Synopsis
Script/Panellists
Arsalan Arif: Hi, everyone. I'm Arsalan Arif with Endpoints News. Thanks for joining us today for Clinical Trials in China: Unlocking the Potential of Advanced Therapies. I'm excited to moderate today's expert panel sponsored by Novotech, internationally recognized as a leading Asia Pacific-centered biotech CRO with global execution capabilities. We've got a great panel to lead our conversation today.
Joining us we have Yi Zhang, director of the Biological Cell Therapy Center at the first affiliated Hospital of Zhengzhou University. Dr. Angela Men, chief medical officer with Zhejiang Haichang Biotech Company Limited. Xiaoye He, Head of Medical and PV at Novotech China, and Charley Sha, Head of Regulatory Affairs with Novotech China. Now, if you have any questions during today's webinar, please hit the Q&A button at the bottom of your screen to join the discussion. This webinar will be available on demand to watch tomorrow. Now I'm going to hand it over to Xiaoye to get us started. Xiaoye.
Xiaoye He: Hello. Thank you. Hello everyone. This is Xiaoye He. I'm the head of Medical and Pharmacovigilance from Novotech China. Today I'm very pleased to share the landscape overview of advanced therapy in China. As we all know, the category of advanced therapy medicinal products may be a bit different between EMA and FDA, but there is no doubt that ATMP falls under the regulatory framework of innovative biological products.
According to a paper published in May of this year which did a global pipeline analysis of advanced therapy medicinal products, we can see majority of the ATMP linked to gene therapy followed by somatic cell therapy, tissue-engineered therapy, and combined therapy. Hemological cancer and lymphomas as well as the genetic disorders are the most targeted therapeutic area of the ATMPs in develop, and gene therapy is the most common type of ATMP in under development for the top five therapeutic areas, except cardiovascular system.
In this area, tissue injured therapy is the most common type followed by somatic cell therapy. If we classify the target indication as cancer and noncancer, we can see noncancer is a bit more than cancer ones, which is a very interesting trend. Advanced therapy in China actually has a long history. You may know or may not know the second clinical trial of gene therapy in the patients of hemophilia B was conducted by Chinese scientists in 1991. China is the first country to approve a commercial gene therapy product in 2003. Unfortunately, China almost lost its leading position in this area partially due to the lack of clear regulatory and politics.
Now China is making remarkable progress in cell and gene therapy development since 2017 due to a series of progressive politics to promote and strengthen under regulatory in this field. China now has become the center of cell and gene therapy, ranking the second worldwide in the numbers of patent applications and registered clinical trial just after United States of America. This put China back to the forefront of cell and gene development globally.
Being consistent with the global applications, most of the cell and gene therapy clinical trials in China are CAR-T therapy. CAR-T R&D globally is particularly focused on a few central priorities, and China is closely aligned with these priorities, such as the attempt to develop universal CAR-T therapy. Efforts to improve CAR-T cell production efficiency, expansion into solid tumor treatments, optimization of CAR-T inclusive treatment protocols. In addition to that, autoimmune disease, infection disease, POEMS syndrome, other disease beyond cancers, CAR-T therapy targeted too in China now.
The fast growth and increase of cell and gene therapy in China are due to a combination of multiple factors. First of all, the support from government is strong and sustained with many positive politics and the regulatories were released by government. The cell and gene development in China has become more and more standardized. Secondly, the number of patients require cell and gene therapy in China is big due to large population base, and the unmet medical needs is obvious in China.
Certainly, Chinese investigators and scientists are continuously making efforts to promote cell and gene therapy development in China. We sees increased clinical trials. It is very important to gain hands-on experience in this field. Besides, China's health care system has also been development, and at the last but not the least, the sufficient funding support is very crucial to the development in China. Promoted by open politics, the increasing in finance is obvious and the private capital is also attracted by the high return in this field, which resulted in the increased private capital inflows.
We see the factors aligned and work together, the outlook of the cell and gene therapy development in China is very positive in the future. Novotech, as the Asia Pacific leading global CRO, has gained rich experience in advanced therapy relevant clinical trials recently. We are also very happy and open to collaborate with more investigators and the clients to promote cell and gene therapy in China in the future.
