3.1 Scientific and prudent attitude towards single-arm trials

Chidamide (Epidaza®, CS055) represents the first drug to be granted conditional approval based on an SAT [1]. It offers a treatment option for patients suffering from refractory, relapsed peripheral T-cell lymphoma who lack alternative therapies. Subsequently, numerous innovative anti-tumor drugs received conditional approvals. Statistical data show that from May 2014 to May 2021, a total of 19 drugs for 26 indications were granted conditional approvals [2].

SATs inherently carry uncertainties that may pose additional risks to patients. To address this, the CDE has issued three guidance [3-5] which detail the regulatory considerations and technical requirements for the use of SATs in NDAs.

SATs, as pivotal studies, must be executed with scientific precision and prudence with a clear and well-articulated drug action mechanism. SATs should be acceptable only in specific scenarios, such as when control studies are infeasible or when the drug exhibits significantly superior efficacy. Moreover, it is advocated to undertake confirmatory studies as early as possible to mitigate the risk of patients being exposed to drugs with uncertain efficacy and safety profiles. On August 25, 2023, the NMPA issued the “Procedures for Review and Approval of Conditional Approval Applications for Marketed Drugs (interim) (Revised Draft for Public Comments)” [6]. It explicitly stipulates that a confirmatory study should be completed within 4 years after the conditional approval. Evidence from the US FDA demonstrates that it is feasible to complete a confirmatory study within 4 years post-marketing if the confirmatory study is to be commenced once an accelerated approval is granted [7].

3.2 The precision medicine of cancer

Biomarkers serve as crucial instruments for achieving precision therapy. From 2010 to 2023, a total of 109 NDAs for 73 distinct anti-tumor drugs incorporated biomarkers to accurately identify the patient demography for therapeutic intervention [8].

As a novel cognitive paradigm for disease identification, the “pan-tumor” classification aggregates diverse tumors into a singular disease category, considering their genesis. This approach is dedicated to the pursuit of universal therapeutic methodologies [9]. As of February 2024, the NMPA has approved 7 drugs for “pan-tumor”, including Envafolimab, Tislelizumab, Serplulimab, Larotrectinib, Pucotenlimab, Entrectinib and Pembrolizumab. The approvals of these drugs underscore the ongoing evolution of clinical practice in the field of oncotherapy in China [8].

3.3 Diversity of population in clinical trials

Patients suffering from various types of tumors exhibit distinct age distributions and organ function. The CDE has issued several guidances (such as the Guidance for the Application of Physiological Pharmacokinetics Models in Drug R&D for Pediatric Populations) [10] to emphasize research among different populations and to enhance the diversity of subjects, thereby providing more reference information for the post-marketing change management of drugs.

Recruiting patients at different stages of cancer also reflects the diversity of the population. It is a classic practice to sequential progress from the later-line to the front-line population. However, this R&D strategy results in the front-line patients being deprived of timely access to new drugs. Consequently, we advocate for the initiation of development in the front-line as soon as efficacy is observed in later-line patients. Sometimes, developing drugs in early-stage tumors is of great clinical value. For instance, immunotherapy may have more pronounced therapeutic effects in early-stage patients who have not yet undergone immune function deterioration [11].

3.4 Control groups reflect the clinical value of drugs

It is important that the control group in a clinical trial accurately reflects the most efficacious treatment options currently accessible to the intended patients in real-world clinical settings. Only under these conditions can the findings of the trial truly reveal the clinical value of the new drug.

Although some imported drugs received approvals in China, their adoption by the Chinese population did not make much difference to the therapeutics landscape due to economic and other burdens. As such, the urgent issue for patients is to receive drugs that are both efficacious and easily accessible. Accordingly, the CDE does not require a head-to-head comparison with imported drugs.

For example, since Trastuzumab was approved in China in 2002, its widespread clinical adoption was constrained by the high price. Consequently, in the clinical trial of Inetetamab, China's first innovative monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), Vinorelbine was selected as the control drug in the randomized controlled trial (RCT) rather than Trastuzumab. The outcomes of this RCT provided support for the approval of Inetetamab in China [12].

With the emergence of innovative drugs and the increase of imported drugs in China, Chinese clinical practices are gradually improving, and the gap between clinical practices in China and in other countries is gradually narrowing. As clinical practice evolves, regulatory requirements are also changing accordingly. In 2020, the CDE issued the “Guidance for Clinical R&D of Anti-tumor Drugs Oriented by Clinical Value [13]”. This document elucidates that innovative drug development should aim highly to provide patients with better (more effective, safer, or more convenient) treatment options.

For example, with the approvals of multiple domestic monoclonal antibodies targeting programmed cell death protein 1 (PD-1), the CDE now requests that the combination of anti-PD-1 with chemotherapy, rather than chemotherapy alone, should be employed as a control group in the RCT study for first-line therapy of late-stage non-small cell lung cancer.

3.5 Select endpoints that best demonstrate clinical benefit

In China, the new “Provisions for Drug Registration” [14] and the accompanying “Guidance for Conditional Approval of Drugs for Marketing (interim) [15]” stipulate that the selection of surrogate endpoints should be based on their predictive capacity for clinical benefit.

For malignant tumors, overall survival (OS) is the gold standard for evaluating the efficacy of drugs. Using appropriate surrogate endpoints can expedite the introduction of drugs into the market, thereby permitting patients to access novel therapies earlier. It is essential that these surrogate endpoints can predict clinical benefit, and their association with OS in the domain of anti-tumor drugs is contingent upon the intrinsic properties of the tumor. The CDE has promulgated guidance for the selection of surrogate endpoints in clinical trials [16, 17].

In instances where the progression of certain tumors is notably rapid, a significant extension of progression-free survival (PFS) is deemed a clinical benefit. Therefore, it is considered appropriate to use PFS as the primary endpoint. A phase III RCT on patients with hormone receptor-positive metastatic breast cancer who had not responded to previous endocrine therapy revealed that the combination of Dalpiciclib, the first domestic cyclin-dependent kinase 4/6 inhibitor, with the elective oestrogen receptor degrader Fulvestrant significantly prolonged the PFS compared to Fulvestrant administered as a monotherapy (15.7 months vs. 7.2 months, hazard ratio of 0.42), with a prolonged OS [18]. Based on the results of this study, the NMPA approved Dalpiciclib for patients with recurrent or metastatic breast cancer in 2021.

Both tumor and anti-tumor therapies cause significant pain in patients and severely impact their quality of life. Therefore, it is recommended that patient-reported outcomes (PRO) be adopted as an evaluation metric of clinical benefit. Although PRO has not yet been used as a primary endpoint for anti-tumor drugs, it helps explain clinical data that cannot be revealed by other traditional assessment metrics.