Nature Comment . . . Zebutini's registration and approval process differences.

BTK inhibitors are one of the areas where China's innovative drugs compete globally and gain a leading edge.
November 15, 2019, zanubrutinib received accelerated approval from the U.S. Food and Drug Administration (FDA) to treat patients with adult cell lymphoma (mantle cell lyoma, MCL) who have previously received at least one treatment, becoming the first Chinese original drug approved for market in the United States.
June 3, 2020, Zebutini was approved for listing by the State Drug Administration of China (NMPA), achieving a breakthrough in the simultaneous development of Innovative Drugs in China and the United States and the successful approval of the "zero" market.
Zebutinib is a representative case worthy of in-depth study in the history of China's innovative drug development. On July 10,
, Nat Rev Clin Oncol (Impact Factor 53.28) published an article by the Chen Xiaoxuan Research Team at Tsinghua University outlining the regulatory process and review considerations of Zebutinib by The Chinese and American drug regulators, discussing potential ways for China and other countries to simultaneously review the approval of drugs.
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the following paper translation: "Simultaneous drug development in several countries can shorten the drug market time, help improve accessibility."
China's deepening drug regulatory policy reforms have also provided increasing lying to research and development companies to include China in their global synchronous development plans.
at the same time, China's biopharmaceutical industry has begun to research and develop innovative therapies for the global market.
BTK inhibitor Zebutinib is the first new molecular entity to be developed by a Chinese company that has been approved by both the FDA and China NMPA, and the drug's listing by the U.S. and Chinese drug regulators is based on data from a key clinical trial in China.
considering that Zebutini has taken a similar approval path in China and the United States, we compared the FDA and NMPA review data requirements, review considerations and processes, and also explored the possible path for China and other countries around the world to cooperate in the simultaneous review and approval of drugs.
Zebutinib, the second-generation BTK inhibitor discovered in 2012, launched the first human clinical study of b-cell malignancies in Australia in 2014 to treat B-cell malignancies, and further expanded cohort studies in the United States and other countries in 2015.
based on preliminary efficacy data, the Drug Review Center (CDE) of the State Drug Administration of China and the applicant Baiji Shenzhou agreed in December 2016 that the future could be conditionally approved for the listing of Zebutinib based on the clinical results of a single-arm phase II trial (BGB-3111-206) for patients with recurrent/difficult treatment (R)MCL in China.
submitted the NDA containing this key test data to NMPA in August 2018 and received conditional approval on June 3, 2020.
similar, the FDA agreed at the pre-NDA communication meeting in August 2018 that Baiji Shenzhou could submit a listing application based on data from BGB-3111-206 and BGB-3111-AU-003, but would require longer clinical follow-up to record patient responses.
Zebbutini's NDA in the U.S. was submitted in June 2019, 10 months later than in China.
subsequently, the FDA accelerated the approval of Zebutini's R/R MCL indicationon on November 14, 2019.
Zebutini's registration timeline and milestones in china and the United States (Photo: Nature Reviews Clinical Oncology) Although Zebutini submitted NDA in China and the United States, the NDA applicationsubmitted in both places at the time of approval contained a similar core data set.
efficacy analysis data came mainly from 86 patients in the key study BGB-3111-206 and 32 r/R MCL patients in the BGB-3111-AU-003 study.
safety analysis data also included studies from BGB-3111-1002, BGB-3111-205 and BGB-3111-210, with a total of 511 patients with B-cell malignant tumors.
Baiji Shenzhou also submitted updated security data to NMPA on roll during the review.
Zebutini in the U.S. and China NDA key clinical data in the BGB-3111-206 study and the BGB-3111-003 study, Zebutini showed a rapid and lasting response.
notable, the total remission rate in R/R MCL patients in the BGB-3111-206 study was 59%, higher than the listed BTK inhibitorib or acalabrutinib.
overall, the FDA and NMPA regulators approved Zebutinib's listing in an accelerated channel (in the U.S., China as a conditional approval) in light of zebuttini's more compelling efficacy data and evidence of well-tolerated safety in a large population.
the approved drug for recurrent/refractive cell lymphoma, this is the first time the FDA has approved a new drug based on key data mainly from Chinese patients.
average, about 22 percent of Asian patients were included in the key trials on which the FDA previously approved the oncology drug.
