Analysis on the influence of the proportion and growth rate of different categories of drug clinical trial research funds on quality improvement in China recently six years

Background: China Food and Drug Administration issued Announcement of Self-examination and Inspection of Drug Clinical Trial Data on July 22, 2015. Great change have taken place since the most stringent drug registration self-examination and inspection in history was launched, among those variety, the cost of clinical trials is one of the important changes. Methods The paper compare the changes in the cost of drug clinical trials on both amount and structures between 3 years before and after self-examination and inspection initiated by the CFDA ,Identify the increase number and composition, analyze the impact of the cost of new CRC, the labor service of researchers, the audit company, the institutional drug management and quality control on the quality improvement of drug clinical trials. Conclusions  According to the article, the emergence and rise in most clinical trials costs are conducive to the quality enhancement of drug clinical trial, the occurrence and continuous increase of CRC costs improve the quality, at the same time, It implies a barriers factor to improve the drug clinical trial quality. To improve the quality of clinical trials, China must regulate the booming SMO market and formulate actively industry standards and qualification certification for CRC.

3 launched. Great changes have taken place in the field of drug clinical trials With the deepening of self-examination and inspection in China in the past three years, among which the cost of clinical trials is one of the important changes.
The purpose of this paper is to analysis the quantity and structure change of clinical trials cost before and after 7.22, explore the corresponding relation between cost change and quality improvement.Both cost and quality changes need multiple cause to one effect,and the two changes as initiator appeared one cause to multiple effect. When two kinds of changes interact with each other alternately, there is a positive correlation interdependent between the changes, In the meantime, which also implies the hidden worry of deviating from the original intention at the increase of investment corresponding the improvement of quality. changes in the cost of clinical trials before and after7.22 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 4 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).  -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 5 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.

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.

documents management fee
There are some differences different hospitals according to Chinese

Centralized management the trial drug at center pharmacy
Professional technique department of the hospital is difficult to achieve dedicated clinical trial drugs management due to in sufficient experience on drug management and limited ability of facilities and equipment in the department not meet the inspection requirements when they undertake clinical trials. GCP center pharmacy equip centralized management of full-time pharmacists who passes through GCP training, which can be better to perform the standard operating procedures of trial drug receiving, storage, distribution, use, residual drug recycling and destruction, etc.

Emergence of audit company
After 7.22, third-party audit institutions sprung up successively which provide clinical trial training, consulting services, and audit comprehensively on-site of clinical trial data and records. Its independent examine mode makes the division of labor refined and specialized.

CRC fee growth
CRC fee growth was the most rapid and significant change in the cost of clinical trials which was clearly showed in figure 1-6.

Investigator fee
The increase of investigator fee are divided into explicit growth which can be clearly shown in figure 1-6 and implicit growth. Implicit growth refers to the addition of CRC, that part non-medical judge work was done by Investigator before is done by CRC now., the Investigators ' labor fee have increased in disguised form because the decrease of Investigators' workload.

The fee of audit company
The audit company usually sends 5 persons to a site for 2 to 3 days on-site audit, and the sponsor needs to pay the audit company fee of 80 to 100 thousand yuan.
The number of site which are audited shall be determined by the evaluation of the sponsor and the request initiating from the clinical trial site and consultation with the sponsor.

Drug management fee, quality control fee
The amount of drug management fee is small, and the fee of each subject generally will charge 200-500 yuan according to the complexity level of the clinical trial, which has played a good role in regulating the management of drugs in the implementation process of drug clinical trials. Before 722, the drug clinical trial research institutions it charged quality control fees is less, part of the drug clinical trial research institution begin charging quality control fees after 722. Fees charged by agencies vary and the overall amount is small. The fees earmark for its specified purpose only so play a relatively important role in quality control.

The relationship between research quality and investment
There is a saying in the industry about the cost and quality of clinical trials: high costs do not surely mean high quality, but low costs certainly cannot make the high quality. Low cost is difficult to guarantee the quality of clinical trials is the consensus in the industry, any step is needed labor and material resources budget.
Research institutions could perform a quality clinical trials for sponsor with limited budget. On the other hand, there are many factors influencing quality. High investment and high cost do not necessarily guarantee high quality.
The price of clinical trials showed a sharp increase nearly 3 years, the quality of clinical trials have obvious change too, but not one to one correspondence between them, both changes are one cause and many fruit, many cause and one result. Price increase is necessary for quality improvement, but not a sufficient condition. Price increase is not positively correlated with quality improvement, certain factors raise prices to improve the quality in some ways, at the same time obstruct the quality improvement in other ways. The lack of industry training and supervision is impeding the rapid development of the SMO industry. New SMO registered spring up at the same time, The shortage of CRC talent has led to a poaching war between SMO companies. CRC frequent jobhopping impetuous atmosphere spreading within the industry, that result in a 14 profit-oriented SMO company short -term development model. It is an ordinary state that training process before the post can be shorten or even free when possible. Another problem is that the management of CRC by SMO company is regulated long-distance supervision. The working districts of CRC are in various hospitals, and the location of SMO company is the registration district. It also makes supervision difficult.
The major of CRC practitioners is mostly undergraduate or even community college graduates in pharmacy or nursing and they are not very excellent individuals In terms of the quality of personnel in the same period same major, in addition, most of them enter CRC industry immediately after graduation, with no working experience and insufficient professional knowledge accumulation. When SMO were limited trained, many incompetent CRCS were sent to hospital to perform CRC functions.
In terms of hospital, when a CRC was sent to site, the investigators' attitude toward the quality of CRC work is excellent CRC is very lucky, usually CRC is very normal, poor CRC is better than none, so we dare not to expect a good CRC, one is better than none. The datasets during and analysed during the current study available from the corresponding author on reasonable request.
All data generated or analysed during this study are included in this published article.

• Competing interests
The authors declare that they have no competing interests.

• Funding
No funding was obtained for this study.

• Authors' contributions
Huafng Chen analyzed and interpreted the study data. Liran Chen was a major contributor in writing the manuscript. All authors read and approved the final manuscript.