Clinical Trial Continuity in Asia-Pacific June 2020

So looking at the macro trends of what's happened over the COVID-19 pandemic period from March through April 2020, […], there's been a significant number of clinical trials that have been initiated in Asia Pacific versus North America. So, you can see that there were over 20 percent more trials initiated in Asia Pacific versus North America [over the period]. And if you drill down to that in a little bit more detail into phase one activity […] there is a two-fold difference between the number of trials that were initiated in the Asia Pacific region versus North America. And just a couple of examples there of different biotech companies that have come to the Asia Pacific region during the pandemic period.

[This study] is looking specifically at oncology trials and the number of institutions that have had disruption in enrolling new patients into their oncology trials. This is quite interesting. So, you can see that of those trials that have been initiated that are currently enrolling, they've reached out to institutions, and they've noted that 80% of those institutions in the US have had a disruption in the ability to enrol new patients to their clinical trials, versus only 40% disruption in the Asia region. So, there's quite significant difference. And I will hand over now to my colleague Yooni Kim, who will talk a little bit about why there is a significant difference between the level of disruption.

Yooni Kim: Okay, thank you Kristyn. [This is] a general view of the COVID-19 situation in major APAC countries. Asia [had] a very painful experience from SARS and MERS in 2003 and 2015. Based on this experience Asian governments could act faster and stronger than others. Public's awareness on the importance of this disease is generally good. That is why acceptance of government actions was good. South Korea was the first location outside of mainland China hit by the COVID-19. Korean government increased testing capability at first. Eventually they could test more than 10,000 people per day. More importantly South Korea's medical and social infrastructure is good. That includes a comprehensive insurance coverage. Testing fee was just 130 USD or was even free of charge in case of people showing COVID-19 symptoms.

South Korea has one of the highest densities of hospital bed in the world (115 per 10,000 people according to WHO data), four times higher than in the USA.

Ethics committee review, and approval was done once a week as normal, and subject screenings and enrolments has never been stopped […] and almost all sites remained opened for CRA monitoring visits.

Moving to Hong Kong, and Taiwan. These were the first locations to close their border to mainland China people to control this outbreak similarly to what South Korea did.

Taiwan is a unique case; […] sites remained open during the crisis and were operating normally. CRA on-site visits were also allowed.

Similar picture in Hong Kong. Patients’ access to hospitals was not a problem. Ethics reviews and trial approval process were unimpacted.

[…] I believe Daniella is better placed to talk us through the COVID-19 situation in Australia and New Zealand. Daniela please.

Daniella Caiazza: yeah, great! Thank You Yooni. yes, I would like to pick it up for ANZ. So, I think similar to Asia, I really believe we learnt, and took a lot of lessons on how Asia responded to this crisis it was very unified, and very rapid response. Really just to try and avoid as much as possible reduce the spread and manage the caseloads across ANZ that we are going to eventuate. If we look first at Australia it was very much a national approach led by our prime minister. He formed a national cabinet with our states and territories, and the key decisions came out very quickly. We had rapid border closures I think having learned from what was going on across Asia. We had a very high testing frequency that continues even today even our caseload is very low, and very manageable. And we mandated a lot of the social distancing requirements from our government. So, it seems that we are quite compliant and very happy to follow the lead. Therefore, we really have reaped the rewards with that in terms of the caseload across the country.

New Zealand was a little bit different; they went in a little bit harder. They are a bit stricter with their lockdown measures, as they were very quick about implementing lockdowns. They had about 10 cases reported, when the country went into severe lockdown, in terms of all businesses and schools closing. Again, they have also closed their borders. They have moved now from this high-level closure, to level two. And with that we have seen across both Australia in New Zealand a lot of our businesses now reopening. And obviously our trial continuity which has been critical as well. So, there were certainly disruptions during the more severe lockdown periods. But as we will see in some sites that are coming up later, we are certainly moving out of that phase now.