As the summary of my presentation, advanced therapy medicinal products have become a fast-growing group of innovative medicines globally. China holds a leading position in basic research, clinical practice, and commercial development in the field of cell and gene therapy. Novotech is in the leading age in this area. Finally, I want to say the journey of advanced therapy development may be long and winding, but is full of promising. Thank you.
Arsalan: All right. Now we're going to up for Dr. Angela Men.
Angela Men: Good morning, everyone. My name is Angela Men from Haichang Biotech. It's my pleasure to join this webinar to share my thoughts regarding MRCT in China. We all know MRCT is not a new concept. Back to a few years ago, this guidance regarding E17 general principles for planning and design of multi-regional clinical trials guidance for industry have been published in English US, EU, and in China. MRCT, the goal of this guidance is to increase the acceptability of MRCTs in global regulatory submissions.
MRCT is defined as a clinical trial conducted in more than one region under a single protocol. Here the definition of a region regarding that, it's a common set of regulatory requirements applied for drug approval. The figure in the middle below area clearly show the difference between the traditional independent strategy, local trials versus the global strategy representative example of MRCTs.
By using the classical way conducting the local trials in A region, B region, the study is conducted in sequential. Therefore, the submission to each regulatory region, it will be in sequential sequence as well. Therefore, there is a delay regarding the submission to different regions. However, by applying the global strategy, the trials will be conducted simultaneously in multiple regions. Therefore, the study results can be submitted to different regulatory agencies at the same time. Overall, there's no delay of its approval.
Why MRCT? Here I listed the key advantages regarding conducting MRCT. It will improve drug development efficiency. It also can have simultaneously submission and review of marketing authorization applications across different regulatory regions, and the patient in different regions will get new medicines earlier. It also helps scientifically understand the treatment effect of different populations under the same regimen. It also helps recruit trial volunteers faster and reduce unnecessary duplication of clinical studies.
What is the function or position of the clinical study in China in the MRCT global strategy? Theoretically, clinical study conducted in China can be part of this global strategy at any stage of the clinical development, including phase 1, phase 2, phase 3, depending on each sponsor's strategy, global strategy. Even the first in human study can be started to be conducted in China. After that, the information collected from Chinese population can be used to support the study design in the other regions as well.
What is the advantages and challenges we are facing to conduct clinical studies in China? Here I listed the major advantages to conduct it in China, and the first one is regarding the diverse patient population. We know China has the largest and the diverse population in the world, and recruit patients in China, it will increase the generalizability of study results. Also, it will help accelerate patient recruitment because we do have a large patient population. It will decrease the time required for trial completion and shorten the development timeline.
As the speaker just mentioned, NMPA also try their best to streamline regulatory process for clinical trials, which will facilitate study initiation and execution in China. Also, the cost in China associated with clinical trial infrastructure, labor, and patient recruitment is relatively low. Therefore, the cost versus effectiveness is higher than conducting in the other regions. Also, with more and more skilled researchers, clinicians have been trained in China, and all those investigators who can contribute to valuable expertise to the trials is increased. Therefore, these are the advantages to conduct such trials in China.
Meanwhile, there are some challenges to conduct it in China as well. Mainly, I will not talk about in detail because of the limitation of the time. However, here I listed the top several ones, including culture and language diversity, logistical complexities, and regulatory hurdles, data quality and standardization, site variability, ethical considerations, and intellectual property protection. Here, we will talk about more challenges, how to face these challenges in the later discussion points, so I will not talk about it in detail.
Here, I will conclude my presentation regarding the … of mitigation strategies, which including early planning, take into all considerations in the study design and the global strategy when we start to think about to conduct MRCT. Also, active and effective communication with the regulatory agencies is always the key to have a success MRCT running. Also, if possible, centralized oversight, have a collaboration with local partnership, standardization of the clinical procedure conduction, active patient engagement, and also regulatory expertise, data management on all of this we can work on to mitigation to make our clinical study in China successfully.
Lastly, I just want to share, this is a review paper published at the end of 2022. It compares international oncology drug approvals for MRCT clinical trials conducted in United States, EU, Japan, and China for all approved oncology drugs from 2010 to 2022 based on 48 new molecular entities information, which have a total of 212 pivotal trials conducted.
