What’s New for Clinical Trials in China?
By Jianqing Chang, Vice President of Drug Regulatory Policy, Tigermed Co., Ltd.
On March 30, 2020, the revised Drug Registration Regulation (DRR) was issued by the State Administration for Marketing Regulation and will be put into effect from July 1, 2020, after six rounds for seeking public comments respectively in 2014, 2016, 2017 and in September, October and December in 2019. This is not only the first revision since the current version implemented thirteen years ago, but also a revision with great changes to support the enforcement of the second revision of Drug Administration Law and first edition of Vaccine Administration Law, both became valid since December 1, 2019, and, to fulfil the purposes and the requirements set by the drug review and approval launched in 2015. Considering the unmet medical needs, industry development and voices, regulatory practice, remarkable achievements of the drug review and approval reforms, successful pilot drug MAH system, notice based clinical trial approval, changes of drug classification, annual report system, best practice of reference countries and etc., the DRR was formulated by the National Medical Products Administration (NMPA).
In the revised DRR, we could read a chapter on expedited approval with four procedures, they are breakthrough therapy designation, conditional approval, priority review and approval, and special approval, in which the scope of application, procedure, support policy and other requirements for each procedure are specified. Clinically needed drugs, pediatric drugs, orphan drugs, drugs for major infectious diseases, vaccines urgently needed for disease prevention and control and innovative vaccines are covered for expedited approval.
“The drug authorities of the State Council shall, within 60 working days from the date of acceptance of a clinical trial application, decide on approval or not for the application and notify the clinical trial applicant; where the applicant is not notified within the stipulated period, the application shall be deemed approved.” This is the only one timeframe specified by the Drug Administration Law. To achieve the objective, it is critical to conduct the Pre-IND communication meeting with CDE, and to have the suspension and termination mechanism once needed to control the risk and protect the trial subjects effectively. “The drug administrative department of the State Council shall optimize the drug review and approval work system, strengthen capability building, establish and improve upon communication, expert advisory mechanism etc., optimize the review and approval process, and improve the review and approval productivity. “ Where safety issues or other risks are discovered during the drug clinical trial period, the clinical trial applicant shall promptly adjust the clinical trial protocol, suspend or terminate the clinical trial, and report to the drug administrative department of the State Council. Where necessary, the drug administrative department of the State Council may order the applicant to adjust the clinical trial protocol, suspend or terminate the clinical trial.”
For clinical trial, it is also the first time for Drug Administration Law to have the contents about the ethical committee review and informed consent. “Conducting drug clinical trials shall comply with ethical principles, formulate a clinical trial protocol, and be subject to review and approval by ethics committee. The ethics committee shall establish an ethics review system, to ensure that the ethics review process is independent, objective and equitable, supervise standardized conduct of drug clinical trials, protect the legitimate rights and interests of trial subjects, and safeguard public interest.” “Conducting a drug clinical trial shall make truthful statement and explanation to the trial subjects or their guardians in regard to the details such as the clinical trial objective and risks, obtain an informed consent letter signed voluntarily by the trial subject or his/her guardian, and take effective measures to protect the lawful rights and interests of the trial subjects.” Independent review of ethics committee is of importance then, ethics committee review shall not rely on the technical review conclusion of CDE any longer.
Highlight the DRR changes related to the clinical trials
Apply for first clinical trial approval
- Where the Applicant submits an application for drug clinical trial after the required studies have been completed, relevant study materials listed in requirements for dossiers shall be provided. Where the application dossiers meet requirements after a formal examination, the application shall be accepted. The CDE shall organize pharmaceutical, medical and other professionals to conduct review for accepted drug clinical trial applications. The decision on whether to approve the implementation for any drug clinical trial application shall be made within 60 days from the date of acceptance. The review results are notified to the Applicant via the CDE website; absence of notice from CDE is deemed equivalent to approval and the Applicant can carry out the clinical trial as per the protocol submitted.
- The detailed guidelines about the requirements of the dossiers are under development by the CDE at the present.
File the protocol of the subsequent phased clinical trials
- Where the application for implementation of a clinical trial is approved, subsequent phased clinical trials shall not be conducted until the Sponsor develops the specific Protocol, obtains the approval from the Ethics Committee and submits the Protocol and supporting materials to the CDE website. That means, it is not required to apply for the permission of subsequent phased clinical trials.
