This webinar looks at Asia’s rare disease clinical trial landscape, why China is an increasingly attractive location for rare disease trials and critical program strategies to consider.


Josh Knowles: Good morning, good afternoon, everyone, depending on where you're joining us from, and welcome to today's webinar. My name is Josh from Business Review Webinars, and I will be your host. It is our pleasure to have Novotech with us today who will be presenting the webinar entitled Accelerating Clinical Trials in Rare Disease.

Today's guest speakers are Shahana Hoque-Ali, Project Manager at Novotech and Dr Yuanxi Xu, Associate Medical Director at PPC Group. Before we begin, I'd like to welcome you to our webinar platform On24. You'll notice that this webinar is browser based. So if you disconnect for any reason, please just click on the link that you received by email to re-join the session. And in order to ask questions, you can send them in via the questions widget. Just type them into the box at the top right-hand corner of your screen and click submit. We will allocate some time at the end of the session to address any questions or thoughts that you may have had. And please use the yellow Help widget if you require any assistance. And you can move, resize, and maximise any of the windows in front of you to get a better view of the slides. But for now, please allow me to welcome your speakers for today. 

Dr Yuanxi Xu: Thanks, Josh. And it's my pleasure to make a presentation of this topic … the panorama … rare diseases study in the Asian Pacific area, especially in South-East Asia. So we need first of all to have some basic understanding of the status quo of the landscape of clinical trials in Asia. As we all know, Asia’s population accounts for over 60% of the world's population, and among them over 1.6 billion, who live in urban centres and will be accessible population. Secondly, the clinical trial density in Asia, especially like China and India, is quite low compared with that in USA, Singapore and Australia, which demonstrates great potential to expand sites in Asian countries. Thirdly, there's a considerable number of key opinion leaders or KOLs and experts in Asia, especially like China, Japan, South Korea. 

The operation medical experts share like 20% to 30% of overall publications in the world. Therefore, how to reasonably use these resources will be conducive to Asia’s success as a promising rare disease translocation. Though Asian countries have made significant progress in the management of rare diseases, they remain key areas for substantial development opportunities. 

Despite being rare, actually the total number of people who suffer from rare disease is not rare, which reaches to 400 million people or 6% to 8% of worldwide population. This is because the number of rare diseases estimates to over 7,000. Among them, over 45 million people in Asia, or around 9% of the region suffer from rare diseases. As we mentioned before, to bridge the gap of promoting orphan drugs research and development at phase II and phase III, Asian countries are currently in the process of implementing or revising their universal health coverage schemes. For example, the action plan launched in 2018 by Asia-Pacific Economic Cooperation, or APEC, accelerated legal frameworks for quick approval of novel drugs in rare conditions, which gradually offsets the insufficient resources for systemic diagnosis and testing rare diseases.

As far as we're concerned, one of the important steps in clinical trials is subject recruitment, especially for rare diseases, due to limited patient pool. In this figure, we can see, in rare disease studies, the median subjects enrolled in Asia-Pacific region is 48 subjects per study versus 33 in the rest of the world. And the recruitment capacity is 1.1 per subject per site per month, almost three times compared with only 0.4 for the rest of the world. Here we need to emphasise the assessment criteria for considering Asian countries as well as the best practice countries.

So actually, there are six important factors, including complete health care system, powerful governance, patient advocacy and rare disease awareness, clinical expertise in patient management, sufficient funding and newborn screening of rare diseases. Each of these items can help Asian countries support rare disease and access to orphan drugs R&D. 

For example, in PNH studies, several big hospitals in China have a complete patient pool for PNH patients, selection under varied situations like treatment …, or under which specific treatment like blood transfusion at three times per month. And the principal investigators from these hospitals are well-known haematologists in China who have rich experience in diagnosis and treatment of PNH.  So whilst the trials will be conducted in these sites, the subject enrolment rate will approximately reach to one subject per site per month or even higher.