Here, as you can see, for the Table 6 on your left, a total of MRCT of 183 studies have been evaluated. Among them, 37 have been completed in China. This is a very decent number, which means MRCT had been well conducted in China.
Then on the Table 8, it shows the different time of the approval comparing between MRCT and a single-country bridging study versus standalone country. The conclusion is that the median time to approval of MRCTs was significantly longer than that of single-country bridging studies. However, it's much shorter than that of single-country standalone studies. Also, MRCT clinical trials primarily involving three regions, US, EU, and Asian areas as the most frequent pattern.
I think by collecting all of this ongoing information, having this kind of systemic review, it will definitely help us to see the advantages of MRCT conducted in China as well as what kind of strategies and lessons we learn we can apply to the future MRCT study design, which will help us to speed up the global drug development. Thank you, all. I'll give it back to the moderator. Thank you.
Arsalan: Alright, thank you very much. Now, you're up next, Charley.
Charley Sha: Hi, everyone. I'm very glad to be here to participate in this webinar to give you a brief introduction on the China IND startup, and also the expedited programs for the marketing application. You can see this slide; this is about the full startup timeline. Even all the advanced therapy product, no matter it's the chemical product or biologic product, this timeline actually can be used for your reference.
Firstly, it's about the pre-IND. The pre-IND totally will take about four months, but it is not mandatory to have a pre-IND in China. If you're going to run a CDE multinational trial to include China, be part of this, you can actually skip the pre-IND stage, which can save you some time, and … some time to prepare the IND documentation. After we get all the IND documentation ready, we can make the IND submission.
The technical review under NMPA for the IND application, 60 working days is a mandatory timeline, but in real case, the timeline will be shorter. During the IND technical review, our startup team will also conduct the site-level startup activity, which include the TCP office submission and also the EC committee submission. In most leading sites, the EC committee process can be conducted in parallel with IND application. After we get all the IND approval and also the EC committee approval and also the contract are signed …, we can make the submission for the HGRAC.
The HGRAC actually is very special for China process. For the HGRAC approval, usually we can get this approval or notification 1 month or 1.5 months after. Then we can be qualified to recruit the subjects. With all this approval, so that EC approval and also the HGRAC approval, we can be qualified to recruit all these patients.
For the IND Dossier, currently, China NMPA adopted the ICH CTD format requirements, which means we will need to prepare the Module 1 to Module 5 if applicable. For Module 1, usually, no tech team will provide you guidance to provide this local administration part. For the Module 2 to Module 5, we commonly follow up the ICH guidance. For the CMC part, there will be some regional requirements. That's for the biological product. Usually, we'll need to supplement some manufacturing and testing records and also some validation report if applicable. The other documents for CMC are about the chromatograms. Just the representative chromatograms will be enough.
For this documentation submission, currently, we can only submit the electronic copy rather than hard copy. We will need to prepare all the documentation in PDF format. Also, we still need to prepare the Word documents for future submission during the technical review. For the language requirement, for all the submission documentation, we need to translate the documentation into Chinese language. Especially for the Module 4 and Module 5, if we're going to submit the whole report, we can only translate the main body of the report, which will be accepted by the authority practice.
HGRAC is the Human Genetic Resource Administration of China. From the early of this July, the authority has already changed the process, which currently we need to get all the contracts sent by all parties, which include the CRO, the sponsor, the leading side, and also the …. We need all these contracts sent before we can make the submission. Also, for the HGRAC submission, currently, we only need to make the online submission. No hard copy will be required.
There will be two scenarios for the HGRAC process. One is the approval scenario. Another is the notification scenario. Commonly, if this is a clinical trial is IND approval rather than IIT, we can go to the notification scenario. In this scenario, the HGRAC can complete the notification process within one to three weeks. If this is an investigator-sponsored trial, results and the approval from NMPA, we have to go to the approval scenario, which means we will need to go through the online submission and get the administration validation done within one week, and then go through the technical review process, which will take 20 working days.
