show that the simple cutoff number of 5 circulating tumor cells probably does not adequately represent the complexity of this prognostic variable,” Dr Giordano elaborated. Regarding how this might impact clinical practice, Dr Giordano suggested that monitoring circulating tumor cell numbers should now be considered a standard test for patients with metastatic breast cancer. Although “the treatment of this condition remains palliative, monitoring of circulating tumor cells can help determine when to modify regimens or discontinue therapy,” he argued. “In other words, this can improve the delivery of personalized therapy.” ■

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New Jersey Hematology and Oncology Center Partners with OncoMed Bayonne, NJ—As demand for their services grew and it became increasingly clear that their practice was becoming a regional center for patients battling cancer, the medical staff at Colanta Hematology & Oncology Center made the decision to build and open an outpatient infusion center that could adequately and comfortably serve their patients. The result was a state-of-the-art infusion center with 20 recliners in a patientfocused environment that is open to serve patients 7 days a week. The medical staff of 3 physicians and 4 nurses, led by practice administrator Romel Colanta, MD, now delivers a broad array of outpatient oncology services, including chemotherapy, albumin, antiemetic, and iron therapy infusions. Additionally, the infusion center staff provides supportive cancer care services, including therapeutic phlebotomy, antibiotic infusion, and electrolyte replacement. They also provide multidisciplinary infusion services for patients referred to the center by gastroenterologists, neurologists, and infectious disease specialists. With the high volume of oncology drugs required to treat their patient panel, the medical staff at Colanta had to make the decision as to how they would supply their patients with oncology medications. If they followed the traditional practice of hematology and oncology providers, they would “buy and bill” the

medications, meaning they would have the responsibility of sourcing and purchasing the medications, storing them, preparing and sometimes compounding them for patients, managing the inventory on an ongoing basis, and dealing with a bevy of insurance prior authorization and reimbursement procedures and requirements in order to get paid.

“The partnership with OncoMed has enabled us to make better use of our capital.” —Romel Colanta, MD Practice Administrator Colanta Hematology & Oncology Center

Although buy and bill traditionally had its benefits, including a substantial margin paid by Medicare and other commercial payers, changes that resulted from the Medicare Modernization Act lowered a margin that sometimes paid physicians 40% over the cost of the drug to just 6%. The Colanta team decided there was a better way. They knew they could outsource the pharmacy function to a pharmacy that was highly specialized in oncology medications. This pharmacy would prepare the drugs under the high-

The outpatient infusion center at Colanta Hematology & Oncology Center comfortably serves patients.

est clinical standards, deliver them just in time for treatment day (thereby eliminating waste), handle all the hassles of insurance prior authorization and reimbursement, and free the center from the challenges of safely storing and dispensing the drugs and the huge, capitalintensive “carry costs” that maintaining such an inventory requires.

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Dr Colanta and his colleagues researched their options and chose OncoMed—The Oncology Pharmacy. OncoMed is an oncology pharmacy, meaning that its sole business is oncology medications. Its specially trained and certified oncology pharmacists work in a technologically advanced pharmacy built exclusively for oncology pharmaceutical prescription processing and dispensing, including a USP <797>-compliant class 5 clean room. To protect the supply chain and ensure a complete and full drug pedigree, all inventories are purchased directly from pharmaceutical manufacturers. The company’s “just-intime treatment-day” service means that oncologists and hematologists in any state in the nation are guaranteed delivery of medications and all therapyspecific administration supplies within 24 hours of placing the order. Given the Colanta Hematology & Oncology Center’s close proximity to one of OncoMed’s regional oncology pharmacy sites, they were eligible to get same day and even emergency stat dose delivery when needed. But what also set OncoMed apart from specialty pharmacies that concentrate on more than one class of pharmaceuticals is the OncoMed care management support team’s ability to work with insurers to get the authorizations that the Colanta Hematology & Oncology Center’s patients need. OncoMed’s team includes

patient care navigators and patient reimbursement specialists who have extensive experience working with insurers, oncology drug manufacturers, and medical foundations. These specialists always know where to go to search for needed funding for patients who are banking on that expertise for their recovery. OncoMed has become a pivotal partner to the Colanta Hematology & Oncology Center by owning the pharmaceutical worry and letting the physicians focus solely on guiding their patients to remission. We sat down with Dr Colanta and asked him about the new center and its partnership with OncoMed. Why did your infusion center choose to partner with OncoMed? The buy-and-bill model that oncologists have always worked under is no longer viable. Physicians can’t make an office run on a 6% margin. Under buy and bill, the average sales price (ASP) + 6% methodology can very quickly go to ASP + 4%, +2%, or -2% if we run into any obstacles in getting reimbursed. And with expensive drugs like chemotherapy, we cannot take that risk. Plus, OncoMed helps patients get funding for medication even after the patient’s insurer has denied coverage. In addition to this new center, you now have 2 additional sites in New Jersey. How has the partnership with OncoMed enabled you to successfully launch and grow the center? When we opened, 90% of what we infused in the clinic was oncolytics. As we have grown, we infuse a far broader array of medications. The backbone of our practice is still chemotherapy, but we have increased our nononcolytic infusions. For patients referred by gastrointestinal practitioners, we infuse infliximab, and for those referred by infectious disease physicians, we provide antibiotic infusions. Some of those drugs are still viable [under buy and bill], but not all. We have been able to devote money that has traditionally gone to purchasing medication and instead expand our services. The partnership with OncoMed has enabled us to make better use of our capital. Continued on next page

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EVOLUTION IN ONCOLOGY PRACTICE MANAGEMENT™ Continued from page 22

