Recently, FDA held an ODAC (Oncologic Drugs Advisory Committee) meeting around the key event in the listing application of Sintilimab, Innovent's PD-1 monoclonal antibody, in the United States. In the end, ODAC rejected the listing application by a vote of 14:1. 

Representative case 

Experts attending ODAC represent the highest level of cancer drug review and supervision in the United States at present. This meeting mainly focused on the key scientific issues in the design and implementation of the clinical trial of Sintilimab ORIENT-11, and gave a deciding veto based on multiple reasons. Usually, FDA will make the final review decision according to the voting results. That is to say, if Innovent decides to continue to promote the listing application of Sintilimab in the United States, additional clinical trials should be carried out following the result of ODAC to prove that the PD-1 monoclonal antibody can be applied to American patients and can meet the demand of clinical practice. 

It is worth noting that Sintilimab was the first case that Chinese pharmaceutical company submitted the new drug application in United States based on Chinese clinical data, which is representative and provides valuable experience for more innovative drugs entering into international market. The focus of FDA can be grasped.

Main deficiencies of ORIENT-11 research proposed by ODAC experts 

ORIENT-11 research is a randomized, double-blind, Phase III controlled clinical research conducted in China to evaluate the efficacy and safety of Sintilimab or placebo combined with peme-trexed and platinum chemotherapy in the first-line treatment of advanced or recurrent non-squamous NSCLC. A total of 397 subjects were enrolled in this research, and they were randomly grouped into two groups by the proportion of 2:1. At the initial stage, they were given Sintilimab or placebo combined with peme-trexed and platinum chemotherapy, and they entered the maintenance stage of Sintilimab or placebo combined with peme-trexed. The focus of the research was progression-free survival, and the secondary focus included overall survival, safety, etc. 

Based on such clinical benefits as significantly prolonging the superior efficacy and good safety of PFS, Sintilimab was approved for marketing in China in early February 2021, and was used in the first-line treatment of NSCLC in combination with peme-trexed and platinum chemotherapy. 

ODAC pointed out many deficiencies of Innovent's ORIENT-11 research. One of the main deficiencies is that the ORIENT-11 research of Sintilimab is only carried out in China, instead of a multi-regional clinical trial, which fails to reflect the differences between Chinese and American patients and the differences between diverse races in the United States. The proposal of the experts means that if the Chinese pharmaceutical companies want to promote Chinese innovative drug entering overseas market, it is necessary for them to carry out multi-center clinical trials worldwide. In addition, different patient groups shall be covered to prove the differences between diverse races. 

Two types of models that can be used for reference 

In fact, from the success of internationalization of innovative drugs in Chinese pharmaceutical companies and healthcare supply companies, there are at least two models for reference, represented by BeiGene and LEGN.US. 

BeiGene was positioned as an international company at the beginning, and it built its own clinical development team in the world with its strong financing ability. After years of extensive global distribution, BeiGene has built up its organizational capacity to independently operate global clinical trials, which can efficiently promote global clinical trials, including those in China. 

As of September 2021, BeiGene has carried out 95 planned or ongoing clinical trials in more than 40 countries and regions, including 38 Phase III or potentially registered clinical trials, with a total enrollment of more than 13,000 people, of which more than half are overseas. BeiGene has a strong ability to control the quality, cost and efficiency of clinical trials. 

Cilta-cel is a Class 1 new drug of biological products for therapy of LEGN.US, which is a chimeric antigen receptor T cell (CAR-T) therapy, and is intended to be used to treat patients with relapsed or refractory multiple myeloma and patients at the front line. 

In December 2017, LEGN.US signed a global cooperation and license agreement with Janssen (Johnson & Johnson), the main content of which is the joint development and commercialization of cilta-cel for the treatment of multiple myeloma. The cooperation with Janssen (Johnson & Johnson) was beneficial for LEGN.US. On the one hand, LEGN.US obtained huge financial support from Janssen with down payment of US$ 350 million, which set a record for the largest down payment authorized by Chinese pharmaceutical companies at that time. On the other hand, LEGN.US can get support in overseas clinical trials, application and approval, market development and other aspects by virtue of Johnson & Johnson's resources in overseas markets.

In 2019, cilta-cel was awarded orphan drug designation and breakthrough therapy by FDA in the United States. In the European market, it also obtained several qualifications granted by EMA. Up to now, based on the clinical trials in the United States, the listing application for biological products in major overseas markets such as the United States, Europe and Japan for cilta-cel of LEGN.US has been submitted.

About  the Author:    

Caicai, a Master of Pharmacy from Shanghai Jiaotong University, used to work in the Institute of Science and Technical Information. Currently as a practitioner in the drug surveillance system, she is good at interpreting industry regulations, pharmaceutical research developments, etc.