After the approval, all the notification complete, the leading site can be started. For the other sites, we still need to file all the other sub-sites information in the system before we can activities the other sites. This is all the startup activities in China, and when we complete the clinical trials in China, we will need to file the marketing application and the … BLA.
There is some … program just like the programs in US. The breakthrough therapy pathway is also available in China. For this breakthrough therapy pathway, we need to make this application before the Phase 3, before the pivotal trial, so we can get some advantage from the authority and get the chance to get the first communication, also to get the support from the authority during the clinical trial development.
The conditional approval pathway, which is similar as the accelerated approval pathway in US. This conditional approval pathway, we need to communicate with the China authority before the NDA or BLA submission. With this conditional approval pathway, we can automatically get the priority review, which is the next expected programs. For priority review pathway, this is only applicable for the marketing application because the 60-working days approval process has been adopted by the PA several years ago, so there's no room to reduce this IND timeline.
For the priority review, there is some criteria for this program. Commonly, for the advanced therapy, usually we can get this qualification. If we can get the qualification of the priority review, there is some advantage for this pathway. We can get all the process accelerated for the NDA or BLA submission, which include, we can get shorter technical review timeline, we can also accelerate the QC test, which is mandatory for all the NDA submission, and also for the inspection process under CFDI, we can also apply to have a shorter timeline.
Another thing is about the ruling submission. For all the submissions, all the NDA and BLA and the priority review, the sponsor can get a chance to actively supplement technical dossier. For this kind of supplement, the technical dossier, we still need to confirm with the China authority before we do that. Comparing with the US and … programs, there's no open drug pathway, this is because currently there's still no official definition on the rare disease. Even we have a list for the rare disease, but there's no official definition. I think that is one of the reasons why there's no open drug designation in China.
Arsalan: All right then. Those are some great presentations. Thank you all. Please continue to submit your questions, and if we run out of time, your questions will be shared with the panelists after today's webinar for follow-up. I just have some questions to throw into the panel as well. Angela, maybe I can pose this question to you first. My question is, what are the strengths of conducting clinical trials of advanced therapies in China, and how do you go about tackling any dilemmas, Angela?
Angela: Hi. I think the advantages conducting the trials in China, just now I presented briefly regarding this one already. I think mainly the first one is China has very large and diverse population. By conducting trial in China, it definitely will increase the generalizability of this study results. Also, the cost itself associated with clinical trials, labors, relatively low, and therefore, the cost-effectiveness is lower than conducting it in the other regions.
Regarding the regulatory support, just as the other speakers presented, even though we are trying to streamlines regulatory process for clinical trials in our own region, however, at the same time, we can tell CDE and NMPA have tried their best to catch up the international pace and then to translate old updated guidance into Chinese, and publish the new guidance to get the feedback from our Chinese scientists, regulators to finalize it based on our own real-world setting.
Also, more and the more innovative clinical trials have been encouraged based on the current updated government policies, regulatory policies have been done. Also, for some rare disease or for the disease situation which has unmet clinical need, and also NMPA CDE has opened the door many different opportunities to speed up to support the drug development.
All of these connected to the International Drug Development Pathway very well, and it's very promising to use the study conducted in China to support its approval not only in China, but also in the other regions as well. I also mentioned when we design the global strategy, MRCT, and some studies can be conducted, even the first in human study can be conducted in China because of those advantages I just mentioned.
This information, not only the traditional way, based on the approval results, we conducted the region study and then … those drug information results and approve it in China. Now I think we have more resources, capabilities to do the first in human study for the new molecular entity in China, and then on the other way to bridge it to the other region.
Definitely, the dilemmas, challenges we are facing also a lot, but I think one major one is regarding the standardization, because the electronic submission, I think all of regular agencies had started to apply to it. Regarding the data management, electronic submission, all of this, if we can be consistent with the other US, EU regulatory agencies, we can quickly apply the data collected at China conducted those global statistical analysis to use those results to support its approval in the multiple regions.
Also, regarding the-- I have to see-- There are some issues regarding the reliability of the data collected in China. Then for that part, I think the consistency and also strictly follow the protocol procedures in details is very important. By having the training and also the standardization, centralized overview, I think the conducting clinical trials in China can overcome these challenges, difficulties, dilemmas, and this data will become more valuable in the MRCT. By doing this, we definitely can attract more clinical studies to be conducted in China.