How does the medication ordering and fulfillment process work with OncoMed? Having an efficient and focused process in place is very important. We have been able to institute a process where we have someone devoted to being our liaison with OncoMed. When a patient comes in and his or her benefits are precertified, we send the person’s case information to OncoMed, and the drugs are sent to us directly, along with all the administration supplies. We get them on a next-day basis, or sooner if needed, and everything is clearly labeled with patient-specific information. That makes a huge difference to us when dealing with OncoMed versus some specialty pharmacies that some insurers have imposed upon us to use, which get the drugs wrong, ship them late, and have no idea of the correct administration supplies. How does the relationship with OncoMed allow you and your team to

focus on what is important? I will give you a “before-and-after” example. Before we worked with OncoMed, 50% or more of our time was spent on managing drug costs and reimbursement. We had 5 people managing pharmacy at the 3 locations; we have been able to reduce that number of employees to 1. Before, we had to continually make sure that we were not underwater on drugs, as reimbursement rates and times fluctuated. OncoMed has made it possible to not devote time and effort on that. Based on your experience, what would you say about OncoMed to hematologists and oncologists considering such a move? It is definitely a relationship that every infusion center or oncologist has to explore. When dealing with narrowing reimbursement margins and delayed reimbursement, ultimately it will be beneficial to switch to OncoMed. ◆

Pharmacists filling orders at the OncoMed facility.

THE LEADERSHIP OF ONCOMED – THE ONCOLOGY PHARMACY

Burt Zweigenhaft CEO, OncoMed

Kevin Askari, RPh President and Chief Clinical Pharmacist OncoMed

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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.

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Linked Databases, Health IT, and Informatics... of Comparative Effectiveness, Health IT and Personalized Medicine. “Oncology demands science. Right now, it feels like cancer research and our engine for research is being distracted by CER, but when put into context, the importance of CER for cancer emerges,” she said. Although the purpose of CER is to assist consumers, clinicians, and payers in treatment decisions, oncology presents a special challenge because of the wide extent of off-label use of drugs. “Off-label prescribing is critical in oncology,” Dr Abernethy suggested, since this is “where effective treatment options are often limited, where the prognosis is dire, and there are many potential uses for any given drug and it’s really pretty much impractical to submit an FDA application for every drug-disease combination. As a doctor, biological plausibility and the potential for emerging evidence that would support the use of a drug for a disease means that I am pretty likely to write a script.” That likelihood has real-world implications. “It is estimated that 50% to 75% of all anticancer prescriptions are actually off-label. This is a big deal,” she said.

“Right now, it feels like cancer research and our engine for research is being distracted by CER, but when put into context, the importance of CER for cancer emerges.” —Amy Abernethy, MD Legislation dating back to 1993 ensures Medicare reimbursement for off-label use of oncology drugs “provided there is authoritative recommendation for use in the compendium,” Dr Abernethy noted. But an Agency for Healthcare Research and Quality–funded review found that the compendia cited little of the available evidence when recommending an offlabel indication and that the methodological quality of the studies was often poor. In addition, the pace of accumulation of evidence within the context of complex cancer care makes thoughtful evaluation difficult. “How can we be confident that we are providing effective treatments?” she asked. “We need value in cancer care.” Although clinical trials are the gold standard for effectiveness, they “are typically narrowly focused and can be too short in duration to capture cer-

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“We want to see to it that the cancer community has the capacity to be wired into this broader national framework.” —Ken Buetow, PhD tain important outcomes, such as overall survival,” Dr Abernethy said. “CER focuses on populations but may not provide insight for the best care of individuals. In oncology, we take care of individuals.” Because “no single study design answers all the questions,” CER must draw from a broad methods’ portfolio, she said. The Institute of Medicine has identified cancer as the prototype for a “rapid learning healthcare approach.” With this, “data collected during routine patient care is fed into an evergrowing, coordinated set of databases,” Dr Abernethy outlined. The system learns by routinely analyzing captured information, integrating it, generating new evidence, and constantly tailoring new insights into personalized care. “Critical to this process is linked information,” she said. “In rapid learning, the care of this individual patient is informed by all the people who came before her, and her care is reinvested into the data stream to contribute to the care of similar individuals in the future.” A first step in developing rapid learning is to leverage information in existing databases, such as patient registries. “We want to promote a method of CER that conserves clinical trial resources for important, prioritized clinical questions. We want to use databases and data mining to explore real-world effectiveness, transfer clinical trials data to populations, and highlight compelling new hypotheses to subsequent study,”

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Dr Abernethy said. “Rapid learning healthcare will contribute continuous real-time knowledge to understand what works for whom and when.” Build It and They Will Share An estimated $48 billion will be spent over the next 4 years on largescale activities to create a national infrastructure for healthcare IT, Ken Buetow, PhD, National Cancer Institute (NCI) associate director for Biomedical Informatics and Information Technology, told the session. The efforts “dwarf anything we would be doing in the NCI related to health information technology,” he said. “However, it is important to note that the current strategies largely are divorced and disconnected from the broader research framework” and have little consideration for how “to

Just Ask: Addressing Patient Data Sharing and Confidentiality A striking example of the relative ease with which motivated patients and the public will share personal and health information is the more than 300 000-strong Love/Avon Army of Women, which hopes to grow its ranks to a million who will aid in the fight against breast cancer. Just 1 e-mail from Dr Buetow resulted in 10000 respondents who filled out an online survey about women’s health within 10 days.

