//
● The FDA requires biosimilars to be highly similar in safety and efficacy to the original drug, and the original drug from the United States is required to be used as a control.
● FDA is becoming more stringent in the inclusion of local populations declared by biotech companies in China and other countries in the United States. ● FDA on-site inspection and evaluation: Henlius' production system is better than that of many U.S. companies in some aspects.
Recently, the trastuzumab biosimilar HERCESSI™ (Chinese trade name: 汉曲优) developed and manufactured by Henlius has been approved by the US FDA for marketing. Although the marketing of the drug in the United States was undertaken by Accord, a partner of Henlius, according to Jun Zhu, executive director, chief executive officer and chief financial officer of Henlius, the key registration application work for the listing of Han Qu was completed by Henlius' own registration team.
"FDA's requirements and guidelines for the review of biosimilars are a complex, comprehensive, and rigorous system that reviews and evaluates submissions in an extremely detailed manner to ensure the safety and efficacy of biosimilars. This is what I remember the most as a registrant. A few days ago, R&D customers interviewed Ms. Li Jin, General Manager of the Pharmaceutical Affairs Department of Henlius. She is responsible for formulating Henlius' global drug administration strategy and coordinating the registration and application of products in domestic and foreign markets.
The FDA also requires the submission of U.S. data
Han Qu You is the first monoclonal antibody biosimilar approved in China, the European Union and the United States, and was previously approved for marketing by the European Commission and the State Food and Drug Administration of China in July and August 2020, respectively.
In 2020~2021, Henlius started the application and registration in the United States. In February 2023, the marketing authorization application of Hanqu You was officially accepted by the FDA. Compared to other markets, Li Jin said that the FDA first has very high requirements for biosimilarity data, which requires a comprehensive comparison of biosimilars and reference drugs, and an assessment of the impact of any differences found.
Ms. Li Jin
Second, the FDA requires biosimilars to be highly similar in safety and efficacy to the original drug. In addition, it is necessary to verify pharmacokinetics, immunogenicity, stability, etc.
Third, the FDA requires manufacturing processes and quality control measures to be similar to those of the innovator within a certain range. Applicants are required to provide detailed production processes and quality control plans, and conduct compliance assessments.
Initially, Henlius submitted a submission to the FDA based on a full set of research data from Europe. "We believe that if the European EMA and the China Food and Drug Administration have already approved, it may be possible to use the existing research data to submit to the FDA, but the FDA refuses. The FDA is very insistent in some areas. Li Jin said.
Since Henlius only compared Han Qu You with the original drug from Europe in the CMC and PK studies and the Phase 3 clinical study, and did not have the original drug from the United States, the relevant study design was challenged by the FDA. Therefore, Henlius has conducted a new CMC and PK study of Han Qu You versus trastuzumab commercially available in the United States, and successfully produced three batches of the product, further verifying the similarity between Han Qu You and the original drugs from different countries. Li Jin was deeply impressed by the fact that the FDA raised hundreds of questions about CMC and clinical aspects. For example, the FDA has extremely high requirements for aseptic procedures and aseptic method development in CMC.
Another profound experience of the FDA is that although the clinical study report (CSR) and clinical data are important in the application process of the biologics license application (BLA), after the completion of the trial, the FDA's focus will shift more to the company's future production. "The FDA will discuss quality standards and evaluate whether the pharmaceutical data is sufficient to support the stability of multiple batches of product and the robustness of the manufacturing system in the future." She said.
The third profound experience of FDA is that even a Chinese biotech company with zero experience with FDA can complete all projects step by step according to FDA guidance. The FDA's guidance will not be too broad, and companies can learn to ask targeted professional questions in their communication. In addition, the FDA is also very flexible in certain situations, and the facility is able to communicate with the FDA within reason.
The Songjiang base welcomes the verification process
Henlius' Songjiang Base (1) is located in Songjiang Industrial Zone, Songjiang District, Shanghai. In 2022, the 24,000-liter production capacity of Songjiang Base (1) was officially put into commercial production of Han Qu You. Since Han Qu You's application to the FDA, the base has been engaged in the comprehensive preparation of FDA GMP inspection.
From the end of July to the beginning of August 2023, the base underwent the FDA's pre-marketing authorization inspection of Han Qu You.
