Trend in Tyrosine Kinase Inhibitor Utilization, Price, and Out-of-Pocket Costs in Patients With Chronic Myelogenous Leukemia

PURPOSE:

Treatment of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs) has improved survival but is associated with significant financial burden. We measured the annual trend in TKI utilization, Medicare gross payment, and patient out-of-pocket (OOP) expenditure from 2007 to 2016.

METHODS:

We used SEER linked to Medicare part-D claims data to identify prevalent CML cases from 2007 to 2016. TKI utilization was measured as the proportion of cases with at least one TKI fill in each year. Average TKI gross payment and median per-member per-month OOP expenditure were calculated from claims data and plotted annually from 2007 to 2016. Year-to-year percent change in gross payment and OOP expenditure was compared with inflation indices.

RESULTS:

The cohort included 3,189 CML cases with at least one TKI claim. The proportion of prevalent patients with a TKI fill in a year increased from 17.9% in 2007 to 52.8% in 2015. The average annual gross payment per 30-day supply of a TKI increased by an average of 12.8% throughout the period from $9,000 to $10,000 US dollars in 2016. There was no increasing trend in median OOP expenditure per 30-day supply, which varied between $450 and $600 US dollars.

CONCLUSION:

Rising TKI use and TKI drug prices place considerable financial pressure on Medicare part-D insurers. Although there was no increasing trend in OOP expenditure, it may be burdensome for Medicare patients who are likely retired on a fixed income. Our findings support legislation that mitigates increasing drug prices to protect the Medicare system and its beneficiaries.

INTRODUCTION

Chronic myelogenous leukemia (CML) is a hematologic cancer characterized by the pathologic BCR-ABL tyrosine kinase protein.¹ Tyrosine kinase inhibitors (TKIs) target the BCR-ABL tyrosine kinase and are indicated as first-line therapy for the treatment of chronic phase CML.² There are currently five US Food and Drug Administration approved TKIs in the United States —imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.

Despite the benefits of TKIs, their high prices have drawn scrutiny because of possible deleterious effects on patients and the health care system.³ The annual list prices of TKIs range from $92,000 for imatinib to $138,000 US dollars (USD) for ponatinib. Although monthly median treatment prices are approximately > $10,000 USD, the median monthly household income of Americans has remained stagnant at $4,000 USD over the last decade.⁴ The price and associated out-of-pocket (OOP) expenditures of TKIs may be financially burdening vulnerable patient groups, especially Medicare beneficiaries who are likely on a fixed income. Medicare drug prices for TKIs indicated for CML fall between $3,632 and $8,429 USD per 30-day supply, and 40% of patients without low-income subsidies have an OOP expenditure more than $913 USD per 30-day supply.⁵ Additionally, studies have shown that cancer drug prices continue to increase after launch,⁶ including TKIs indicated for CML.⁷

The financial burden of cancer therapy, or financial toxicity, is associated with impaired medication access.⁸ Among Medicare beneficiaries with CML, patients who face relatively high OOP expenditure without drug subsidies have a lower probability of initiating a TKI.^9,10 In a commercially insured population, patients with CML in the top quartile of OOP expenditure were more likely to be nonadherent and discontinue therapy.¹¹ Thus, trends in drug pricing and OOP expenditure greatly affect Medicare beneficiaries. Existing research on price and OOP expenditure of cancer oral medications does not focus exclusively on the CML population and/or does not capture price and OOP expenditure trends across time. Additionally, research on the expected expenditure of TKI therapy for CML can serve as a resource for providers and patients to help inform treatment decisions. Therefore, the aim of our study is to describe the annual trend in TKI utilization, price as measured by Medicare payments, and patient OOP expenditure across time in patients with CML from 2007 to 2016.

METHODS

Data Source and Population

We used the SEER cancer registry linked to 2007 to 2016 Medicare claims data. The data contain information on patient demographics, cancer diagnosis, Medicare insurance status, and prescription claims.¹² We collected claim-level data on Medicare gross drug payment and patient cost-sharing and patient-level data on year of diagnosis, sex, race, insurance type, subsidy status, and SEER region. We also collected data on neighborhood poverty status by linking CML cases to the census tract file.