bring all this information together and to support all these invaluable uses of information that will be in the system.” Dr Buetow continued, saying “the primary infrastructure that is being constructed is around primary care delivery in the context of individual physician offices, with very little knowledge or interest in how…to go about interconnecting all of this information so that the whole can be more than the sum of the parts.” Dr Buetow sees a unique opportunity for cancer researchers and providers to lead in healthcare IT. “We want to see to it that the cancer community has the capacity to be wired into this broader national framework, but more importantly, that we will be an example for how we can interconnect and use this information in powerful and meaningful ways.” Led by the American Society of Clinical Oncology, NCI has been working on the creation of “smart” electronic health records (EHRs). The records use a common structural organization so that provider data “is in the same form as data we use in clinical trials research,” Dr Buetow pointed out. Such standards are important to facilitate information sharing by all users. Community physicians are “hungry in terms of what we can give them” in the best science tools and infrastructure. “They really want to be part of that framework” and have access to state-of-theart treatments, protocols, and tools to see how patients are performing. The EHRs are part of the Institute's Cancer Biomedical Informatics Grid and will enable collection of cancer diagnostic and staging information, treatment plans, and patient outcomes in the care setting. Clinical information can be fed into an electronic clinical report form as well as personal health records for use by consumers. Web-based tools will allow consumers and patients to record their personal information and treatment responses. Data on patient encounters can be fed into a patient outcomes resource that can help physicians individualize care, aid patients in understanding their options, and enable researchers to query data. In order to protect confidentiality, information would be stripped of common identifiers. Information collection “could also be done in a manner in which people are consciously providing data,” he said. “The patient can be incredibly important to drive the next generation of studies.” ■

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$3 Million to Toss a Life Ring? Has monopoly pricing gone too far? By Patricia Williams Washington, DC—Three million dollars to toss a life ring? That’s what the pharmaceutical industry would charge, the director of Medical Ethics at Harvard’s School of Medicine suggested at the 101st Annual Meeting of the American Association for Cancer Research (AACR), held April 17-21 in Washington, DC. “You are drowning and will live 30 more years if I throw you a life ring. Can I charge you $100 000 per QALY (quality-adjusted life-year)—$3 million?” asked Dan Brock, PhD. “The size of the benefit does not tell us the cost,” he said. “Pharma can set any price it wants and believes it can get.” Dr Brock and other speakers at the special session on Clinical Cancer Research as an Engine for Improving Patient Care—But at What Cost? expressed serious concerns about the impact of monopoly pricing by the pharmaceutical industry and skyrocketing costs for cancer treatments in the absence of significant gains in survival and outcome. “Progress in the therapy of cancer continues to be incremental,” said Antonio Fojo, MD, PhD, head of the Experimental Therapeutics Section in the Medical Oncology Branch at the National Cancer Institute. “Unfortunately, drug costs are not incremental.” Rising Costs, Affordability, and the Question of Benefit All but one of the 10 most expensive drugs in the United States are for cancer, said Thomas Smith, MD, professor and chairman of Hematology/ Oncology and Palliative Care at the Virginia Commonwealth University (VCU) Massey Cancer Center. Most new cancer drugs cost between $6000 and $10000 per month, with some therapies reaching the $20 000 per month range, but there is little difference in overall survival between them, he indicated. The cost of new therapies for breast and colorectal cancer has increased more than 100 times in the past decade, but the improvement in overall survival is less than 1%, said Dr Smith. The United States spends twice as much as any other country on cancer but has the same survival for most diseases, he said. Avastin “does not ‘rescue’ the dying cancer patient,” Dr Brock emphasized. Its use for breast or lung cancer

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costs between $200 000 and $300 000 per QALY and is not covered by the National Health Service in Britain, he noted, where the company didn’t even provide data for it to be considered by that organization. “The bar for what we call significant has fallen,” said Dr Fojo. “If Avastin and cetuximab are an important part of the therapeutic armamentarium 7 years from now, we have failed miserably.”

be difficult to achieve because of Congress’ reluctance to pass measures that could be seen as rationing care. Restricting active therapy to patients with a high performance status can curb costs, suggested Dr Smith, as can limiting therapies with no chance for cure and limited benefit (eg, fourth-line chemo). “Most people can learn that they cannot be cured,” he said, noting a VCU study that

“If Avastin and cetuximab are an important part of the therapeutic armamentarium 7 years from now, we have failed miserably.” —Antonio Fojo, MD, PhD Insurance costs have doubled in the past 8 years, meaning fewer people can afford these new treatments, Dr Smith pointed out. “One other distressing thing here ethically is the new tier that has been added to health insurance,” said Dr Brock. New fourth tier policies require a percentage copay, meaning that a 20% copay for a drug with an annual cost of $100 000 results in a $20 000 outlay that many patients cannot afford. Such an approach is based not on value but ability to pay. Treatment decision makers have little incentive to weigh true costs against benefits, Dr Brock said. Most cancer patients have insurance and are concerned only with out-of-pocket costs, and some oncologists receive substantial income from using new drugs for patients. Dr Brock asserted that the US Food and Drug Administration (FDA) approved some new uses in the absence of any evidence of clinical benefit and believes this is a step in the wrong direction for value in cancer care. “We need a willingness to ration even ‘last chance’ care at the end of life” and to not cover very high-cost, marginal interventions, he said, but he also acknowledged that such a move will probably not come without a national healthcare system. Short of this, covering last-chance therapies only in clinical trials or for registry patients and authorizing the Centers for Medicare & Medicaid Services (CMS) to negotiate drug prices may be solutions. Although the CMS is explicitly prohibited from negotiating prices, “this may change,” Dr Brock ventured. A much larger step would be transforming the new comparative effectiveness program to a cost-effectiveness program. Dr Brock acknowledged that this may

observed no distress in 27 such truthful patient education sessions. Fears of abandonment can be reduced with better, less costly end-of-life care such as hospice. “It’s not going to be easy to discuss costs” with patients, Dr Smith warned, noting that physicians only discuss prognosis with patients about 39% of the time. “We have to get past the hurdle of being able to give people bad information about their disease and do it without damaging them” before discussing costs. Instilling Efficiency in the Process Physicians drive care costs by what they do and don’t do, with many oncologists choosing the chemo that makes the most profit for the practice and giving too much chemo near the end of life to little benefit, Dr Smith suggested. “Without chemo and supportive drug profits, oncology is a poorly paid, difficult specialty,” he said. Any solution will require realtime monitoring of physician performance and new payment models. He also called for more scrutiny of physician-owned labs, radiology, and infusion services. Dr Smith suggests getting rid of “routine” tests whose use is not supported by evidence, and said patients can be convinced they don’t need tests through discussions that a specific test doesn’t work. “Clinical treatment and development of new treatments are inefficient,” said David Parkinson, MD, a former Tufts University clinical researcher and current CEO of Nodality, a biotechnology company developing biological characterization tests to aid in clinical decision making and drug development. Rational, “efficient” treatment requires a biological understanding of

