Since the State Food and Drug Administration (SFDA) in China regulated the clinical trial industry with an amendment of the Chinese Good Clinical Practice (GCP) guidance, both the quality and integrity of clinical research have improved significantly, resulting in the recognition of more and more Chinese trial results by the international pharmaceutical community. This paper outlines the major regulatory practices related to conducting clinical trials in China.
Since the 1990s, Good Clinical Practice (GCP) has made its way to China through international academic communications and exchanges as well as through investments of many multinational pharmaceutical companies in China, resulting in the increase of clinical trials. With the growing globalisation of the economy in the 1990s, more and more pharmaceutical joint ventures, wholly-owned enterprises and global contract research organisations (CROs) drove the adoption of international standards for clinical trial conduct in China, resulting in a favourable atmosphere for the success of GCP in China. However, many sponsors and CROs looking to establish themselves in this key region need to understand the complexities of GCP-compliant practices of clinical studies in China.
Major laws, regulations and guidelines related to drug studies in China should be as followed:
Although China’s GCP standards are essentially the same as those in the ICH E6 guideline, there are some differences. Some examples of such differences between China GCP standards and the ICF E6 guideline include:
In addition, imported drugs, biological products and blood products should be tested by NICPBP; other chemical products or TCM products may be tested by corresponding provincial drug control institutions or by sponsors themselves.
While the clinical trial permission is applied to SFDA, the sponsor may prepare the initiation of clinical studies. First of all, the sponsor should look up the certified clinical institutions that meet the medical speciality and other logistic requirements of the clinical trial. A pre-study site visit is necessary for sponsor to verify the qualification of the clinical institutions that will undertake the clinical trial. The sponsor shall sign a Clinical Trial Agreement with the leading and the participating institutes selected for the clinical study, and then provide the SFDA approval document, the draft Informed Consent Form, Investigator’s Brochure and jointly improve the clinical trial protocol with reference to technical guidelines. When a clinical trial agreement is negotiated with a clinical institution, a number of documents must be collected from the clinical institutions. Most of these are required by the SFDA regulations and the IEC submission, although some sponsors may require their own additional documents. Both the sponsor and the investigator must have copies of each of these documents. The conclusion after IEC reviews the clinical studies could be:
Once the agreed conclusion is obtained, the sponsor may initiate the trials at the selected clinical institutions. Trainings on the investigator and relevant staffs who participate in clinical trials are mandatory and should be completed before the trial is initiated. These trainings include but are not limited to:
If a sponsor discovers that an institution conducting clinical study is in violation of relevant regulations, or is not following the clinical study protocol, the sponsor shall try to correct the situation. For serious violation, the sponsor may request to suspend or stop the clinical study and shall submit a written report to SFDA and the relevant IEC.
SFDA may request the sponsor to amend the clinical study protocol, suspend or stop the clinical study in any of the following circumstances:
Study monitoring on the conduction of clinical trials is one of regulatory requirements sponsor should take. The frequency of the study monitoring should be dependent on the actual length and needs of clinical trials, and the focus of the study monitoring should be placed on:
During the clinical study, in case a large range or unexpected adverse reaction or serious adverse event occurs, or there is evidence to prove that the investigational drug has significant quality problems, SFDA may adopt emergency mandatory administrative measures to suspend or stop the clinical study, and the sponsor and institutions must immediately stop the study. Any SAE should be reported promptly to SFDA through a national safety web report system.
It is important that the reported data completely and accurately reflects the findings and events of the clinical trials. It is well recognised that the good data management practice is the foundation of good clinical practice. The key areas of the good data management practice have been regulated by SFDA as followed below:
Outcomes of any clinical trials are required to be reported to SFDA in the clinical study report setting. When the CDE is technologically reviewing the NDA application, the sponsor or relevant investigators may be invited to have defenses on the questions and give information about the project and/or the outcomes.
Expectations for laboratories performing biosample analyses in clinical studies
Any laboratories that perform the biosample analyses in clinical studies have to be qualified and operated based on the special regulations targeted to the management of laboratories serving in clinical studies. A management system of quality control in allocation to independent QA staff is essential. Any software and hardware used in the collection, analysis, report and archive of lab data as well as data receiving and transferring are expected to be validated, deployed and implemented according to the GCP-compliant SOPs. The lab facilities and environments, including waste disposal, material handling, reagents administration etc., are expected to meet specifications. The process management of contract administration, standard operation practice and lab data management are regulated in details.
As global sponsors and researchers are aware, both the breadth and level of clinical research activities is on the rise in China. The SFDA has taken great strides to regulate the process of clinical trials on the basis of GCP standards by strengthening international communications and applying learnings from a number of trials, ensuring consistency of compulsory regulations with the global pharmaceutical community. Overall, the SFDA has made it a priority to become more transparent in its regulated activities, offering an improved regulatory environment that enables more sponsors to derive value from data obtained in studies in China. As the spirit of “One World, One GCP Standard,” the SFDA should look to further improve its measures of drug administration, inspection and supervision as it continues to evolve and help drive innovation in drug development.
Safety Monitoring in Clinical Settings
A monitoring and reporting process of drug safety profiles has been recently regulated. The key procedures and requirements of drug safety profiles are as follows:
It is mandatory for pharmaceutical companies and investigator sites to appropriately complete and submit “Reporting Form of Drug Adverse reaction/event” for any adverse events they are aware of.
Domestic drugs developed and manufactured by local pharmaceutical companies should be reported with all AEs related to the drugs in the monitoring period of new drugs; other domestic drugs should be reported with new and serious adverse events.
Foreign drugs developed and manufactured by foreign pharmaceutical facilities should be reported with all AEs related to the drugs since they are granted to an import permission into China from the first day of approval up to five years; after five years, the foreign drugs was then required to report new and serious adverse events.
Any new and serious adverse event (NSAE) of drugs should be reported in 15 days after they are firstly aware, of which death report should be submitted immediately. Other adverse events of drugs should be reported within 30 days after they are firstly aware. Any follow-up information are expected a submission without delay.
When serious adverse events of imported drugs or domestic drugs that are used and occurred oversea (including collections or found from spontaneous reports, post-marketing clinical researches and literature reports) are received, drug enterprises should complete the “Reporting Form of Drug Adverse Events Occurred Oversea” and submitted to the state monitoring center of drug adverse events in 30 days after they are received. Once the source reports or relevant information are requested by the state monitoring center of drug adverse events, the drug enterprises should complete the submission in five days.
Except individual drug AEs, the drug group AEs are required to be reported via a submission of“Basic Information Form of Drug Group Adverse Event.” A drug group AE is defined as any harmful or threaten event to body health or life of certain herbs in relative density of period and geographic area by the same batch of drug, which needs to have urgent interventions.
An annual reporting system of drug safety updates in the monitoring period of drugs is essential except the regular AEs/SAEs monitoring and reporting practices.