The benefits of running clinical trials in China

Let’s move to the next. I think everyone is quite aware that it has been more challenging than ever before, for drug development, I mean. The key question remains how to maximise the product potentials. On the one hand, how to improve clinical trial efficiencies and a shortened duration to market. On the other hand, how to weigh more market share across the globe and maximise the product life cycle. I think those two things are the main challenges our tech are facing. 

There are many other challenges that our tech is facing as well, for example the low research and development efficiencies, R&D model selection, it is easier single therapeutic area or multiple therapeutic area indication, also the uncertainties around COVID-19. All these other challenges and risk our tech are facing. For sure there are more to consider, but today I am more focused on the R&D efficiencies, in particular on the operational or operation efficiency and why including China in clinical trial would be a good option to improve the efficiency. We all know that China is the most populous country in the world, with 1.4 billion people, which is three times than that in the US. The enrolment, while this is quite well known, is normally much, much faster. While for sure, many biotechs may also have concerns in China over regulatory complexities, the site and PR capacity, the data quality for submission and there is rising labour costs. 

These are the main four aspects I want to highlight and apart from the four points, there are still other factors to consider. The first one is COVID-19. I mean China, this is a global-wide pandemic and China is recovering very fast. I have seen a figure showing that in February last year, with the outbreak of the pandemic, the in-and-out patient flow dropped almost half in February. Just in five months, I mean by July last year, the flow, the in-and-out patient flow came back almost to normal. This means that China has well controlled the COVID-19 which reduced the risk of patients unable to come into schedule with clinical trials, which we really need for clinical trial.

Then the second one is we have seen a China-US decoupling in the past two years, there are conflicts in many areas, but still MNC, multinational companies’ confidence in China remains high because in the last two years we have witnessed a lot of MNC China both in strategic partnership. 

The third one is pressure on the national reimbursement drug listing, short for NRDL. This is a key value driver, which will be updated annual. But anyway, for any drug companies, this policy will accelerate the listing timeline and also cause greater price prior, but anyway this often creates a chance for a second launch, in particular the impact from the volume-based purchasing, it’s like a price/volume trade off. This is something that biotech and any other pharmas need to consider seriously. 

The fourth one is the digitalisation; this is an inevitable industry trend. MNCs increasing, emphasising the digital analytics in China, it’s partnering with the local high-tech company, leveraging the big data insight and double down on real work evidence study. All these are really good aspects. 

Lastly, HGRAC regulation, I mean the Human Genetic Resource Administration., also Charley mentioned on this. I want to highlight that with biosecurity law, of the People’s Republic of China, will be effective on 15 April this year, only one month later. But essentially, I think I want to highlight that human genetic resource management is explicitly stated in the law, however this should not cause any panic to any biotechs, as long as the company is conducting the study and applying for human genetic resources in a reasonable and complying way. Normally two or like Charley mentioned, one or 1.5 months also will be required for the review and approval before the fact can be initiated. 

So essentially, I think this pretty much covers my thought on this topic. Thank you.

Ms Tsang: Thank you, Tony. I’m Louisa. I’m representing the Chinese University of Hong Kong. For the next two slides I would like to give a very brief introduction and summarise the site and the advantages of Hong Kong for conducting clinical trials. A little bit of an introduction regarding the Chinese University of Hong Kong and you can call CUHK as well, so for CUHK, so far, I think we have conducted more than 200 clinical trials so far, which are mostly the global and from multinational pharma clinical trials. We have quite a number of experienced KOLs and a lot of experience in conducting pharma-sponsored clinical trials. Nowadays or the recent year, we do have more biotech company clinical research as well.

For our university, we rank in the top 100 best global universities in the world and so regarding the facility, the sites that are in our CUHK, we have established a very advanced and high technology Phase 1 clinical trial with the support of the government. It opened in 2014 and we can accommodate up to 28 beds. For this Phase 1 Clinical Trial Centre, we are conducting both Phase 1 healthy volunteer clinical research and also patient research as well.

