Following the 7.22 storm, along with CFDA's stringent requirements for clinical trial quality, the biggest changes have been the emergence of Site Management Organization (SMO) and the increase in clinical trial costs in Clinical trials in recent years, as well as less obvious changes such as the increase in audit companies and the centralization of drug management in research site.
1. SMO sprang up like mushrooms and Emergence of audit company
An SMO provides clinical study coordinator services, and sends CRC to the hospital to assist in the implementation of the clinical trial and performs the nonmedical judgment duties authorized by the Principal investigator(PI). SMOs began to develop in 2008 in China and remained small scale until July 22 2015.Then, the number of SMO expanded rapidly, and the staff of SMOs increased, with one SMO growing to include nearly 600 CRCs within one year of its establishment.
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. It's independent examine mode makes the division of labor refined and specialized.
2. Growth of clinical trial cost
2.1 CRC service fee
The increase in CRC fee was the most rapid and significant change associated with the cost of clinical trials, which is clearly shown in Fig. 1–4.
2.2 Investigator labor fee
The increase in the investigator labor fee is divided into explicit growth, which can be clearly shown in Fig. 1–4, and implicit growth. Implicit growth refers to the addition of the CRC, in that part of the nonmedical judgment work that done by CRC. The Investigators' labor fees have increased in disguised form because of the decrease in their workload.
2. 3 Audit company fees
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 a fee of 80 to 100 thousand yuan. The number of site that are audited is determined by the evaluation of and in consultation with the sponsor and at the request of the clinical trial site.
2. 4 Drug management fee and quality control fee
The drug management fee is small, and each subject is generally will charge a fee of 200–500 yuan according to the complexity level of the clinical trial, this method has played a positive role in regulating the management of drugs in the implementation of drug clinical trials. Before 7.22, the drug clinical trial research institutions charged lower quality control fees, and some institution began charging quality control fees after 7.22. The fees charged by agencies vary, and the overall amount is small. The fees are earmark for this specified purpose and therefore play a relatively important role in quality control .
3. 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 necessarily mean high quality, but low costs certainly cannot yield high quality. The consensus in the industry is that low cost cannot guarantee the quality of clinical trials, and any step is requires a budget for labor and material resources. Research institutions could perform high-quality clinical trials for a 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 over nearly 3 years. The quality of clinical trials also undergoes obvious change, but there is no direct correspondence between them . Both changes can have one cause and many subsequent effects or many causes and one effect.
4. When CRC involvement hinders progress in the quality of clinical trials in some respects, the following measures must be implemented.
4.1 The growing SMO companies need to be regulated
Most of the cost increases in clinical trials are positively correlated with quality improvements, but the increase in costs caused by the booming development of SMO and the improvement in the quality of clinical trials should be viewed in two aspects The CRC service fee paid by the sponsor to the SMO accounts for approximately 30% of the total investment in clinical trials, which cannot be underestimated. The intervention of the CRC has undeniably provided convenience and some assistance for investigators to improve the quality of clinical trials. However, there are also disadvantages associated with the deficient abilities of the CRC, the investigator absence of the management of clinical trials and the excessive dependence of the investigator on the CRC.
4.2 Absence and disadvantages associated with the CRC needs to be prohibited
After 7.22, the research institutions that undertake clinical drug trials asked CRCs to facilitate trials at the time of signing the agreement with the sponsor or contract research organization (CRO). The CRC agreement is a separate triple agreement is generally independent from the main clinical trial agreement and is signed by the sponsor (or CRO), SMO and the hospital (research institution). Since the financial management of Chinese public hospitals does not allow payment to be easily sent to businesses such as SMOs, it is stipulated in the triple agreement that the sponsor or CRO shall remit money to the SMO, and the SMO shall send a CRC with a relevant professional background and GCP training to the hospital to assist with the investigator’s work. The CRC must sign a confidentiality agreement concerning the work content when the principal investigator authorizes and assigns the CRC tasks of nonmedical judgment. The persons responsible for the work content performed by the CRC are principal investigators, subinvestigators,when the CRC is incompetent, hospitals (research institutions) have the right to require the SMOs to replace him or her with a competent CRC.
The lack of industry training and supervision impedes the rapid development of the SMO industry. Newly registered SMOs have sprung up, and the shortage of CRC talent has led to a war between SMO companies. CRCs frequently job hop, and an impetuous atmosphere is spreading within the industry, which results in a profit-oriented short-term development model among SMOs. The training process before a new CRC takes up the post can be shortened or even omitted. Another problem is that the management of CRCs by SMOs is regulated via long-distance supervision. The CRCs work in various hospitals in different districts, and the SMO functions in the registration district, which also makes supervision difficult.
