1. Changes in the cost of clinical trials before and after 7.22
There are different visit procedures and difficulty levels in different clinical drug trial protocols. In recent years, diabetes and cancer drugs have been frequently involved in clinical trials because the input costs of similar drugs are comparable. For example, we can analyze the change in the amount and composition of the clinical trials cost. In this paper, the data come from the First Affiliated Hospital of Wenzhou Medical University, Tianjin Medical University General Hospital and Wuhan Union Hospital. Since multi-center clinical drug trials are generally signed contracts at the same price at every center, the three hospitals can represent the average cost level over the period in China.
This paper focuses on the costs involved in the agreements signed by the hospitals during innovative drug phases II and III and generic drug random controlled clinical trials and analyzes 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 or researcher meetings. The unit of measurement is RMB yuan.
1.1 Change trend of clinical trial costs from 2013 to 2018 (taking the drug for glycemic control as an example)
The paper selects programs with similar visiting frequencies and observation periods and compares the costs of the clinical trial agreements signed three years before and three years after July 22, 2015. (Note: in the chart below, the cost for 2015 is before July 22; for approximately half a year after 7.22, the overwhelming majority of Chinese hospitals endured a shock period in terms of contract signing).
1.1.1 The change in the global clinical trial cost during 2013-2018
Fig.1 shows the cost and composition of clinical trials for innovative drugs for glycemic control from the United States and European countries in agreements signed by hospitals in the territory of China from 2013-2018. The most significant change in absolute value and proportion is paid to the clinical research coordinator ( CRC ) of the SMO (site management organization). From 2013-2018, the average amounts paid were 0, 0, 0, 8052, 13,154, and 14,865, respectively, presenting remarkable changes before and after 7.22 and indicating an increasing trend year by year. The average investigator fee from 2013 to 2018 was 21,312, 22,086, 21,830, 24,055, 23,898 and 26,219, respectively, for which the general change is not obvious, and the slight increase is related to inflation. The average number of research subjects submitted to laboratory and imaging examination in 2013-2018 was 935, 968, 985, 992, 987 and 997, respectively, which barely changed over the period because the examination fee was set, the hospital charge standard was approved by the price department, and the charge standard change did not happen in these years. The average amount of transportation subsidy from 2013 to 2018 was 1150, 1097, 1116, 1235, 1184 and 1183, and the transportation subsidy was usually between 150 and 200 for a single visit. The document management fee remained unchanged for all 6 years at 2000 per case for 15 years. Since July 22, 2015, the drug management fee has been 500 per case, which entails an obvious but small change in amount.
1.1.2 The change in Chinese clinical trial cost during 2013-2018
Fig.2 shows the cost and composition of clinical trials for generic drugs for glycemic control in agreements signed by hospitals in the territory of China during 2013-2018. The most significant change of absolute value and proportion is paid to the CRC of the SMO. From 2013-2018, the average amounts of 0, 0, 0, 3530, 5065 and 8120, respectively, presented remarkable changes before and after 7.22, with an increasing trend year by year. The average investigator fee from 2013 to 2018 was 5800, 5675, 6035, 9126, 11,112 and 11,293, respectively, with a clear general change. The average number of research subjects submitted to laboratory and imaging examination in 2013-2018 was 965, 983, 968, 972, 969 and 991, which barely changed because the examination fee is set, and changes proposed by hospitals are approved by the price authority. The average subject transportation subsidy from 2013 to 2018 is 0, 200, 330, 650, 950 and 960; the cost of a single visit was not counted, and either a little fee was paid when the clinical trial was completed or there was no transportation subsidy before 7.22. The transportation subsidy for each visit ranged from 100 to 150 after 7.22. The fee for document management was not counted. The drug management fee was 500 per case after July 22, 2015.
Comparing Fig.1 and Fig.2, the investigator fee and cost to the CRC in a multi-center clinical trial are significantly higher in global clinical trials than in China clinical trials. In addition to the difference between sponsors’ economic power, multi-center clinical trials around the world focus on innovative drugs, while the majority of Chinese clinical trials concern generic drugs.
1.2 Composition and proportion of clinical trial costs 3 years before and after 7.22 (taking lung cancer drugs as an example)
Cancer drugs are common subjects of clinical drug trials in recent years, so the cost of cancer drug clinical trials is representative. We take the cost of lung cancer drugs, which includes 18 to 20 visits excluding the lifetime visits and unscheduled visits; for example, compare the cost of clinical trials before and after July 22, 2015.
1.2.1 Composition and proportion of the costs of clinical trials with global trials sponsors
18.104.22.168 Composition and proportion of costs of clinical trials with global trials sponsors within China 3 years before July 2015
The average fees from 2013-2015 are shown in Fig.3, as follows: the investigator fee was 30,697, or 64.09% of the proportion; the subject examination fee was 11,847, or 24.73% of the proportion; the subject transportation subsidy was 3355, accounting for 7.00%; the document management fee was 2000, accounting for 4.18%.
