Published Online: May 09, 2012
Rena M. Conti, PhD; Meredith B. Rosenthal, PhD; Blase N. Polite, MD; Peter B. Bach, MD, MAPP; and Ya-Chen Tina Shih, PhD
Purpose: The use of anticancer drugs (chemotherapies) is an important determinant of national spending trends. Recent policies have aimed to accelerate generic entry among chemotherapies to generate cost savings.
Methods: We examined the effects of generic entry on the choice of chemotherapy for the treatment of metastatic colorectal cancer (MCRC) between 2006 and 2009 using autoregressivemoving average modeling with case control. A nationally representative sample of oncologists and patients with cancer (aged >65 years) was employed to estimate the magnitude and significance of the impact of the generic entry of irinotecan in February 2008 on the number of administrations of irinotecan compared with oxaliplatin.
Results: The generic entry of irinotecan resulted in a 17% to 19% decrease (P <.001) in use among elderly patients with MCRC compared with oxaliplatin. The results were robust to multiple sensitivity checks.
Conclusions: This study provides novel and robust estimates of the decline in use of a chemotherapy to treat a common cancer in the elderly after patent expiration. The results suggest estimates from a previous Office of the Inspector General report of the potential savings derived from the generic entry of irinotecan for public payers are an overestimate, likely confounded by oncologists’ response to financial incentives, changes in scientific evidence, and promotional activities. As calls for improving the quality and cost efficiency of oncology increase, future empirical work is needed to examine the responsiveness of oncologists’ treatment decision making to incentives among patients of all ages and insurance types.
(Am J Manag Care. 2012;18(5 Spec No. 2):e173-e178)
The increasing use of drugs in the specialty medical care setting is an important determinant of national prescription drug spending trends.1,2 Cancer is the second-leading cause of death in the United States, and Medicare is the largest insurer of cancer-related treatment.3 The use of physician-administered specialty drugs is central to contemporary cancer treatment among the elderly (aged >65 years).1,4-6 For the elderly insured under Medicare, physician- administered and some oral anticancer drugs (chemotherapies) are covered and reimbursed under the Part B program; in contrast, most oral drugs used in primary care are covered under Part D. Physicians purchase Part B drugs from wholesalers, paying wholesale acquisition costs (WACs), and are reimbursed by Medicare, paying average sales price (ASP) plus 6%.
The generic entry of patent-protected drugs is considered to be an important cost-containment policy in the United States.7 The loss of patent protection for drugs increases competition among manufacturers and consequently decreases prices.8 In practice, physician reimbursement declines for the use of Part B drugs in the care of Medicare-insured patients after generic entry (the Centers for Medicare & Medicaid Services [CMS] rely upon US Food and Drug Administration [FDA] approval and authoritative compendia, like the National Comprehensive Cancer Network [NCCN], to determine what uses of physicianadministered anticancer drugs to cover and reimburse).9 Several federal policies aim to accelerate access to generic drugs and consequently reduce spending by Medicare.10 A 2009 report released by the Office of the Inspector General (OIG) recommends CMS consider reducing the 6-month lag between generic entry and CMS reimbursement declines for Part B drugs, thus generating significant savings.11 Others have suggested the adoption by CMS of other policies to encourage guidelineconsistent and cost-conscious specialty treatment choices.12,13
The anticipated cost savings to CMS of policies that would accelerate access to generic drugs and/or close the physician reimbursement lag for the use of Part B drugs to treat the elderly are predicated on the assumption that the use of the drug undergoing patent expiration would remain constant after generic entry.14-16 Also, challenges to the so-called Paragraph IV section of the Hatch-Waxman Act, providing 180-day marketing exclusivity for generic manufacturers first to file an abbreviated new drug applications to the FDA, are active areas of litigation. Court decisions commonly hinge upon whether use of the molecule in question is constant before and after generic entry occurs in the US market. Previous research has examined whether this assumption is justified in practice, focusing exclusively on observed changes in treatment patterns associated with the generic entry of Part D drugs.17-20 Lackdawalla et al,17 Berndt et al,18 Huskamp et al,19 and Huckfeldt et al20 found that Part D drug patent expirations coincided with stabilization or declines in use of the drugs across branded and generic formulations up to 12 months after patent expiration. We are aware of no empirical research examining whether the generic entry of Part B–covered chemotherapies is associated with changes in use.21
We examined the effects of patent expiration on the use of chemotherapies for the treatment of metastatic colorectal cancer (MCRC) among the elderly between 2006 and 2009 using interrupted cross-sectional time series methods with case control. MCRC is a good cancer with which to examine the potential impact of generic entry on treatment use among the elderly, because colorectal cancer is the third-most prevalent cancer in the United States, and the average age at MCRC diagnosis is 70 years.3
