Criteria and regulatory considerations for the conditional approval of innovative antitumor drugs in China: from the perspective of clinical reviewers

Abstract

Before the State Council of the People's Republic of China issued the “Opinions on the Reform of the Examination and Approval System of Pharmaceutical and Medical Devices” [1], several problems existed in China's drug evaluation and approval system. The long approval time and low efficiency of new drug marketing seriously affected the enthusiasm for drug innovation. To this end, the current “Drug Registration Regulation” (DRR) [2] was initiated by the National Medical Products Administration of China and officially implemented on July 1, 2020. To encourage clinical value-oriented drug innovation, four expedited drug programs were first proposed, including breakthrough therapy drugs, conditional approval, priority review, and special approval procedures. For drugs listed in the expedited programs, the drug regulatory authorities and professional technical institutions should provide policy and technical support, prioritize the allocation of communication and review resources, and thereafter shorten the review time as much as possible. The breakthrough therapy drug procedure is mainly devoted to the drugs used to prevent and treat diseases that threaten lives or seriously affect the quality of life. More evaluation resources, such as priority communication and more flexible discussion forums of pivotal registration trial design, should be assigned to breakthrough therapy drugs that show obvious clinical advantages during early clinical trials [3, 4]. The purpose of the conditional approval procedure is to “shorten the research and development time of clinical drug trials, making these drugs accessible as soon as possible for patients with critical diseases who can no longer wait” [5, 6]. The priority review procedure is devoted to reducing the waiting time in the marketing authorization application process by implementing a shorter review deadline, giving priority to the arrangement of inspection and verification, and accepting rolling supplementary technical information. The special approval procedure is an accelerated procedure set up to meet the needs of the public for prevention and treatment drugs when there are potential public health emergencies or when public health emergencies occur. Among the four expedited programs, conditional approval is directly aimed at shortening the time of drug clinical trials, and its supporting policies and approval standards attracted more attention from the industry than the other three programs. Conditional approval may be applied for medicines targeting serious life-threatening diseases for which no effective treatment is available, or medicines that are urgently needed in public health, if the following conditions are met, there are evidence supporting the efficacy and predicting the clinical values of the drugs, or for vaccines that are urgently needed in special circumstances and whose benefits are assessed to outweigh the risks. When comparing with the other applicable situations of conditional approval, “drugs for serious life-threatening diseases without effective treatment” has relatively wider potential applicable objects whose clinical design requirements and review standards are more likely to receive persistent focus with greater regulatory challenges. China's conditional approval has similarities with the United States accelerated approval pathway [7], European Union (EU) conditional marketing authorization [8] and Japanese conditional early approval [9], but differs in details [10]. The current DRR has only been implemented for 2 years, while some China innovative antitumor (including hematological malignancies) drugs have been approved for marketing based on the concept of conditional approval before its official implementation. Additionally, tumors are the most common indication type to be conditionally approved following the conditional approval procedure coming into force. As of October 1, 2022, 60 of the 77 conditionally approved drugs (calculated by indications) in China are tumor-related. Thus, tumor indications are the forerunners and active practitioners of conditional approval, as well as the relatively mature indications for regulatory consideration. To make the process and standard of technical review of conditionally approved drugs more open and transparent, this paper was developed to demonstrate the criteria of conditional approval in China from the perspective of clinical reviewers of the Center for Drug Evaluation (CDE) with antitumor innovative drugs as the entry points. Additionally, the key challenges faced by regulators in the implementation of conditional approval were also summarized with suggestions to provide directions and ideas for program optimization. After the applicant applied for the conditional approval procedure, the decision-making process and evaluation dimensions of the CDE review department attracted much attention. Reviewers’ key considerations and general criteria in the decision process of the conditional approval applicability are shown in Figure 1. The applicability of conditional approval of an innovative drug should be supported with its own clinical data rather than the experiences of other drugs with similar action of mechanism. In the absence of reliable historical data, applicants should consider conducting small randomized controlled trials as a basis for decision-making on the applicability of conditional approval. Applicability decision tree of the working procedures for conditional approval of innovative antitumor drugs. Abbreviations: RCT, randomized controlled trial; ORR, objective remission rate; CRR, complete remission rate; DOR, duration of remission; PFS, progression-free survival; DFS, disease-free survival; EFS, event-free survival; OS, overall survival. Noticeably, it is impractical and unfair if all conditional approvals apply a quantified and rigid decision criterion, as the innovativeness, the understanding of the product mechanism and disease, and the urgency of medical needs of the target indication population vary and affect the technical requirements of the conditional approval. Since clinical value orientation is the core of the conditional approval process, the review department's suggestions in each communication address the temporal clinical needs of the target treatment population at the time when communication occurs. Drug approval for marketing depends on the treatment available to the target indication population at the time of regulatory decision-making and the therapeutic advantage identified from the clinical data. This means that applicants should adjust their research and development strategies in time once important changes have arisen in clinical practice. The specific process and decision-making criteria for accelerating the marketing registration process have attracted wide attention since the date of implementation. Tumor indications account for the highest proportion of the indications of conditionally approved drugs for marketing. The new antitumor drug research and development companies pay close attention to the perspectives and criteria that the CDE tumor indication team typically uses to evaluate the clinical advantages of antitumor drugs. The publication of the technical considerations formed in the review process can enable the industry and academia to better understand the review conclusions of the regulatory agencies and can also help research and development companies to more specifically summarize and analyze the clinical research results of new drugs to improve the clinical development efficiency of new drugs. At the same time, during the implementation of China's conditional approval procedure, there will inevitably be technical and management problems. Only by constantly summarizing and sorting these out can problems be solved or working procedures be continuously optimized. As a direct practitioner, CDE must be open and transparent in order to maximize the incentive effect of accelerating the marketing registration process to encourage innovation. This would serve to allow patients to benefit from drug innovation as soon as possible. We hope this article can help new drug developers and trigger more thinking and discussion on China's conditional approval procedure. Research concept and design: Zhimin Yang, Limin Zou, and Yueli Qi. Collection and/or assembly of data and policy: Limin Zou, Yueli Qi, Yongling Jiang, Ling Tang, Yu Du, Boyuan Zhao, Yanzhe Sun, Jun Ma, and Meiyi Xiang. Analysis and interpretation of data and policy: Limin Zou, Yueli Qi, Yongling Jiang, Ling Tang, and Yu Du. Writing the article: Limin Zou and Yueli Qi. All authors approved the final manuscript. The authors would like to acknowledge Professor Lin Qiu of Harbin Institute of Hematology and Oncology for writing assistance. The authors declare that they have no competing interests. Not applicable. The datasets used during the current study are available from the corresponding author on reasonable request. Not applicable. Not applicable.

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