22.214.171.124 Composition and proportion of costs of clinical trials with global trials sponsors within China 3 years after July 2015
The average fees from 2016-2018 are listed in Fig.4, as follows: the investigator fee was 40,187, or 44.37% of the proportion; the subject examination fee was 12,053, or 13.31% of the proportion; the subject transportation subsidy was 4200, accounting for 4.64%; the document management fee was 2000, accounting for 2.21%; the drug management fee was 500, accounting for 0.55%; and the CRC fee was 31,624, accounting for 34.92%.
1.2.2 Composition and proportion of Chinese clinical trial costs
126.96.36.199 Composition and proportion of the costs of Chinese clinical trials within China 3 years before July 2015
Fig.5 shows the average fees from 2013-2015, as follows: the investigator fee was 18,930, or 71.91% of the proportion; the subject examination fee was 5395, or 20.49% of the proportion; the subject transportation subsidy was 2000, accounting for 7.60%l; and no document management fee was charged.
188.8.131.52 Composition and proportion of the costs of Chinese clinical trials within China 3 years after July 2015
The average fees from 2016-2018 are shown in Fig.6, as follows: the investigator fee was 23,400, or 47.85% of the proportion; the subject examination fee was 6252, or 12.78% of the proportion; the subject transportation subsidy was 2250, accounting for 4.60% the drug management fee was 500, accounting for 1.00%; the CRC fee was 16,500, accounting for 33.74%; and no document management fee was charged.
Comparing Fig.1 with Fig.3 and Fig.4 for clinical trials with global trials sponsors or comparing Fig.2 with Fig.5 or Fig.6 for Chinese clinical trials, the composition and proportions of the cost are similar for the clinical trials for glycemic control drugs and cancer drugs. One difference is that the clinical trials for cancer drugs involve more imaging and laboratory examination, which have higher costs and represent a larger proportion of the fees.
1.3 Analysis of the cost change
1.3.1 Investigator fee
The increase in the investigator fee of global clinical trial cost is not obvious, and eliminating inflation, the amount shows little change in Fig.1. Fig.2 shows that the cost of the Chinese multi-center site grew notably by 30-40% after 7.22.
1.3.2 CRC fee
The CRC fee shows the most significant change. There were few CRC fee expenditures before July 22, 2015, but fees increased year by year from 2016 to 2018. As shown in Fig.1, the amount and proportion of CRC fees associated with multi-center clinical trials for glycemic control drugs from 2016-2018 were 8052 (22%), 13154 (32%) and 14865 (32%), respectively. As shown in Fig. 2, the amount and proportion of CRC fees associated with the Chinese multi-center clinical trials for glycemic control drugs from 2016-2018 were 3530 (24%), 5065 (27%) and 8120 ((37%). Fig.4 shows that the mean CRC fee for multi-center clinical trials for cancer drugs global from 2016 to 2018 was 31,624, and the proportion was 34.92%. Fig.6 shows that the mean CRC fee associated with the Chinese multi-center clinical trials for cancer drugs from 2016 to 2018 was 16,500, and the proportion was 33.74%.
1.3.3 Drug management fee
7.22 promoted the standardized management of drugs in good clinical practice (GCP)central pharmacies and the process of clinical drug trials; due to the low amount of this fee, it represented only approximately 1% of the total investment in clinical drug trials,this article does not foucus on drug management fee.
1.3.4 Document management fee
There are some differences between hospitals in terms of Chinese and global clinical trials. According to the 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, after the completion of clinical drug trials with global trials sponsors, the documents generally must be kept for 15 years. While the documents from global trials are preserved freely for all 15 years, in China, after the first 5 years following a trial’s completion, hospitals charge 1500-5000 every year for the 6th to the 15th years, on the basis of the case amount and number of documents. After 5 years, the documents from completed clinical trials in China can be handed over to a qualified third party specified by the sponsor; in such cases, although hospitals continue to store the documents for inspection, they rarely charge a fee.
1.4 Related cost changes not covered by the clinical trial agreements before and after 7.22
Change is obvious in terms of monitoring and auditing, which mainly concern the input of human activity. After 7.22, along with rigorously CFDA inspections of concomitant drugs, adverse events (AE) and serious adverse events ( SAE) need to be monitored in hospital information system(HIS), laboratory information systems (LIS) and picture archiving and communication systems (PACS) to ensure that a combination drug, especially a combination drug prohibited by the protocol, AEs and SAEs are recorded completely and without omission. In recent years, the risk-based monitoring advocated by the sponsor has improved the monitoring efficiency to some degree, but in general, after 7.22, 15-20% more time is spent monitoring in the hospital, and the corresponding labor cost increases by 15-20%.
After 7.22, the attention sponsors pay to auditing has significantly increased, and the frequency of audits of hospitals has increased significantly. Generally, the sponsor pays the fees and entrusts a third-party audit company to carry out the audit. Another change concerns the tax. Because the State Administration of Taxation changed the value added tax rules two years ago in China, and the clinical trial cost in the invoice billing system was within the scope of the tax, when sponsors remit money to hospitals, the added 6% tax must be paid. Thus, there was a 6% increase in the total amount of money the sponsor had to pay. The tax cost has nothing to do with the 7.22 event, but the universal implementation of the tax law reform occurred close to 7.22.