Circular of the General Office of the CPC Central Committee and the General Office of the State Council on Deepening the Reform of Review and Approval System to Encourage Innovation in Drugs and Medical Devices

VCBeat (WeChat ID: vcbeat) has learned that on October 8, 2017, the General Office of the Communist Party of China Central Committee and the General Office of the State Council issued the “Opinions on Deepening the Reform of the Review and Approval System to Encourage Innovation in Drugs and Medical Devices,” and circulated a notice requiring all regions and departments to earnestly implement the guidelines in light of their actual conditions.

(1) The qualification accreditation of clinical trial institutions shall be subject to record-filing management. Institutions that meet the conditions for conducting clinical trials may, after registering and filing with the designated website of the food and drug regulatory authority, accept commissions from drug and medical device registration applicants to conduct clinical trials. The principal investigator of a clinical trial shall hold a senior professional title and have participated in more than three clinical trials. Registration applicants may engage third-party organizations to assess and certify whether the clinical trial institutions meet the required conditions. Investment by non-governmental entities in the establishment of clinical trial institutions is encouraged. The administrative provisions for clinical trial institutions shall be formulated by the China Food and Drug Administration in conjunction with the National Health and Family Planning Commission.

(II) Support clinical trial institutions and personnel in conducting clinical trials. Support medical institutions, medical research institutions, and pharmaceutical higher education institutions in conducting clinical trials, and incorporate the evaluation of clinical trial conditions and capabilities into the grading and accreditation of medical institutions. Establish a separate evaluation and assessment system for medical institutions conducting clinical trials; beds used exclusively for clinical trials shall not be counted towards the total bed count of the medical institution, and performance indicators such as bed efficiency, turnover rate, and utilization rate shall not be mandated. Encourage medical institutions to establish dedicated clinical trial departments and staff them with professionalized clinical trial investigators. Improve the incentive mechanism for performance-based salary distribution to ensure the income level of clinical trial investigators. Encourage clinicians to participate in technological innovation activities for drugs and medical devices, and ensure that clinical trial investigators are treated equally with clinicians in terms of job promotion and professional title advancement. Allow overseas enterprises and research institutions to conduct synchronous new drug clinical trials in China in accordance with the law.

(3) Improve the mechanism of ethics committees. Clinical trials shall comply with ethical standards, ensure that subjects are provided with sufficient trial information before voluntary participation, understand and sign the informed consent form, and protect the safety, health, and rights and interests of subjects. Clinical trial institutions shall establish ethics committees responsible for reviewing clinical trial protocols of their institutions, examining and supervising the qualifications of clinical trial investigators, overseeing the conduct of clinical trials, and accepting inspections by regulatory authorities. Regional ethics committees may be established as needed to guide the ethical review work of clinical trial institutions; they may accept commissions from institutions lacking conditions for ethical review or from registration applicants to conduct ethical reviews of clinical trial protocols, and supervise the conduct of clinical trials. Departments such as health and family planning, traditional Chinese medicine administration, and food and drug regulation shall strengthen management guidance and professional supervision over the work of ethics committees.

(4) Improving the efficiency of ethical review. Prior to submitting an application for clinical trials, the registration applicant shall first submit the clinical trial protocol to the Ethics Committee of the clinical trial institution for review and approval. For multi-center clinical trials conducted within China, upon completion of the ethical review by the lead site’s Ethics Committee, other participating sites shall recognize the review conclusions of the lead site and shall not conduct duplicate reviews. National Clinical Medical Research Centers and clinical trial institutions undertaking projects supported by National Science and Technology Major Projects and the National Key R&D Program shall integrate resources to establish a unified ethical review platform and gradually promote mutual recognition of ethical reviews.