malignancy, development of targeted therapeutics, and biological characterization of individual patients, he said. Providers continue to classify tumors on the basis of morphology and size although “it is becoming increasingly clear we see enormous biological diversity” in patients. “We have a lot to learn from car mechanics,” he said as he displayed a slide of a parking lot full of cars, every one of which has something wrong. “A mechanic would lift the hood, diagnose it, and give an individual car a specific therapy. He would not treat red cars all the same way and silver cars all the same way.” It “is necessary for us as a community to redefine malignant disease.” Development of targeted therapies “is one thing industry can do very well. The missing element is rational ‘efficient’ treatment,” he said. There is still a lack of tools for biologically driven therapies and tests validated for real-world use.

“You are drowning and will live 30 more years if I throw you a life ring. Can I charge you $100 000 per QALY— $3 million?” —Dan Brock, PhD Dr Parkinson described cultural and regulatory hurdles that must be overcome in order to achieve biologydriven clinical decision making. Diagnostic test reimbursement is “a disaster,” summarized Dr Parkinson, with uninformative lab tests and inefficient therapeutics application wasting valuable healthcare dollars. Scientific culture focuses more on publishing papers than producing real-world products, he said, with “more biomarker meetings than there are biomarkers.” In recent years, “the FDA has been so under-resourced [and] they are just now getting resources to look at this field.” The agency has clearly indicated it is moving to regulate, a move he thinks is “quite appropriate.” ■

Free AACR Webcasts and Podcasts Online More than 80 hours of selected AACR Annual Meeting talks are available as free online webcasts. Visit www.aacr.org.

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An Early Look at New Drugs on the Horizon By Patricia Williams Washington, DC—A first look at new cancer therapies was the focus of the 6th annual New Drugs on the Horizon symposium held as a special session at the American Association for Cancer Research (AACR) annual meeting. These new agents are still in development or the early stages of clinical testing in humans, but researchers believe their targeted mechanisms of action may lead to more effective therapies for a variety of cancers. TAK-700 A 17,20-lyase inhibitor Preliminary phase 1 clinical trial results in 27 patients with metastatic castration-resistant prostate cancer (CRPC) are encouraging, Masuo Yamaoka, associate director of Pharmacology Research, Takeda Pharmaceutical Company Limited, Japan, told the session. Most cases of prostate cancer initially respond well to hormone therapy, but resistance can develop rapidly, leading to CRPC. Treatment options are limited and chemotherapy with docetaxel is often associated with serious adverse effects, he said. Prostate cancer is an androgen-sensitive disease. TAK-700 was selected for its ability to inhibit 17,20-lyase, a key enzyme in androgen synthesis. Preclinical trials of TAK-700 in monkeys (both castrated and intact) showed the agent rapidly (within 1 day) inhibited androgen levels in the blood as well as testosterone and cortisol. Phase 1 human testing found that patients treated with ≥300 mg TAK700 twice daily had a decrease in prostate-specific antigen (PSA). The agent was well tolerated and there were no dose-limiting toxicities. The safety and efficacy of TAK-700 and the use of concomitant prednisone are being further assessed in the phase 2 portion of the study, Dr Yamaoka reported. MEHD7945A A 2-in-1 antibody Genentech’s 2-in-1 antibody is designed to target epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), members of the epidermal growth factor receptor family that play an important role in tumorigenesis. Numerous antibodies and tyro-

sine kinase inhibitors (TKIs) are commercially available against EGFR but not for HER3, which has impaired kinase activity. This third member of the family is also implicated in cancer and is a target for drug development, said Gabriele Schaefer, a scientist at the biotechnology company. Blocking more than 1 of the receptors may be more effective in treating cancer or preventing the development of drug resistance. Dr Schaefer and her colleagues generated a “2-in1” antibody capable of binding HER3 and EGFR with high affinity. Preclinical studies show that the antibody blocked signaling pathways in various cancer cell lines and was effective in squamous cell carcinomas of the head and neck, non–small-cell lung, colorectal, and pancreatic cancers. The 2-in-1 antibody was more effective than monospecific antibodies against the HER family. The HER2 receptor is well known for its role in very aggressive breast cancer. HER3 plays a critical role in HER2 and EGFR-driven tumors and “is in the spotlight now” because it has been shown to mediate drug resistance, she said. Tumor model studies show that MEHD7945A may be more potent than monospecific antibodies and may even be effective in some tumor types that do not respond to existing EGFR-targeting therapies. A pilot safety study in cynomolgus monkeys comparing MEHD7945A to cetuximab administered every week for 6 weeks showed a delayed onset, lower incidence, and reduced severity of skin rash compared to cetuximab. “MEHD7945A is well tolerated” Dr Schaefer told Value-Based Cancer Care. “We also did not see any new toxicities related to MEHD7945A treatment.” NMS-1116354 More than a Cdc7 kinase inhibitor This agent has antitumor activity in solid and hematologic cancer models, has good oral availability, is synergistic in combination with other approved drugs, and is currently in phase 1 studies. Preclinical studies show that NMS-1116354’s unique mechanism of action makes it active on cell lines that are resistant to conventional chemotherapeutic agents, including cisplatin, Francesco Colotta, MD, PhD, vice president of Nerviano Medical Sciences in Nerviano, Italy,