The majority of CRC practitioners are mostly undergraduate or even community college graduates in pharmacy or nursing, and their professional skills are poor. In addition, most of them enter the CRC industry immediately after graduation, with no working experience and insufficient professional knowledge accumulation. In addition to the inadequate training of SMO companies,many incompetent CRCs are sent to hospitals to perform CRC functions.
From the perspective of the hospital, the investigators consider themselves very lucky if an excellent CRC is sent to their site; a CRC of average quality is normal; and even a incompetent CRC is better than none. In other words, the investigators dare not expect a good CRC, considering that any CRC is better than none.
While the CRCs have low-quality skills, they have plenty of time to assist the investigators; on the other hand, the investigators are too busy with clinical work and his patients to focus on the clinical trials. In such a state, CRCs perform the duties of many of the investigators and even the principal investigators. The principal investigators’ work is to sign for authorizations, then engage in clinical work, hand over the clinical trial work to CRC, When the clinical trial forms is need to be signed during the subsequent trial, these forms are all signed by the primary investigator and the investigator after the CRC has filled in and prepared. Most of the time, the contents of the signed forms are not asked before the primary investigator and the investigator hurriedly sign them. Another common phenomenon concerns the CRCs’ use of the investigators’ account and password authorized by the sponsor for logging into the EDC (electronic data capture system). when CRC used the investigators ' account and passwords to fill out numerous forms, the investigators ignored the review before the investigator and primary investigator signed it, so the process and date completed by the CRCs have not been verified by investigators Blind signatures, error-ridden process and content and the investigators’ leaking of EDC account passwords to CRCs mean that the monitoring of the clinical trials may not cover the whole process and entail hidden dangers in clinical drug trials.
4.3 The phenomenon of sponsors and clinical trial institutions kidnapped by SMOs needs to be improved
A hospital or clinical trial institution requires a sponsor to provide a CRC for a clinical trial; the sponsor remits the funds and entrusts the task to an SMO; and the SMO provides CRC services and sends a CRC to the clinical trial site. The long-distance supervision of the CRC by the SMO works poorly, and there is a lag in the evaluation of CRC work quality in clinical trials site..In that situation, timely and effective feedback is lacking. Once a CRC's incompetence is discovered, the effects on the quality of the clinical trial and the trial schedule are irreversible. The long-distance supervision by the sponsor and the SMO cannot effectively control the quality of CRCs. If the hospital office managers and investigators of clinical trials find that a CRC does not meet the quality requirements and a replacement of CRC is required, the hospital staff must consider the time and opportunity costs of CRC turnover. There are risks. For example, the replacement CRC may also be incompetent; it takes time for the new CRC become familiar with the work; interactions with different CRCs may also lead to mutual buck-passing due to the work handover when problems arise. The current shortage of CRCs and scarcity of high-quality CRCs have led SMOs to “kidnap” bidders in terms of service price and “kidnap” hospitals and investigators in terms of service quality.
4.4 New CRC models should be explored
In addition to the SMOs providing CRCs, individual hospitals, such as Zhongshan Hospital Affiliated of Fudan University, Beijing 301 Hospital, Hunan Cancer Hospital and Cancer Hospital Affiliated of Sun Yat-sen University, established their own CRC teams to assist with clinical trials. Their purpose is to create a high-level and stable CRC team that can assist investigators in accomplishing high-quality clinical drug trials, turning from the model of outsourcing CRC services from SMOs to the model of training, employing and supervising CRCs within the hospital itself. The hospitals’ own CRCs account for a small proportion of the total number of CRCs currently employed by SMOs. Each model for supplying CRCs, either outsourcing from SMOs or providing CRCs within the hospital, has advantages and disadvantages. CRCs sent by SMOs can cover clinical trial sites in cities across the country, but the personnel sent by SMOs to hospitals need to undergo a process of familiarization and be accepted by hospitals. A CRC team within a hospital has many advantages in undertaking local work, but it cannot support the clinical trial needs of other hospitals.
There are no universally recognized regulations on CRCs in current China, and some professional associations are actively formulating industry standards and qualification certifications for CRCs. For example, the Professional Committee of Pharmaceutical Clinical Trials of Guangdong put forward the Guangdong consensus on CRC management, and the Alliance of Pharmaceutical Clinical Trial Institutions issued CRC industry guidelines. Despite the efforts of the sponsors, hospitals and even SMOs, there are no clear and commonly accepted operational standards.
From a positive perspective, 7.22 has opened up a new situation of quality requirements for clinical trials, but much remains to be accomplished in the gradual and ongoing process of improving clinical drug trials. Only cooperation and continuous collaborative efforts can lead to progress.