I think it is probably a good time now to move into the regulatory guidance across the region. And again, I will start off speaking first of ANZ, and then I will hand back to Yooni for Asia. Look though the health authorities were mobilized very quickly and released a lot of joint statements on the recommendations for our clinical trial continuity during COVID-19. In terms of Australia, we are very much governed by the regulations that were released by the FDA, and the EMA. But certainly, we needed our own local regulatory guidance to be followed. So, in terms of Australia it really was a collaboration between the Department of Health, all our state and territory health departments, and our National Health and Medical Research Council which came together, and really released very thorough guidance on how we should approach continuing clinical trials, and our clinical trials that were ongoing across the sector. So, there was a lot of guidance around virtual EC meetings, a lot of our ethics committees would normally meet once a month. However, now they were going to virtual they were able to have these meetings more often. They were certainly expediting review for protocol amendments related to ongoing protocols but also very much expediting review for protocols related to COVID-19 trials; whether it be IP, or vaccine there was a lot of work and guidance on how to conduct remote monitoring. Obviously, we could not. But there was disruption to our team's going to site. So instead of having that on-site face-to-face approach, we certainly needed to follow their recommendations on remote monitoring.

Tele-health has become a much bigger factor now in control continuation, and that is really having the patient's not having to go into the facilities. So, there was a lot of guidance around how they could continue to have their trial procedures at sites that were not their primary clinical trial site. And then, of course there was all the guidance around director patient IP supply that was pretty much across ANZ was governed by that the organization's I mentioned earlier.

New Zealand's similar approach; more disruption, of course. Because they were in higher lockdown initially, but they certainly had their ethics committees released similar sort of guidance around those key trial procedures for continuity.

Hannah Tarrant: […] we are managing a diverse spectrum of trials across a variety of phases, therapeutic areas. We have a diverse client base, and […] country mix. And so, we needed to take a consistent approach from a company perspective, while allowing each study team to identify the most applicable course for their specific study. Yeah, it is not a one-size-fits-all situation.  and I've actually looked back to see and how Novotech was affected, and we saw this first with our China affiliate back in January. And then as Yooni mentioned we saw the cascade effect across several of our Asia countries first, as they rapidly responded to the outbreak early, and such as Singapore, Hong Kong, and South Korea. And gradually scaling our approach as the situation escalated and moved into March with impact across nearly all the APAC countries, including Australia and New Zealand.

And as a company we were well positioned with all our staff to be able to continue their roles and working from home due to our IT infrastructure. And in terms of the trial continuity and leading our project management teams response to the COVID-19 pandemic, the primary focus was ensuring the teams had clear guidance and a framework with the necessary resources available to them, and to allow them to rapidly navigate and this unusual situation and with the flexibility that was needed though. So, as always we continue […] high level of regulatory compliance, and as Yooni mentioned, with regular review and alignment of the guidelines being released within the APAC region, and also those being released by the FDA and EMA on an ongoing basis. And Novotech has that local expertise, as Yooni mentioned, allowing that real-time knowledge of the current environment in that country and the regulatory guidelines and being filtered to project management team so that we could tailor our response in each country and for each study appropriately. So, communication has been even more important than usual, and we have had to respond to the situation rapidly, and in a coordinated manner, with regular updates to our clients on the evolving situation across the region. And we also ensured information was shared internally across the team with clear centralized communication. We have had weekly project management meetings and a COVID-19 FAQ focusing on sharing lessons learned across the teams, and with information being received from multiple pathways. This has been channelled through to a central repository for all teams to easily reference.

The key messages underpinning all our strategies have been obviously participant safety comes first and the focus on minimizing site burden, and considering approaches that do not burden the medical profession, and striking and acceptable balance between appropriate oversight, and the capacity at the site. And as I've heard many times during the last couple of months this has been exceptional circumstances, so we've really been encouraging our project management team to think strategically; being flexible and changing the way we work. And keep in mind all stakeholders as we make decisions so that subjects, site staff, institutions, the ethics committees, sponsors, and CRA team.

Risk management has been a key focus for the project managers at a study, regional, and site level. This has been critical to ensuring the most appropriate action for each trial. And we provided our team with an updated risk management plan template to assist them with this assessment, and with close support from our team of project directors and encouraging ongoing reassessment as the situation changes. And we've already touched on contingencies that the agencies accepted, and that we implemented across the region, and including remote monitoring, home nursing for IP administration, and study visits ,and increase use of telehealth, direct to patient IP supply and via our QA approved vendors, and alternate trial sites being established, and localized assessments being performed.

We really provided a framework for efficient reporting of these: just in case contingencies to the ethics and health authorities, along with the necessary updates to the subject informed consent per the local guidelines. And we found that all parties have been cooperative, and open to suggestions. And willing to work together and through the process to identify alternate solutions to maintain trial continuity wherever possible. And obviously, were safe to do so.