The analysis exploits the presence of 2 close therapeutic substitutes for MCRC: one underwent generic entry in February 2008 (irinotecan), whereas the other (oxaliplatin) was available only in branded formulation during this period. According to the NCCN Drugs and Biologics Compendium, contemporary treatment for MCRC involves multiple drugs; the gold standard for first- and second-line MCRC treatments is either irinotecan, fluorouracil, and leucovorin (FOLFIRI), first approved in 1996, or oxaliplatin, fluorouracil, and leucovorin (FOLFOX), first approved in 2002. Randomized controlled trials released in 2005 suggested FOLFIRI and FOLFOX produce equivalent mortality and morbidity gains among patients with MCRC.22 In practice, FOLFOX is the preferred therapy over FOLFIRI for elderly patients because of the perceived relative adverse effect profile of FOLFIRI, mainly involving diarrhea. In 2007, guideline-recommended therapy for first-line treatment of MCRC was altered to
include FOLFIRI and FOLFOX as well as bevacizumab plus FOLFOX, bevacizumab plus FOLFIRI, and combinations including capecitibine. Between February and March 2008, generic entry into the irinotecan market was significant; 6 biopharmaceutical firms received FDA approval.11 Concurrent with generic entry, clinical evidence supporting irinotecan and oxaliplatin use in MCRC changed. In April 2008, a randomized controlled trial supported the use of FOLFOX in combination with bevacizumab as a potential first-line therapy. 23 At the American Society of Clinical Oncology (ASCO) meetings in 2007 and 2008, Van Cutsem et al24,25 presented results of the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, supporting the use of FOLFIRI with cetuximab therapy as first-line therapy.26 New evidence supporting the use of irinotecan in combination with cetuximab in secondline therapy (EPIC trial [Erbitux Plus Irinotecan for Metastatic Colorectal Cancer]) was also released.27 We are unaware of any other changes in guideline-recommended treatment for MCRC based on a search of the ASCO annual meeting proceedings (accepted abstracts searched from 2005 to 2010), NCCN guidelines, and the FDA approvals website.
Consequently, the example allows us to study potential changes in the use of 1 chemotherapy (irinotecan) after generic entry, holding constant the impact of treatment choice on likely patient benefit and unaffected by coincident changes in patient composition or available therapeutic substitutes. The potential biases introduced into the analyses resulting from concurrent changes in multidrug recommended regimens are addressed under Discussion.
The IntrinsiQ Intellidose data system (IntrinsiQ, Waltham, Massachusetts) provided data on a population-based cohort of US oncologists to measure aggregate prescribing behavior and patient usage of selected oncologic therapies from 2006 to 2009.28 IntrinsiQ data are collected via the Intellidose software system, a pharmacy tracking system intended to improve chemotherapy dosing and enhance administrative billing. IntrinsiQ captures clinical data from all patients treated by participating physicians, including administration and dose of chemotherapy, duration and date of treatment, stage of cancer diagnosis, and line of therapy. Monthly data volume includes 570 reporting physicians, 19,500 patients, 47,000 office visits, and 135,000 drug administrations. The drug administrations, patient counts, and clinical rationales reported by participating physicians are monitored in real time for record completeness by a team of cancer nurses and weighted by IntrinsiQ to be nationally representative of oncologists practicing in the United States using the American Medical Association master file, monthly tumor and patient prevalence estimates, and monthly sales for each agent from the National Sales Perspectives of IMS Health (Danbury, Connecticut). For this study, we obtained from IntrinsiQ nationally weighted drug administrations and patient counts for MCRC overall, by drug, and by line of therapy among patients aged >65 years.
We employed standard interrupted cross-sectional time series analysis to examine the relationship between physician choice of treatment (irinotecan- or oxaliplatin-based therapy) and the generic entry of irinotecan for elderly patients with MCRC. The main outcome of interest was administrations of irinotecan and oxaliplatin before and after the generic entry of irinotecan in February 2008; the secondary outcome was patient counts.
To identify the timing of price declines of irinotecan for the elderly, we examined trends in the difference between the Medicare reimbursement limit (ASP plus 6%) and the WAC per milligram of irinotecan and oxaliplatin between 2006 and 2009. The Medicare reimbursement limit for these drugs was obtained from the CMS reimbursement rate database.29 The WAC for each drug over time was obtained from First Data Bank.30 The difference between ASP plus 6% and WAC for irinotecan increased on its generic entry in February 2008 and then declined by approximately 85% in September 2008, coincident with Medicare reimbursement declines. The difference between ASP plus 6% and WAC for oxaliplatin was constant between 2006 and June 2009. In August 2009, this difference was observed to decline substantially after a district court decision allowed the generic entry of oxaliplatin under a Paragraph IV challenge (Paragraph IV of the Federal Food, Drug, and Cosmetic Act allows 180-day exclusivity to companies that are the first to file abbreviated new drug applications against holders of patents for branded counterparts). Consequently, the analysis time frame is limited to 24 months before and 15 months after February 2008 (January 2006 to June 2009).
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