Arsalan: Thank you very much for your question. Now let's ask-- Dr. Yi Zhang, let's bring you into the discussion now. What are the strengths of conducting clinical trials of advanced therapies in China? Can you please explain to us how would you tackle … dilemmas?
Yi: I'm a physician and also a scientist. I totally agree with Angela. She just told us about from the company side to consider this kind of question. For me, from a hospital side, I think-- Of course, Angela told us just right now, China, we have a large population, a lot of us. I'm working in the cancer field, and a lot of cancer patients, and also for the late-stage cancer patients who have not very good treatment strategies for them. That's why more and more cancer patients in China realize that the clinical trials can be accepted, can be other choices for them, one of choices for their treatment strategies.
That's why in this year, … more and more the patients are willing to join the clinical trials. I just started …. more than …. 10 years ago. 10 years ago, I came back, when I came back, and when I try to run the clinical trial, very few patients realize this is a good choice for them, maybe a better choice, also other choices for them, but now more and more, especially for the late-stage patients, they have tried a lot of different treatment options. Now they realize this is another choice for them, it is another …
I think in China, even the government and also the hospital, the officers, they realize also if they run more clinical trial, and also for them, it is a good choice, it will recruit a lot of the patients, and the even the recruiter, high rank of scientists will join them. Even in my hospital, the dean always encourages us to run the clinical trials in these years. Thanks.
Arsalan: Thank you. Thank you very much. Charley, what about you, what are your opinions on this question, the strengths of doing clinical trials for advanced therapies in China and the dilemmas?
Charley: For the advantage, obviously, China has a large population, just like Dr. Men and Zhang said, so I'm going to talk something about the challenge. The challenge, I think, still, even we can see that the R&D timeline is not very longer than the US or EU parts, so we still need to face the timeline for the HGRAC, which is mandatory to run a clinical trial in China, but fortunately, the HGRAC has decided to change the process. I suspect that the timeline can be shorter.
Also, another challenge previously is about how to export the samples, the specimen to outside China. Previously, it takes very long time, but in future, I expect the timeline can be shorter, and also, we can get more approval for the exports under the HGRAC.
Arsalan: How about, Xiaoye?
Xioye: I would like focus on more talking about the dilemmas, especially about the advanced therapy relevant to clinical trials. As we all know, advanced therapy medicine products are not the same, especially very different to the conventional products in many ways. It's relevant to clinical trials usually have stricter improvement criteria, requires the cross-functional support engagement, like nursing, ICU doctors, pharmacy, to ensure the pre- and after-care safety, and also requires closer engagement between the investigators and the patients to well manage the patient's high expectation on this promising treatment option.
To meet these goals is not easy, especially due to some unique local challenge. For example, in China, there is no official national referral system. We also lack of a well-established electric record system, without sufficient data integrity and data sharing. Also, there may be some relatively limited interaction among the different departments which raise the potential risk of patient compliance during the treatment journey. I think when we select a site, it is very important to fully assess the site's capability and the qualification, such as the site's capability of their patient recruitment, consent discussion, treatment process, safety, efficiency, follow-up, et cetera.
Once there are some hospitals can meet these criteria, we can consider them as the center of excellence sites, and these sites can-- it's very important to propagate the standard for cell and gene therapy to the surrounding hospitals. It also will be critical to set up the proper platform to promote the patient screening and boost the recruitment process. That's all I want to say. Thank you.
Arsalan: All right. Thank you very much. Now I have another question here as well that I'd like to bring up and ask. What are some of the opportunities that are ahead and maybe some of the challenges that are ahead? Yi Zhang, let's ask you first about some of the opportunities and the challenges that are ahead.
Yi: You mean the challenges in clinical trials? Yes?
Arsalan: Yes.