And the sites have responded by issuing their own policies. So, we have also been guided by them to ensure mutually agreeable strategies. We have successfully conducted remote SIVs where appropriate, and we have got our first remote investigator meeting planned for July. We have reassigned CRA resources to manage state border closures. We have on-site monitoring […], and we have continued to proactively review the supply chains for IP lab kits, and sample shipment across the region. And underlying all of this has been strategic thinking and flexibility and by all the teams.  

And we have also had to consider the trial data, and therefore cross-functional collaboration with our biometrics and medical writing team. We updated our processes and our CTMS systems enable consistent reporting of COVID-19 related protocol deviations, and any disruption to subject participation due to COVID-19. This will allow for easy identification, for subsequent analysis by the stats team, and for inclusion in the clinical study reports per the FDA guidelines. Consideration has been needed around how and data is collected in the EDC, where we have followed processes outside of the standard trial practice. So, for example, where local lab data has been collected instead of central lab data. And alongside that CRF completion guidelines and data management plans have been updated. We have also worked together to ensure consistent updates to the statistical analysis plans and in relation to protocol deviation handling, and level of data handling where necessary.

Finally, our medical team has provided close guidance all our teams during this time and with the reduced on-site monitoring there's been an increased level of medical oversight of the trial data internally, and also guidance on handling COVID-19 positive subjects on the study. So, some of these contingencies have not been needed in every country, and but we are well-placed now across the region to manage whatever the future may bring. So, I will now hand over to Daniella to cover some more about the monitoring in the region.

Daniella Caiazza: Thank you Hannah. Just listening to all that I really you know reiterate a whole lot of what you said and I think we've had great success in really rapidly implementing a lot of these strategies across our studies, and a across our regions really by taking you know a very consistent pragmatic approach. Working within the guidelines, listening to our sites, having our key Operations teams on the ground, and really leveraging our critical, and well-established site relationships to enable this trial continuity even under the acute phase of the pandemic in some of the countries.

This slide on the screen really shows you now that the landscape across APAC is changing again; we have seen again now after those critical months of managing the caseload and trying to put in the processes. We now as a region we have done so well to manage that, that we have seen an overall less disruption, which is fantastic across our region, and sector.

And now we can see that we are moving particularly; if we look at monitoring in those graphs there, you can see, even just within the last three weeks we've moved having started with 90% of our monitoring on site, to over 70% remote. We are now shifting back, and those sites are opening being able to manage the caseload and be able to get our CRAs back on site we have also seen high rate of site activities increasing across the region. And by that we mean studies that may have been put on hold - whether it be feasibility or start-up are now starting to open. Again, and ongoing and enrolling trials where patients may have been paused for any new patients to join those trials now; they are also opening as well.

So, we are in this unique position where we are in a region where we are really leading the recovery. I guess in this post-acute COVID-19 phase, and working again very closely with our sites, so, that we can work within the guidelines. Make sure we are not overburdened in them, but absolutely continuing with out with our trials into the future, which is great.

Just moving to the next slide I think really what was critical for us was to stay ahead of all of these of this rapidly evolving situation across all of our regions, and to make sure that we communicated that to our sponsors. I mean we totally appreciated that our sponsors would be anxious about how their trials would be continuing during this time. So, we thought the best approach would be to prepare some client bulletins. I guess again using all the expertise we have in our local regions. So, on a fortnightly basis for the last couple of months now Novotech has been releasing a bulletin for each region, and it really is a great snapshot of where we are at that point in time. It shows the caseload for COVID-19 in that country. Some key critical trial insights are also listed, and then we have a look at the high-level status of each of some top ten biotech sites in each location. They have been well received from what we are hearing, and we will continue to do this again as the months progress. Just so that we really do have that great communication tool for our sponsors and give them confidence on how we are progressing in terms of clinical trial continuation.

So, on that note I think it is a good time to bring in Alex he has been waiting patiently while we have all been going through our slides. We are very pleased to have Alex from TG therapeutics join us for the webinar. And he can offer us from a sponsor's perspective how he has felt. Him and his team have felt in terms of continuation of their clinical trial program during COVID-19. So, I will hand over to Alex.

Alejandro Ricart: Thank you very much. A brief introduction of the TG Therapeutics. TG Therapeutics is a clinical stage bio pharmaceutical company dedicated to their treatment of b-cell diseases. And we have five clinical programs, and with five registration directed studies in chronic lymphocytic leukemia, Non-Hodgkin lymphoma, and multiple sclerosis. Our pipeline includes novel targeted Asians and immune therapies. And we are collaborating with Novotech in three different studies; three oncology studies - phase one studies, one of them is a first in human, and one phase 2b study; that one the Phase two is one of the registration directed study.