File Development Safety Update Report
- The Development Safety Update Report shall be submitted to the CDE website once a year within two months each year after the approval of clinical trial application. The CDE may require the Sponsor to adjust the reporting period according to the review status.
- In case of any suspected unexpected serious adverse reactions (SUSARs) and other information indicative of potential serious safety risks during drug clinical trials, the Sponsor shall timely report to the CDE according to the relevant requirements. The Sponsor may be required to modify the Protocol, Informed Consent Form, Investigator’s Brochure and take other risk control actions based on the risk level, or to suspend or terminate the drug clinical trial if needed.
- The draft Specific Requirements for Development Safety Update Report was formulated and released by the CDE for seeking public comments on November 8, 2019.
Apply for additional indication(s)
- Where additional indication(s) is/are to be added to a drug with approved clinical trial(s), the Applicant shall file a new drug clinical trial application, and the clinical trial shall not be conducted until approval.
- Where additional indication(s) is/are added to an approved drug and for which clinical trial is required, a new drug clinical trial application shall be filed.
File Annual DSUR or apply for variations during the clinical trial
- For any modifications to the Protocol, any non-clinical or pharmaceutical changes or discoveries during the clinical trial, the Sponsor shall evaluate their potential impact on subjects’ safety with reference to the applicable technical guidelines as required.
- Changes that would not affect the safety of subjects, as evaluated by the Sponsor, can be directly implemented during the trial and shall be reported in the DSUR, whereas for those that might potentially affect the safety, a supplementary application shall be filed. The CDE shall decide whether to accept the supplementary application within 60 working days from the date of acceptance, and notify the Applicant of the review result on the CDE website; absence of notice from CDE is deemed equivalent to approval.
- In case of change in Sponsor, the Sponsor after the change shall assume relevant liabilities and obligations in drug clinical trials.
Suspend or terminate the clinical trial
- If safety issues or other risks are identified during a drug clinical trial, the Sponsor shall timely modify the Protocol, suspend or terminate the clinical trial if needed, and report to the CDE.
- In any of the following circumstances, the Sponsor may be required to modify the Protocol, and suspend or terminate the clinical trial: (I) the ethics committee fails to perform its duty; (II) the subjects’ safety cannot be adequately ensured; (III) the Sponsor fails to provide the DSUR as required; (IV) the Sponsor fails to handle and report SUSARs in time; (V) there is evidence to prove that the drug used for the clinical trial is not effective; (VI) a quality problem of the drug used for the clinical trial occurs; (VII) there is a fraud in the clinical trial; (VIII) there is any other GCP violation.
- Where there is any large-scale of unexpected adverse reaction during the clinical trial, or there is evidence to prove any serious quality issue(s) of the drug used for a clinical trial, the Sponsor and the Research Institution(s) shall immediately discontinue the trial. Drug regulatory authorities may order to modify the Protocol, suspend or terminate the clinical trial if needed.
- To resume the clinical trial, a supplementary application shall be filed after the rectification is completed, and the clinical trial may not be resumed before the approval is granted. The approval for drug clinical trial shall become void if no application is submitted, and no approval is issued for clinical trial resumption within three years upon suspension of this trial.
- Any clinical trial terminated shall not be resumed until a new application for clinical trial is submitted and approved.
- Based on the considerations of the administrative measures and technical guidelines from reference countries and the situations in China, for seeking public comments, the draft guidelines of General Risk Management, Suspension and Termination during Clinical Trials was issued by the CDE for seeking public comments on November 13, 2019.
Three years validation period of clinical trial approval
- Drug clinical trials shall be conducted within three years upon approval. The approval shall be void if no subject signs the informed consent within three years upon the approval of clinical trial application.
Register and disclose clinical trial
- Prior to the commencement of the trial, the Sponsor shall upload the trial protocol and other information of the drug on the China Drug Trials Registration and Information Publication Platform. Throughout the drug clinical trial, Sponsor shall continue to update the information and upload the information such as the trial results at the end of the drug clinical trial. Uploaded information will be disclosed at the platform, and the Sponsor shall be responsible for the authenticity of the information.
- The specific requirements for clinical trial registration and information, such as the responsibility entity, registration criterial, scope, principles and ways could be found from draft the Management Rules of Clinical Trial Registration and Information Publication, which was issued by CDE for seeking public comments on November 8, 2019.
Initiate risk based inspection, risk-based extended inspection、for-cause inspection and routine administrative inspection
- The objective is to verify the authenticity and consistency of the application dossiers and commercial production conditions for marketing, and, when necessary, extended inspection activities are to be conducted for manufacturers, suppliers or other trustees of drug substances, excipients and immediate packaging materials and containers.