THE FDA considered the main factors in its acceptance of Chinese-based clinical data, including population representation, racial disparities, and sufficient data on the safety of white patients.
, nMPA CDE, in its acceptance of overseas data, emphasized that it would focus on racial sensitivity analysis, data extliding and consistency between research.
as a condition of rapid approval, both regulators have asked Baiji Shenzhou to continue to confirm Zebutinib's efficacy in Phase III trials (BGB-3111-306; NCT04002297).
's rapid approval after a prioritized review of similar data demonstrates the scientific regulatory principles and requirements consistent with U.S.-China drug regulation.
However, the NMPA approval time is six months behind the FDA and shows the difference between China and the United States in the drug review and approval mechanism.
procedures, both agencies are required to conduct pre-NDA meetings, NDA acceptances, information form reviews, technical reviews, GCP or GMP on-site inspections prior to formal approval.
however, differences in review cycles and processes have led to a time difference between approvals between China and the United States.
for example, the FDA improves the integrity of filings by accepting rigorous prior NDA data volume reviews to reduce the availability and multiple rounds of reviews.
, in contrast, NMPA usually requires one or two rounds of data replenishment and review. in addition,
, the FDA's technical review and on-site inspection are conducted side by side, and the NDA initiates on-site inspections after acceptance, while NMPA's on-site inspections are usually carried out after confirmation of pharmaceutical production processes and quality standards.
in the case of Zebutini, the GCP on-site inspection was conducted after the completion of the first review of the NDA declaration materials, while the GMP on-site inspection was conducted after the completion of the supplementary information review.
based on the risk-based inspection concept, NMPA conducted a dynamic full-process inspection of Zebutini's new manufacturing facility in China, and the FDA conducted a spot check based on the good compliance and quality control records of its U.S. production suppliers.
, the entire review cycle was further extended by the drug sampling and inspection in China after the on-site inspection.
Zebutini's review and approval schedule for NDA in china and China (Photo: Nature Reviews Clinical Oncology) Zebutini's 21-month NDA approval in China is a relatively special case, influenced by a number of factors.
the average NDA for other drugs qualified for priority review in China in 2019 is a 12-14-month approval cycle.
for example, the PD-1 antibody drug Triprism and Cindilli sepidal, developed by local Chinese companies, and ometinib, a third-generation EGFR inhibitor, have fewer than 12 months of approval periods.
external factors may also have affected Zebutini's approval cycle, such as the 2020 new crown outbreak that could affect the progress of on-site inspections.
Although China's drug reviews have made significant progress, there are still a number of areas that regulators will consider in the future, including optimizing the review process, refining information submission requirements, and more adequate review resources.
the fact that NMPA has begun to implement a number of optimization measures, such as the Measures for the Administration of Drug Registration, which came into effect on 1 July 2020, future technical reviews of drugs will be conducted in parallel with on-site inspections, specifying the timing of the initiation and completion of inspections.
the new version of the Drug Registration Management Measures while encouraging a reduction in multiple rounds of reviews, which may result in follow-up documents that require more detailed information for reporting and make the entire review process more standardized.
In addition, real-time review of information prior to formal submission to the NDA can also shorten the approval cycle.
, for example, the FDA begins implementing the Real-Time Oncology Review Program (Real-Time Oncology Review, RTOR) in 2018 to speed up the review process for oncology drugs.
adequate data information and input communication with the Global Drug Enforcement Agency can help accelerate the review and approval of drugs in several countries.
since 2019, the FDA has been working with regulators in Australia and Canada to conduct simultaneous drug reviews under the Orbis program, an initiative of the FDA Center for Oncology Excellence that provides a guideline for simultaneous submission and review of oncology products among international partners.
in today's continuously innovative research and development ecosystem and improving regulatory environment, we look forward to a joint review by China's drug regulatory agency and other regulatory agencies around the world in the near future to enable drug development and approval to go hand in hand, ultimately enabling the drug to reach more patients worldwide and earlier.
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