(5) Optimize the approval procedures for clinical trials. Establish and improve a communication mechanism between registration applicants and review agencies. Before accepting applications for drug clinical trials and medical device clinical trials requiring approval, the review agency shall hold meetings with the registration applicants to provide opinions and suggestions. If the food and drug regulatory authorities do not issue any negative or questioning opinions within a specified period after accepting the clinical trial application, it shall be deemed as approved, and the registration applicant may conduct the clinical trials in accordance with the submitted protocol.

During the clinical trial, if there are changes to the clinical trial protocol, major pharmaceutical changes, or non-clinical study safety issues, the registration applicant shall promptly report the changes to the review agency; if safety and other risks are identified, the clinical trial protocol should be modified, and the clinical trial should be suspended or terminated in a timely manner. The drug registration applicant may either conduct tests on the clinical trial samples themselves or entrust a testing institution to issue an inspection report, which should be submitted along with the samples to the drug review agency, ensuring that the actual samples used in the clinical trial match those submitted. Optimize the approval process for human genetic resource activities involving international cooperation during clinical trials to accelerate the progress of clinical trials.

(6) Acceptance of overseas clinical trial data. Clinical trial data obtained from multi-center trials conducted outside China may be used to support registration applications in China, provided that they comply with the relevant requirements for drug and medical device registration in China. For drugs and medical devices applying for market approval in China for the first time, the registration applicant shall submit clinical trial data addressing whether there are any ethnic differences.

(7) Support for expanded access clinical trials. For drugs and medical devices currently under clinical trial that are intended to treat serious, life-threatening diseases with no effective therapeutic alternatives, if preliminary observations suggest potential benefit and ethical requirements are met, they may be used for other patients within the institutions conducting the clinical trials after obtaining informed consent. The safety data generated from such use may be submitted in support of registration applications.

(8) Strictly investigate and punish data falsification. The signatory of the clinical trial entrustment agreement and the clinical trial investigator are the primary persons responsible for clinical trial data and shall bear legal liability for the reliability of such data. Establish an inspection model based on risk and review needs, strengthen on-site inspections and for-cause inspections of non-clinical studies and clinical trials, and make inspection results public to society. Data from inspections that are not passed will not be accepted; where issues of authenticity exist, cases shall be promptly filed for investigation, and legal liability shall be pursued against the responsible persons at non-clinical study institutions and clinical trial institutions, those providing false reports, registration applicants, and contract research organizations in accordance with the law. Those who refuse, evade, or obstruct inspections shall be subject to heavier penalties in accordance with the law. Registration applicants who proactively identify problems and report them in a timely manner may receive reduced or waived penalties at the discretion of the authorities.

(9) Accelerate the review and approval of drugs and medical devices urgently needed for clinical use. For drugs and medical devices urgently needed to treat diseases that seriously endanger life and for which there are no effective treatments, as well as those required for public health purposes, conditional marketing approval may be granted if early- and mid-stage clinical trial indicators demonstrate efficacy and predict clinical value. Enterprises shall develop risk management plans and conduct research as required. Efforts to encourage the research and development of new drugs and innovative medical devices will be strengthened; priority review and approval will be granted to new drugs and innovative medical devices supported by National Science and Technology Major Projects and National Key R&D Programs, as well as those undergoing clinical trials at National Clinical Research Centers with recognition from the center’s administrative authorities.

(10) Support the research and development of drugs and medical devices for the treatment of rare diseases. The National Health and Family Planning Commission, or industry associations (societies) entrusted by it, shall publish a catalog of rare diseases and establish a patient registry system for rare diseases. Applicants for the registration of drugs and medical devices for the treatment of rare diseases may apply for exemptions or reductions in clinical trials. For drugs and medical devices for the treatment of rare diseases that have already been approved for marketing overseas, conditional approval for market entry may be granted; enterprises shall formulate risk management plans and conduct studies as required.