So, as you can imagine a critical piece in our clinical development […] we have enrolled 104 patients in Asia Pacific region across 22 sites in Australia, South Korea, and Hong Kong. Some examples of studies specific approaches to mitigate COVID-19 pandemic impact in our studies. For example in one of our phase 1 studies, […] all the sites in Australia continued normal recruitment activities, and adopted COVID-19 contingency plans; including direct to patient transfer of investigational product, clinical, and remote monitoring. So that phase one study has had no disruption at all.

For the first thing human the drug is a large molecule so the treatment is intravenous treatment and we have I could say minimal disruption. Investigators ensure they can include subjects for immediate screening when the restrictions were lifted, and most of the restrictions were lifted. So, we are okay now to screen and enrol patients. Again […] I think minimum disruption.

The phase 2 study had clinical sites in South Korea so interim monitoring visits were booked as soon as possible when sites in South Korea reopen. And we instituted direct to patient transfer of investigational product. That study is our pivotal study with Novotech in Asia. So, I would say also minimal disruption.

Kristyn Munro: Excellent, thanks so much Alex. I guess at this point now we will move into the Q&A section and we have received quite a few questions. So, I will go through these. The first ones probably best placed for Hannah so can you give us a few examples I think specific examples of contingency actions that were put in put in place to facilitate trial continuity?

Hannah Tarrant: Kristyn so, I think we have covered and quite a few contingencies during the presentation and maybe just to provide a specific example which really demonstrates the strategic thinking by all stakeholders involved, and also and the flexibility from the agencies. So, we are running a glioblastoma study sites in Australia. And the IP is supplied from Korea. And during the peak of the outbreak all cargo shipments at that time had stopped from Korea. So, like IP could not be transferred into Australia and this issue is identified I think late on a Friday, and the Novotech team worked over the weekend to identify that the sponsor had the same IP in the US but for another study. And so Novotech applied to the Australian regulatory body, which is the TGA, and for an exemption to import the IP from the US instead and then re-label it local labelling regulations in Australia for that specific study and before dispensing to a subject. And so, clearance was actually given by the TGA on the Monday and this quick action led to no disruption to the patient dosing. So, I think it's a great example where multiple parties came together and showed flexibility and trial continuity was achieved.

Kristyn Munro: Thanks Hannah. Next questions probably best place to Yooni and maybe Hannah. And to what extent two health regulations across the Asia back region tolerate protocol deviations due to the disruptions with the COVID-19 pandemic?

Hannah Tarrant: Yeah, I can maybe add to that as well just from Novotech project management side. We revised our CTMS system, as I said enabled us to clearly identify any protocol deviations and disruption to the study due to COVID-19. And that has then led to being able to easily report protocol deviations, per the ethics and Health Authority reporting guidelines in each country.

Kristyn Munro: Thanks Hannah. And next one is what are the challenges posed by remote monitoring activities, and will remote monitoring replace on-site activities? A bit of a double barrel. And Daniella perhaps?

Daniella Caiazza: Yeah, I can certainly pick that one up. Look as I said you know we went from over 90% of our trials where visits were conducted on-site, to within two weeks, over 75% of them moved to remote. So, with that, anything that you do that quickly on that scale is going to offer challenges. So, you know it has been said already but it was what was critical was getting their SOPs in place, training up our teams, following our regulatory guidelines, making sure the sites were engaged in that process. This continues to be for the sites that still are being visited, where the monitoring is done remotely, it still continues to be a burden on them particularly if they still start a verification, where all the privacy issues, all of that needed to be sorted, and we needed to ensure that we were keeping patient safety,  privacy considerations frontmost. But still obviously continuing to have that oversight issues have been around IP you know how we do our IP accountability. A lot of our pharmacies closed across the region due to COVID-19. Obviously, they were preparing for managing all the factors that were involved under dealing with patients who had COVID-19. So, there was a lot of areas that needed thought again we worked very closely with the people with our teams on the ground, keeping those relationships going with our sites. So, that we could continue as much as possible with these remote visits.

And really there was only probably a couple of weeks where we were putting all these processes in place and then we saw a massive uptick in the remote visit. So, started happening across the region it was very important for us obviously we wanted to ensure we had that oversight. But we really wanted to use these visits as a way of continuing our site engagement, making sure that we were constantly speaking with our sites, assisting them as much as possible, and keeping really our studies front of mind for them, so that we could work together, and then as we as we as we're seeing now moving on to the next phase, we've kept that great engagement going with our site teams.