VALUE-BASED CANCER CARE

June 2010

told the session. Most widely used anticancer drugs target the elongation step of DNA synthesis, which invariably results in a DNA damage response. NMS1116354 targets the initiation step of DNA replication to avoid a DNA damage response. The agent induces apoptosis in cancer cells but does not induce cell death in normal fibroblasts, he said. NMS-1116354 inhibits Cdc7 kinase, which “is involved in at least 2 key cellular processes which are relevant to cancer,” said Dr Colotta—initiation of DNA synthesis and the DNA damage response. It also downregulates Mcl-1, a protein that cancer cells depend on for survival. Mcl-1 is associated with

the mechanism for tumor resistance to treatment with different drugs, and is a key survival factor for chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia, lymphoma, and in solid tumors such as hepatocellular carcinoma, Dr Colotta said. Preclinical studies have shown excellent activity in several in vivo models, including breast, colon, ovary, and hematologic cancers, he reported. Two phase 1 trials are ongoing in patients with solid tumors testing different schedules of administration, one at the University of Texas in San Antonio and the other at the Institut Gustave-Roussy in Cedex, France. ■

With Loss of Tumor Supressor, Herceptin Resistance Increases Overexpression of a specific type of microRNA (MiRNA-21) can interfere with the targeted cancer therapy with trastuzumab (Herceptin), according to research presented at the AACR meeting. MiRNA-21 blocks the actions of the gene known as PTEN, which acts as a tumor suppressor and is involved in regulating cell proliferation and death. Mutations in the PTEN gene play a role in many types of cancer and influence both the development of breast cancers and their response to treatment. According to senior author Dihua Yu, MD, PhD, “Herceptin is the most successful example of targeted cancer therapy,” Dr Yu noted. “But only about one-third of patients benefit from this therapy as a single agent.” PTEN loss is a key reason. ■

Reaching for Consistency... Continued from page 11 recurrent disease in 10 years, which is significant, given that the cost of a course of adjuvant chemotherapy in our population ranged from $16 000 to $25 000. Finally, the KRAS test was advocated by the National Comprehensive Cancer Network in early 2009 to predict the effectiveness, or lack of effectiveness, of Erbitux/ Vectibix (cetuximab/panitumumab) treatment in colon cancer. Erbitux/ Vectibix-based regimens cost between $20 000 and $30 000 per course. On the heels of KRAS, we soon expect the endorsement of the BRAF mutation marker, as well as the absence of the P-TEN marker, to identify an additional 30% of the potential Erbitux/Vectibix treatment population where these agents will not be effective. In summary, genetic testing and biomarker identification is a significant step in the right direction of predicting the clinical outcome of a treatment regimen, preventing unnecessary patient exposure to

adverse effects, and avoiding the expenditures associated with administering ineffective chemotherapy. Numerous tests to help better target therapies are available on the market today. The burden rests with the payers to evaluate these tests and determine whether their results are consistent enough, and if these results are predictive to outcomes. Although the final outcome of the Myriad Genetics case has yet to be decided, the issues raised in the legal process—foremost among them patient access to these tests and the patentability of genetic materials—have served to raise awareness of the value of genetic testing and of targeting therapy among the payer community. Surely that is a good thing. ■ References 1. Bach PB. Limits on Medicare’s ability to control rising spending on cancer drugs. N Engl J Med. 2009; 360(6):626-633. 2. Elkin EB, Bach PB. Cancer’s next frontier: addressing high and increasing costs. JAMA. 2010; 303(11):1086-1087.

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Radiation with Pemetrexed a Possibility By Colin Gittens Geneva—Combining high-dose pemetrexed (Alimta, Eli Lilly) with concurrent radiation for lung cancer is feasible, according to results of a phase 1 study presented at the 2nd European Lung Cancer Conference. Administering pemetrexed at high doses with radiation may increase the effectiveness of treatment. Prof Françoise Mornex, head of the Department of Radiotherapy Oncology at Centre Hospitalier Lyon Sud, and colleagues conducted the first trial of the drug in combination with radiotherapy and cisplatin chemotherapy in patients with stage III (locally advanced, but not metastatic) lung cancer.

Higher tolerance afforded by pemetrexed allows the patient to receive higher cytotoxic doses. Nine patients with unresected stage III non–small-cell lung cancer (NSCLC) were first given 2 cycles of chemotherapy, 3 weeks apart, with 500 mg/m2 of pemetrexed plus 75 mg/m2 of cisplatin. This was followed by 2 cycles of combined chemotherapy and radiotherapy, where doses of pemetrexed began at 400 mg/m2 and were then escalated to 500 mg/m2 and 600 mg/m2. Cisplatin and radiotherapy at 66 Gy/33 Gy fractions over 7 weeks remained constant. Of 10 patients initially treated, 1 dropped out due to disease progression; 7 completed all 4 cycles of chemotherapy and 8 completed the radiotherapy. In a press release discussing the study, Prof Mornex said that pemetrexed “appears to be the only thirdgeneration agent that can likely be recommended safely at full dose in trials with concurrent radiotherapy.” This is important, because concurrent radiation and chemotherapy often necessitates lowering the chemother-

apy dose because of excessive toxicity. The higher tolerance afforded by pemetrexed allows the patient to receive higher cytotoxic doses during radiation, which increases the chance of killing cancerous cells.