China, as the country with the largest number of population in the world, and over 17 million orphan diseases affected populations has substantial potential to attract US and Western biotechs to run trials here. Accordingly, China's government has launched favourable policies to stimulate orphan drug industries and lower the cost of drug R&D. In 2020, the Ministry of Finance announced a second batch of anti-cancer drugs and drugs for rare diseases subject to the value-added tax VAT policy. In addition, supporting measures have been providing … from special organisations dealing with rare diseases, like Chinese Medical Association, Shanghai Medical Association, Shandong Province and some like that. And public awareness has been aroused in rare disease China network and … network and many patient advocacy groups and families are devoted to providing information and individual disease profile and improving patient access to health care and attendance in more clinical trials.

Shahana Hoque-Ali: Thank you, Dr Yuanxi, for your presentation. I’m Shahana Hoque-Ali and I'd like to take the following part of the presentation, starting with understanding the key feasibility questions to investigate. The major challenging issue within the clinical trials industry all over the world is finding patients for trials. And this is more difficult in rare disease clinical trials. With smaller populations being impacted by rare diseases, finding patients, screening and recruiting becomes a highly difficult operation for many researchers. Conducting clinical trials feasibility is crucial in rare diseases for the following reasons. Firstly, disease progression. In rare diseases, the underlying disease mechanisms and … progression of the disease, including variability in diseases, is not always well understood. Identifying appropriate subpopulations for a trial and identifying which symptom relief is most important for patients and caregivers will really help with study development. 

The next point is health care reimbursement. This can be a big policy hurdle before a drug can even reach a patient. Differences remain in reimbursement and pricing systems, depending on geographical location, and based on factors such as healthcare budgets across different states. Consequently, patient access is often unpredictable and restricted while reimbursement strategies from manufacturers are fragmented and complex, contributed by the high prices of many orphan drugs, often combined with limited trial clinical evidence. 

Similar to what healthcare reimbursement options are, the local current standard of care and treatment options can also differ across the region for specific rare disease. And this needs to be taken into consideration when we are looking at what the best countries are to set up the sites in. 

Population heterogeneity. In fact, 60% of rare diseases present with significant heterogeneity, which makes it very hard to diagnose patients. It’s undoubtedly the main reason why the journey from diagnosis takes on average six years from onset of symptoms. We need to rethink how we access patient data from data drawn from electronic medical records to information about medication response and medications … We also need to better understand the factors that contribute to data about their disease.

The patient and caregiver’s perspective cannot be understated. We must appreciate a patient will be concerned about the effects of coming off existing treatment, which is often a requirement of joining a trial for investigational therapies. They'll also be concerned for what the feasibility is for these patients getting to the site, depending on where they’re located. And conducting regular study visits. They may appreciate conversation about how to mitigate the effects of coming off the existing treatments and some reassurance about all the tests and procedures involved. Also, there are different options that are being looked at, which may help the patients who live further away from the site to be able to enrol in the studies, for their ease.

In order to support the acceleration of rare disease programs, one of the key attributes we need to consider are firstly, it's vital to be working with the local and regional experts who are not only able to accurately identify the correct subset of patients, understand the disease, but also utilise the knowledge of the current local standard of care in that region. 

Also, having direct access to a long-standing relationship with investigators, KOLs and sites means we're able to have open dialogue. And this is especially important during the long and challenging recruitment process for rare disease studies. Also, it's much more conducive when developing risk management plans together. Again, having highly experienced medical monitors which are regionally based, means they are better likely to have connections to the site and investigators in order to support them to the best of their ability. 

Once the site is … the challenge is quite different … to establish and implement management systems and techniques are effective and responsive to the needs of the trial. All clinical trials need the same coordinated process and systems, and it's crucial that every effort is made to implement a robust governance structure and risk management plan to ensure trials are run …and managed efficiently. 

One of the major challenges of rare disease clinical trials is patient recruitment and retention. About 30% of the phase III studies fail due to enrolment challenges. Patient engagement is therefore an increasingly relevant topic. Putting the focus on the translation of scientific bench side discovery to the patient's bedside is key in keeping the patients informed and engaged in their treatment.