(11) Strictly regulate the review and approval of injectable drug products. The conversion from oral formulations to injectable formulations shall be strictly controlled; if an oral formulation can meet clinical needs, the marketing authorization for the corresponding injectable formulation will not be approved. The conversion from intramuscular injection formulations to intravenous injection formulations shall be strictly controlled; if an intramuscular injection formulation can meet clinical needs, the marketing authorization for the corresponding intravenous injection formulation will not be approved. Applications for mutual conversion among large-volume injections, small-volume injections, and sterile powders for injection will not be approved unless they demonstrate significant clinical advantages.

(12) Implement joint review and approval of drugs with their pharmaceutical active ingredients and packaging materials. During the drug registration application process, active pharmaceutical ingredients (APIs), excipients, and packaging materials shall be reviewed and approved concurrently; separate approval numbers for APIs will no longer be issued. The APIs, excipients, and packaging materials that have undergone joint review and approval, along with their quality standards, will be published on a designated platform for selection by relevant enterprises. Marketing Authorization Holders (MAHs) shall be responsible for the quality of the APIs, excipients, and packaging materials selected for the production of drug preparations.

(13) Support the inheritance and innovation of traditional Chinese medicine (TCM). Establish and improve a registration management system and technical evaluation framework that aligns with the characteristics of TCM, properly balancing the preservation of TCM’s traditional advantages with the requirements of modern drug development. For innovative TCM drugs, emphasis should be placed on novel therapeutic effects; for improved new TCM drugs, clinical application advantages should be demonstrated; TCM products based on classical prescriptions shall be reviewed and approved according to simplified standards; and natural medicines shall be reviewed and approved in accordance with modern medical standards. Enhance the capacity for clinical research on TCM. TCM registration applications must submit materials assessing market value and resource utilization, highlighting a clinical value-oriented approach to promote the sustainable use of resources. Encourage the research and development of traditional proprietary Chinese medicines using modern scientific and technological methods, encourage the development of new TCM drugs by leveraging the advantages of traditional TCM dosage forms, and strengthen quality control of TCM products.

(14) Establish a system for priority review and approval of drugs subject to compulsory patent licensing. In circumstances where public health is under significant threat, drug registration applications for which compulsory licenses have been granted shall be given priority in review and approval. The specific circumstances constituting a significant threat to public health and the procedures for initiating compulsory licensing shall be prescribed by the National Health and Family Planning Commission in conjunction with relevant departments.

(15) Establish a Catalog of Marketed Drugs. Drugs newly approved for marketing or having passed the consistency evaluation of quality and efficacy for generic drugs shall be included in the China Catalog of Marketed Drugs, with their attributes specified—such as innovative drugs, improved new drugs, and generic drugs consistent with the originator drugs in quality and efficacy—as well as information on active ingredients, dosage forms, specifications, marketing authorization holders, granted patent rights, and periods of experimental data protection.

(16) Explore the establishment of a drug patent linkage system. To safeguard the legitimate rights and interests of patent holders, reduce the risk of patent infringement for generic drugs, and encourage the development of generic drugs, we will explore the establishment of a linkage system between drug review and approval and drug patents. When submitting a registration application, the drug registration applicant shall disclose the relevant patents involved and their ownership status, and notify the relevant drug patent holders within the prescribed time limit. In the event of a dispute over patent rights, the parties may file a lawsuit with the court; during this period, the technical review of the drug shall not be suspended. For drugs that have passed the technical review, the food and drug regulatory department shall make a decision on whether to approve marketing based on the effective judgment, ruling, or mediation statement issued by the court. If no effective judgment, ruling, or mediation statement is obtained within a specified period, the food and drug regulatory department may approve marketing.

(17) Launch a pilot program for the patent term extension system for pharmaceuticals. Select certain new drugs for the pilot, and provide appropriate patent term compensation for delays in market launch caused by clinical trials and review and approval processes.

