New Developments in China’s Drug Change Management Regulations
The Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) recently released the Acceptance Review Guideline on Biological Products Changes (for Trial Implementation). It is the latest development in China’s regulations of drug change management since the promulgation of the newly amended Drug Administration Law in 2019 and more than 20 regulations and technical guidelines. It is essential for pharmaceutical companies doing business in China to fully understand these new developments in order to comply with the regulatory requirements for drug change management.
A. Latest Developments in China’s Drug Change Management Regulations
The legal framework of China’s drug change management is primarily set out under the following five laws and regulations: Drug Administration Law, Drug Registration Regulation, Administrative Measures on Drug Postmarketing Changes (for Trial Implementation) (the Measures on Drug Postmarketing Changes), Administrative Measures on the Supervision of Drug Manufacturing, and Good Manufacturing Practice for Drugs. These laws and regulations establish the general principles of drug change management in China, categorize and manage drug changes according to time of occurrence and types of changes, and require sponsors, marketing authorization holders (MAHs), and drug manufacturers to obtain approvals and submit notification filings or annual report filings, as applicable.
1. Premarketing Change Management
a. Drug Change During Clinical Trial
Article 29 of the Drug Registration Regulation requires that whenever there is a clinical trial protocol change, non-clinical or pharmacological change, or new discovery during drug clinical trial, the sponsor shall evaluate its impact on the safety of the study subjects. If it is believed that there is no impact on the safety of the study subjects, the sponsor may implement such change directly and report in the safety update report during the clinical research and development; if there may be additional safety risks to the study subjects, the sponsor must submit a supplementary application.
b. Drug Change During Review and Approval of Marketing Authorization Application
For any change during the review and approval of a marketing authorization application, Article 40 of the Drug Registration Regulation provides that where there is a significant change that may impact the safety, efficacy, and quality controllability of drugs, the applicant shall withdraw the original registration application and conduct a supplementary study before submitting a new application. For changes not involving review of technical contents, such as a change to an applicant’s name and registered address, the applicant shall notify the CDE in writing and submit supporting documents.
2. Postmarketing Change Management
a. Determination and Communication of Drug Change Classification
The Drug Registration Regulation classifies postmarketing changes as major, moderate, or minor changes based on the risk levels of such changes on the safety, efficacy, and quality controllability of drugs. CDE has also promulgated relevant technical guidelines that help MAHs to determine the classification of changes.
If an MAH is unable to classify the drug change after conducting research and verification according to the technical guidelines, such MAH may communicate the problem to the drug regulatory authorities in accordance with the Measures on Drug Postmarketing Changes. Domestic MAHs may communicate with provincial-level regulatory authorities according to the procedures determined by such provincial-level regulatory authorities, and foreign MAHs may communicate with the CDE according to the procedures for communications during the drug registration.
b. MAH Change
According to the Measures on Drug Postmarketing Changes, a change of MAH is a major change subject to prior approval, and it can be divided into three categories: (1) change of domestic MAH, (2) change of foreign MAH, and (3) transfer of manufacturing from overseas to China for a drug manufactured abroad but already marketed in China. For changes of domestic MAHs or foreign MAHs, the MAH after the change must file a supplementary application with the CDE. For transfer of manufacturing from overseas to China for a drug manufactured abroad but already marketed in China, the domestic applicant must file a new registration application in accordance with the requirements and procedures of drug marketing registration application; the applicant may submit pharmacological materials as well as non-clinical and clinical study materials (if applicable) that were included in the original overseas registration application. If meeting the requirements, that drug can serve as a reference listed drug.
For changes such as those to the name of an MAH, the name of a manufacturer, and manufacturing address, the MAH shall submit notification filings to the provincial-level drug regulatory authorities. For similar changes to drugs manufactured outside China, the MAH shall submit notification filings to the CDE.
c. Manufacturing Site Change
The Measures on Drug Postmarketing Changes provide that where there is a drug manufacturing site change, the formulation, production processes, and quality standards of that drug shall remain the same after the change; if different, the MAH shall conduct a thorough study, evaluation, and necessary verification, and the MAH shall manage the change through prior approvals, notification filings, or annual reports.
For a domestic MAH or manufacturer changing its own manufacturing site, or for a domestic MAH changing its manufacturer, the MAH shall conduct a study, evaluation, and necessary verification, and the MAH shall file an application for change of the drug manufacturing license with the provincial-level drug regulatory authority. A foreign MAH who changes its overseas drug manufacturing site to a new overseas site shall conduct a study, evaluation, and necessary verification, and this foreign MAH shall manage the change through a supplementary application or notification filing.
d. Other Changes
The Measures on Drug Postmarketing Changes also govern changes to other drug registration matters, including changes to the manufacturing processes such as equipment, sources and types of active pharmaceutical ingredients (APIs), excipients, and packaging materials, technical specifications, and quality standards, as well as changes to APIs. MAHs or API registrants shall classify the changes and manage the changes through prior approvals, notification filings, or annual reports.
The Measures on Drug Postmarketing Changes also regulate the management of changes that have occurred prior to the effective dates of the Drug Administration Law and Drug Registration Regulation. Under the following two circumstances, it is not necessary to submit a new application for such changes: (a) if the MAH or the manufacturer has implemented the changes by following the previous regulations and technical requirements governing the management of manufacturing process changes, and the MAH or the manufacturer studied, validated, and proved that the changes would not affect the drug quality; or (b) if the manufacturing processes have been approved by or re-registered with the regulatory authorities.
e. Procedures for Changes
According to the Measures on Drug Postmarketing Changes, for major changes, an MAH shall file a supplementary application with the CDE, submit study materials, and implement such changes after approval. For moderate changes, an MAH shall submit the notification filings to the CDE or provincial-level drug regulatory authorities; upon submission of the requisite notification materials, the notification filings are deemed to be complete and the moderate changes can be implemented. For minor changes, an MAH shall describe the changes in an annual report.
B. Liabilities for Drug Change Management Violations
Drug registration applicants, MAHs, and manufacturers can be liable for any violation of drug change management regulations. Potential penalties for violating companies include a warning, order to correct, confiscation of illegal gains, drugs, APIs, excipients, packaging materials, and manufacturing equipment, monetary penalty, order to cease business and operation, access restrictions, and even revocation of drug approvals, drug manufacturing licenses, and drug distribution licenses. The responsible persons may face confiscation of illegal gains, monetary penalty, debarment, and even detention.
Pharmaceutical companies doing business in China now have more clarity on the rules with respect to drug change management, but these companies also face more regulatory requirements and compliance challenges after the promulgation of Drug Administration Law in 2019, Drug Registration Regulation in 2020, the Measures on Drug Postmarketing Changes in 2021, and many implementing technical guidelines. Accordingly, pharmaceutical companies should thoroughly understand the regulatory requirements and closely monitor the development in this area. If you have any questions on any of the above topics, please do not hesitate to contact us.
© Arnold & Porter Kaye Scholer LLP 2021 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.