Pemetrexed is currently indicated for the treatment of pleural mesothelioma and already has an established role in treating metastatic NSCLC. Prof Mornex suggested that the findings “will have an impact on clin-

ical practice in the near future. This regimen is already being studied in several ongoing clinical trials around the world; it may become the treatment of choice in the future for concurrent chemoradiation schemes.” ■

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Accelerated Radiotherapy Brings Survival Benefit By Colin Gittens Geneva—Giving lung cancer patients radiotherapy more frequently and over a shorter period of time provides an overall survival benefit, according to the results of a meta-analysis presented at the 2nd European Lung Cancer Conference. These positive results were found for both non– small-cell lung cancer (NSCLC) and small-cell lung cancer, although the study was not sufficiently powered to detect a statistically significant difference between the standard and modified radiotherapy regimen for smallcell lung cancer. The meta-analysis was conducted by Cecile Le Pechoux, MD, and colleagues from Institut Gustave-Roussy in Villejuif, France, and analyzed 2279 patients with nonmetastatic lung cancer from 10 trials. They found that in the 8 trials dealing with NSCLC, modified fractionation of the radio-

therapy improved overall survival compared to conventional radiotherapy, resulting in an absolute benefit of 3% after 5 years (ie, 3% more of the patients were alive after 5 years) in the modified fractionation groups. “The clinical benefit we found was small, but comparable to the benefit found in other meta-analyses concerning non–small-cell lung cancer,” Dr Le Pechoux said. The standard treatment for lung cancer patients is combined radiochemotherapy, but the benefit of accelerated radiotherapy regimens has been unclear, as different randomized trials have given contradictory results. In discussing earlier work in this area in the press release announcing her findings, Dr Le Pechoux commented that “the most recent metaanalysis evaluating the best way to combine radiotherapy and chemotherapy in NSCLC…showed that con-

Keep a Close Eye on Heart and Liver Transplant Patients By Colin Gittens Geneva—Patients receiving heart and liver transplants are at greater risk of developing lung cancer, and physicians caring for these patients should screen for the disease in order to maximize the chance of detecting the malignancy early. These findings were reported at the 2nd European Lung Cancer Conference, and were described as the largest study to date looking at the development of lung cancer in transplant recipients.

Physicians taking care of transplant recipients should have in mind the increased risk of cancer and integrate this risk factor. —Julien Mazieres, MD, PhD The study was coordinated by Julien Mazieres, MD, PhD, of Hopital Larrey, Toulouse, France, and followed a group of 2831 patients who received organ transplants at Toulouse Hospital between February 1984 and September 2006. Overall, 0.85% of them developed lung cancer after transplant. Dr Mazieres elaborated on these findings, saying, “We observed that 10 lung cancers occurred after kidney transplantation (0.5%), 8 after liver

transplantation (1.3%), and 6 after heart transplantation (2.8%). This difference is statistically significant.” As to why the higher number of lung cancers in heart and liver transplant recipients, Dr Mazieres speculated that it “may be because more of these patients have a heavy smoking history compared to kidney transplant recipients.” The average number of packs per year was 75.2 for heart transplant patients, 40 for liver transplant recipients, and 28.5 for kidney transplant recipients. It has long been known that the immunosuppressive drugs given to transplant patients increase their risk of developing new cancers, commonly cancers of the lips and skin, lymphoproliferative disorders, and Kaposi’s sarcoma. By knowing what to expect, physicians should screen patients for cancers for which early detection and treatment is associated with a better prognosis, particularly skin cancers, the authors say. Doctors should also consider screening for lung cancer. “We can reasonably think that a close follow-up including chest examination and x-ray is easy to do and useful,” Dr Mazieres said. “At least, physicians taking care of transplant recipients should have in mind the increased risk of cancer and integrate this risk factor in their follow-up to improve the survival of these patients.” ■

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June 2010

comitant chemoradiation (with a 5year survival rate of 15.1%) is superior to sequential chemoradiation (5year survival rate of 10.6%) and the best results shown in randomized tri-

als in small-cell lung cancer–limited disease show 5-year survival rates of 20% to 25%. Thus there is need for improvements of both radiotherapy and chemotherapy.” ■

Two Steps Forward... mice. Human bodies quickly recognized these drugs as foreign particles and rapidly attacked them. This rendered the medicines ineffective or, worse, toxic. A biotech company didn’t develop the first really effective antibody drug, ReoPro for the treatment of heart attacks, until 1995. But it was just a fragment of an antibody, and still had features of both mouse and human cells, limiting its benefits. Eventually scientists figured out how to make drugs using the structures of human antibodies. But they still contained mouse particles. The first of these “chimeric antibodies” was the cancer drug Rituxan launched in 1997. It has transformed how we treat lymphoma by improving survival while reducing treatment side effects. Scientists “humanized” these antibody drugs still further with the launch of the breast cancer drug Herceptin in 1998. But it wasn’t until the approval of the colon cancer drug Vectibix in 2006 that the first “fully human” cancer antibody medicine arrived. Ipilimumab is part of this new wave of “fully human” antibodies, developed using technology that industry perfected in the late 1990s. Being “fully human,” the drug is perfectly matched to bind and disable its target—in this case a protein that can prevent our bodies from attacking the cancer cells. In contrast to the 30 years of painstaking science that underpins Ipilimumab, the drug Crizotinib is the product of discoveries made just in the last decade. It proves that the time between basic science and its translation into new drugs is increasingly shortened as our tools for developing drugs become more sophisticated. Crizotinib blocks an aberrant protein called ALK that’s critical for the spread of cancer cells. The gene it targets was fully discovered in December 2007. Researchers unveiled a study at ASCO of 82 advanced lung-cancer patients with the protein abnormality. The drug shrank or arrested tumors in more than 90% of them.

Continued from cover

Advances that flow from our mapping of the human genome enabled the drug’s rapid development. Its value to patients is also harnessed by our ability to read the genes in each person’s tumor and see if a patient is susceptible to the medicine. Like all fragile ecosystems, the critical path for translating basic scientific principles into effective medicines is susceptible to outside forces. Lately, these are policies that shrink the incentives that drive the capital investment needed to underwrite these long and risky endeavors, or growing regulation by the Food and Drug Administration that makes it harder to get treatments to market. Most ominous, the journey from lab to treatment is at risk from activists’ and regulators’ growing suspicion of the collaboration between the academic researchers who uncover basic science and the drug industry that is able to design and manufacture medicines. Yet that hand-off from researcher to manufacturer was behind Ipilimumab, Crizotinib and many of our best cancer treatments. Too many policy makers don’t fully grasp how dissimilar and specialized these fields really are. Now Congress is endeavoring to investigate scientists who get National Institutes of Health research grants and also collaborate with industry. The future promises much shorter periods between the uncovering of vital scientific principals and their conversion into useful medicines. Severing the links between the academic researchers that firm up basic science and the industries that craft medicines is the surest way to reverse this trend. ■ Dr Gottlieb, a former official at the Centers for Medicare and Medicaid Services, is a fellow at the American Enterprise Institute, a practicing internist, and a member of the editorial board of Value-Based Cancer Care. He’s partner to a firm that invests in healthcare companies. Reprinted with permission © Scott Gottlieb. Originally printed in the Wall Street Journal, June 5, 2010.