(18) Improve and implement the system for protection of drug trial data. When submitting a registration application, drug registration applicants may simultaneously submit an application for trial data protection. A certain period of data exclusivity shall be granted for independently obtained and undisclosed trial data and other data submitted by registration applicants for innovative drugs, drugs for rare diseases, pediatric-specific drugs, innovative therapeutic biological products, and drugs that have successfully challenged patents. The data exclusivity period shall be calculated from the date of market approval of the drug. During the data exclusivity period, marketing applications for the same variety from other applicants shall not be approved, except where the applicant has independently obtained the data or has obtained consent from the applicant who has received marketing authorization.

(19) Promote the generic production of drugs. Adhere to the equal emphasis on encouraging innovation and promoting generic drug production to reduce the medication burden. Regularly publish lists of drugs whose patents have expired, terminated, or been invalidated, and for which no generic applications have yet been filed, so as to guide the research, development, and production of generic drugs and improve public access to medications. Improve relevant technical guidelines for research and evaluation, and support the development of biosimilars and generic drug-device combination products with clinical value. Accelerate the consistency evaluation of quality and efficacy for generic drugs.

(20) Leverage the principal role of enterprises in innovation. Encourage pharmaceutical and medical device companies to increase R&D investment, strengthen the development of new products and continued research on marketed products, and continuously improve manufacturing processes. Permit research institutions and researchers to apply for clinical trials, provided they assume relevant legal liabilities. For new drug and innovative medical device R&D and related technical research conducted with state fiscal appropriations, where the outcomes are converted as job-related scientific and technological achievements, the employing entity may establish regulations or agree with researchers on the methods, amounts, and timeframes for rewards and remuneration, so as to motivate researchers’ participation and promote the transfer and conversion of scientific and technological achievements.

(21) Support the clinical application of new drugs. Improve the dynamic adjustment mechanism for the National Reimbursement Drug List, explore the establishment of a negotiation mechanism for medical insurance payment standards for drugs, and promptly include new drugs in the scope of basic medical insurance coverage in accordance with regulations to support new drug research and development. Localities may, based on the needs of disease prevention and control, promptly include new drugs in the centralized procurement scope for public hospitals. Encourage medical institutions to prioritize the procurement and use of new drugs with clear efficacy and reasonable pricing.

(22) Promote the comprehensive implementation of the Marketing Authorization Holder (MAH) system. Timely summarize the pilot experience of the drug MAH system, promote the revision of the Drug Administration Law, and strive to roll it out nationwide at an early date. Allow medical device R&D institutions and researchers to apply for marketing authorization for medical devices.

(23) Implement the legal responsibilities of Marketing Authorization Holders. Drug Marketing Authorization Holders shall bear full legal responsibility for preclinical research, clinical trials, manufacturing, sales and distribution, and adverse reaction reporting. They must ensure that submitted research data and clinical trial data are authentic, complete, and traceable; ensure that manufacturing processes are consistent with approved processes and that production remains continuously compliant; ensure that the quality of each batch of marketed drugs is consistent with the submitted samples; conduct continuous post-marketing studies on approved drugs; promptly report any adverse reactions; assess risks; and propose improvement measures.

The marketing authorization holder of a medical device shall bear full legal liability for the design and development, clinical trials, manufacturing, sales and distribution, and adverse event reporting of the medical device. The holder shall ensure that the submitted research materials and clinical trial data are authentic, complete, and traceable; conduct post-market studies on marketed medical devices; promptly report any adverse events; assess risk situations; and propose corrective actions.

Enterprises, institutions, and individuals entrusted by the marketing authorization holders of drugs and medical devices to conduct research and development, clinical trials, manufacturing, sales, and distribution shall bear the responsibilities prescribed by laws and regulations as well as those stipulated in the agreements.

(24) Establish a system for marketing authorization holders to directly report adverse reactions and adverse events. Marketing authorization holders shall bear primary responsibility for reporting adverse reactions and adverse events; those who conceal such information or fail to report within the prescribed timeframe shall be subject to strict penalties in accordance with the law. The food and drug regulatory authorities shall investigate and analyze reported adverse reactions and adverse events, and as appropriate, order marketing authorization holders to take measures such as suspending sales, recalling products, and improving quality control.