To this end, Henlius conducted dozens of simulated inspections in the early stage, and sorted out the production system, process, actual operation, warehousing and quality system one by one in strict accordance with the terms of the FDA inspection to ensure that all processes and operations meet FDA standards. External third-party inspectors with FDA inspection experience were also invited to conduct a detailed assessment of the site from various angles.
Compared to the one-week inspection cycle of the regulatory authorities in the European Union, Brazil, etc., the FDA's inspection time is longer. The FDA's inspection team stayed at the Matsue base (1) for two full weeks to conduct a comprehensive inspection of the base.
The first task of the FDA inspectors before visiting the site was to ask Henlius to prepare GMP-related documents. They delve into and mark up key documents beforehand, then travel from Maryland to their base in Shanghai with a thick stack of materials to conduct detailed on-site inspections. Li Jin recalls that the first day of the FDA's work revolved around documentation to ensure that the documentation was complete, after which they would consult with the quality director for detailed information on the issues of concern.
In order to meet the FDA's requirements for information and consultation, Henlius' manufacturing and quality departments formed a dedicated team to quickly locate the section corresponding to the FDA's questions in the thick data and present them to the FDA inspectors. In addition, the company has a large number of international personnel who are proficient in English to ensure the smooth progress of on-site inquiries and respond to questions raised by the FDA.
Li Jin said the F.D.A.'s inquiries were highly targeted. For example, for a particular batch, FDA will review the batch records in detail and ask further questions about the data and written records that are in question. If there is a deviation, Henlius needs to explain how to deal with it, and as long as it can provide a reasonable explanation, the FDA will usually approve it.
During that time, the heads of all relevant departments at Henlius Songjiang Base (1) lived near the company to answer FDA questions at any time. The FDA inspectors enter the site from 8 a.m. every day, review a lot of information, ask various questions, and are busy until 8 p.m., working long hours and with great intensity.
Whenever the FDA inspectors leave, the base personnel will immediately hold a meeting to review and summarize the day's inspection content in a timely manner. If the FDA raises a problem that needs to be addressed urgently, Henlius staff will handle the problem on the same day. The next day, FDA will review the previous day's issue again, and if the facility has handled it appropriately and has been approved by it, it will move forward with the review of the next issue.
Henlius team review meeting during the verification Photo courtesy of Henlius
In addition to reviewing the data, the FDA's second job is to conduct in-depth inspections at the production site. FDA will ask about the company's two-week manufacturing plan, including drug substance production time, formulation manufacturing schedule, quality inspection schedule, and product release and cleaning work dates. According to the schedule, the FDA, accompanied by the company's personnel, conducts on-site inspections of the entire production and quality process every day, observes each step of the process of the operators, and compares it with the description in the application materials to ensure the consistency of the two. Any discrepancies or violations will be documented by FDA.
Songjiang Base (1) successfully passed the FDA on-site inspection. Photo courtesy of Henlius
The third part of the FDA audit is to find the original data and materials from various computer files and systems to verify whether the original records are consistent with the results of the company's performance. In case of inconsistencies, FDA will document them as a finding. The production base based on Henlius has a complete GMP manufacturing system and strict management, and no serious defects were found during the FDA on-site inspection.
In the end, the Songjiang base (1) passed the inspection of the FDA. FDA inspectors spoke highly of Henlius' manufacturing quality system, which they said was better than many European and American companies in some aspects. "Through the strict inspection of the FDA, the entire production quality system of Songjiang Base (1) has been further improved, which not only improves the production efficiency and product quality of the base, but also ensures that it meets the high standards of the FDA." Li Jin said.
Since then, Henlius has undergone a joint inspection by the European Union and Brazil, "and these two regulators also believe that our factory is more complete than many overseas companies." Speaking of this, Li Jin smiled proudly.
Registration strategies from Europe to emerging markets
When summarizing the experience of FDA registration and application, Li Jin emphasized the high degree of scientific nature and high standards of FDA. She believes that in recent years, there have been three major changes in the FDA's requirements for MRCT: first, the inclusion requirements for the inclusion of local populations declared by Chinese and other biotech companies in the United States are more stringent; The second is to emphasize the rationality of the sample allocation of multi-ethnic populations in the U.S. trial; The third is to implement new regulations on the optimal dose selection of oncology drugs before phase 2, encourage more detailed ramp-up trials, and strengthen the rigor of dose evaluation.
