Good Clinical Practice-Compliant Clinical Studies in China

Daniel Liu,  Director China Development Medidata Solutions Worldwide

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.

Beijing, 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. 

Legal and Regulatory Basis for Drug Researchers

Major laws, regulations and guidelines related to drug studies in China should be as followed:

  • Drug Administration Law of People’s Republic of China
  • Regulations for Implementation of the Drug Administration Law of the People’s Republic of China
  • Drug Registration Regulation
  • Regulation for Drug GCP
  • Provisions for Handling Malpractices in Drug Research and Registration (interim)
  • Rules for Drug Clinical Study
  • Provisional Rules for Drug Research Record
  • Measures for Clinical Research Supervision
  • Guideline of Drug Clinical Trial
  • Rules for Statistics in Clinical Study
  • Guidance of Ethic Review for Drug Clinical Trials
  • Measure for Drug Clinical Trial Institutions Qualification (interim)
  • Management Guide of Laboratories Serving to Biosample Analyses in Clinical Trials (interim)
  • Management Measures of Reporting and Monitoring Adverse Events of Drugs

Characteristics of Clinical Trials Conductions in China

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:

  • ICH E6 GCP calls for investigators to report only unexpected and serious AEs to IRB/ECs, but the GCP standards in China (Chapter 3, Article 10) state that, “any serious events that occur during the trials shall be reported to the Ethics Committee.”
  • The Chinese GCP standard states that the investigator must sign the informed consent form, while the ICH E6 GCP states that the subject and “the person who conducted the informed consent discussion” need to sign the informed consent.
  • SFDA requires the clinical institution to set up a special administrative office with full-time staff to provide oversight on clinical trial activities and outcomes. The office must strictly implement relevant laws and regulations and establish a quality assurance system for the clinical trials according to GCP. Quality Assurance is responsible for auditing the authenticity and standardisation of the clinical research, ensuring that SOPs, science and compliance in the clinical trials, ensuring that the safety and rights of the subjects are protected and ensuring the accuracy and completeness of the clinical data obtained. Some elements of these responsibilities are directly assigned to the investigators in ICH E6.
  • All clinical trials in China should be conducted within clinical institutions (hospitals) that obtained, from SFDA, a certificate of qualification to serve as an authorised clinical trial site in relevant medical specialities.
  • Without a certificate of qualification to conduct a clinical trial (issued by SFDA), a clinical institution cannot undertake a clinical trial in China. Such a certificate is granted after an application and then the pass after an on-site regulatory inspection.
  • The drug products used in the clinical trials must be submitted to the National Institute of the Control of Pharmaceutical and Biological Products (NICPBP) for an assay. Without the certificate of analysis issued by NICPBP, the institutional ethics committee (IEC) will not approve the clinical study. 
  • Clinical studies cannot be initiated at clinical institutions until the sponsor and investigator receive the approval letter issued by SFDA.
  • Clinical studies must be initiated only after the IEC issues an approval letter.  The IEC should be registered to SFDA.  The submission package provided by the investigators and sponsors to the IEC generally includes, but is not limited to:
  • The SFDA approval letter
  • Certificate of Analysis for the drug issued by NICPBP or corresponding institutes
  • Investigator Brochure
  • Clinical Protocol (attached with the list of principal investigator and clinical staff members and their resumes)
  • Sample of Informed Consent Form
  • Case Report Form
  • Relevant subject recruitment materials
  • Resumes of principal investigators
  • Other approval, comments or disapproval evidences by other IEC on the protocol, if appropriate.

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.

Major Provisions to Run a Clinical Trial in China

Clinical Study Procedures

Before clinical trials

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:

  • Agreed
  • Agreed after necessary revision
  • Disagreed
  • Terminated or suspended previous approved clinical trial

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: 

  • GCP
  • Clinical protocol
  • Trial flow procedure
  • Relevant SOPs
  • ICF requirements and procedure
  • Establishment and maintenance of source documents and study files
  • CRF completion
  • Trial milestone expectation

During clinical trials

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:

  • The Ethics Committee has failed to perform its duty or
  • The safety of the subjects cannot be effectively ensured
  • Serious adverse event was not timely reported
  • The clinical study progress report was not submitted in a timely fashion
  • The completion of the clinical study is more than 3 years behind the original completion date and there are still no results which can be evaluated
  • Evidence that the investigational drug is not any effective
  • Quality problems in the drug used for clinical trials
  • Fraud in the clinical study
  • Other circumstances violating GCP.

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:

  • Protection of rights, safety and well-being of human subjects
  • Subjects status, including enrolment rate, eligible rate and compliant rate to the approved protocol/amendments
  • Principal investigator behaviours, including compliance with the approved protocol/amendments, SOPs, GCP and other regulatory requirements
  • Reporting data integrity, including accuracy, complete and reliability, adequate informed consent process, consistence of medical records and lab results relative to CRF.

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.

At the end of clinical trials

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:

  • Procedures for the entry, verification and validation management of reported data
  • Management for data queries of any errors, omissions or items requiring clarification or changes to collected data detected during the trial, by computer edits or during the data analysis
  • Expected requirements for database lock
  • Measures for statistical analysis of the reported data
  • Generation of a clinical study report.

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.

Looking Ahead

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.

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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.

Author Bio

Daniel Liu

Daniel Liu is the Director of China Development at Medidata Solutions. Since receiving his PhD in pharmacology, Daniel has dedicated his career to management and operations of global clinical studies, working with such companies as Novartis, Pfizer, Schering-Plough and Johnson&Johnson. He is a member of the DIA China advisory council, a board member of the DIA global training committee and author of the book “Clinical Trial Methodology of Medicinal Products.

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