The population included prevalent CML cases (ICD-0-3 codes 9863 and 9875) between January 1, 2007, and December 31, 2016. We required that CML cases have Medicare part-D enrollment and at least one TKI fill. The study period was restricted from 2007 to 2016 because the Medicare part-D claims data were first available in 2007 and claims follow-up ended on December 31, 2016.

Study Variables

The patient pay amount was used to measure OOP expenditure. It represents the amount not reimbursed by a third party (eg, copays, coinsurance, and deductibles) and excludes other payments made on behalf of the beneficiary. Medicare part-D gross drug payment was used to measure drug price, which is the sum of ingredient cost, dispensing fees, and sales tax. Gross drug payment does not reflect the negotiated amounts between insurers and manufacturers.

Median per-member per-month (PMPM) OOP expenditure was calculated by aggregating OOP expenditure and dividing by the aggregate total days’ supply of all claims occurring throughout a calendar year at the patient level. The resulting expenditure per day was multiplied by 30 days to calculate PMPM OOP expenditure, which reflects expenditure for a 30-day supply each year. Patients with low-income subsidy status during the year were excluded because of minimal cost-sharing requirements. Average annual part-D gross payment per claim of a 30-day supply was calculated by aggregating gross drug payment and dividing by the aggregate total days’ supply of all claims occurring throughout the calendar year across all patients. The resulting amount was multiplied by 30 days to arrive at the gross drug payment for a 30-day supply.

Analysis

We identified prevalent CML cases from 2007 to 2016 and whether the patient received a TKI in each year to calculate the annual proportion of patients treated. Among patients treated each year, the average part-D gross payment per 30 days across all TKIs and stratified by TKI was plotted across time from 2007 to 2016 to qualitatively evaluate trends. Similarly, median PMPM OOP expenditure across all TKIs and stratified by TKI was plotted across time from 2007 to 2016 among patients without low-income subsidies. OOP expenditure was further stratified according to the type of insurance drug plan that the patient was in at the start of the year to evaluate trends across plan types (eg, employer/managed care/regional preferred provider organization [PPO] and traditional Medicare part-D). Year-to-year percent change in part-D gross payment and OOP expenditure was calculated using the formula $\left({\text{cost}}_{\text{year}+1}-{\text{ cost}}_{\text{year}}\right)/\left({\text{cost}}_{\text{year}}\right)$ and qualitatively compared with changes in inflation rates derived from the Personal Health Care price index and Consumer Price Index-Medical, respectively.¹³ Annual OOP expenditure data for a TKI in which the number of patients was < 11 were not reported per Medicare privacy restrictions.

RESULTS

Of 73,705 leukemia cases, we identified 6,206 cases of CML. Among CML cases, 5,879 patients had Medicare part-D and 3,189 patients had at least one TKI fill. The mean age at the time of diagnosis was 67 years, and the number of patients diagnosed was similar year-to-year (Table 1). Most patients were male, White, and of non-Hispanic ethnicity. Most patients had a traditional Medicare part-D plan or a managed care prescription plan at the time of diagnosis, and < 3% of patients had a low-income subsidy at the time of diagnosis. The annual prevalence of CML increased annually and reached more than 4,000 cases in 2015 (Fig 1A). The proportion of prevalent patients with a TKI fill in the year increased from 17.9% in 2007 to 52.8% in 2015.

TABLE 1.

Baseline Characteristics of TKI Users at the Time of Diagnosis (2007-2016)

FIG 1.

(A) Annual proportion of patients with prevalent CML treated with a TKI. The SEER data does not contain newly diagnosed CML patients in 2016 and data in this year was excluded. (B) Trend in TKI Medicare gross payment per 30-day supply stratified by TKI. FDA approval year: imatinib (May 2003), dasatinib (June 2006), nilotinib (October 2007), bosutinib (September 2012), and ponatinib (December 2012). Dates were obtained from accessdata.fda.gov. (C) Annual percentage change in gross payment per 30-day supply across all TKIs compared with annual percentage change of the PHC index. CML, chronic myelogenous leukemia; PHC, Personal Health Care; TKI, tyrosine kinase inhibitor; USD, US dollars.