"These changes have undoubtedly brought new challenges and tests to Chinese companies. Chinese companies need to adapt to these changes as they prepare for FDA filings. Li Jin said.
She believes that if a localization company wants to go international, it must go through a comprehensive training. For example, while domestic companies have done an excellent job in laboratory discovery, clinical research, and CMC, they still need to change their mindset when moving these results from experiments/trials to registration documents to ensure that all research results are presented accurately and completely in a manner that complies with international registration norms.
Due to Henlius' in-depth understanding of regulatory approval pathways in different countries and regions, the company has launched 5 products in China, 2 products globally, and 19 indications approved for more than 40 countries and regions, covering Asia, Europe, Latin America, North America and Oceania.
In addition, more than 50 marketing applications have been accepted by drug regulatory authorities in China, the European Union, Canada, Singapore, Thailand and other countries and regions. At the same time, the company has obtained more than 70 clinical trial approvals in China, the United States, the European Union, Australia and other countries or regions. So far, Henlius has successfully transformed from biotech to biopharma through the two-wheel development model of "biosimilars + innovative drugs", with a significant year-on-year increase of 67.8% in revenue in 2023 and a net profit of RMB546 million compared with 2022.
When summarizing the clinical and regulatory strategies of these countries, Li Jin pointed out that the biggest challenge is how to adjust and declare different countries based on the same set of data to the greatest extent, and to formulate different registration strategies for each country. For Chinese opera actors, Henlius first selected Europe and China as the first batch of listing countries, and then promoted the submission of listing applications in Australia, the United States, South America and Southeast Asian countries.
In the application process, except for China, the registration and declaration materials of other countries are mainly based on Europe. In general, the regulatory requirements are the same across countries, but there are differences in details and technical issues. Enterprises need to flexibly adjust their reporting strategies when registering across borders.
Perception of many years of registrants
Li Jin has been working in the field of R&D and registration for decades, and has witnessed the growth of China's drug policy reform and CDE. She deeply felt that the CDE review system had gradually been brought into line with international standards. In recent years, with the vigorous development of Chinese biotech companies, CDE has actively formulated various R&D guidelines and communicated with enterprises, especially in the field of new technologies such as ADC and cell therapy. In addition, the CDE Review Competency Day has put forward higher requirements for registrants from the scientific level, prompting them to continuously improve their professionalism and communication skills.
The pressure on registrants is enormous as the pharmaceutical, preclinical and clinical trials have already achieved results, and the final burden falls on the registrants' shoulders, who need to engage in in-depth exchanges and negotiations with the most stringent regulators in each country. In his early years, Li Jin worked in a local company from R&D to the registration department, and later had the opportunity to join a foreign pharmaceutical company, and learned the process of a multinational company in an all-round way. With the reform of China's drug administration, one of her main tasks as a registrant was to systematically explain to the headquarters of foreign companies the connotation and logic behind China's regulations, as well as how the company's strategy should be formulated in order to respond to the regulations.
Li Jin has formed a unique thinking in the long-term registration work. She believes that registrants not only need to convey information, but also have a deep understanding of R&D and regulatory requirements, and become a bridge between the internal and external supervision of the enterprise, rather than a simple "mouthpiece". They need to have a lot of R&D knowledge, have a clear judgment on the timing of the application and the prospect of approval, and effectively communicate the company's ideas to the CDE to achieve the approval goals.
Talking about the future registration layout and planning of Henlius in the world, Li Jin said that the company will closely cooperate with the overall internationalization strategy, and does not rule out the possibility of setting up full-time registration personnel in more overseas regions in the future.
In addition, Henlius will also strive to establish a stable and efficient supply chain system to ensure the stable supply of products. At the same time, the company will also focus on post-market change management, and work closely with the production team to build and maintain an efficient and robust production and supply system.
"I am very proud to have been a drug registrant for many years, and I love this profession very much." She finally said.
Edit | Dai Jialing [email protected]
Issue 2102 in total