Four our Phase 1 Clinical Trial Centre, it is located in the Prince of Wales Hospital. Prince of Wales Hospital built a relationship with Chinese University Hong Kong where PWH is the teaching hospital of CUHK and PWH is also the flagship hospital in the cluster, so a bit like further elaborating in Hong Kong the dividing all the public hospital in Hong Kong into clusters according to their geographic area. PWH is the flagship one that feeds and nurturing this cluster. We have about 1600 beds here. We have a big hospital, we have most of the facilities here, a lot of units that you can name, including AAP and including outpatient clinic as well.

For the accreditation, in our hospital we have 16 research units been accredited by NMPA, so that means our clinical trial data can be used for registration processing in China as well. Because we are quite keen for clinical research in CUHK and PWH as well, we have established an organisation called Clinical Research Management Office, which is CRMO in short. The main scope of function for the CRMO is to facilitate a clinical trial within the cluster and within the hospital as well because we understand that it is quite difficult sometimes for pharma companies or biotech to approach the hospital without the information on which investigator they would like to find. We provide a service starting from matching of investigators to easy submission and as well as monitoring service and site management service, so it is what we like CRMO to support, the clinical trial in the site as well as for the sponsor as well.

As I just mentioned, we have the Phase 1 Clinical Trial Centre, which is attached and located in Prince of Wales Hospital, which was established in 2014. Certainly, as I mentioned at the very beginning of the presentation, for CUHK and PWH, we do have experience in working with biotech companies as well, so just some examples of biotech companies we have been working for.

For the next slide, I will share about the key advantage to conduct chemical trials and while Hong Kong is so attractive to do clinical research here. When compared to other big countries, we do not have a very big population pool, we have only eight million population, but we have a very dense population here because we have a small place and then we have eight million people living here, so we rank number four in the world as a densely populated place. We do have very high clinical trial activities because in Hong Kong we have more than 40 public hospital in Hong Kong, so we have conducted more than 300 clinical studies over the past five years. 

Apart from we have a very dense population, I think one of the advantages of Hong Kong is that most of the secondary and tertiary medical care will be backed to the public hospital in Hong Kong, so that means you can easily access your patient pool and also easily access to the subject by doing the clinical trial in public hospitals in Hong Kong. We do have government funds, because our government is very supportive of R&D in Hong Kong, including clinical research. We do have government R&D incentives. We have three types of different incentives. We have one type that you can collaborate with the institute, like for example, CUHK in Hong Kong, then you can only pay 50 per cent of the R&D fund and the other 50 per cent will be funded by the government, Innovation Technology Fund, is what we call the government fund. The other one we call the Cash Rebate Partnership Research Program. That program is the sponsor certainly need to work together with an institute, like CUHK in Hong Kong and then you need to pay up front for 100 per cent of your clinical research or the R&D cost. You can apply for the rebate and if it is successful, you can get 40 per cent reimbursement back for your R&D costs. 

The 50 per cent collaboration scheme I just mentioned and also the 40 per cent reimbursement scheme that I mentioned just now, you can apply for both, not meaning that you can just apply for one, but you can apply for both. For example, if you invest $2 million for clinical research, first of all you can apply for the collaboration program, so if it is successful, you need to pay $1 million for your R&D cost and the other $1 million paid by the government fund. Then after you finish the study or the clinical trial, you can apply for this rebate program for 40 per cent reimbursement. If this is successful, you can have up to 40 per cent reimbursement back to your R&D costs. So that means for a $2 million clinical research, eventually you only need to pay $600,000 for the R&D costs, so it is quite one of the attractions and advantages for doing clinical trials in Hong Kong.

Certainly, I agree with Tony that clinical research start-up timeline is very important and one of the key points to attract the pharma company to come to your place to conduct clinical trials. In Hong Kong we do have a quite fast start-up, so for instance submission in Department of Health that is the regulatory approval, you can get it in six to eight weeks. The EC regulatory submission you can do in parallel. As I mentioned, in the first light, our site we have a new list being accredited by NMPA and so that means our data can be submitted in NMPA and also, we can use the data to EMA and FDA at the same time. That means you can conduct a clinical trial in one site and you can get multiple submissions globally. I think this is the end of my sharing and back to you.