Overall, the average annual part-D gross payment per 30 days of each TKI increased from 2007 to 2016 (Fig 1B). Imatinib, which was US Food and Drug Administration approved before Medicare part-D implementation, had a gross payment of approximately $3,000 USD per 30-day supply in 2007, which increased to about $9,000 USD in 2016. Dasatinib and nilotinib had initial annual gross payments per 30-day supply of about $3,800 and $6,200 USD, respectively, which increased to more than $9,000 USD in 2016. Bosutinib had an initial annual gross payment per 30-day supply of about $5,500 USD, which then increased to about $9,800 USD in 2016. Ponatinib had the highest initial annual gross payment per 30-day supply at about $9,900 USD in 2013, which increased to about $19,800 USD in 2016. Finally, generic imatinib was released into the US market in 2016, and the initial annual gross payment per 30-day supply was about $7,800 USD.

Across all TKIs and except for the years 2015 to 2016, the annual percent change was double digits throughout the period (Fig 1C). The average annual increase was 12.8%, which greatly exceeded the average 2% annual percent change in the Personal Healthcare index. The period with greatest gross payment growth was from 2008 to 2011 when percent increase was sustained at about 18% year-to-year. The increase from 2015 to 2016 was the smallest change across the period at about 0.3%.

Median PMPM OOP expenditure across all TKIs among patients with no subsidies remained relatively constant between $450 and $600 USD throughout the period and was highly variable (Table 2). Stratified by TKI, imatinib, dasatinib, and nilotinib decreased in median PMPM OOP expenditure from 2010 to 2011 (Appendix Fig A1A, online only). However, PMPM OOP expenditure increased thereafter, which was then followed by sharp decreases for nilotinib and imatinib from 2015 to 2016. In contrast, both bosutinib and ponatinib increased dramatically from 2013 to about $660 and $1,000 USD PMPM, respectively, in 2016. The median PMPM OOP expenditure for generic imatinib in 2016 was about $600 USD.

TABLE 2.

Median per-Member per-Month Out-of-Pocket Expenditure Across All TKIs Among Patients With No Subsidies

Across all TKIs, median PMPM OOP expenditure among patients with employer, managed care, or PPO drug plans was slightly lower relative to patients with traditional Medicare part-D plans throughout the period (Appendix Fig A1B). The percent change in Consumer Price Index-Medical remained relatively constant with an average 3% annual increase (Appendix Fig A1C). In comparison, median PMPM OOP expenditure across all TKIs decreased from 2009 to 2011, with the greatest percent decrease at nearly 20% from 2010 to 2011. The median PMPM OOP expenditure increased about 5%-8% year-to-year from 2011 to 2015 before a 5% decrease from 2015 to 2016.

DISCUSSION

The treatment landscape for cancer therapy has shifted from the use of nonspecific chemotherapeutic agents to targeted therapies such as TKIs.¹⁴ We found an annual increase in the proportion of patients on a TKI. This likely reflects the increased use of TKIs because of its superior efficacy relative to non-TKI chemotherapy^2,15 and improved survival.¹⁶ The TKI treatment rate of CML cases was 54% and may be considered low considering the benefits of therapy, but this finding is consistent with other studies using SEER-Medicare. Shen et al¹⁷ reported a treatment rate of 16.5% (including patients with atypical CML, BCR-ABL negative CML, and myelomonocytic leukemia), whereas Winn et al¹⁰ reported a rate of 68.2%.

Although TKIs provide significant benefits, its high price must be considered. We found that the part-D gross payment per 30-day supply of TKIs increased from 2007 to 2016 at an average of 12.8% year-to-year, exceeding that of medical inflation, which remained constant at about 3%. By 2016, gross payment per 30-day supply of a TKI reached about $9,000 USD. Although there was a clear trend in increasing gross drug payment, the PMPM OOP expenditure generally fluctuated between $450 and $600 USD. Generic imatinib was released into the US market in 2016 with a gross payment per 30-day supply of about $7,800 USD and a median PMPM OOP expenditure of about $600 USD. Notably, gross payment increases across all branded TKIs was < 1% from 2015 to 2016, presumably because of the market entry of generic imatinib.

Our finding of increasing drug price as measured by Medicare gross payment over time, exceeding medical inflation indices, is consistent with current evidence. Based on average sales prices of 10 patented intravenous drugs approved between 1997 and 2012 indicated for various cancers, the inflation-adjusted median percent price increase was 6%.⁶ Shih et al⁷ evaluated prices of oral cancer medications indicated for various cancers among Medicare beneficiaries and found an average 12% increase in price from 2007 to 2012, whereas the prescription drug consumer price index increased 3% annually. We found a similar 12.8% average increase in price from 2007 to 2016 among TKIs indicated for CML. The median price per month in 2012 was found to be $7,763 USD, whereas we found the median price per month of TKIs indicated for CML to be about $6,630 USD in 2012.