This is an example of a phase I study of an orphan metabolic disease where the Western sponsor was looking to accelerate their clinical development in this orphan indication. The project timelines were 14 months from study start to last patient enrolled, with the start-up taking six months and recruitment taking eight months. During this period, the recruitment rate was 106%. There was another rare immune program where a US late-stage biotech company was developing a treatment for a rare blood disease study for two phase II studies. These studies were awarded to Novotech in 2018 and sites were included across Australia, New Zealand, Hong Kong and South Korea. They returned with a phase III study for the same disorder in 2020. Why bring the studies to APAC? Asia is quickly becoming a clinical research powerhouse facilitated by a large treatment naive patient pool which is enabling us to have a faster recruitment and high trial engagement opportunities. Also, since the competitor drug is not reimbursed, it also contributes to this fast recruitment. There's access to a large volume of sites, so 30 sites initiated for the blood disease treated patients in this study alone.

The region's knowledgeable physicians and key opinion leaders provide an attractive environment for clinical trials and facilitate speedy trials, while low healthcare spend by many governments in Asia make clinical trials an attractive way for patients to access innovative therapies in these countries. Also, data from clinical trials in Asia is now routinely being accepted as part of FDA and CMA and other regulatory submissions, which also makes this an attractive opportunity. Thank you for listening to our presentation. And I'd like to hand over to Josh for the Q&A slides.

Josh Knowles: So, thank you very much. Just a reminder for the audience, in order to ask questions, send them in via the questions widget. Just type them into the box at the top right-hand corner of your screen and click Submit. But for now, we've had some in already, mainly for Dr Yuanxi. The first one is asking, Do you consider an understanding of the natural history of a rare disease condition or demographic group to be essential to the planning and execution of a study? And if so, why? 

Dr Yuanxi Xu: Okay, so that's a good question. So personally speaking, the answer is absolutely yes. The actual meaning of rare refers to special insidious diseases occurring in a very small number of population or specific cohort by Caucasian or Africans. So a natural history study is an observational study that follows the course of a disease in individuals to better understand how a disease develops, and how it may be treated. And natural history studies aim to identify demographic, genetic or environmental variables that correlate with the disease development and outcomes.

As in demographic study, it's also required due to - some rare diseases are characterised by significant regional distribution. For example, PKU, Phenylketonuria, an inborn error of metabolism that results in decreased metabolism of the amino acid, which can lead to intellectual disabilities, seizures, behavioural problems and mental disorders, has the highest documented rate in Turkey with one out of 2,600 births, whilst England and Japan have extremely low rates with fewer than one case of PKU in 100,000 births. Natural history and demographics can help investigators understand the various phases of the disease, the probability and risk of development, the consequences of the ongoing treatment, and the variation in symptoms and effects of the rare diseases. 

To summarise, before execution of a rare disease study, it is necessary for us to identify the patient population, development of clinical outcome assessments, development of biomarkers and design of externally controlled studies based on natural history and demographic investigation. 

Josh Knowles: Brilliant. Thanks very much. We've got another question here asking; in terms of study design, do you feel patients are more willing to participate in a rare disease trial if the study design is open label or crossover versus a randomised placebo-controlled trial? And if so, why do you think this? 

Dr Yuanxi Xu: Since the number of trials on rare disease is still limited, I can just make some comments in my personal point of view. And technically speaking, there should be no significant difference between these two designs, I mean open label versus placebo control studies. As in most cases, … therapy for rare diseases is allowed to our patients and the placebo group is actually based on this routine therapy anyway. However, due to the particularity of the rare, most patients suffer from long-term pain, or a long history of failure of routine drugs, So a number of patients may have strong desire in pursuing novel drugs in trial and this is probably their thought deep down in heart. Therefore, I think the patients with rare diseases may be a bit more interested in trials like single-arm open-label studies with investigational drugs because they know what kind of drug they use and probably can see the hope in the treatment of their disease. Yeah, that’s all.

