There are different visit procedures and difficulty level in different drug clinical trial protocols. In recent years, diabetes, cancer drugs were frequently carried out in clinical trials field, because the input costs of Similar drugs are comparable, Take them for example, we can analyse the change of the amount and composition of the clinical trials cost. In this paper, data come from The First Affiliated Hospital of Wenzhou Medical University, Tianjin Medical University General Hospital, Xiehe Hospital Tongji Medical College Huazhong University of Science and Technology. Since multiple-center clinical trials of drugs are generally signed contracts at the same price at every centers, the three hospitals can represent the average cost level at the same period in China.
This paper focuses on the costs involved in the agreements signed by the hospital during innovative drug phase II, III and generic drugs random controlled clinical trials, make some analysis on the monitoring, audit and tax input of the sponsor. It does not involve the costs of phase I clinical trials, clinical trials data management statistics, cold chain logistics, and researcher meetings. The unit of measurement is RMB (RMB yuan).
1.1 change trend of clinical trial cost from 2013 to 2018 (taking diabetes glycemia controlling drug as an example)
The paper select the program which have similar visiting frequency and observation period, compare the costs of the of clinical trial agreement signed three years before and after July 22, 2015. (note: in the chart below, the cost of 2015 is before July 22, after7.22 the overwhelming majority of Chinese hospitals had endured a shock period for about half a year in contract signing)
1.1.1 The change of global clinical trial cost during 2013–2018
During 2013–2018, each cases innovative glycemia controlling drugs cost amounts and composition of United States and European countries signed by hospital clinical trial agreement in the the territory of China are shown, as Fig.1.The most significant change of absolute value and the proportion is paid to the SMO’s (Site Management Organization) CRC (Clinical Research Coordinator). 2013–2018, the average amount respectively: 0, 0, 0, 8052, 13154, 14865,it presented remarkable change before and after7.22, and have a increasing trend year by year. The average amount of the investigator fee from 2013 to 2018 was 21312, 22086, 21830, 24055, 23898 and 26219 respectively, which general change is not obvious and the slight increase is related to inflation. The average amount of subjects research relevant laboratory and imaging examination respectively in 2013–2018: 935, 968, 985, 992, 987, 997, that barely changed because the price of examination fee is set and changed by hospital are approved by the price authority, The average amount of subjects transportation subsidy from 2013 to 2018 respectively is: 1150, 1097, 1116, 1235, 1184 and 1183,the transportation subsidy usually is between 150 and 200 for a single visit. The documents management fee remains unchanged for 6 years at 2000 per case for 15 years. The drug management fee has been charged since July 22, 2015 at 500 per case, which obvious but small change on amounts.
1.1.2 The change of Chinese clinical trial cost during 2013–2018
During 2013–2018, each cases generic glycemia controlling drugs cost amounts and composition signed by hospital clinical trial agreement in the the territory of China are shown, as Fig.2. The most significant change of absolute value and the proportion is paid to the CRC of SMO company. 2013–2018, the average amount respectively: 0, 0, 0, 3530,5065,8120,it presented remarkable change before and after7.22, and have a increasing trend year by year. The average amount of the investigator fee from 2013 to 2018 was 5800,5675,6035,9126,11112, and 11293 respectively,which general change is obvious. The average amount of subjects research relevant laboratory and imaging examination respectively in 2013–2018: 965,983,968,972,969,991,that barely changed because the price of examination fee is set and changed by hospital are approved by the price authority. The average amount of subjects transportation subsidy from 2013 to 2018 respectively is: 0,200,330,650,950,960,cost of single visit wasn’t counted and a nominal fee was paid when the clinical trial was completed, or there was n’t transportation subsidy before 7.22.it was ranging from 100 to 150 after 7.22. fee of documents management wasn’t counted. The drug management fee was 500 per case beginning after July 22, 2015.
Comparing fig1 and fig2, The investigator fee and cost of CRC in global multiple-center clinical trial is significantly higher than that fees of China. Besides the gap of sponsor economic power, the global multiple center clinical trials focus on innovative drug while the majority of China clinical trials are generic drugs clinical trials.
1.2 Composition and proportion of clinical trial cost amounts 3years before and after 7.22 (taking lung cancer drugs as an example)
Cancer drugs are common varieties of drug clinical trials in recent years, so the cost of cancer drugs clinical trials are representative. we take the cost of lung cancer drugs which there are 18 to 20 visits excluding the lifetime visit and unscheduled visit as example, compare the cost of clinical trials before and after July 22,2015.
1.2.1 Composition and proportion of global clinical trial cost
220.127.116.11 Composition and proportion of global clinical trial cost 3 years before July 2015 within China
The average of 2013–2015 was showed as Fig 3. Investigator fee 30697, 64.09% of the proportion, the subjects examination fee 11847, 24.73% of the proportion, the subjects traffic subsidy 3355, accounting for 7.00%, documents management fee 2000, accounted for 4.18%.