With entry of generic imatinib in 2016, we observed gross payment increases for all TKIs except for imatinib, which decreased by 2.3%. The gross payment per 30-day supply of generic imatinib in 2016 was about $7,800 USD. When compared with the gross payment of branded TKIs (except ponatinib) that ranged from $9,000 to $10,000 USD in 2016, the gross payment of generic imatinib reflects a 13%-22% discount. Compared with typical price discounts of a single generic competitor ranging from 39% based on average manufacturer prices and 31% based on invoice prices, the gross payment for generic imatinib may be considered relatively expensive compared with its branded competitors.¹⁸ Of all TKIs, ponatinib was the most expensive and exhibited the highest gross payment increase from about $10,000 in 2013 to nearly $20,000 USD in 2016.

With several branded TKI agents in the market indicated for first-line therapy with no differences in overall survival,² the increase in gross payment is contradictory to a decrease that would be expected with interbrand competition.¹⁹ Such was the case for the treatment of hepatitis C in which sofosbuvir had a launch price of $84,000 USD in 2013, and the branded competitor glecaprivir/pibrentasvir was subsequently launched at a lower price of $26,400 USD.²⁰ The increase in price may be partly explained by the prohibition of Medicare part-D by law to exclude cancer drugs from formularies, which limits its ability to pressure manufacturers for lower prices and diminishes the effect of competition. In the United States, oncology accounts for the largest proportion of specialty medicine spending at $39 billion USD in which protein kinase inhibitors were the biggest driver of growth.²¹ In the context of increasing CML prevalence¹⁶ and TKI use, gross payment for TKIs will place a substantial financial burden on Medicare part-D, which faces the majority of drug costs and accounts for about 40% of national health expenditures.²²

In contrast to increasing gross payment, median PMPM OOP expenditure followed no clear trend and fluctuated between $450 and $600 USD. Imatinib, dasatinib, and nilotinib OOP expenditure dropped nearly 20% in the period 2010 to 2011. This significant reduction in median PMPM OOP expenditure was also reported by Shih et al⁷ across various targeted oral cancer drugs. During this period, the Affordable Care Act (ACA) began to close the coverage gap and provided a 50% discount to branded pharmaceuticals when beneficiaries reached the coverage gap.²³ Although the discounted percentage of branded pharmaceuticals increased annually until complete closure of the coverage gap in 2020 per the ACA, the median PMPM OOP expenditure increased 5% to 8% annually from 2011 to 2015. With gross payment annually increasing after 2011, ACA provisions might have minimized increases in OOP expenditure. Like the trend observed in TKI gross payment, median PMPM OOP expenditure decreased from 2015 to 2016 when generic imatinib entered the market.

Stratified by type of drug plan, median PMPM OOP expenditure was generally lower for patients enrolled in an employer, managed care, or regional PPO plan. In 2016, the median PMPM OOP expenditure was about $400 USD for a TKI with employer, managed care, or regional PPO plan, whereas the median PMPM OOP expenditure was about $600 USD in patients with traditional part-D plans. This is consistent with the findings reported by Shen et al⁵ who reported that 44% of patients with traditional part-D paid >$900 USD per 30-day supply compared with 36% of patients with managed care or regional PPO plans. In stratifying by TKI across all plan types, there was a general trend toward a decrease in OOP expenditure for imatinib, dasatinib, and nilotinib, although there was an increasing trend in the OOP cost of bosutinib and ponatinib. The increase in OOP expenditure for these two TKIs may be due to the recent approval in 2012 and relatively small market share.

Despite no increasing trend in OOP expenditure, it is very likely that Medicare beneficiaries are financially burdened. A median PMPM expenditure of $450-$600 USD may be burdensome for patients who are likely retired and who have a median annual per-capita income of $26,200 USD.²⁴ This burden is evident when compared with patients with commercial insurance in which the median OOP expenditure for the first 30-day supply for a TKI was $42 USD.²⁵ High OOP expenditures have been associated with decreased TKI access in patients with CML^9-11 and also across various cancers that are treated with specialty cancer drugs or oral cancer therapies.^26-30 High OOP expenditures will likely price-out patients whose treatment cost is a large proportion or exceeds income, thus leading to disparities in TKI access.