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

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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. Continued on page 19

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

Thanks to New Therapies By Colin Gittens 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

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

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VBCC PERSPECTIVE

Premarket Policies May Generate the Best Value By Jayson Slotnik, JD, MPH

he Patient Protection and Affordable Care Act (PPACA), which is Congress’ latest attempt to reform our healthcare system, creates 3 new entities that will test new payment methodologies or compare current treatments in an attempt to determine better value for our healthcare dollar. In addition, Congress also enhanced the clinical trial process and created a new process to hopefully expedite new technologies to the marketplace. It is a shame that Congress did not focus more on these premarket policies, as they have the potential to bring greater value to our healthcare system. Although the 3 newly created entities were significantly debated and somewhat controversial, many both in and outside the healthcare system do not even know about these premarket improvements. Comparative effectiveness was perhaps the most controversial because of its potential ability to be used to reduce access to the “losing” comparator. Opponents called this “government-run healthcare”; supporters claimed the intent is to inform the clinical decision-making process. We shall see. The law states that by September 23, 2010, the PatientCentered Outcomes Research Institute (PCORI) will exist to assist patients, clinicians, purchasers, and policymakers in making informed health decisions by advancing the quality and relevance of clinical evidence through the conduct of research comparing the clinical effectiveness, risk, and benefits of 2 or more medical treatments, services, or items. Medical treatments, services, or items is defined to include healthcare interventions, protocols for treatments, care delivery, procedures, devices, diagnostics, drugs and any strategies used in the treatment, management, and diagnosis of or prevention of illness. The law also prohibits the institute from mandating coverage or reimbursement for any payer, public or private. Second, PPACA creates a new Center for Medicare and Medicaid Innovation (CMI) within the Centers for Medicare & Medicaid Services (CMS). By January 1, 2011, the secreJayson Slotnik, JD, MPH, is an attorney at Foley Hoag, LLP and an editorial board member of Value-Based Cancer Care.

tary shall select models to be tested where the secretary determines that there is evidence that the model addresses a defined population for which there are deficits in care leading to poor clinical outcomes or potentially avoidable expenditures. The CMI could examine alternate treatment and payment methodologies for treating cancer, such as bundled payments and/or payment for adherence to clinical guidelines. Lastly, PPACA creates a new Independent Payment Advisory Board (IPAB) whose major purpose is to develop proposals that will reduce the per capita rate of growth in Medicare spending. The IPAB’s first annual proposal will be submitted to Congress and the president no earlier than 2014 and may cover a wide range of reforms, including changes to the payment methodology for therapies that treat cancer. The IPAB must submit a draft copy of its recommendations to the Health and Human Services (HHS) secretary for review by September 1 of each year. By March 1 of the following year, the secretary is required to submit the results of the secretary’s review to Congress. The IPAB must submit its recommendations to Congress and the president by January 15 of each year, beginning in 2014. Once receiving the recommendations, if Congress does not enact alternative measures that achieve the same level of savings or otherwise act to block the recommendations, the secretary of HHS would be required to implement the IPAB’s recommendations. Cancer-specific Premarket Policies Each of the initiatives just discussed will receive a great deal of attention and financial resources, and the results may be used to change current policy in the name of improving value within our healthcare system. Hopefully, 2 other policies will receive equal footing because they will certainly enhance cancer care. First, congressional changes to insurance law now require group and individual plans to cover routine patient costs of qualified individuals who participate in certain approved clinical trials. The new policy, however, excludes costs for the investigational item, device, or service itself as well as items and services that are provided solely to satisfy data collection. Despite some of the limitations, this new policy is a dramatic improvement that will hopefully provide for greater clinical trial par-

VALUE-BASED CANCER CARE

June 2010

ticipation, further enhancing clinical and scientific knowledge around cancer care. This is real value. The change with perhaps the greatest potential impact is the creation of the Cures Acceleration Network (CAN) within the Office of the Director of the National Institutes of Health (NIH). The CAN is directed to engage in a number of activities, including awarding grant money to support “revolutionary advances” in translating scientific discoveries from bench to bedside and to accelerate the development of “high-need cures.” A high-need cure is defined as a drug, biological product, or device that is needed quickly to diagnose, mitigate, prevent, or treat harm from any disease or condition; and for which the incentives of the commercial market are “unlikely to result in its adequate

or timely development.” PPACA also directs the CAN to coordinate with the US Food and Drug Administration (FDA) regarding review and approval of high-need cures, including by establishing regular communication with the FDA regarding CAN activities and ensuring that CAN activities are synchronized with the approval requirements of the FDA. PPACA only authorizes $500 million for the CAN for fiscal year 2010 and such sums as necessary for subsequent fiscal years. Congress has not yet appropriated the funds for the CAN, thus the program will not be operational until the funding is received by the NIH. Hopefully, Congress will recognize the value in getting such urgently needed therapies to market, and not just focus on postmarket therapies. ■