Josh Knowles: Brilliant. Thank you very much. We've got another question asking what aspects need to be considered when developing a medical monitoring plan?

Dr Yuanxi Xu: Okay, so, the medical monitoring plan or the MMP, should first of all include an assessment of risks inherent in the execution of the protocol. Due to specially rare diseases, the patients may be more vulnerable and prone to meet the risk of severe adverse event and even death. So, basically speaking, it is essential to assess eligibility criteria much more carefully to determine which are critical to trial integrity and for subject protection. Additional components of MMP should include assessing the protocol specific risk-based monitoring considerations around the timing and collection of safety and efficacy endpoints, concern on special biomarkers of rare diseases, extra visits and prolonged follow-up visits are all required in MMP. A relatively specific MMP will demonstrate as follows: proactive planning … to risk mitigation, training for site and CRAs that focus on the areas of highest concern and improve proper compliance and … data quality. 

Josh Knowles: Brilliant. Thanks very much. We have another question asking How common practice is remote patient monitoring for rare disease programs? 

Dr Yuanxi Xu: Okay, so this question is also based on my previous experience in medical monitoring. Remote monitoring was commonly used in the management of something like hypertension, based on mobile phone, or continuous glucose monitoring, or CGM, in type 2 diabetes patients or some other chronic diseases in their follow-up visits. However, with the development of novel drugs, R&D in rare diseases, more emphasis has been made on such patient monitoring. Recently, there are three major monitoring ways, including centralised remote review, real time remote review and routine remote review that are used in rare disease trials to monitor patients’ data like patient sampling and key lab results. And each approach offers some unique advantages, ensuring the quality of data in the trial and protection of subjects. 

In addition, something like mobile health or mHealth technologies have the potential to revolutionise how clinical research is conducted in the future. Something like wearable devices, remote sensors and the development of mobile device applications, some apps, they all assist in constant monitoring of patients for safety and efficacy of approved and investigational compounds. So I think the future will require a greater understanding and interpretation of available information from multiple sources, including … and big data sources. 

Josh Knowles: Brilliant. Thanks very much. One more here asking, could you provide a description of lessons learned or challenges faced in past rare disease clinical studies and how strategies can be applied to overcome these.

Dr Yuanxi Xu: Yes. For the lessons learned and challenges confronted from previous days, I would still like to use the PNH as an example, the paroxysmal nocturnal hemoglobinuria. So when conducting the phase I study, it was found to be hard to collect the required number of patients in one country, but needed to pull the patients from several countries in South-East Asia, like Malaysia, Singapore, Indonesia. However, due to COVID-19 pandemic in 2020, the transferring accommodation of the patients were pretty tough, since how to keep them safe on a long journey was a big challenge.

Another obstacle I met was in the phase II study since the drug used for PNH may cause conditional bacteria and virus infection, so the vaccination for each patient is mandatory. However, due to the cross-national study, the vaccines in different countries are varied and some vaccines are not registered, or even not allowed to use in adults in most cases, like haemophilus influenzae B. So, the strategy or common measure we should use is to fully understand the story of the … disease, especially the safety commitment and basic requirement to initiate – it is a better choice to make a checklist of steps to not only anticipate and minimise some unforeseeable delays, like traffic …, … international trial but also identify obstacles like COVID-19 quarantine in many countries that will require a concerted effort on the part of many stakeholders to mitigate.

Josh Knowles: Brilliant. Thanks very much for those. So it looks like we've had some more questions come in. This one here is asking, Enrolment of patients on rare disease studies typically takes longer than those non rare disease trials so how does a CRO manage this period? What strategies do you employ to keep site staff engaged, motivated and enthusiastic about the study?

Shahana Hoque-Ali: Thank you, Josh, for that question. So it is true that enrolment does take longer on these rare disease studies and what we tend to do to keep the site staff engaged and motivated is to ensure that we have very, very good communications with the staff on the site. And we ensure we provide them with all of the information that we have for themselves and for the patients, really keep them up to speed on what's going on, and where we are with things. That keep them engaged and involved in the progress of the study overall. 

