Regulatory flexibilities balancing unmet needs, benefits and risks in the approvals of imported cancer drugs in China: a cohort study from 2012 to 2021.

Background: China has historically relied on importing new drugs to fulfill domestic clinical needs. However, stringent requirements for local clinical trials for these imported drugs has often delayed their market approval, restricting timely access for patients. To address this issue, China has implemented regulatory flexibility in certain contexts, allowing for expedited approval processes when appropriate. This study aimed to evaluate the characteristics of novel cancer drugs qualifying for flexible approval in China from 2012 to 2021, focusing on pivotal trials features, clinical benefits, safety profiles, and unmet medical needs. Methods: This cohort study identified all newly imported cancer drugs and their indications approved by the China's National Medical Products Administration (NMPA) from 2012 to 2021. Indications meeting standard requirements were categorized as regular approvals, while those supported by limited clinical data from Chinese patients were classified as flexible approvals. Development strategies, pivotal trials characteristics, and clinical outcomes were extracted from publicly available review documents and drug labels. Unmet medical needs were assessed based on two dimensions: the availability of standard-of-care treatments and the novelty of medicines. We compared the pivotal trial characteristics, efficacy end points, safety (serious adverse events) and the extent of unmet clinical needs, between flexible and regular approvals using Chi-square tests. A random-effects meta-regression was conducted to examine the association between flexible status and hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). Findings: Among 59 novel cancer drugs approved for importation to China between 2012 and 2021, 56 products with 92 indications were included in this analysis, based on the availability of their review documents. Of these, 48 indications (52%) qualified for flexible approvals, while 44 indications (48%) received regular approvals. The median number of Chinese patients involved in the datasets for flexible approvals was significantly lower than for regular approvals (27 [IQR, 0-62] vs. 165 [IQR, 99-245], p < 0.001). Flexible approvals were more frequently supported by early-phase (18/61 vs. 1/60, p < 0.001) and single-arm (22/61 vs. 1/60, p < 0.001) pivotal trials, with response rates frequently used as the primary endpoint (24/61 vs. 1/60, p < 0.001). Meta-regression analysis revealed that flexible approvals were associated with improved OS (HR 0.61 vs. 0.72, p < 0.01), and a weaker association for PFS (HR 0.39 vs. 0.51, p = 0.03). The rate of serious adverse events was slightly higher, but not significantly, in the flexible approval group than the regular approval group (43% vs. 35%, p = 0.06). Flexible approvals were more likely to be indicated for diseases with no available existing drugs (31/48 vs. 10/44, p < 0.001) and for first-in-class drugs (21/48 vs. 9/44, p = 0.03). Interpretation: China's regulatory flexibility in approving imported cancer drugs has enabled access to therapies with limited domestic clinical data. These decisions are largely associated with the potential for greater clinical benefits and the need to address unmet medical needs. The approach offers valuable insights into regulatory considerations for global regulatory practices. By adopting similar regulatory flexibility, other nations could enhance drug accessibility and promote more adaptive regulatory practices. Funding: This work was funded by National Natural Science Foundation of China (72374119, 82102886) Beijing Natural Science Foundation (7242114) and Beijing Nova Program.