Assessing the impact of the Provincial Reimbursement Scheme on the use of Targeted Anticancer Medications in Zhejiang, China: A Controlled Interrupted time-series Analysis CURRENT STATUS: POSTED

Background: High prices of targeted anticancer medications (TAMs) subject patients to extreme financial burden. To alleviate problems with access and affordability, 6 TAMs were newly listed in the Provincial Reimbursement Drug List (PRDL) in Zhejiang, China in February 2015. To evaluate the implementation of the PRDL policy, this study examined differences in the hospital purchasing volume (HPV) and the hospital purchasing spending (HPS) of 6 listed TAMs pre- and post-enlistment and comparing with 4 other unlisted TAMs. Methods: Interrupted time-series analysis was employed using the pharmaceutical procurement data of 6 newly listed TAMs (study group) and 4 unlisted TAMs (control group) from 22 tertiary hospitals in Zhejiang, China dated between January 2014 and March 2017. Results: After February 2015, the average HPV per month increased significantly by 34.6 defined daily doses (DDDs) (p<0.001) and the average HPS per month increased significantly by USD 6614.9 (p<0.001) for the listed TAMs in the study group (n=6); neither the average HPV nor the average HPS changed significantly for the unlisted TAMs in the control group (n=4). Although only 4 of the 6 listed TAMs exhibited significant decrease in the monthly HPV and HPS individually, the daily cost of each TAM decreased after enlistment. Conclusions: The PRDL policy has shown positive effect on promoting the access to and improving patients’ affordability of TAMs in Zhejiang. The government should conduct further price negotiations and include more TAMs with clinical benefits into reimbursement schemes to relief patients’ financial burden and promote access. after failure of one prior after of


Introduction
Cancer has been the leading cause of death and a major public health problem in China with increasing incidence and mortality. (1, 2) In 2015, about 4 million new cancer cases were reported, of which 2.3 million were new cancer deaths, (3) ranking first of major disease mortality. (4) Lung cancer ranks the first in the incidence of cancer in China, followed by gastric cancer, colorectal cancer, and liver cancer. (3) Anticancer medications are important part of cancer treatment. Although anticancer medications are the key to gains in overall survival for a patient with cancer, their use may subject the patient to an extreme financial burden due to high prices. (5) Especially for targeted anticancer medications (TAMs), high prices have raised major concerns over their affordability. (6) Related studies showed that high medication cost of cancer has caused a serious economic burden on patients in China, especially for the 4 most common cancers (lung cancer, gastric cancer, colorectal cancer, and liver cancer). (4,(7)(8)(9)(10) Adequate health insurance coverage of anticancer medications could promote access and better outcomes for cancer patients. (11)(12)(13)

Method Study design
We used interrupted time series (ITS), the strongest quasi-experimental design (17) to analyze changes of medication use following the implementation of PDRL policy. The enlistment announcement of 6 TAMs was made on February 5, 2015 and thus we selected February 2015 as the breakpoint. To strengthen our design, in addition to the 6 TAMs newly listed in the PRDL in the study group, we selected 4 other unlisted TAMs in the Zhejiang reimbursement scheme as the control group (bevacizumab, erlotinib, bortezomib, recombinant human endostatin) (see Supplementary Table 1).
We hypothesized that the impact on the HPV and the HPS of the listed TAMs in the study group would be different before and after the breakpoint, and from the unlisted TAMs in the control group.

Data Sources
We used the data from China Medicine Economic Information (CMEI), a large database of public hospital medication procurement records in mainland China. (18) We extracted data of the 6 TAMs in the study group and the 4 TAMs in the control group purchased by 22 tertiary hospitals from Zhejiang province between January 2014 and March 2017. Aggregated procurement data included the HPV and the HPS of the TAMs selected in this study, as well as their dosage form, strength, purchase time, the Anatomical Therapeutic Chemical (ATC) code (19) and manufacturer. Detailed information about the 6 listed TAMs in the study group was provided in Table 1. Ethical approval was not required according to the relevant requirements for conducting this type of survey in China. ‡Therapeutic Class: Summarized from indications in the manufacturers' instructions of products approved by NMPA.