Mr Arif: All right, thank you very much Louisa and thank you to the entire panel over here. Let’s actually go right to our question-and-answer session; I’m really excited about this. Let’s start with you, Tony, Tony Zhou, the Head of Clinical Operations at SIMR biotech. When it comes to CRO choices in China and Asia, what are the key elements that you’re looking for, Tony?

Mr Zhou: Well this is quite a good question. For myself, I worked in biotech and prior to joining SIMR I also worked in biotech, so for a small biotech, we need partners to work with us to gather and delivery a study. My thought is, firstly, clearly define the trial scope, whether it a China-alone study or a regional study or a global study, so the scope really determines what sort of CRO you can choose. Nail down a shortlist of CROs you want to further look at, so this is the first step you may want to look. 

Then later on, the second step will be to really assess the CROs in different aspects. For example, their experience in the targeted indication, either in Phase 1 or 2 or 3 studies, so depending on what you are looking at really. Then the second aspect is team experiences, in particular the PM, the PM capacity, the experiences and also the functional lead, the CRO team, whatever, this is the overall assessment of the team, resources, experiences, et cetera. Also, the third aspect is really on the trial cost. We are a small biotech, but we are trying to look at more cost-effective CRO while can deliver quality data. I think that is essentially the considerations I will look at when selecting a CRO.

Mr Arif: Wonderful. You’ve listed several benefits for biotech conducting clinical trials in China, anything else that you could add to that, Tony?

Mr Zhou: Well I think that pretty much covers the main advantage in China, faster IND process. At the beginning IND is faster, for INDA, the later stage, will be also comparable with that in the EU countries, even faster. In EU, our average is around 12 to 13 months to get approval. In the US it is essentially the same as what we have in China now. Essentially overall, the process in China becomes much, much quicker and efficient, so this is really attractive for many biotechs.

Mr Arif: Okay, well let’s go into my next question. This is really for the entire panel over here. Can you elaborate on the process of involving sites? How is it different in China involving sites, how does that differ from the US and Europe? Maybe Charley or Louisa?

Ms Tsang: Maybe I come first. I think maybe I represent Hong Kong, so I think in Hong Kong we don’t see any difference in the site process in Hong Kong compared to US or in Europe as well, because we are doing the same that we get in the ICN regulatory submission and also for the international guideline, which GCP and declaration have helped synching, so not much different on that. So including the document for approval is still the same because we are from GCPs so that is why we can align with all the data submission and also recognise in the worldwide on how to run the clinical trial in Hong Kong, so there is not much difference. That is why it is one of the key advantages and attractions in Hong Kong.

Mr Arif: Interesting. Anything else to add Charley or Tony?

Mr Sha: I think regarding the GCP just mentioned by Louisa, in China, the EC actually can also be accepted in China but we did have a local GCP just revised recently actually, but the new GCP in China is actually quite similar with ICH GCPs, so in practice I don’t think we have a major difference between the China side and the US side and we all follow the ICH GCP or similar as a GCP. But actually I have to say, in China, when you involve the sites, the procedure may be a little bit different with the US or Europe, because when we want to start a trial at a site in Europe, besides the ethic committee or IRB, there is actually another team we name as GCP Office in these sites. So firstly you need to go to the GCP Office to set up your project and then you go to the ethics committee for approval, so that is kind of quite local practice.

Also, another difference that I know you ask when you summarise and then you need to involve the investigator before you get your summaries of IND, because you need the investigator to sign the 15-72 form, which means you have already maybe even changed the PI, but before, when you summarise and you need to get the standard form, but in China we do not require that. So the health authority, actually we do not require the sponsor to confirm who will be the investigator doing the IND summations, so you can decide your investigator later in the IND technical review or after you get IND approval, also you can make a change at any time. I think that is some difference.

Mr Arif: Very good. Louisa, a question for you, how does your organisation work with and facilitate clinical studies at Prince of Wales Hospitals for sponsors, especially for biotech start-ups?