Given the continual increase in TKI gross drug payment and relatively high OOP patient expenditures, our findings reinforce the need to support legislation that limit increasing cancer drug prices.³¹ Such legislation would penalize manufacturers who increase drug price at a greater rate than inflation by mandating a rebate to Medicare that would equal the difference between the actual price and inflation-adjusted price. The legislation would also allow Medicare to negotiate drug prices with manufacturers. If passed into law, these acts may protect Medicare part-D insurers and its vulnerable population from the increasing price of cancer therapy.

Our study has several limitations. First, drug price was based on Medicare gross payment, which does not reflect the negotiated price between plans and manufacturers.³² Therefore, our measured prices may not reflect the trend in negotiated prices. Based on limited data from Medicare, the rebate reflective of all branded drugs in 2014 was 17.5%.³³ With no further competition entering the TKI market for CML beyond 2012, it is likely that the rebate between 2012 and 2016 remained near 17.5%. Assuming that the discount remained constant and observing an upward price trajectory through this period, the negotiated prices would be expected to follow an upward trend. Second, although we normalized patient OOP expenditure into a 30-day supply, the reported OOP expenditure reflects fills occurring through different Medicare coverage phases with varying cost-sharing requirements. Since the coverage phase is dependent on the cumulative amount of OOP expenditure that the beneficiary has paid for all drugs, the OOP expenditure for a TKI will vary based on the starting month of TKI treatment and other prescription drugs. However, patients are likely to enter the catastrophic coverage phase within the first fill for a TKI.⁵ Therefore, median PMPM OOP expenditure is weighted toward initial TKI fills in a year, which are the most expensive. Additionally, OOP expenditure was likely reflective of maintaining therapy as prevalent patients accumulated across time. Third, Medicare beneficiaries may not pay the entire OOP expenditures if they qualify for charitable organizations or manufacturer patient assistance programs that cover the cost of TKIs. However, since we excluded patients with low-income subsidies who are likely to qualify for charities and Medicare beneficiaries are typically excluded from patient assistance programs, the population likely faced the full OOP expenditure. Finally, the interpretation of the results is limited to Medicare beneficiaries.

In conclusion, we found an annual increase in TKI Medicare gross payment exceeding medical inflation but found no trend in OOP expenditure. Increasing gross payment and relatively high OOP expenditure may be burdensome to Medicare and its beneficiaries. Our findings support legislation that mitigates increasing drug prices to alleviate financial burden on Medicare and its beneficiaries.

Appendix

FIG A1.

(A) Median per-member per-month OOP expenditure among patients with no subsidies stratified by TKI. FDA approval year: imatinib (May 2003), dasatinib (June 2006), nilotinib (October 2007), bosutinib (September 2012), and ponatinib (December 2012). Dates were obtained from accessdata.fda.gov. Data points containing less than 11 patients were excluded: dasatinib (2007,2008), nilotinib (2008, 2009), bosutnib (2012), and ponatinib (2013). (B) Median per-member per-month OOP expenditure across all TKIs among patients with no subsidies and stratified by prescription plan type. (C) Annual percentage change in median per-member per-month OOP expenditure across all TKIs compared with annual percentage change of the CPI-M. CPI-M, Consumer Price Index-Medical; Emp, employer; MCO, managed care organization; OOP, out-of-pocket; PDP, part-D plan; PPO, preferred provider organization; TKI, tyrosine kinase inhibitor; USD, US dollars.

AUTHOR CONTRIBUTIONS

Conception and design: Brian Talon, Gregory S. Calip, Daniel R. Touchette

Financial support: Daniel R. Touchette

Administrative support: Daniel R. Touchette

Provision of study materials or patients: Gregory S. Calip, Daniel R. Touchette

Collection and assembly of data: Brian Talon

Data analysis and interpretation: Brian Talon, Todd A. Lee, Lisa K. Sharp, Pritesh Patel, Daniel R. Touchette

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Trend in Tyrosine Kinase Inhibitor Utilization, Price, and Out-of-Pocket Costs in Patients With Chronic Myelogenous Leukemia

The following represents disclosure information provided by the authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/op/authors/author-center.

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