Critical Insights into the Evolving Drug Approval Process in China

Precis:

Efforts have been put forward to improve the therapeutic development process in China and more novel therapies have been approved in recent years. It is important to develop and test novel therapies in China given differences in metabolism and tolerance compared to other populations.

Yang et al summarize new oncology therapeutic approvals in China in the article “Characteristics of clinical trials of new oncology drugs approved in China”¹. This paper provides a unique window into the drug approval process in China and its evolution in recent years.

The authors focus on 29 first approvals in China between 2015 and 2021 and highlight United States Food and Drug Administration (FDA) approvals over this time as a comparator. While many aspects of trial design have dramatically improved in the last few years in China and are now comparable to those in the United States, there remain unresolved issues regarding implementation and operational details of trials.

China has made great strides in the drug approval process with more than 60% of novel oncology therapeutics approved through accelerated pathways. Ninety percent of pivotal clinical trials used surrogate endpoints, half were non-randomized or had no control group, and duplicate development with no evidence of clinical advantage over current therapies occurred frequently. The governing body, the Chinese National Medical Products Administration (NMPA), issued a guideline requiring the best current standard of care as a comparative arm for clinical trials in 2021. Prior to this half of trials were non-randomized or did not have a control group.

There were 90 FDA-approved oncology drugs from 2015–2021, 32% of which were first in class as compared to 0% first in class from China. Small molecules targeting EGFR, KDR, PARP, PDGFR, FLT1/4, FGFR, BTK, and BCR-ABL accounted for the majority of approvals in both the USA and China. A number of PD-1/PD-L1 inhibitors were developed in both countries. Despite China having over four times the population of the United States, less than half the number of interventional clinical trials were initiated in China (4910 vs 1726) from 2000 to 2021. There has been a dramatic increase in the number of clinical trials in China since 2015 following a reformation in the registration process. Many drugs approved originally in the USA are eventually approved in China. In recent years, many oncology therapeutics were available in China less than 4 years after FDA approval. Pharmaceutical companies around the world are trying to launch drugs faster in China.

While the landscape of cancers in China is different than the USA, a similar strategy, which is rather new compared to a decade ago, of seeking approval in less common or rare cancer types is often used. The approval is then expanded to other cancer types. The expedited review processes can be utilized to acquire faster approvals given unmet medical needs in uncommon or rare cancer types. While orphan drug designation does not exist in China, other expedited review processes are in place. Both orphan drug designation and other expedited review processes have led to faster therapeutic approvals by the FDA². There has been significant recent effort to improving the clinical trials process in China; however there remain concerns regarding the ability to conduct high-quality clinical trials in China which include issues with ethical review, registration, implementation, and reporting³. These issues lead to oncology therapeutics developed and initially approved in China having difficulty achieving similar efficacy results that would lead to subsequent approvals internationally.

Traditionally, oncology therapeutics have been approved for cancer and line of therapy. With the advent of next generation sequencing and molecular profiling, tissue-agnostic approvals where therapies are authorized regardless of cancer type, but instead based on a specific molecular marker are moving forward in the FDA. Current tissue-agnostic approvals in the USA include but are not limited to PD-1 inhibitors for TMB-high (pembrolizumab) and MMRd/MSI-H (pembrolizumab, dostarlimab), NTRK inhibitors for NTRK-fusions (larotrectinib, entrectinib), combination BRAF and MEK inhibition with dabrafenib and trametinib for BRAF V600E, and the RET inhibitor selpercatinib for RET fusions⁴. Five of these therapies were approved with the tissue agnostic approval prior to 2022. There is also pemigatinib, an FGFR1–3 inhibitor, approved for relapsed or refractory myeloid/lymphoid neoplasms with FGFR1 rearrangement⁵ and a partial agnostic approval for belzutifan, a hypoxia-inducible factor inhibitor, for Von Hippel-Lindau disease requiring therapy for renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors⁶. The FDA has also issued guidance for tissue-agnostic drug development in oncology to outline differences compared to traditional therapeutic development⁷. Envafolimab is a subcutaneous PD-1 inhibitor approved in November 2021 for MMRd/MSI-H which marked the first tissue-agnostic approval in China⁸. Tislelizumab is a PD-1 inhibitor which was subsequently approved for MMRd/MSI-H solid tumors in China⁹.

The authors comment that there are many “me too” approvals in China as therapeutics are being approved for the same target with similar mechanisms of action. A guidance issued in 2021 expressed there must be some benefit over the best approved agents for new therapies developed in China. While traditional FDA oncology approvals were based on overall survival advantage and more recently surrogate end points such as response or progression-free survival, there are other potential benefits that should be considered in therapeutic development. A “me-too drug” may be more potent than the prototype, it may be more effective in patients with resistance, toxicities may be lower, drug-drug interactions may be different, it may have different secondary targets, and it may lead to lower pricing in the similar therapeutics¹⁰. In some cases, there may even be synergy in giving two similar therapies together. Two HER2 inhibitors, trastuzumab and pertuzumab, in combination with docetaxel were shown to have improved efficacy over trastuzumab and docetaxel alone¹¹. Thus synergy can occur by giving two distinct therapeutics for the same target¹². First-in-class therapeutics can have significant toxicity and developing similar therapies for the same target will be critical. A non-inferior therapy with less toxicity would be beneficial especially for targeted therapies that patient may remain on for months or even years. As an example, alpelisib is a PIK3CA inhibitor approved for breast cancer; however, it has been noted to have significant toxicity including hyperglycemia, rash, and diarrhea which can limit the ability to continue therapy¹³. Thus, the development of additional PIK3CA inhibitors would be beneficial for improved quality of life and tolerability.

Only 6 of the 29 therapies approved first in China have achieved FDA approval. Three of these drugs received international approvals at first submission. There were no novel targets amongst the therapies first developed in China compared to FDA-approved therapies. However, it is critical to develop therapies designed for the Chinese population and also important to run clinical trials on FDA-approved therapies in the China or in predominantly East Asian populations. Pharmacogenomic differences can exist between the Asian population and the predominantly white population tested in most United States-based clinical trials. Several key enzymes in the CYP2D6 and CYP2C subfamily can vary considerably between these populations which can alter efficacy or increase toxicity¹⁴. Asians are more commonly poor metabolizers of CYP2C19 and carriers of the HLA-B*15:02 allele which can increase toxicities of therapies¹⁵. Fluropyramidines such as 5FU and capecitabine have previously been shown to have lower toxicity in East Asian populations as compared to white populations, thus it may be beneficial to provide higher doses to this population for optimal efficacy¹⁶.

In summary, it is important to develop and test novel therapies in China, given differences in metabolism and tolerance compared to other populations. Efforts have been put forward to improve the therapeutic development process and more novel therapies have been approved in recent years in China.