China: Amended Drug Registration Regulation to Strengthen and Streamline New Drug Regulation
On March 30, 2020, the State Administration for Market Regulation (SAMR) enacted the Amended Drug Registration Regulation (DRR) as part of its efforts to strengthen and streamline its regulation of the pharmaceutical industry. The DRR seeks, on the one hand, to further confirm a series of changes made in drug evaluation and approval in recent years, and, on the other, to implement in full a series of processes proposed in the Drug Administration Law (DAL), including who is authorized to market drugs (“marketing authorization holder”), implied licensing for clinical trials, priority evaluation of drugs, and management of changes after drugs are launched on the market, clearly specifying requirements for procedures for drug registration and rights and obligations of all people, in order to form a comprehensive system for the management of drug registration. The DRR will take effect on July 1, 2020.
As one of the basic principles of drug administration expressly proposed in the DAL, risk administration is now part and parcel of the DRR. Risk management specifies risk minimization through a process of risk identification, assessment and control.
I. Strengthening Risk Management of Clinical Research and Ensuring Drug Safety
1. Development Safety Update Report (DSUR)
DRR aims to set up comprehensive information reporting on safety risks in clinical research by establishing the Development Safety Update Report system (DSUR system), to ensure the quality of clinical trials and the control of corresponding risks.
Article 28 of the DRR provides that the sponsor of a clinical trial (Sponsor) shall, on a regular basis, submit via the website of the Center for Drug Evaluation of the NMPA (CDE) safety update reports (SUR) during the development of any drug. These reports must be submitted once a year no later than within two months of each anniversary of the approval of the application for the drug clinical trial. CDE has the discretion to require the Sponsor to adjust the reporting period depending on the outcome of the review.
In addition, DRR obliges the Sponsor to report any suspicious and unexpected serious adverse reactions and any other information pointing up potential serious safety risks to the CDE in a “timely manner”. This is distinct from the information provided to DSUR, in order to ensure that regulators are made aware of the severity of safety risks and can strengthen any risk controls that may be needed. Where the clinical trial program, consent form, investigator’s brochure, or anything else, needs adjustment, the applicant of the clinical trial may be asked to suspend or terminate the clinical trial to ensure the safety of those people taking part in the trial, if that is considered necessary.
2. Management of Changes During Clinical Trials
Clinical research is a key stage of drug development. During clinical trials, changes in pharmacology and clinical protocols will inevitably occur as the Sponsor obtains greater knowledge about the drug. This can also lead to adjustments and improvements in how the drug moves from clinical trial to manufacturing.
Article 29 of the DRR stipulates that during a clinical trial, if there are any changes to the trial, or if there are non-clinical or pharmaceutical changes, or where new information of discoveries come to light, the Sponsor must carry out an assessment of the impact of those changes on the safety of those taking part in the trial. If a Sponsor’s assessment is that the safety of the individuals will not be adversely affected, the Sponsor may continue to implement the trial and report accordingly in the SURs. Where the Sponsor assesses that the risks to the safety of those participating in the trial have increased, it must submit a supplementary application.
3. Four Accelerated Approval Pathways
The DRR implements changes to the country’s accelerated approval channels, as per the earlier draft DRR and guidelines released by the CDE in November 2019. According to the DDR, four accelerated approval channels would be established:
- a new breakthrough therapy designation (BTD), which are to be used during drug clinical trials;
- conditional approvals for urgently needed drugs based on surrogate outcomes and end points or other clinical datasets;
- priority reviews covering market approval filings; and
- special review for drugs needed for major public health
The timeline for prioritized marketing review would be reduced to 130 working days, and to 70 for urgently clinically needed drugs and rare disease products not yet available in China.
II. Strengthening Risk Management post-Marketing
1. Marketing Authorization Holder (MAH)
Within the DRR, there has been set up the marketing authorization holder (MAH) system. This stipulates that those applying to register new drugs must be an enterprise or a drug development institution with corresponding legal responsibilities. Foreign applicants must designate a corporate legal representative in China to handle any drug registration or related matters.
China is ramping up its controls of drug development, registration, and post-market supervision; imposing more stringent safety rules on both clinical and non-clinical drug research institutions; integrating registration licenses; and clarifying inspection procedures and follow-up processing. The central government will hold businesses to account, specify obligations for drug development, registration, and production, and clarify the division of powers and responsibilities related to supervision and inspection. The authorities will also review penalties imposed for transgressions and crackdown on data fraud and other illegal activities.
2. Classification of Changes in Drug Production
Article 79 of the DAL stipulates that changes in the drug production process shall be subject to classification according to the degree of risk and impact. The DRR uses the classification of Classes I, II and III (which have been in use since 2008), which also apply to the management of any changes. All changes are classified, whether these changes cover examination and approval, are in connection with record filing, relate to the risk profile of the drug, or affect the safety, effectiveness and quality controllability.
According to Articles 78 to Article 80 of the DRR, significant changes in the production process, changes in key contents of instructions, and the transfer of drug marketing authorization by MAH holders are generally identified as high risks, in which case the MAH will need to submit a supplementary application for approval. For any moderate change in the production process, change in package labels, drug repackaging and any other circumstances with moderate degree of risk and impact, the MAH will need to file those changes to the CDE or the competent provincial authority. Any minor changes in the production process, entailing low risk to safety, effectiveness and quality, need only be reported in the MAH’s annual report.
3. Conditional Approval for New Drugs
In order to encourage the research and development of new drugs for which there is high clinical demand and to accelerate the marketing of drugs where there is urgent clinical need, the applicant may apply for conditional approval. These will be those drugs used to treat serious life-threatening diseases where there is, as yet, no effective treatment, or drugs and vaccines urgently needed for public health purposes, provided the clinical research data show their curative effects and predict clinical value. The applicant must satisfy the risk management requirements set out in both the DAL and the DRR in order to receive conditional approval for new drugs.
With respect to drugs that have been granted conditional approval, MAHs will need to continue to adopt continuing risk management processes even after the drugs are marketed, clinical trials are completed and research finished within specified time limits, and to submit a supplementary application for approval, pursuant to Article 66 of the DRR. Post-marketing risk management measures, usually in the form of risk management plans, shall contain information on how to identify known risks and potential risks in how the drugs are clinically working, and put forward plans for pharmacovigilance activities that minimize risk, aggregate all drug safety risk information and include measures to reduce risks using information analysis and evaluation.
Further refinements were made to the conditional approval system, with the release by DCE on April 30th of a draft proposal (Draft Proposal) setting out further review and approval procedures, covering detailed procedures, specific requirements, application scope and qualification criteria. According to the Draft Proposal, the special review and approval process is applied to:
- drugs that treat diseases which are seriously life-threatening and where there is no effective treatment and for which clinical studies confirm the efficacy and forecast the clinical value of the drugs;
- drugs urgently needed for public health, where their efficacy has been proved in clinical trials; and
- vaccines needed for a major public health emergency, or urgently needed by the National Health Commission, where the benefits are considered to outweigh
If the applicant plans to file for a conditional approval, a class II meeting1 application shall be submitted to the CDE and written opinions shall be obtained before the filing. If the drug is already classed as a BTD drug, a class I2 meeting will satisfy.
If the early meeting with CDE and subsequent evaluation confirm the eligibility for a conditional market approval filing, the applicant may file simultaneously alongside new drug registration application. The drug registration certificate is then issued, along with such post-marketing clinical trial or study requirements including the due date.