Ms Tsang: Okay, thank you for the question. So as I am representing CRMO, I just mentioned that because we are now not only big pharma, we would like to have more biotech companies to come to our site for doing clinical research as well. We understand therefore most of the biotech right now, especially some of the more of the quite established companies, so maybe they don’t have any experience in clinical trials, so our organisation CRMO would like to start from the consultation, like protocol red tape, so we can give some advice on how to write the protocol so you can match the need of your product and also match the situation in the country as well, in the place you would like to conduct the clinical trial as well.

Then, as I just mentioned, some match of the clinical principal investigator or potential investigator, sometimes it’s a challenge for a new start-up biotech company because they don’t have any experience in your place in conducting clinical research. So we can help them to match the right investigator for them and then we can also do the ethics committee submission on behalf of the investigator and prepare the document. I just mentioned just now, we have quite a number of government grants they can apply because for biotech companies, they can apply for the government grants, so some kind of foundation support for their clinical research. We can also help to submit an application in the government grant as well because you need to write a proposal for the government. We do have experience in writing such proposals, working together with the sponsor. 

Apart from that, I know that for the biotech company, like Tony just mentioned, they are looking for good CROs for start-ups that are starting to come to study for them as well, so CRMO can serve as a CRO as well, to help them to match the investigator for the site management as well. It is for monitoring and even writing the study process report, it is what we can provide as a support for them. What we would like to do is provide a one-stop-solution for the biotech company so that they come to us and then we can solve all the problems for them. Like for example, if they are looking for Phase 1, because some of the biotech companies, they have a product that just after the animal study, they just want to start the human clinical research, we also have a Phase 1 Clinical Trial Centre so that you can have the Phase 1, 2, 3 clinical trial in our site so that the investigator has got experience of your product and then hopefully we can help the biotech company to speed up their product registration.

Mr Arif: Okay, very good. Louisa, can you share with us how the COVID situation has affected your site activity in Hong Kong?

Ms Tsang: I think at the very beginning we do have some but not many of the effects, because we are just our operation here, so like for example, all the EC submission right now, we can it online and then we can have even the clinical trial agreement negotiation or even the clinical trial signature, we can accept the e-signature. We adjusted our position and operation here quickly. For the patient visit or the subject visit, I don’t see any effect on that because the patients still need to come back for their treatment and any kind of research visit, so I can say that not much effect right now, everything back to normal, so because we are just ourselves in a very tiny place.

Mr Arif: Yes, congratulations on that, thank you.

Ms Tsang: Thank you.

Mr Arif: I have a question for you and Charley here about the regulatory pathways in Hong Kong. Do they differ any than in mainland China?

Ms Tsang: I think for the document that we need to submit, maybe Charley you can add on top of it, so not much difference on that. We still need to submit a protocol ICF and all those documents, so it is not much on that. In Hong Kong we do have our own regulatory submission, but certainly after our regulatory submission as I mentioned, so we are LMP accredited, so if you would like to use Hong Kong data to submit to China, you need to choose an LMP accredited site, which I just mentioned our hospital is one of the accredited sites that you can choose. Charley?

Mr Sha: Yes, there is actually three sites in Hong Kong actually accepted by China Mainland LMPA. When you conduct a trial in these three hospitals, actually the data can be considered as local data. That is an advantage for conducting a clinical trial in Hong Kong. But actually regarding the difference between Hong Kong and China Mainland, I think Louisa mentioned the dossier is actually very similar, yes, the technical dossier, it is the same, but there is actually a difference because in China Mainland they were, oh we need to translate all the English documents into simplified Chinese, which means that will take some time to get the dossier prepared for submission in China. Also, my understanding is China Mainland may have more local dossier requirements, such as more than one administrative document, application form for the (43:30) and also the DMF for these kinds of the main documents; we do have more requirements and more strict requirements, I think.

Another thing is timelines. The regulation pathway in China I think is a little bit more complicated because for your first trial they may be required to apply for pre-IND which will take three months and for IND three months and also for some we have to get the HGRAC approval, which will be an addition one or two months. The timeline may be a little bit longer in China, so that is a fact that I have to make on that. 