CER: Use, Controversy... Continued from page 18 leukemias. Most pathway initiatives to date have been “conventional,” based upon collaboration between physicians and payers and utilizing the framework of tumor-specific guidelines from the National Comprehensive Cancer Network. The result has been selection of a limited number of treatment regimens for each tumor type and/or stage of disease. The idea is to reduce treatment variability for a given tumor, while maintaining appropriate clinical outcomes coupled with lower cost to the payer and the patient. Value Picture Requires Long View Finally, as Steven Weinberger from the American College of Physicians notes in this article, a physician/ patient interaction that considers the full clinical and financial situation is truly at the heart of generating the best “value” for the patient. A 2007 survey of 114 oncology practices across the United States (produced in collaboration by the American Society of Clinical Oncology and the Administrators in Oncology and Hematology Assembly) identified the type and level of services offered to the patient by the practice. The survey documented that, even at that point in time, 86% of practices surveyed “evaluated the physician’s treatment plan in the context of a patient’s insurance coverage and financial resources.”4 Although these cancer-based examples exist, there is no doubt that larger, more comprehensive changes with CER are coming, as outlined in this article. No matter what the focus for

change, there are several questions that require honest, objective answers as change is considered and implemented, including some that are quite controversial: • How will payers and organizations rank the evidence for drugs and biologics that demonstrate noninferiority, if the data demonstrate limited incremental benefit related to adverse events or cost of care? • What standardization, if any, can be derived to compare data across the growing number of observational trials—and is standardization required? • How will decisions around hospice be integrated into CER decisions for the patient with metastatic disease, and will end-of-life decision points become more apparent through CER? No matter the changes, it remains paramount that any analysis includes patient-centric variables related to access to care and compliance, along with all other clinical, safety, and cost factors. ■ References 1. Humana Medical Coverage Policy: Taxanes— Abraxane®, Taxotere® and Taxol® (nab-paclitaxel, docetaxel and paclitaxel). March 25, 2010. http://apps. humana.com/tad/tad_new/Search.aspx?searchtype= beginswith&docbegin=T. Accessed May 20, 2010. 2. WellPoint, Inc. WellPoint is first health benefits company to release CER guidelines for use in evaluating pharmaceuticals. www.wellpoint.com/pdf/CER Guidelines.pdf. Accessed May 20, 2010. 3. WellPoint, Inc. Use of comparative effectiveness research (CER) and observational data in formulary decision making evaluation criteria. www.wellpointnextrx.com/shared/noapplication/f1/s0/t0/pw_ b145032.pdf. Accessed May 20, 2010. 4. DaVanzo J, Doherty J. Evaluating support services in office-based oncology practice: collaboration between ASCO and AOHA. J Oncol Prac. 2007;3(4):204-207.

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June 24 Regional Economic and Management Symposia, Seattle, WA Contact: Association of Community Cancer Centers, 11600 Nebel Street, Suite 201, Rockville, MD 20852. 301-984-9496 or www.accc-cancer.org. July 11-14 Translational Cancer Medicine 2010 USA, San Francisco, CA Contact: AACR, 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106. 215-4409300 or www.aacr.org.

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MEETINGS CALENDAR

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October 1-2 9th International Kidney Cancer Symposium, Chicago, IL Contact: Kidney Cancer Association, PO Box 96503, Washington, DC 20090. 800850-9132 or www.kidneycancer.org. October 8-9 Personalized Cancer Therapy and Prevention, Houston, TX The University of Texas M. D. Anderson Cancer Center CME/Conference Services

Contact: See address above October 8-10 35th ESMO Congress, Milan, Italy Contact: European Society of Medical Oncology, Via La Santa 7, 6962 LuganoCH, Alessia Mora. 41 (0) 91 973 19 19 or www.esmo.org October 8-10 9th Annual Controversies in Breast Cancer: Adjuvant and Neoadjuvant

Therapy, New York, NY Contact: Physicians’ Education Resource, 3500 Maple Avenue, Suite 700, Dallas, TX 75219. 888-949-0045 or www.cancerlearning.com. October 12 The Association for Value-Based Cancer Care First Annual Meeting, St Louis, MO Contact: www.valuebasedcancer.com

July 16-17 Best of ASCO—San Francisco Contact: ASCO, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 571-483-1351 or www.asco.org. July 23-24 Best of ASCO—Boston Contact: See address above August 7-13 AACR/ASCO Methods in Clinical Cancer Research Workshop, Vail, CO Contact: See address above

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

August 14-17 Personalized Interdisciplinary Cancer Treatment: The Importance of Timing, Houston, TX 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 www.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 www.cancerlearn ing.com. September 12-15 Joint Metastasis Research SocietyAACR Conference, Philadelphia, PA Contact: See address above September 26-29 Scripps Cancer Center’s 30th Annual Oncology Nurses Symposium, San Diego, CA Contact: Scripps Conference Services & CME, 11025 North Torrey Pines Road., Suite 200, Mail Stop SCRC 200, La Jolla, CA 92037. 858-652-5400 or www.scripps.org/conferenceservices. September 27-30 AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Denver, CO Contact: See address above September 29-October 2 27th National Oncology Economics Conference, St Louis, MO Contact: Association of Community Cancer Centers, see address above. 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: See address above

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VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright © 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V1238

NO. 2

03/10

www.ValueBasedCancer.com

2 of 2

In Previously Untreated Multiple Myeloma I M P O R TA N T 3 - Y E A R U P D AT E — S U S TA I N E D B E N E F I T UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Patients Without Event

80 70 60 50 40 30 20 10

■ VELCADE+MP (n=344) ■ MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Kaplan-Meier estimate.

Months

▼ Patients treated with VELCADE® (bortezomib) + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone ▼ The overall survival benefit was sustained despite subsequent treatments ▼ Median duration of VcMP treatment was 46 weeks/54 planned ▼ At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELCADE in combination with MP vs 15 months for MP alone (P=0.000002)

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page. VELCADE is indicated for the treatment of patients with multiple myeloma. *VISTA, a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. †VcMP=VELCADE + melphalan/prednisone (MP).

For Patient Assistance Information or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION 2, or visit www.VELCADE.com.