Kristyn Munro: Thanks. The ever-present quality question: may be one for you Hannah, how do you ensure quality with less presence on site?

Hannah Tarrant: Thanks Kristyn. Yeah, it is an important question, and I think really having a robust remote monitoring process as being key, as Daniela mentioned. You know, we have really focused on ensuring our team are trained on our remote monitoring SOP, and processes. We rolled our additional training across the clinical and project management teams during this time. And making sure that these structured remote visits cover all aspects of the clinical trial, and the CRAs have the resources to ensure that they are performed effectively. For example, detailed annotated reports and we revised all our CMPs. That remote monitoring, alongside additional internal listing reviews has been the key.

And as I mentioned from a project management perspective risk assessment are being performed continually and by the PM's to identify study specific priorities and implementing contingencies to ensure focus on key areas. And actually now as we're moving out of the immediate response to the situation, we're now taking the time to look back, and our QA team is focusing on reviewing some of the contingencies that were implemented on studies and to ensure that they have been done in a compliant manner during that rapid response period. And as we see the site's start to open, we are providing clear guidance to the CRA s as to priority tasks that they should focus on whilst on site, because obviously the on-site time will be limited. So, a combination of factors coming together to ensure quality.

Kristyn Munro: Thanks Hannah. One for Alex; from a sponsor perspective so for US biotech’s that do not have staff in Asia or experience running trials in Asia Pacific, what are the challenges or benefits of involving sites in the Asia pacific region?

Alejandro Ricart: So, thank you. As a sponsor you are targeting in a cancer a disease has a higher incidence like gastric carcinoma, or hepatocellular carcinoma in Southeast Asia. Or, for example melanoma which the incidence is higher, the highest in the world, in Australia or New Zealand. Also, a need if you are applying for regulations marketing application in some countries like China, and Japan, and Taiwan; you need to have clinical data in those populations.

But I think for phase one studies most important is the availability of patients with relapsed refractory disease, that are available to enrol in phase one studies and the amount the number of phase one studies cope and the phase one units in Asia. The rate is very favourable, and recruiting is a very important point for clinical studies. As well as the clinical date and the clinical data quality is very good in Australia and in other countries in the region.

So, some of the challenges will be logistics you know you need to import the drug, sometimes you need to collect clinical samples, and ship those samples outside the region. So sometimes you have vendors analysing those samples in North America, or Western Europe.

I think one challenge is to consider, and to keep in mind is your budget. We are medium-sized company, and we have a great CMC team, and so those logistics issues, we take account of those. But I think the balance is favourable because if you know recruitment, and good clinical data is crucial, then you can handle the challenges.

Kristyn Munro: Excellent, thanks Alex. I think in the interest of time we might just have one last question. And I will direct this one to Daniella. In the first instance but I think we'll probably it'll probably be a bit of a team effort what proportion of Novotech studies were delayed because of COVID-19? And what is your opinion of where we are heading now? Daniella did you want to pick that up?

Daniella Caiazza:  yeah, I can start with that. So, look, we made sure that we adapted our CTMS so that we could capture this accurately on an ongoing basis. So, I think thinking back to sort of March time we probably had just over 20 percent or so of our studies that were I guess put on hold. And in terms of delays that sites where were not open to receiving feasibilities, or if they were in start-up phase, or SIVs they were postponed. And, if they were ongoing trials, that same sort of cohort of sites would not enrol any new patients. But obviously ongoing patients would continue. What we see now, and I just had a look at this couple of days ago we are looking at around six percent now of our protocols are in that sort of on hold bucket. So, it has been a great you know over two months; we have certainly turned the corner and coming out of that now.

Kristyn Munro: I think that will draw our questions […]. So sorry to those that we were not able to address the questions. But we will certainly get back to you on your requests.

Arsalan Arif: Thank you, thank you. I really enjoyed the in-depth discussion on trial continuity I know our audience is really going to appreciate hearing all that in-depth experience that you guys have had. I really appreciated how much information you guys give. We did have a lot of questions so any questions we were not able to get to, we are going to endeavour to get to those offline. Again, I want to thank my panel Alejandro Ricart, Hannah Tarrant, Yooni Kim, Daniela Caiazza, and our moderator Kristyn Munro. From EndPoints news, I am Arsalan Arif. Thanks for joining us.