- The CDE may decide whether to conduct risk-based R&D site inspection according to the level of drug innovation and previous inspection findings.
- The CDE may decide whether to conduct risk-based manufacturing site inspection according to the category, process, facility, previous inspection findings and other factors of the product to be registered.
- Rules, procedures, time limit and requirements for initiation of drug registration inspection shall be developed and issued by the CDE, and those for implementation of drug registration inspection shall be developed and issued by the CFDI.
- Drug regulatory authorities at provinces, autonomous regions and municipalities shall conduct daily supervision and inspection in respect of compliance of GLP and GCP by research institutions performing non-clinical safety evaluation and clinical trial institutions, ensuring that they remain compliant with the statutory requirements.
Apply for Breakthrough Therapy Drug Procedure during clinical trial
- Innovative drugs or modified new drugs for the prevention and treatment of diseases that are seriously life-threatening or seriously affecting the quality of life, provided there are no effective preventive and therapeutic options available for the concerned diseases, or there are significant clinical advantages as supported by the sufficient evidence over the existing therapeutic options.
- The Applicant may, in the key stage of a clinical trial, apply for communication with the CDE.
- The Applicant may submit clinical trial data generated at each stage to the CDE. Based on the existing study data, CDE will give feedback to the Applicant with comments or suggestions on the protocol
- Drugs indicated for treating the diseases seriously life-threatening and for which there are no effective therapeutic options, if clinical trials have demonstrated the efficacy and predicted the clinical value;
- Drugs urgently needed in public health if clinical trials have demonstrated the efficacy and predicted the clinical value;
- Vaccines urgently needed to respond to major public health emergencies or other vaccines considered urgently needed by the National Health Commission if their benefits outweigh risks as evaluated.
- The Applicant shall communicate with the CDE with respect to the conditions for the marketing authorizations and post-marketing research commitment, after which, an application for a Marketing Authorization may be filed if such conditions and research are confirmed.
Dispute resolution before the review conclusion is made
- During the drug registration period, once the review conclusion is “negative”, the CDE shall inform the applicant of the reasons for the “negative” conclusion, and the applicant may file an objection to the CDE within 15 working days. The CDE shall make a comprehensive evaluation with the objection filed by the applicant and give feedback to the applicant.
- If the applicant still has an objection to the comprehensive evaluation result, the CDE shall, as per regulations, organize an expert advisory committee for discussion within 50 working days and make a final review conclusion with the expert discussion results taken into account.
The CDE issued the draft Dispute resolution Procedure of Drug Evaluation Conclusion for seeking public comments on November 26, 2019.
Discuss the new opportunities and challenges of clinical trials.
The up to sixty working days timeframe of clinical trial approval remains the most remarkable and encouraging achievement. In the old days before and the early stage of the drug review and approval reform, for China to join in the simultaneous global development, we had to face the painful obstacle mainly caused by the prolonged clinical trial approval, now it is removed by the law. The further improvement of the communication between the applicant and the CDE as well as the expert consultation system will be of great help to the drug development that are exploratory and risky by nature. The pathway is outlined clearly for the various situations occurred usually during clinical development, such as PSUR or supplementary application. The foreseeable approval timeframe in the future is also related to the introduction of the risk-based site inspection and registration lab test to be conducted in parallel with technical review. The breakthrough therapy drug procedure and conditional approval procedure during clinical trial as well as priority review and approval during the NDA stage will expedite the drug registration progress and shorten the drug lag thoroughly.
The clinical trial approval is accelerated, then, how to control the risk, how to protect the trial subjects’ rights, the revised DRR puts forward the higher requirements by enhancing the development in-process administration, from filing, review and risk-based site inspection till suspension even termination once needed, etc. As to the liabilities of drug entire lifecycle, law violation such as false data, clinical trial initiation without approval, non-compliance with GCP and improper handling of situations during clinical development, may lead to heavier cost.
Encouragingly, the revision of DRR has optimized the overall review and approval framework, systems, principles and procedures. It becomes another important milestone to foster the fast growth of pharmaceutical industry and to further satisfy the unmet medical needs of publics in China.
To support the implementation of the DRR and to strengthen the administration of the entire-lifecycle of drugs, there are 50+ supporting documents or technical guidelines are to be drafted and issued in the coming months.