(25) Conduct re-evaluation of pharmaceutical injections. Based on advances in pharmaceutical sciences, carry out re-evaluation of marketed pharmaceutical injections, striving to basically complete this task within approximately 5 to 10 years. Marketing authorization holders shall conduct a comprehensive analysis of the research data submitted at the time of initial approval and post-marketing continuous studies, and undertake research on product composition, mechanism of action, and clinical efficacy to assess safety, effectiveness, and quality controllability. Products that pass the re-evaluation shall be eligible for the preferential policies associated with the consistency evaluation of quality and efficacy for generic drugs.

(26) Improve the post-market re-evaluation system for medical devices. Marketing authorization holders shall proactively conduct re-evaluations of marketed medical devices based on scientific advancements and adverse event assessment results. If a re-evaluation reveals that a product cannot ensure safety and efficacy, the marketing authorization holder shall promptly apply for cancellation of the marketing authorization. Concealing re-evaluation results or failing to submit a required application for cancellation shall result in revocation of the marketing authorization and legal penalties in accordance with the law.

(27) Standardize the academic promotion of pharmaceuticals. Marketing Authorization Holders (MAHs) must register the list of medical representatives on websites designated by the food and drug regulatory authorities and disclose such information to the public. Medical representatives are responsible for the academic promotion of pharmaceuticals, introducing drug-related knowledge to healthcare professionals, and soliciting opinions and suggestions regarding clinical use. Academic promotion activities conducted by medical representatives shall be carried out openly and registered with the designated departments of medical institutions. It is prohibited to assign pharmaceutical sales targets to medical representatives, and it is prohibited to provide medical representatives or personnel of related enterprises with data on the number of prescriptions issued individually by physicians. Cases where medical representatives mislead physicians in the use of drugs or conceal adverse drug reactions shall be seriously investigated and dealt with; any engagement in pharmaceutical business activities under the guise of medical representatives shall be investigated and penalized as illegal operation of pharmaceuticals.

(28) Improve the technical review system. Establish a technical review system with review as the core and inspection and testing as support; improve the project manager system for reviews, the meeting and communication mechanism between review agencies and registration applicants, and the expert advisory committee system; strengthen internal management and standardize review processes. Form drug review teams composed primarily of clinical medicine professionals, along with experts in pharmacy, pharmacology and toxicology, statistics, and other relevant fields, to be responsible for new drug reviews. Form medical device review teams composed of professionals in clinical medicine, clinical diagnostics, mechanics, electronics, materials science, biomedical engineering, and other relevant fields, to be responsible for the review of innovative medical devices. Except for technical secrets such as manufacturing processes, all review conclusions and their bases shall be fully disclosed to accept public supervision. Unify the review standards for Class II medical devices and gradually achieve unified national review.

(29) Implement confidentiality obligations for relevant personnel. Personnel involved in regulatory activities such as the acceptance and review, evaluation and approval, and inspection and testing of drugs and medical devices shall be obligated to maintain the confidentiality of technical secrets and test data submitted by registration applicants. Violations of confidentiality obligations shall be subject to accountability in accordance with laws and disciplinary regulations, and the outcomes of such actions shall be made public; cases suspected of constituting crimes shall be referred to judicial authorities for criminal liability. Improve the management of registration application materials to ensure that access and reproduction are fully traceable.

(30) Strengthen the capacity for review and inspection. Include the review of drugs and medical devices in the scope of government-procured services to provide standardized and efficient review services. Accelerate the informatization of the review and approval process for drugs and medical devices, formulate technical requirements for electronic submission of registration applications, improve the electronic Common Technical Document (eCTD) system, and gradually achieve electronic submission and review/approval for various types of registration applications. Establish product archives for marketed drugs and medical devices.