The last thing, I think there is another thing about the technical review fee. In US it is free, in Hong Kong, it is quite low, right? If I am correct, it is about US$200 for the technical review fee for this kind of IND. But in China we need US$55,000 for one product IND. This is not very high, but you still need to pay for it, but for this kind of technical review fee, when you submit for the marketing approval, this fee can be deducted from the IND review fee. So that is the situation in China.

Mr Arif: Okay, very good. Another question for you, Charley, about the China regulatory environment. Let’s talk about the speed of IND and NDA approvals for innovative therapies like cell and gene therapies. What can you tell us about how China is doing that, vis-à-vis other regulatory bodies?

Mr Sha: I think for this, you just mentioned, for these quite innovative therapies, such as for gene, for cell therapies, so actually these products usually they target for medical needs, for very late stage of the cancer and for patients who have no other therapy options to choose. So for these products, I have to say, in China health authority they attach more importance to these kinds of products and also just from the middle of last year, the new regulation, the drug registration regulation coming into effect and that actually starts from new policy, not quite new but they have already tried for well, such as the priority review, for the breakthrough designation and also the conditional approval. You have to see that this is quite similar as the US for these policies to accelerate the development for this kind of innovative product.

Also in fact, as we all know, there is a lot of cell therapy or gene therapy companies in China for local manufacturers for this kind of product and also, such as breakthrough designation, as I know, several cell therapy products have already received the breakthrough designation, which means they have more opportunity to get, in terms of communication with authority and also, they will be qualified to apply for conditional approval. With limited clinical data, they can get a conditional approval very quickly, so that is the case in China. For gene therapy, for cell therapy, in recent years the NMPA has already released several technical guidance, just to make it quite clear for what is criteria for their review. So they do have set this kind of product as priorities. 

Mr Arif: Louisa, question for you. Let’s talk about patient recruitment. Could you talk to us about some of the major challenges that you have in recruiting patients and how does your centre manage these challenges?

Ms Tsang: This is a very challenging question. Maybe I can talk about it in two aspects. First of all, as I mentioned in my presentation, Hong Kong is a very densely populated place, but not has a very big population pool. I think the challenge in recruitment will be if we are doing a Phase 3 clinical research, because for Phase 3 clinical research you need quite a big patient pool, so it may be a challenge to get so many patients compared to the other places of very high population. But how we resolve that is we will position ourselves in doing early phase clinical research, for example, Phase 1 or Phase 2, because the requirement, the patient number, will be much less and then so we have no problem doing that.

The other aspect is regarding the protocol writing because I understand that for some of the pharma companies or including biotech companies, they would like to fund patients compared to some kind of treatment, maybe even treatment in each patient for the clinical research. But it may be a challenge in Hong Kong because in Hong Kong we are quite advanced in our medical system, so most of the patients are under very good treatment, under the advanced medical care in Hong Kong. Our suggestion to the pharma company of the biotech company is that when you come to Hong Kong, maybe it is better for you to discuss with the potential investigator on what type of treatment or standard treatment the patient is now on in Hong Kong so that you can kind of adjust your protocol for the inclusion/exclusion criteria so that you can match the patient who is in Hong Kong to make the recruitment more easier in Hong Kong. That is my suggestion and comment on that.

Mr Arif: Okay, wonderful. Let me open my next question up to the entire panel over here. The trials that are conducted in China and Asia, are they accepted by regulatory bodies in other regions, like here at the FDA and in Europe?

Ms Tsang: Maybe ladies first? Okay, so because I think it is no problem at all, like for example, in Hong Kong we do have FDA inspection before, so we have gotten a very good result in those FDA inspections, it implies that our data being submitted to FDA without any problem. Also I can share some experience in or Phase 1 Clinical Trial Centre as well that we do have a clinical research, which after completing the study, we got with Switzerland, approval on the data and also get the product registered with Switzerland as well. Then because Phase 1 Clinical Trial Centre is one of the NMPA accredited sites, so our data also has been submitted in NMPA in China as well. I don’t see any problem in doing clinical trials in Hong Kong and doing multiple submissions for approval.

Mr Arif: Tony or Charley, anything to add on that?

