Accelerating clinical development in China & the US
Arsalan: Hi, everyone, Arsalan Arif here with Endpoints News, and we’re at ASCO virtually this year, to discuss accelerating clinical development in China and the US. We’re sponsored by Novotech, and I’m excited for today’s discussion. Joining us we have Peter Luo, the founder and CEO of Adagene. Nancy Snowden, Head of US Operations at Novotech. Jin Li, medical oncologist at Tongji University in Shanghai, China. Vivian Gu, the Chief Medical Officer and Head of Clinical Development and Research at Novotech PPC China, and Susan Dallabrida, the CEO of SPRIM Consultancy, and Chairman of the Advisory Board of ObvioHealth.
If you have any questions during today’s webinar, our panellists have reserved some time; hit the Q&A button at the bottom of your screen as soon as you think of your question. This webinar will be available on demand tomorrow to share it or re-watch it with your colleagues.
Now before we begin, we have a brief presentation by Vivian.
Vivian: Good morning. It’s my pleasure to share with you acceleration of oncology clinical development in China. Oncology clinical trial in China rises rapidly in the past five years. In 2021, 40% of all clinical trial activity in China was in oncology area, with a significant number for Phase 1 studies. This means China has become a major focus for western biotech companies.
The number of clinical trials sponsored by western biotech in the small and mid-size pharma increased significantly in the past five years, especially the number of Phase 1 and Phase 2 studies. However, compared to the US, the clinical trial density in China is still relatively low. China offers large availability of resources. China has 1.4 billion population, which accounted for 20% of the world’s population. China has a lower cost of clinical trials, 25% to 40%, lower than the western locations. China has a big pool of active trial investigators and large local healthcare investment funds.
The number of clinical trials sponsored by biotech companies increased significantly over the past five years. CAGR is above 40%. The number of clinical trials sponsored by western countries conducted in China increased even more faster; the CAGR is above 60%. The number is only 18 studies in year 2016, but the number increased to more than 200 in year to 2021.
China accounts for a significant number of new cancer cases and shows leadership in CAR-T cell therapy. In 2020, there were 4.5 million new cancer cases in China. This accounted for 24% of the newly diagnosed cancers, in 30% of the cancer related deaths worldwide. Among all the CAR-T studies, about 60% involved China.
China shows high patient recruitment rates, which I believe is the best interest of most biotech companies. According to the recommended analysis, China shows enrolment period 25% shorter than the US, and 20% shorter than Europe. China shows four times faster medium patient recruitment rates than the US and Europe. You can see the number listed here.
Chinese government continues to encourage biopharma innovation. It sets clear direction on innovation and biotech, in 14th Five Year Plan, which was effective from March 2021. It promotes biotechnology innovation, reinforces accelerated approval. Continues to align with ICH, with more than 70% of ICH guidelines have been implemented in China. NMPA re-elected as member of ICH Management Committee in June 2021. China harmonised IP protection with global, with new patent law effective from June 2021.
The NMPA has reduced the regulatory burden for clinical trial submission to accelerate reviews and to facilitate study process. The upper path is the regulatory pathway for starting up the clinical trials in China. In total, it takes about eight months to start up the study in China. However, if you waive the pre-IND meeting, it can save you another three months, which only take in total five months to start up the study in China. This is very similar to the start-up timeline in most western countries.
Here are some key considerations. First, pre-IND is generally required only for initial IND. For protocols already approved in US, EU, pre-IND can be waived, depending on the sponsor’s decision. IND package prepared in parallel with pre-IND with required dossier translation. EC submission and EC approval can be conducted in parallel in some study sites in China. You can even get the EC approval before the IND approval. And the approval within 16 working days is strictly followed by NMPA. Human Genetic Resource Administration approval is additional required, which usually takes six to eight weeks. Overseas data can support NDA in China. But for most studies, and most compounds, Chinese patient data are still required.
Here is the new paradigm to accelerate entry into China. Enter local market without setting up your own manufacturing facility in China. Leverage the network of local biotech companies, CROs, research institutions. Always consider to include China in early drug development, which will be benefit for the later stage of development. Utilise overseas clinical trial data for CTA filing, and to initiate late stage clinical trials in China. File an NDA by utilising overseas clinical trial data is also possible for some cases. Access fast track channels for drug approvals in China, such as BTD priority review conditional approval.