(31) Implement responsibility for inspections throughout the entire process. The National Medical Products Administration shall organize inspections of the research and development processes of drugs and medical devices, as well as compliance with the Good Laboratory Practice for Non-Clinical Studies, Good Clinical Practice for Drug Trials, and Good Clinical Practice for Medical Device Trials. Provincial-level or higher food and drug regulatory authorities shall be responsible for inspecting the manufacturing processes of drugs and medical devices and compliance with Good Manufacturing Practices. Municipal and county-level food and drug regulatory authorities shall be responsible for inspecting the distribution processes of drugs and medical devices and compliance with Good Supply Practices. Where issues are identified during inspections, investigations and penalties shall be imposed in accordance with laws and regulations, and risk control measures shall be taken promptly; cases suspected of constituting crimes shall be transferred to judicial authorities for criminal liability. Penalties for illegal acts shall be enforced against responsible individuals, and the results of inspections and penalties shall be disclosed to the public.

(32) Build a professionalized inspector workforce. Leverage existing resources to accelerate the development of the inspector workforce, forming a professionalized team with full-time inspectors as the main body and part-time inspectors as a supplement. Implement a graded management system for inspectors, strengthen inspector training, enhance the provision of inspection equipment, and improve inspection capabilities and standards.

(33) Strengthen international cooperation. Deepen multilateral and bilateral exchanges on regulatory policies and technologies for drugs and medical devices, actively participate in the formulation and revision of international rules and standards, and promote the gradual realization of international sharing of review, inspection, and testing standards and results.

(34) Strengthen organizational leadership. All regions and relevant departments must fully recognize the significant importance of deepening the reform of the review and approval system to encourage innovation in pharmaceuticals and medical devices. They shall attach great importance to the reform and innovation of the review and approval processes for pharmaceuticals and medical devices, support them as a crucial component in building an innovative nation and promoting the development of high-tech industries, strengthen overall coordination, refine implementation plans, improve working mechanisms, and ensure the effective execution of tasks. We must adhere to the application of rule-of-law thinking and methods in advancing reforms, continuously improve relevant laws, regulations, and institutional frameworks. Where reform measures involve amendments to laws or require corresponding authorization, such amendments shall be proposed in accordance with established procedures, or implementation shall proceed only after authorization by the legislative body.

(35) Strengthen coordination and collaboration. Fully leverage the role of the inter-ministerial joint conference mechanism for the reform of the review and approval system for drugs and medical devices, and promptly study and resolve contradictions and problems encountered during the reform. The national drug regulatory authorities shall play a leading role, ensure the concrete implementation of the reforms, and coordinate and advance the execution of tasks. All relevant departments shall perform their duties in accordance with the law, collaborate through division of labor, and form a synergistic force for reform. The development and reform departments shall support the development of high-tech pharmaceutical products and incorporate the construction of clinical trial institutions into the key content of healthcare institution development. The science and technology departments shall strengthen planning and guidance for pharmaceutical sci-tech development, and ensure the implementation of sci-tech plans (special programs and funds) related to the research and development of new drugs and innovative medical devices.

The departments of industry and information technology shall strengthen planning and guidance for the development of the pharmaceutical industry and reinforce the production guarantee of clinical medications. The finance departments shall ensure funding for the review, approval, inspection, and testing of drugs and medical devices. The human resources and social security departments shall facilitate policy support under medical insurance to promote the development of new drugs. The health and family planning departments shall enhance guidance on the establishment of clinical trial institutions, strengthen the management of ethics committees, and provide training for clinical trial investigators. The intellectual property departments shall effectively protect intellectual property rights related to patents for drugs and medical devices. The administrations of traditional Chinese medicine shall advance innovation in traditional Chinese medicine.

(36) Conduct effective publicity and interpretation. Promote the significant importance of encouraging innovation in pharmaceuticals and medical devices through positive publicity, strengthen the interpretation of key policies and major measures related to the reform of the review and approval system, promptly address hot topics of concern to all sectors of society, proactively respond to public concerns, reasonably guide expectations among various stakeholders, and create a favorable public opinion environment for the implementation of the reforms.