On Aug. 25, 2023, China National Medical Products Administration (NMPA) released the revised draft of Work Process for Conditional Approval of Drug Marketing Authorization Applications (Trial).
Conditional approval is one of the four expedited programs for drug registration in China, with its general regulations briefly stated in the Provisions of Drug Registration.
Since July 2020, China has been implementing the mechanism for conditional approval, but the revised draft indicate the regulator’s attempt of guiding the stakeholders away from leveraging the incumbent mechanism to market similar products.
The attempt is implicit in the requirement that “when one drug is conditionally approved, CDE, in principle, will not consent to the clinical trial application for a drug with the same mechanism, target, and indication aimed for conditional approval”. This requirement is meant for preventing too many companies pouring resources into the same target.
Another noteworthy limitation for the industry is that before submitting the application for conditional approval, the applicant should start the confirmatory clinical trial and then complete the trial within 4 years.
The draft imparts a tone that the regulators is becoming stricter about conditional approval instead of generously nodding to drugs as long as they are clinically needed.
1. Background for Revising the Conditional Approval Process
In China, a small fraction of conditionally approved drugs received full approval. Among the 75 drugs conditionally approved from 2020 to 2022, only 8 achieved full approval (data from CDE's 2022 Drug Evaluation Report). China's drug regulator may worry that after getting the conditional approval, companies did not make sufficient efforts to do the subsequent studies and thus failed to get full approval.
There may also be a concern that companies are crowding on the same lane. According to Yaozh’s statistics, tumor treatment accounts for 79% of the conditionally approved drugs. Too many overlapping researches could lead to wastes of clinical resources.
Hence, from the requirements specified below, we can see that CDE sets limitations for companies applying for conditional approval, and determines the time scale for subsequent studies after conditional approval.
2. Application Scope of Conditional Approval
During the clinical trial stage, any of the following three categories of drugs (including traditional Chinese medicines, chemical drugs, and biological products) are eligible for conditional approval application
1) Drug for serious life-threatening conditions which currently have no effective treatment; and the drug’s existing clinical data have demonstrated the drug's effectiveness and supported its clinical value.
2) Drug urgently needed for public health*; and the drug’s existing clinical data have demonstrated the drug's effectiveness and supported its clinical value. *The drugs needed by public health should be proposed by National Health Commission (NHC) or relevant departments.
3) Vaccines that are recognized by the NHC that they are urgently needed for severe public health emergencies*, or for other urgent needs; and as evaluated, benefits outweigh risks. *Vaccines urgently needed for severe public health emergences should be prophylactic vaccines for Class II and Class I public health emergencies identified by the Emergency Provisions for Public Health Emergencies and National Public Health Emergency Response Plan.
3. Conditional Approval Process
3.1. Applicant submits the application for early-stage communication (category II meeting)
The applicant, who has sufficiently evaluated the proposed drug during the clinical trial, is encouraged by China NMPA to communicate with the Center for Drug Evaluation (CDE), NMPA’s affiliate that conducts technical review of drug applications, on the following items:
Clinical research plan for conditional approval;
Design of the pivotal clinical trial and determination of efficacy endpoints;
Other prerequisites for conditional approval;
Design and implementation plan of the post-marketing clinical trial, etc.
3.2. Applicant submits the application for pre-NDA communication (category II meeting)
Before handing in the new drug application (NDA) to CDE, the applicant should communicate with CDE about the prerequisites for conditional marketing authorization, post-marketing research, deadline for the research, etc. The communication should take place after the launch of confirmatory research, which means the first subject has joined in the clinical trial.
The applicant can also communicate with CDE on the priority review if the applicant intends to make the drug prioritized in the CDE’s review process. If the proposed drug has been admitted as a breakthrough therapy, the applicant can apply for having a category I meeting with CDE.
3.3. Applicant submits the application for conditional approval
After getting CDE’s consent in the previous rounds of communication, the applicant can submit the application for conditional approval to CDE, along with NDA and supporting technical documents.
The application for priority review can also be submitted altogether with the above applications.
3.4. CDE reviews and approves the application for conditional approval
If the drug is conditionally approved after review, the applicant will receive the drug registration certificate, on which the expiration date, the required post-marketing research, and the research’s deadline will be stated. In principle, the deadline will be no later than 4 years from the approval date.
The expiration date of the drug registration certificate will be determined according to the deadline for the post-marketing research and CDE’s review of the research result.
3.5. Applicant conducts post-marketing research stipulated in the conditions
For the conditionally approved drug, the applicant should take risk management measures, complete clinical trials within time limits, and report the research progress to CDE every 12 months since the conditional approval.
If the stipulated clinical trial cannot be conducted due to objective reasons, the applicant can submit a supplemental application and, if get approved, revise the original clinical trial plan.
If the stipulated clinical trial cannot be completed within the time limit, the MAH can submit a supplemental application to continue the clinical trial after the deadline. During the prolonged research, the drug should be suspended from sale. After getting the patients’ consent, the applicant can continue using the drug on them until the course of treatment is completed.
3.6. MAH applies for full approval
When approaching the end of post-marketing research, the MAH of the conditionally approved drug should submit a supplemental application for full approval.
If approved, the drug registration certificate’s valid period will be 5 years, same as those for drugs that go through the routine application process (without conditional approval) to obtain full approval. The 5 years is from the date when the supplemental application is approved.
If the post-marketing research cannot prove the conditionally approved drug’s benefits outweighs risks, CDE will dismiss the supplemental application and issue a disapproval note to the MAH. As a result, the previously issued drug registration certificate for conditional approval will be annulled by NMPA.
4. Other Requirements
3.1. Conditionally approved drugs, before getting full approval, should not be admitted as reference listed drugs (RLDs).
3.2. For drug products/indications that are conditionally approved, only after full approval can the MAH applies for drug registration certificate renewal within the six months before the 5-year valid period is due.
3.3. The MAH of the conditionally approved product/indication cannot be changed before the product/indication is fully approved.
Contact BaiPharm if you’d like to know more about drug regulations in China.
Related
breakthrough therapy designation (BTD)
conditional approval (CA)
priority review (PR)
special approval (SA)