With that I would like to conclude why consider China for clinical trials. There are a lot of advantages of including China into clinical trials; favourable regulatory environment, cost and timeline benefit, favourable government policy, availability of resources, increasing healthcare focus, demographics and the disease burden. With that I would like to conclude my presentation, and I thank you for your attention.
Arsalan: Thank you, Vivian. I really appreciate that, laying the foundation today over here. Actually, can you tell us a little bit more about how this is facilitated, the acceleration of clinical research in China?
Vivian: Okay, thank you. I think a lot of efforts actually have been made by the China authority to facilitate the clinical research, mainly to shorten the study timeline, and also to improve the study quality. Since 2018, the IND approval timeline has been shortened to 16 working days, which actually was strictly followed by the NMPA.
Arsalan: Very good. Very good.
Vivian: Yes, actually, this allow most companies can join the global trials, because in the past, because the start-up timeline is very long in China, a lot of companies have no chance to join the global trials. But with this start-up timeline shortened, a lot of companies can join the global trials.
Arsalan: Nancy, let’s shift, and let’s talk about oncology over here. You’ve led US operations at Novotech for some time. Share with us the biggest shift you’ve seen in the last five years in oncology clinical development strategies please.
Nancy: Certainly. We’ve seen a significant shift in terms of the number of APAC biotechs that are wanting to expand their development programs here in the US, specifically China-based companies. Additionally, we’ve seen many of our US biotechs and pharma companies wanting to understand more about China, and the change in the regulatory landscape there, as Vivian thoroughly went over, and how they can expand and accelerate their development programs by including China.
And as companies expand into the new territory, critical to that success are having those on the ground resources with specific local knowledge of the regulatory and political landscapes. The on the ground resources help bridge that gap of understanding in local market dynamics. And we can provide great insight into how we can help work with companies at all phases of development, given the wealth of experience our on the ground resources have in both regions of US and China.
We can ensure greater understanding of the requirements that companies need to be mindful of, to set a pathway for regional success. In addition to what Vivian was saying earlier, a certain percentage of patients have to come from the US to gain US approval. So that is also critical, and opens up, of course, an entirely different market, and consider (10:08) population here.
Arsalan: Are there any other, for development strategies in China looking to expand their programs in the US besides what you just mentioned, are there any other considerations?
Nancy: Well, for the clients, they need to have, and we can provide, the regulatory landscape at an agency level, as well as a university and local site level. And that’s where some of our early China biotech clients were surprised, or didn’t have that knowledge, but we provide that knowledge for them. Outside of the sciences driving the development, there will always be the practical components of shortening timelines. And in that vein, there’s great diversity in the method of site-based regulatory and contract approval.
Some sites, university versus private, will negotiate contracts and regulatory submissions and approvals in tandem. Other sites require the contract to be done first, before they will submit to the IRB. And then lastly, some sites require IRB review and approval prior to contract negotiation. And if the IRB determines there’s an inordinate risk, then they wouldn’t have gone through all the cost for resources to develop the contract.
What we’ve done to avoid some of those sorts of delays, is we’ve negotiated over 500 master agreements with sites of all sizes and types, university teaching, private smaller sites, the Veterans Administration sites, so that we don’t meet with that delay in project start-up.
[Subjects] in site cost disparity is another generally unanticipated issue for our new AsiaPac clients, specifically China of late, and that there’s a differential in how healthcare costs are covered. And also, there is a whole process that you have to go through; for anyone that receives government funding, there is a committee that says, okay the (12:20) can’t get paid for what the government is already paying for. And if they are, then they’ll lose the government funding. So there are a lot of logistics and practical considerations, but they all impact your timeline, and your ability to get to market, or to the next phase of trial.
Arsalan: Sounds good. Sounds good. Thank you for that. I want to encourage the audience to keep getting your questions in, I’m going to get them here to the panel soon. I also want to now turn to Peter Luo, CEO and founder of Adagene. So Peter, what do you consider the opportunities and challenges China biotechs face? But how can they be solved by doing research in the US? Can you share some insight on that?