18.104.22.168 Composition and proportion of global clinical trial cost 3 years after July 2015 within China
The average of 2016–2018 was listed as Fig 4. Investigator fee 40187, 44.37% of the proportion, the subjects examination fee 12053,13.31% of the proportion, the subjects traffic subsidy 4200, accounting for4.64%, documents management fee 2000, accounted for 2.21%, drug management fee 500, accounting for 0.55%, CRC fee 31624, accounted for 34.92%.
1.2.2 Composition and proportion of Chinese clinical trial cost
22.214.171.124 Composition and proportion of Chinese clinical trial cost 3 years before July 2015 within China
As Fig 5,the average of 2013–2015 was displayed. Investigator fee 18930, 71.91% of the proportion, the subjects examination fee 5395, 20.49% of the proportion, the subjects traffic subsidy 2000, accounting for 7.60%, documents management fee not is charged.
126.96.36.199 Composition and proportion of Chinese clinical trial cost 3 years after July 2015 within China
The average of 2016–2018 was showed in Fig 6. Investigator fee 23400, 47.85% of the proportion, the subjects examination fee 6252, 12.78% of the proportion, the subjects traffic subsidy 2250, accounting for 4.60%, drugs management fee 500, accounted for 1.00%, CRC fee 16500, accounted for 33.74%, documents management fee not is charged.
No matter comparing fig1 and fig3、fig4 of global clinical trial or comparing fig2 and fig5、fig6 of Chinese clinical trial，the composition and proportion cost are similar between the glycemia controlling and cancer drug clinical trial.One difference is that the cancer drugs clinical trial involve more imaging and laboratory examination, so which have higher costs and a larger proportion on fees.
1.3 Analysis above cost change
1.3.1 Investigator fee
The increase of investigator fee of global clinical trial cost is not obvious, eliminating inflation factor, the amount almost a little change from fig1.Fig2 shows the cost of Chinese multiple-center site grew obviously and It’s up 30–40% after 7.22.
1.3.2 CRC fee
CRC fee Is the most significant part of the change., There were few CRC fee expenditures before July 22 2015,but it increased starting from 2016 to 2018 year by year. As fig1, the amount and proportion of CRC fee of global multiple-center glycemia controlling drugs 2016–2018 are respectively 8052 (22%), 13154 (32%), 14865 (32%). As fig2, the amount and proportion of CRC fee of Chinese multiple-center project of glycemia controlling drugs 2016–2018 are 3530 (24%), 5065 (27%), 8120 ((37%).Fig 4 shows the mean of global multiple-center cancer drugs clinical trial CRC fee from 2016 to 2018 was 31624 and proportion was 34.92%.Fig 6 shows the mean of Chinese multiple-center cancer drugs clinical trial CRC fee from 2016 to 2018 was 16500 and proportion was 33.74%.
1.3.3 drugs management fee
The 7.22 incident promoted the standardized management of drugs in GCP central pharmacy and the process of drug clinical trials, due to the low amount, only about 1% of the total investment in drug clinical trials.
1.3.4 documents management fee
There are some differences different hospitals according to Chinese and global clinical trials. In terms of Good Clinical Practice of Pharmaceutical Products [SFDA order No. 3, Effective on September 1, 2003] Article 52:” The investigator shall keep the documents of the clinical trial for five years after the completion of the trial.” 1 However, when the global drugs clinical trial finished, the documents are generally required to keep for 15 years, the documents global trial was preserved freely with reference to China’s domestic the first 5 years when it was completed, the charge standard of 6 to 15 years, on the basis of the done cases amount and documents size, hospitals charge 1500–5000 every year. Toward the documents after 5 years finished Chinese clinical trial if the it were handed over to a qualified third party specified by sponsor, although hospitals will continue to be stored for inspect, rarely charge fee.
1.4 Related cost changes not covered by the clinical trial agreement before and after the 7.22 incident
Change is obvious in monitoring and audit mainly on the inputs of human activity. After 7.22, along with CFDI inspect strongly in concomitant drugs、adverse events(AE) and serious adverse events(SAE) of subjects, monitor need to check the Hospital Information System（HIS）、 Laboratory Information System（LIS）、picture archiving and communication systems（PACS）of hospital in the process of monitoring, to ensure that a combination drug, especially a combination drug prohibited by the protocol, AE and SAE are recorded Completely without omission. In recent years, the risk-based monitoring advocated by the sponsor has improved the monitoring efficiency certain to some degree, but in general, after 7.22, monitoring will spend 15–20% more time in the hospital, and the corresponding labor cost will increase 15–20%.
After 7.22, the attention paid by sponsor to the audit has been significantly increased, and the frequency of audit received by hospitals has increased significantly. Generally, sponsor pays the fees and entrusts a third party audit company to carry out the audit. Another change was tax. Because The State Administration of Taxation changed the Value Added Tax( VAT) rules two years ago in China and clinical trial cost in invoice billing system belonged to the scope of tax, when sponsors remit money to hospitals, the added 6% tax must be paid, there was a 6 percent increase in the total amount of money that the sponsor had to pay. The tax cost has nothing to do with the 7.22 event, but the time of the reformed tax law universal implementation was almost in line with the 7.22.