Outcome Measures
The primary outcomes we included were the average HPV per month and the average HPS per month of the study group and the control group, as well as the HPV per month and the HPS per month for  -179.7 *, p < 0.05; **, p < 0.01; ***, p < 0.001; †Study group: 6 targeted anticancer medications newly listed in provincial reimbursement scheme in Zhejiang; ‡Control group: 4 targeted anticancer medications unlisted in provincial reimbursement scheme; §Absolute change: changes at 12 months after the policy implementation The changes in the average daily cost of listed and unlisted TAMs The average daily cost of the 6 listed TAMS in the study group declined after the policy implementation (Fig. 2). Before February 2015, the daily costs of TAMs from both groups were stable.
After enlistment in the provincial reimbursement scheme in Zhejiang, the daily cost of the 6 listed TAMs in the study group experienced an abrupt decrease while no significant change was observed about those in the control group.
The changes in the HPV per month, HPS per month and daily cost of listed TAMs Each of the listed TAMs in the study group experienced significant increases in the HPV per month and the HPS per month after enlistment on the PRDL except for nimotuzumab and imatinib ( Fig. 3; Table 3). The HPV per month of trastuzumab increased by 172.8 DDDs (p < 0.001) by the end of observation. Other listed TAMs like gefitinib (80.0 DDDs, p < 0.05), rituximab (11.7 DDDs, p < 0.05) and cetuximab (6.3 DDDs, p < 0.05) also increased significantly in HPV per month. Similarly, there were significant increases in the HPS per month for these 4 listed TAMs with trastuzumab exhibiting the most increase in spending ($23187.6, p < 0.001). As for nimotuzumab and imatinib, there was no statistically significant change in HPV or HPS even 12 months after enlistment in the provincial reimbursement scheme. †Absolute changes: changes at 12 months after the policy implementation The daily cost of each of the 6 listed TAMs in the study group all declined following the PRDL policy implementation (Fig. 3). The daily cost of each of the 6 listed TAMs was stable before February 2015 and remained so until an abrupt decrease observed after March 2015. Out of the 6 listed TAMs, the cut in the daily cost of nimotuzumab was the greatest (from about $160 to $120).

Discussion
Our study showed that, after enlistment on the PRDL, the average HPV per month and the average HPS per month of the anticancer medications selected in this study increased significantly in Zhejiang province. Furthermore, the average daily cost of these newly listed anticancer medications declined shortly after the enlistment and remained stabilized overtime. These findings suggested that the PRDL policy was successful at encouraging the use of anticancer medications, promoting the access and improving patients' affordability.
The time of the PRDL policy implementation in this study was set as February 2015 when 6 TAMs were newly enlisted on the PRDL in Zhejiang province. The average of the HPV per month for the 6 listed TAMs increased significantly after the enlistment and throughout the study period. This shows that the provincial reimbursement scheme was an effective way to promote the use of anticancer medications, which is consistent with previous studies. (15,25,26) This is especially evident when comparing gefitinib (listed TAM) and erlotinib (unlisted TAM) as shown in this study. Both of these medications were first-line TAMs for non-small-cell lung cancer patients with somatic EGFR mutations in China. (27) Erlotinib was also a second-line TAM after failure of at least one prior chemotherapy regimen. However, we found that the HPV per month and the HPS per month of gefitinib increased significantly after enlistment of the PRDL while there was no change for erlotinib. Such differences suggest that the tertiary hospitals had a higher tendency to purchase medications listed in the provincial reimbursement scheme emphasizing the positive role that the PRDL policy may play in encouraging the use of anticancer medications.
TAMs have been the focus of cancer drug development over the past two decades, (28, 29) which meanwhile have raised major concerns over their affordability due to skyrocketing prices. (30) In this study, we found that the daily cost of the 6 expensive TAMs successfully decreased after enlistment, which reflected the improvement in patients' affordability. According to the reimbursement policy,  to TAMs using claim data or prescription data. Patients in secondary hospitals should also be enrolled.

Conclusion
The PDRL policy has shown positive impact on promoting the use of anticancer medications and month and the HPS per month of expensive anticancer medication increased significantly at hospital level and thus the out-of-pocket expenses were reduced at patient level. However, further study with claim data or prescription data is needed to provide more evidence on how patients' access to different anticancer medication changes with provincial reimbursement inclusion policy. Our government should conduct further price negotiations and include more anticancer medications with clinical benefit into reimbursement schemes to relief patients' financial burden and promote access.