Peter: Okay, so I think maybe I would like to share different aspects about this. I think in terms of clinical development, I think in Chinese (13:19) tests, I think one of the major thing is global differentiations. And because China has been known for a lot of (13:30) PD1 and all this, which I think Professor Li actually has an article talking about, you can use other PD1 to do shower. So the question, I think, for the Chinese (13:45) is, can you do that global division of product developments? I think that’s extremely important.
And the second is, if you can do that, then this will allow the clinical trial go beyond in China, because globally, the PI are looking for novel therapy for patients who fail the standard therapies. If you have that differentiations, especially if you can show that clinically, and then you undoubtedly show a lot of PI, to motivate them to enrol patients for your studies. And there will be (14:26) like a Novotech, a company like Novotech, because they have a very strong footing in Asia Pacific areas. And also the regulatory system there, in different area, very different.
So there’s a good advantage, for example, Australian system, that’s very flexible, and the PI has a lot to say, more than regulators. And I think sometimes this is good, if you’re doing something so (14:57), and that you need a PI who is in the field, that know what the patient needs, that have their only understanding. And this allow you sometimes you even have a difficulties seeing FDA. You might get a chance, a [second] chance for the PI there to look at this; for example, our product in the CTLA-4 of two antibody antibodies against (15:22), and also with a masking technologies.
And we did initially, in the US, have one incidence, but you know, then we put a lot of restrictions. But we went to Australia, and the PI look at this, they believe the data we generated, and in fact, we did that very successfully. And we’ll be able to use that data, come back to US and to China, and right now, our anti CTLA-4, we’re dosing the patient, that 15 milligram per kilogram, to clean up that, and to show to the people it’s really safe. And our (16:00), we just done 20 NBK. And we just recently released the news in the ASCO, we’re only observe in so far dose escalation, only grade 1 observed in the patient treatment related. And then we continue to see those in the patient, not a limit of four cycles, we just done that continuously. So patient even go beyond more than 10 cycles.
So that kind of data really makes the PI raise the (16:30), and then we go back to China. actually, just today. they approve us to restart those levels to 15 NPK, originally really concerned about this kind of thing. So I think that kind of thing is extremely valuable.
And of course another thing we feel so exciting is, whilst we started combo with PD1, our peer already have patient list for us, so this is (16:58).
Arsalan: Almost (16:58). Best of luck with that. And we wish you the best of luck with the research over there. I want to turn to a Professor Li now. So I understand you’re a leading oncologist in China, many years of experience leading trials in oncology. I would like to hear from you, and for the audience, can you share with us what you have seen over the last few years in terms of the acceleration of clinical development from your position? You’re on mute.
Jin: Yes, sure. As mentioned by Ms Gu, Vivian just told you that in the past the several decades in China, the government, they pay more attention to the drug development, because at that time China is in a very poor position. So the people have to pay more attention to the food. So in western countries, usually where you meet together in the morning, you said, “Good morning”, “Good afternoon”. But in China, we (18:10) we said, “Have you had the breakfast?”. Why do we say that? That means that food is very important for us. But in recent years when the economy is much more better in China, and now the government think – I mean, not only the government, but also the people, think that the health is more, could be pay more attention right now. So we have to do something.
So in 2017, the Chinese government just released regulatory reform that accelerate the process of new drug development, both in China and western country, all the drugs could be put into the that situation. So right now, the CD only needs 60 working days for a process of new R&D. So that’s a big step, because it used to be very long when you apply R&D before, so maybe some half a year or even one year, the process. So in western country, the global industry, they usually the develop the drug first in European countries or the States, then come to China. But right now, after the Chinese government released that new policy, so everything seems different.
So also they released a new idea that means that you have to convince your drug is better than before, better than standard treatment. So that is the patient centred policy, or clinical value guiding the clinical study. So that is a very big change than before. So right now, the big hospital, there we set up a centre specifically for clinical study, even in Shanghai, even 20 or 30 big hospital, they have that, the group of the doctors, to pay more to do the job as Phase 1 or Phase 2. And so it’s a really a big step.
Arsalan: That is a big step. Yeah. I’ve been fortunate to see from Endpoints News, we have been covering drug development in China, and it’s very fair to say they’ve made leaps in the past 10 years, giant leaps in terms of drug development, and it’s been fascinating to see. So I really do appreciate the conversation with someone who like you is leading cancer trials to see what it’s like on the front lines over there for cancer drug development. Would you be able to help, and maybe anyone else on the panel help be able to tell us the major differences in the roles of a private investigator in clinical trials in the US versus China? Is there any major differences in the roles of a PI between that in the US and China?
