Background
According to the World Health Organization (WHO) Global Cancer Observatory (GLOBOCAN) [
1], lung cancer brings with the highest age-standardized mortality (18.6 per 100,000), as evidenced by the 1.76 million deaths worldwide in 2018. Fortunately, the treatment of lung cancer has witnessed several major breakthroughs in the past decade. Targeted therapy and immunotherapy have become the first line options for selected patients. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for EGFR mutation lung cancer patients. Routine EGFR TKIs, including gefitinib, erlotinib, afatinib, and osimertinib, can shrink tumor, prolongate overall survival (OS) and improve quality of life compared to standard chemotherapy [
2].
Activating EGFR mutations occur in 10–20% of patients with non-small-cell lung cancer (NSCLC) in North America and Europe and up to 60% in Asia [
3]. Inequalities exist in the availability and affordability of these drugs. Carbonnaux M et al. [
4] conducted a prospective survey to evaluate EGFR-TKI availability in 192 countries in 2014. Respectively, erlotinib, gefitinib, afatinib and icotinib were routinely available in 86%, 73%, 38%, and 5% of the responding 74 countries. In these countries, the cost exceeded 1000 dollars per month in 39%, 35%, and 50% of patients using erlotinib, gefitinib, and afatinib under public or private mandatory health insurance systerms.
It is necessary to improve the availability and affordability of EGFR TKIs considering the high incidence of EGFR mutation (about 60%) in Chinese NSCLC patients [
3]. Before 2016, gefitinib, erlotinib, and icotinib were on the Chinese market but not covered by the national insurance systerm (Table
1). The Chinese government held the first round of national price negotiation with manufacturers in 2016.
Table 1
Information about the EGFR-TKIs
Gefitinib (original) | First | AstraZeneca (UK) | Feb 2005 | Jan 2017 | ¥ 510.00 to ¥ 235.80 (Jul 2016) |
¥ 235.80 to ¥ 228.00 (Sep 2018) |
Gefitinib (generic) | First | Qilu (China) | Feb 2017 | Jan 2017 | ¥ 176.00 to ¥ 158.40 (Apr 2018) |
¥ 158.40 to ¥ 80.00 (Apr 2019) |
¥ 80.00 to ¥ 27.50 (Dec 2019) |
Erlotinib | First | Roche (USA) | Mar 2007 | Jul 2017 | ¥ 601.24 to ¥ 195.00 (Jul 2017) |
¥ 195.00 to ¥ 182.25 (Jan 2019) |
¥ 182.25 to ¥ 81.00 (Sep 2019) |
Icotinib | First | Betta (China) | Aug 2011 | Jan 2017 | ¥ 429.28 to ¥ 396.43 (Jan 2015) |
¥ 396.43 to ¥ 199.86 (July 2016) |
¥ 199.86 to ¥ 192.15 (Jan 2019) |
Afatinib | Second | BoehringerIngelheim (German) | Feb 2017 | Jan 2019 | _______ |
Osimertinib | Third | BoehringerIngelheim (German) | Mar 2017 | Jan 2019 | _______ |
In 2017, three types of TKIs (gefitinib, icotinib, and erlotinib) were enrolled in the reimbursement list, with a reimbursement rate of 50% [
5]. The generic gefitinib was marketized in December 2016, and its monthly cost was significantly lower than that of the original drugs (¥ 5280 VS ¥ 7074) [
6]. Several rounds of national price negotiation have been held since 2017, and the monthly cost of TKIs has reduced gradually [
5,
7,
8]. In January 2019, afatinib and osimertinib were covered by the national health insurance [
5,
7] (Table
1).
In China, the coverage rate of the basic medical insurance has increased from 90% in 2010 to 95% in 2019 [
9]. Therefore, the consumption and expenditure of EGFR TKIs might have undergone some changes. Nanjing, a city in eastern China, has a developed economy. The aim of this study was to investigate the trends in the consumption and cost of EGFR TKIs in Nanjing from 2010 to 2019, and to evaluate the influence of medical insurance and price negotiation on these trends.
Discussion
Our study showed the obvious trends in the consumption and cost of EGFR TKIs in Nanjing from 2010 to 2019. Reimbursement, price negotiation, and generic drug replacement all played a role in increasing the number of DDDs. Our findings provide valuable evidence for the government and health organizations to adopt measures to improve drug availability and affordability.
EGFR TKIs have prolonged the survival of NSCLC patients with EGFR mutation [
13]. However, the cost of TKIs has remained relatively high [
13]. As reported in a US community-based study between January 1, 2008 and January 1, 2015, the total mean monthly cost during TKI therapy was $20,106 in advanced NSCLC [
14]. In Serbia, the cost was 21.233€ in the first month after diagnosis among patients treated with TKI therapy, was much higher than the mean cost of all adenocarcinoma patients (1.317€) in 2013 [
15]. In Southeast Asian low- and middle-income countries, only 15% of patients have access to erlotinib in 2011 [
16]. In our study, the average monthly cost of EGFR TKIs was Ұ16,430.76, far beyond the average monthly household income [
17]. This may explain the low and unchanged consumption of TKIs in 2010–2015.
DDC is an indicator that guides the price-making of pharmaceutical products on the market [
11]. Previous studies have reported that price is a determinant of drug consumption [
13,
18,
19]. Hence, we analyzed the correlation between DDC and the number of DDDs. As expected, the DDC was negatively correlated with the number of DDDs (Fig.
4). Fortunately, approaches have been taken to reduce drug cost, such as reimbursement policy, national price negotiation, generic drug replacement, low-price drug replacement.
More inclusive health insurance could significantly increase drug affordability. Previous studies have reported that Medicare Part D [
20] and Medicaid [
21] in America, public and private insurance in Canada [
22] have increased drug consumption and decreased out-of-pocket costs. Similar results were also observed in our study. Gefitinib, icotinib and erlotinib were enrolled into the national health insurance in 2017 [
5], and afatinib and osimertinib in 2019 [
8]. Thereafter, the consumption of each TKI increased significantly (Fig.
5 and Table S
1).
In response to increases in drug prices during the past few decades, Germany passed the Pharmaceutical Market Restructuring Act, known as AMNOG in 2011. In this act, price negotiations decreased treatment cost by an average of 24.5% [
19]. In China, several rounds of price negotiations about EGFR TKIs have been held, which reduces DDC and increases the number of DDDs (Fig.
5 and Table S
1).
Previous studies have shown that generic drug replacement could lead to significant cost reduction. In the study of Rwagitinywa J et al. [
18], utilization of low-price generic antiretroviral drug significantly reduced the cost of HIV treatment in Denmark. But in France and Czech Republic, the drop in the cost of antiretroviral drugs is more related to the lower price of brand drugs than to the availability of generic drugs. In our study, the available generic gefitinib and China-made icotinib significantly increased the consumption of EGFR TKIs (Fig.
5 and Table S
1).
There are some limitations in our study. First, the data contained no information on patients’ compliance with therapy; the term “consumption” is used for the quantity of drug prescribed but does not indicate how much the drug is administered. Second, we did not access the prescription switch between EGFR TKIs after reimbursement and price negotiation. Third, we did not access the clinical benefit of cost reduction.
Conclusion
The consumption of EGFR TKIs was relatively low because of their high cost from 2011 to 2015 in Nanjing. The accessibility and affordability of these drugs have been improved by national policies since 2016, such as reimbursement, price negotiation and generic drug replacement. Accordingly, the DDC of EGFR TKIs decreased gradually, and the number of DDDs of EGFR TKIs increased annually ever since 2016. Further efforts are needed to translate the higher consumption of EGFT TKIs into clinical benefits.
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