Josh Knowles: Okay, brilliant. Thanks very much. What tactics do you see sites typically employ to keep patients engaged, motivated and enthusiastic as well?

Shahana Hoque-Ali: Again, it's a long process, but the patients who come and enrol in part of the clinical studies are often invested in these studies already. They're invested in wanting to kind of find better treatments, so they're already quite motivated. However, the rule of thumb always goes back to again, communicate openly, meaning you respect that these patients are giving up their time and, you know, to ensure that we keep the schedule on track, we ensure that we give them all the information that they need, and whatever else, you know, we can on the progress of the study. And really the same thing as keeping the site staff engaged, just communicate and make things easy for them where possible. So for patients, I think we mentioned it during the presentation, where patients have difficulty getting to the site, you know, look at alternatives and how they can perhaps have some phone visits or a video call, you know, where possible where the protocol allows, replace the site studies to make it easier for them..

Josh Knowles: Okay. Brilliant. Thanks very much. We've got another one here asking what travel support initiatives have you engaged in to help bring patients from remote areas outside the major cities to sites? Does this involve working with vendors? And if so, what services do they offer?

Shahana Hoque-Ali: So I think we started covering it in the session before but yes, there is about 70% of potential participants who live more than two hours away from study centres, just a general kind of statistic, so it's always, I think - in this day and age, with COVID, we're really learning that there are alternative ways for the patients to come into the site, conduct a visit. And we have been innovative more so now than before.

So there are a couple of options available. One’s a phone health visit, so the study nurses administer treatments ... One's a virtual visit with the study doctor via video or phone. And then there's also another option becoming available and becoming quite popular actually - the digital technology in wearables where they can the upload patient data remotely. This can not only help with the, you know, travelling for the patient, but it can also give a more kind of real selection of data from time, and not just a cross-sectional assessment of when the patient comes into the site for their visit. So this is, you know, all an interesting and very exciting area. And I think there are quite a few vendors coming up in the digital technology and wearables area. Again, we need to take into consideration what the limitations of the protocol would be and, you know, where they allow these to be taken up. But there's definitely options now available. 

Josh Knowles: Brilliant. Thanks very much. We've got another one here asking, Are there rare disease research networks or patient advocacy groups you have a relationship with? If so how do you leverage the relationships with these groups to support rare disease studies?

Shahana Hoque-Ali: So for rare disease patient population groups it's very, very important to have connections to the advocacy groups or patient groups because, you know, that is an important resource for identifying the patients and finding patients. Also to support these advocacy groups, these information groups, because it is such a rarity - information in the disease areas is often a rarity so yes, we have developed, we do have relationships with different advocacy groups.

Josh Knowles: Brilliant. Thank you very much. We've got one more here asking, Are there additional costs involved with rare disease trials that sponsors need to consider?

Shahana Hoque-Ali: This question, it would be difficult for me to answer because the costs would really differ depending on different studies but I can't really think of any specific costs, additional costs, apart from it’s a long … process so these studies can take a long time. But also you're not enrolling as many patients so the per-patient cost is less. So it's, you know, it's-it's a difficult question to answer.

Josh Knowles: That's completely fine. Thank you very much. That's all we've got time for today. If your question wasn't answered today, do not worry. I'm sure our speakers and 

Novotech will get back to you about them. But that just leaves me to thank Shahana and Dr Yuanxi for what was a great presentation, and to Novotech for sponsoring this session.

To the attendees you'll receive an email shortly telling you how you can access the on-demand version of this webinar or you can access this through our website, which is We look forward to sharing further webinars with you so please do keep an eye out on the website just mentioned. And follow us on Twitter at BR Webinars for daily updates. And join our LinkedIn group Business Review Webinars. Thank you to the speakers and to everyone who attended today and I hope you have a fantastic rest of the day. 

Read in Full