Jin: I don’t think there’s a big difference right now. In the past 10 years, many of the doctors are trained in States. So they have the same policy, so same TCP guideline. So I think there’s no big difference between the PI or the investigational team for a clinical study. So they just follow ICH. And I don’t think there are some differences. So even in China, as we have a big population of the patients, we have our big population of doctors, so even we have a quicker process of Phase 1. You know that recently, if you start the Phase 2, Phase 3 trial in western or in China, usually China will have more quicker recruiting the patients. And the quality of clinical study is also quite good right now.
Arsalan: Wonderful. Let’s turn to Susan -----
Peter: Actually, I can echo too what Professor Li said. We got his PhD students (22:56) joined us, who’s trained under Professor Li, and we’ve also got the (23:01) and also got (23:04) lab (23:07).
Jin: Yeah, in [start], yeah.
Peter: Yeah. So as you can see, that standard is quite internationalised.
Arsalan: Yeah, yep. Yep. No, it’s wonderful to see that. Let’s turn to Susan Dallabrida now. So Susan, I understand, we’re hearing more about technologies, I’ve been hearing about all the decentralised trials and hybrid approaches, but can you share with us more about how that approach is manifested here in the United States?
Susan: Certainly. Since COVID, there was definitely an acceleration in the movement from traditional site-based trials to both hybrid clinical trials and fully decentralised clinical trials. And what we’ve seen in the US is there’s a number of advantages with this approach. The obvious being safety, as COVID and COVID variants will continue to be with us for the foreseeable future. But there are also logistical considerations where DIY kits are being shipped to patients’ and caregivers’ homes, instead of having to make the trek to a brick and mortar site, and the patient burden associated with those travel.
Further, patient pools that are proximal to brick and mortar sites that we’ve seen in the US are essentially tapped out and overused. And the conduct of clinical trial either fully or partly from one’s own home enables certain populations that were out of reach to participate in a clinical trial. This is essentially critical when we think about oncology clinical trials, because oncology clinical trials have become more sophisticated with baskets and umbrellas, and frequent recruitment. And with these frequent requirements to have specific mutations, and also the need to know immediately when standard of care fails.
So one of the things that we incorporate in our approach is recruitment using social media-based approaches, where we cannot only find the untapped pools with recruitment speeds of typically two to four times a traditional brick and mortar site, but we are also able to pre-identify, and have ready and waiting, oncology populations who we think may be about to fail standard of care.
Another aspect is that patient preference, we have conducted two research studies within the last year, inquiring whether patients would prefer to participate in a clinical trial from home or a site, and we have resoundingly seen on both a US and a global scale, that over 85% of the population is choosing to do everything from home, be trained digitally on their own smartphones, and do their own vitals. For example, we conducted an interventional COVID clinical trial, and patients were monitoring six vitals from their home. It was simple things like body weight, temperature, blood pressure, and oxygen saturation. But they were also doing six-lead EKGs with ease.
And so what we are seeing trending, especially in the US right now, is a population wanting to take a self-help approach to clinical trials in general. And while there was some initial scepticism regarding safety, what our experience has been is that by having a virtual clinic site team with an MD, a nurse, a PI, a sub-I study coordinators, who can bidirectionally communicate with patients every day, via chats and email and phone calls, we find that patients are taking advantage of this, and would actually prefer it over going to or calling their clinical site.
Arsalan: Are there any endpoints that lend themselves to a hybrid approach?
Susan: Absolutely. There’s a number that lend themselves, especially in oncology clinical trials. For example, in a traditional site-based study, patients would typically be asked nonspecific quality of life questionnaires on something like a monthly basis. And as an endpoint and outcome specialist, there are a few things that are very wrong with this approach. One, a quality of life instrument is generally insensitive, and a distal endpoint. And patients are largely unable to report accurately on such topics over spans of time with large recall periods.
And then there is a very human phenomenon that patients experience a deer in headlights experience during an oncology clinical visit; they’re stressed, already stressed to learn what’s happening with their cancer. And we know that only about 10% of the clinical information that is conveyed during these physical visits actually gets through to the patient.