Mr Zhou: Essentially, I think this is, I mean if you look at the MRCT trial in China, I mean you can see a trend more and more are coming to China for trials. So this data partially was for China registration and the other is indeed using the China data for global registration. I can give you a brief example, a simple example, that we have. Previously I was involved in a [BG] study, it is a listed company in the US and its product, PDE inhibitor, some of the data was generated in China. I know FDA came to China for inspection and successfully passed inspection, so that is one example for your reference. 

Also I see for [RCH E17], the government really, on the principles of planning, on the design and marketing and the purpose is really to how the data can be used across borders. It seems like that is what I saw. But definitely, when you have the data in China for clinical trial, special care should be taken with regard to medical practice, diagnosis, et cetera, so that may be different from country to country. But anyway, if you choose China to participate, you should carefully consider this, either while stratification carefully or whatever else procedures can be taken. Charley, can you add on?

Mr Sha: Yes, thank you. For this kind of question, I think for the global trial we need to not only for the China trial can be accepted by the other authorities such as the US FDA or EMA, but I think we should also-----

[Connection lost for Mr Sha]

Mr Arif: I think we have lost Charley here for a second over here. But we have five minutes here left for our webinar but I’m just going to go ahead and move on to our next question until we get Charley right back over here. Louisa, I’m going to direct it to you, so it’s a question related to language of study related documents in Hong Kong. Are there any translations that are needed?

Ms Tsang: The answer is no; no translation is needed. In Hong Kong all the submissions, the ethics committee submission and also the regulatory submissions, we are using English protocol and IB investigator will show us all in English. For informed consent forms, we do need to have translation only on informed consent form, both Chinese and English version submitted for approval. It is quite simple. 

Mr Arif: Wonderful. We just have a couple of minutes left here on our webinar. We do have Charley back over here, welcome back Charley. I am going to open this question up for the entire panel over here. Maybe Charley or Tony, if we could start with you, if you were to provide one or two pieces of advice to biotechs looking to conduct trials in China, what would it be? Charley, what’s your piece of advice?

Mr Sha: I think the most important is that when you target through, you want China, global development, just as we discussed previously, in China we do have an accelerated regulatory pathway, but I have to admit that compared to the US or Hong Kong or some other countries, the regulatory pathway is still a little bit longer than other countries and also, we have local requirement, local language requirement, local documents requirement. So my suggestion, if you want to work in China, get the preparation started as soon as possible, so then you can save your time. It just means we all want to save time to get these trials initiated, so just get prepared as soon as possible.

Mr Arif: Be prepared as soon as possible, that’s your piece of advice, Charley Sha. Okay, Tony Zhou, how about you, piece of advice for biotechs looking to run trials in China?

Mr Zhou: Well I think the biotech should have a clear clinical development plan at an early stage. If they are determined to go to China or AP regions, evaluate thoroughly. If their internal capacity is sufficient enough to conduct trial, is with a CRO or by themselves or would like to find a partner to co-development or [lessen staff] because this is from strategy to buying. Also, I mean lastly, China is a homeland for clinical trials and sometimes a must-win market, so Charley mentioned regulatory reform continuing, I see biotech really should seriously consider if they are going to China or not.

Mr Arif: Okay, wonderful, thank you. Louisa Tsang, what about you, some piece of advice for biotechs looking to conduct trials in China, something that you do every day it seems?

Ms Tsang: Yes, so I think as Tony just mentioned, we do have a Phase 1 Clinical Trial Centre, come to use our Phase 1 Clinical Trial Centre so that you can proceed to Phase 2 and Phase 3, no need to search for any other site for your clinical research. The other thing is, well make use of our government fund, do apply for it and work together with the institution to apply for the government fund.

Mr Arif: Okay, all right. With that, that will conclude today’s webinar. I want to thank our sponsor, Novotech and all of our expert panellists, Charley Sha, Louisa Tsang and Tony Zhou. I’m Arsalan Arif for Endpoints News. Thank you for joining us and we hope to see you at a future session. Thank you everybody. 

Mr Zhou: Thank you.

Ms Tsang: Thank you.

Mr Zhou: Bye-bye.

Ms Tsang: Bye-Bye.

Mr Sha: Bye.