Regulation update in real-world research of unregistered drug and change during drug application review

The Implementation Measures for Carrying out Real-World Research on Unregistered Imported Drugs with Urgent Clinical Needs in Hainan, China

Real World Evidence has been allowed to be used as supplemental evidence of clinical evaluations in the application for marketing authorization of the imported drugs for urgent clinical needs with the NMPA in China since 2019. On April 29, 2021, Hainan branch of the NMPA (“Hainan MPA”), and the Administration Bureau of Hainan Boao Lecheng International Medical Tourism Pilot Zone (“Lecheng Bureau”) jointly released the Service Guideline for Carrying out Pilot Real-World Research for Imported Drugs in Hainan Boao Lecheng International Medical Tourism Pilot Zone (“2021 Service Guideline”), launching the pilot real-world research program in Hainan Province. The 2021 Service Guideline is very brief and only provides the general procedure for the application for enrolment in the pilot program. In practice, despite it is said that being enrolled in the pilot programs provides foreign drug companies with multiple opportunities to communicate with the NMPA, the Center for Drug Evaluation of the NMPA (“CDE”) and Hainan MPA, facilitating the registration procedures for marketing authorization of the imported drugs for urgent clinical needs, according to a report of the CDE, since 2019 and as of August 5, 2022, only 10 products have been enrolled in the pilot real-world research program in Hainan Province, 3 of which have been approved for marketing authorization by using real-world data. 
On November 16, 2022, the CDE, together with Hainan MPA and Lecheng Bureau, released the Implementation Measures for Carrying out Real-World Research on Drugs (“2022 Implementation Measures”), which became effective on the same day. Compared to the 2021 Service Guideline, the 2022 Implementation Measures set forth further detailed procedural requirements for the application for enrollment in the pilot real-world research program, including how the CDE would interact with Hainan MPA in this regard. 
The 2022 Implementation Measures additionally set forth working procedures for applying for formal communications with authorities, and specifically point out that applicants are allowed to apply for communications with authorities (i) after submitting the application for enrollment in the pilot real-world research program, (ii) during the real-world research, (iii) prior to the application for marketing authorization, and (iv) during the authorities’ review process of the marketing authorization. Applicants’ inquiries would first be reviewed and answered by the Hainan MPA, and Hainan MPA would forward the inquiries to the CDE when it views it as necessary. 
Furthermore, according to the 2022 Implementation Measures, under the following circumstances, applicants shall exit from the pilot real-world research program: 

• where the applicant has not carried out the real-world research within 3 months after the enrolment, or suspends the research after 3 months and does not have a plan to continue (unless due to force majeure);

• where the applicant has not carried out the real-world research according to the approved plan, or does not report when there is a substantial change in the protocol;

• where the pilot plan cannot be implemented and there is no alternative;

• where there are issues in the authenticity of the research data;

• where the applicant violates relevant laws and regulations, and the authorities view it necessary to exit; and

•  where the applicant gives up initiatively.

With the 2022 Implementation Measures, the pilot real-world research program seems less mysterious to the public. It also demonstrates the authorities’ supportive attitude towards the faster registration process of imported drugs with urgent clinical needs by using the real world evidence collected in the real-world research program in Hainan. 

The Working Procedures for Changes during the Review Period of Drug Registration Applications

With the release of the Working Procedures for Changes during the Review Period of Drug Registration Applications (For Trial) (“Procedures”) on November 9, 2022 by the Center for Drug Evaluation of the NMPA (“CDE”), which came into effect on the same day, the drug companies now are provided with a clearer procedure in place on how to apply for the non-technical changes (such as the change of local agent and/or marketing authorization holder) during the drug review period with the NMPA  
The Procedures specially apply to the non-technical changes to be applied during the NMPA’s review of clinical trial applications (“CTA”), new drug applications (“NDA”), supplemental applications, and renewal applications of imported drugs. The CDE indicates in the Procedure that the applicants are encouraged to communicate with the CDE in advance on the proposed changes. In general, the timeline of technical review of the drug registration will not be affected by the change application raised in accordance with the Procedures. Please note that (a) any significant changes in the NDA that may affect the safety, efficacy and quality controllability of the drug (i.e. technical changes) and (b) the change of applicant entity in the CTA are explicitly excluded from the applicable scope of the Procedures, which means that in the registration application stage, the NDA applicants need to withdraw the drug registration application at issue and submit a new application after supplemental research if there is any technical changes, and in the clinical trial stage, the CTA applicants also need to withdraw the application and submit the new one if there is any change of applicant entity.

We have summarized the changes that can be applied and cannot be applied in details in the table below:

Authored by Lu Zhou, Jessie Xie, and Carol Shao.