So we also know that patients fundamentally subscribe to the notion that because they have cancer, they should expect to feel lousy, and they frequently don’t take the time to call their doctors. What we have seen through studies over the years, is that oncology patients monitored on a daily basis for their symptoms in which algorithms or programs indicate when specific thresholds are crossed, they actually have better outcomes; less pain, fatigue, nausea, vomiting, and overall improved symptom scores.
And this is due to the fact that clinicians are reaching out to make adjustments in medication, reminders, lifestyle, having them come back to the clinic, a variety of interventions, and the patients are actually receiving better care. And they prefer to have this burden lifted off their shoulders, and end up having more communication with their clinical sites.
And what are very interesting in recent years, we’ve seen several publications on this, is that oncology patients’ symptoms not only improve when they’re monitored daily using [E-Pro], but survival is extended when patients are monitored for their symptoms and rescue and pain medication on a daily basis. And that having these alerts and close monitoring when thresholds are crossed, it not only significantly improves quality of life, but it actually extends life.
And in fact, last year, we did a six-month COVID registry with oncology outpatients at St Joseph’s in France. And many of the patients requested to remain on the study after we ended the study. They were just so reassured to know that someone was watching over them on a daily basis, and they had an easy point of contact. And this phenomenon has been repeatedly evidenced in the literature as well.
Arsalan: All right. Let me pose a question to the panel here. This comes actually from our audience. A great question here. Maybe this is best answered by Vivian. But let me let the panel weigh in here; “In which situations or therapeutic areas or indications is foreign data acceptable for regulatory approval in China? So with reference to bridging study requirements for local data, even Phase 1 and 2 trial data seems to be acceptable, not just registrational studies. Could you comment on this, please?”.
Vivian: Okay, thank you for the question. I think it’s a very good question. Actually, the NMPA issue guidelines how to use the foreign data for Chinese registration purpose. So it details in that guideline how to use the foreign data. In summary, I will say that, if it is the rare disease, the unmet needs is very high, then probably you have the chance to purely use the foreign data, there even no need to run a clinical trial in China at all, you can purely use the foreign data for China registration purpose.
However if the disease incidence rate is relatively low, but not that low, and the unmet need is high, but not that high, probably you have to run that clinical trial in China as well. You can use the bridging study, utilising the overseas data plus this bridging study for the China registration purpose. But if for those disease, the prevalence is high, like the diabetes disease, like the COPD, even if you have the foreign data, still, you have to run full sample size clinical trial in China. So that’s all.
Arsalan: Wonderful. Before we get to my next question, I just want to actually – and I rarely do this, read a comment from the question section. But I’m going to read a comment here. This is actually from Martin Murphy here. “Professor Jin Lee should be credited with helping to train many rising stars in clinical oncology that prepare China for the opening up of China, that allowed Phase 1 cancer clinical trials to begin. Professor Lee, as a former President of CSCO, Chinese Society of Clinical Oncology, has been a leader in developing cancer clinical trial capabilities across China. Congratulations”. So I just wish to say that to you, sir.
Jin: Thank you for your comments. And I think that the CSCO has some course of training a new Investigator, for example, the young doctors for the clinical study. We are usually, each year we have some training program for Phase 1, sometimes for Phase 2, organised by CSCO, sometimes the CSCO Foundation. And I think that, because we have a lot of hospitals in China, and they hope that every hospital there can have their team to help industry to develop the new drug.
Right now, it seems there are more than five or even maybe 800 hospitals registered in the government for doing clinical study right now. So for oncology, more than 300 hospitals, they can do a very good clinical study right now. So it seems good. But we hope that we can shorten the gap between China and the western countries. Still in the western country, they do a very good clinical study, they start the clinical study very early, I mean, maybe 20, 30 years ago, but right now, in China, we only have 10 years’ training. So we have to train the doctors further. So I think in the future, when the Chinese doctors participate more and more global studies, they will do a better job, I think.
Arsalan: Well, we wish you best of luck in furthering that. It’s always a good thing when more and more hospitals are involved in getting involved in clinical trials. And so it’s been an honour to see the progress that’s been made over there. And I even wish that here in the US for even more of that to even happen in both ways. So So again, thank you for your foundational work there, and it’s clear that even the audience can tell over there. So appreciate that.