Yi: Okay. Of course, the first thing is that … in the formal, the real, the clinical trials are encouraged, as I mentioned, just by the government and the just in these years, as in the 10, 20 years, I think the more and more regulatory and also the guidelines, also everything such as the professional CRC and the CRE also it should become more and more professional. That is the first thing. Second thing is the, of course, even all the strategies and the procedures for the total process for the clinical trials, such as from recruiting the patients, or managing the patients, and the follow-ups patients, all this process, the whole procedure should be more and more really set up properly.
Of course, I think, as I mentioned, this year has already improved a lot, but still, we should get much better management for this whole process. The second thing is also, for the different clinical trials such as IND, also for IIT, maybe they require different regulatory. For this one, for Chinese government realize this, we are trying to make a more detailed, more process guidelines for these different trials.
Arsalan: All right. Opportunities and challenges ahead. Who else on the panel would like to take this question? Anyone else who has answer for this question about the opportunities and challenges ahead for clinical trials? Charley or Angela?
Angela: Sure. I'd like to quickly add a few points. The challenges. Just now we mentioned that China has a large patient population. However, while a diverse patient population can be at advantage, but meanwhile, recruiting and returning participants who meet specific trial criteria can be challenging as well due to varying disease prevalence rates. In addition, I think culture, language diversity is also another challenge. By conducting study in China, we need to make sure consistent communication, training, and adherence to protocols across regions. In addition, ethical consideration. Ethical standards, practice may differ among regions. Therefore, necessary careful attention to patient rights, informed consent, and ethical review processes needs to be definitely taken into consideration.
Also, regarding the data quality and the standardization, we need to make sure consistent data collection and maintaining data quality across diverse sites, which is very crucial for generating reliable and valid results which will be used to support NDA and BLA submission. Overall, we are facing these challenges for the clinical trial. However, I still put very high promise regarding it.
I think almost all of us know this news, early last month Moderna strike a deal worth up to 1 billion to develop, produce mRNA drugs in China. I think this decision, not only based on the advantages we just mentioned during our webinar, but also there's a large market, large need, and also large collaboration for those type of new product development.
Arsalan: Okay, wonderful. Xiaoye or Charley, anything to add here to this discussion?
Charley: For the opportunity of the advanced therapy, I think this is very clear that China central government just released a notice, a guidance just to encourage all the cell therapy, gene therapy, which has already been approved oversea, the … encouraged to conduct the clinical trial in China, and also to locally transfer the manufacturing inside of China is encouraged. How about the other product which is still in the R&D stage? Even it is clearly that the oversea approve to the product is encouraged. It doesn't mean the product still … this stage is not encouraged.
The NMPA always just emphasize that all the innovative product is encouraged, which include the advanced product. Mainly the cell product and also the gene therapy product. This is the opportunity. There's still some challenge, because for all the cell product, because this is about the regulation under the customers to export and import cell products. The human cells is still take some time. Sometimes it's not easy to import a trial or import cell product inside China. For gene therapy product, I think there's no problem. Always you can just-- such as for the small RNA product, which actually was classified as chemical product, so there's no hurdle to import or export this kind of product.
Arsalan: Opportunities and challenges, Xiaoye He, we'll give you the last word.
Xiaoye: Okay. I think the understanding of clinical trial in China has been improving a lot these years, which is very important for the patient recruitment, either from patient side or from the hospital physician side. The challenge is still existed due to some China local factors. For example, the study design. When we consider the study design, I think we need to--
Especially for China standalone or China as a part of the MRCT study, the study design should be fully cover all the unmet needs from local country because the prevalence of the disease in China may be a bit different from other countries, and that the disease map may also be different. This will all reflect the local unmet medical needs. When we consider the study design, we need to focus on the real medical need and target the design which can really benefit the patients. That's all I want to say. Thank you.
Arsalan: All right, and thank you very much to our entire panel because that's all the time that we have for today. I want to thank you to everyone in the audience for joining and submitting some great questions today. Thanks to our panel for sharing their time and their expertise. We appreciate Novotech for sponsoring today's discussion and all of their discussions at Endpoints webinars. Thank you, Novotech. If you'd like to watch this webinar again or to share it with your colleagues, a link for on-demand viewing will be shared with you tomorrow. I'm Arsalan Arif for Endpoints News. Thank you for joining us, and we hope to see you again at a future Endpoints webinar event. Thanks again.