Let me ask another quick question here from the panel. Can we provide – perhaps Vivian again – some colour on the kind of local data that is mandated in China? So the comment is, it seems it’s not just PK and PD data, but also efficacy and safety outcomes?
Vivian: Yes. If you want to register your drug China, local data usually are required. But now you have the chance to use the multinational clinical trials. But for China registration purpose, usually the sample size required by the NMPA is around 15 to 20% of the global trials. So if you have Chinese patients from the global trials, around 15 to 20%, and the Chinese patient efficacy data, the trend is in line with the global result, then you have the chance to use this global study for the China registration purpose.
Jin: Yes, but sometimes for a very, very good drug, and the unmet needs in China, sometimes the global industry could also apply for new drug, in China, even there is no Chinese patients participate in clinical study. But actually, if it is a global study, I mean, the Chinese, maybe not in China, but Chinese, the population in western countries, they live there. If you have that data, it could also apply for the (36:37) in China, yes.
Arsalan: That’s very interesting.
Vivian: Yes. The other comment, actually, I would like to add a few comments, is that in terms of different strategy the Chinese authority, the NMPA, used to facilitate a clinical trial, not only the ideal proper timeline was shortened to 60 working days, but also they also adopt some fast track (37:02), for example, like the breakthrough (37:06) prior to review, and also the conditional approval. All this will facilitate to shorten the clinical development in China. So this is very similar to those, the fast track (37:18) which was adopted by the FDA.
Arsalan: Okay. Sounds good. So Professor Li, are there any other opportunities that you see for companies looking to expand into China? What else could you comment on? Because it was exciting to hear from you about the unmet need, and about having western companies apply for, but help us understand what some other opportunities are for companies looking to expand to China?
Jin: Yeah, I mean, the unmet need, that means that there’s no available drug in China. For example, the [vemurafenib], it’s a BRAF inhibitor. But actually, they didn’t do any clinical study in China, but they get the indication in China. So that means that if you have some, do some global study, but actually there are some Chinese population in that study, even China did not participate the clinical study, you can apply.
But vice versa, also, I mean, just talking about the [COVID] drug in the west and China, I think not only for the global industry, but also for the Chinese domestic industry also, they could do the simultaneous trial in western and in China, so they can merge their data together to apply for the indication from both Sates or China. So for example, recently, maybe more than 10 Chinese domestic company in our site for Phase 1, they also apply for Phase 1 in States and the European country. We do clinical Phase 1 simultaneously. For example, the [Kuluin] biotech, they have a top two ADC, that right now they do the clinical study, both in China and the States. I think many of global study, they do the same. For example, (39:36), they do a KRAS inhibitor, they do the clinical study for pancreatic cancer in States, and do the other indication in China for the colorectal cancer. So right now more and more industry, they do both in – I mean, they do the clinical study both in western and China, they try to help more patients.
Arsalan: Wonderful. Really appreciate that. We’ve just got time for one last question. I’m going to give the last question to Nancy, here, leading Novotech operations; “What would you say have been the key benefits for US companies when they’ve expanded their programs to include China?”.
Nancy: Obviously, patient recruitment and compliance, and expanding [AOL] relationships, not only in the US and Europe, but also in China, to help provide insights into the development of compounds, and the direction of the – how the protocols are developed, and that sort of thing.
With China’s global approach and focus on innovation in the recent years, they’re gaining a lot of attention. While the sites like Dr Li’s are growing, it’s not as though those sites didn’t exist before, but our insights into what is possible in China, because of the open flow of information and publications, and that sort of thing. So knowing that you have the continuity of data, of course, is paramount in determining any safety and efficacy profile of the product.
And then, of course, having diversity in the patient population, to know any minor differences that there may be in patient subsets and that sort of thing. So that’s basically it, I think.
Arsalan: Okay. Well, that’s all the time that we have for today. I want to thank everyone in the audience for tuning in. And I want to thank our entire panel for sharing their time and their expertise. It has really been a fascinating session. I also want to thank Novotech for sponsoring this discussion and Endpoints webinars. If you want to re-watch this or share with your colleagues, a link will be available on demand, and it will be sent to you tomorrow. I’m Arsalan Arif for Endpoints News. Thanks for joining us virtually again at ASCO, and we hope to see you at future Endpoints News events. Thanks again everyone.