Webinar: Special Populations in PHEs (III): Cancer

Dr. Cecilia Chisholm opened the meeting by highlighting that the webinar included expert panellists from around the globe. The panel members then introduced themselves and shared some of their recent professional endeavours and projects with the audience.

A question to Professor Richard Sullivan: How has COVID affected the ongoing oncology clinical studies?

Professor Richard Sullivan explained that trials and clinical studies in many countries around the globe were suspended or wholly shut. At the beginning of the pandemic, there was an incredible amount of uncertainty regarding which particular interventions would lead to increased risk for cancer patients. Amongst all the chaos, the best approach was a precautionary principle. However, clinical studies are restarting again in many areas. Although critical studies, particularly phase-I studies, continued with great oversight during the pandemic as these couldn’t be shut down, but a wide-scale shutdown in regard to clinical studies was in effect. Some of the interesting questions are:

1) Which clinical trials should be restarted again?
2) How to restart them despite a great deal of uncertainty in term of the ability to redeploy the staff back to these clinical studies

We will see dramatic downturns in general public support, especially in RD (Research and Development). The Cancer Research UK (CRUK) institutes already saw a 20% reduction in funding. As a result, clinical studies in the future will be subjected to great uncertainty.

A question to Professor Igor Bondarenko: What changes have you had to do in Ukraine to try and keep certain clinical trail running and ensure the safety of your staff as well as your patients during the pandemic?

Professor Bondarenko stated that it had been 18 years since their first cancer patient was randomised. And since then, 4,200 patients have received treatment in clinical trials, which totals up to 365 trials. He then mentioned that their faculty had 382 patients who were treated in 29 different trials. The main problem they faced was how to keep their patients safe from the ongoing pandemic. They had a large number of patients and staff who gathered at one site, which posed serious risks of viral infection. They had shut down the facility two days earlier than the national lockdown to ensure the people’s safety. As a result of these safety precautions, they were able to perform the maximum number of clinical procedures that were planned to perform in the last three months. However, the enrolment level of cancer patients decreased by three times than normal. Nevertheless, the faculty was able to treat 315 patients in 23 open-trials. The procedure to ensure safe-mode of operation and show reliability to the sponsors, participants, and patients remained the biggest challenge. Other challenges included:

1) Keeping the patients separate and preventing the gathering of huge numbers simultaneously.
2) Improving site management by implementing automatic site management systems, remote monitoring, and remote staff work, among many other things.

Professor Bondarenko then stressed on the fact that current times are very crucial as more companies are proposing new clinical trials. The industries and businesses are reopening and helping us achieve high goals.

A question to Dr. Mariam Hassan: What changes have you seen in Pakistan? And how have you decided on which trials to continue and which to stop? Have you had to change treatments? And what sort of modifications had to be made in the clinical trials?

Dr. Hassan explained that any changes or implementations made when faced with the pandemic are only as good as the context within which they are implemented. Pakistan’s cancer facilities were already suffering even before the pandemic. The research is not a priority in countries like Pakistan, where healthcare infrastructure struggles with the provision of essential care services. Despite that, Dr. Hassan goes on to say that research is essential as, without data, there cannot be appropriate planning in countries such as Pakistan. As the pandemic started, there was widespread fear and panic. The majority of the polices and models that were implemented across the world, were coming from high-income countries. These countries could sustain full-fledged lockdowns over an extended period of time. And many developing countries like Pakistan had a similar initial approach to adopt these strategies. However, they soon realised that their socio-economic reality would not allow for such an approach. And even within the same country, there was a wide disparity in the socio-economic status of the population. There was a group of people who could sustain complete lockdown, but a large percentage of the population comprised of daily wagers who simply couldn’t survive this strategy. And this group of population is the same that is eligible for the clinical trials that we conduct. As a result, resource allocation was a big challenge. We soon had to rapidly align our resources dedicated to research. Questions were raised if the research was even a priority at such times. The Shaukat Kanum Cancer Hospital is a nonprofit organisation that is run by donations by the people of Pakistan. It is a state-of-the-art facility and aims to provide critical-care services, which are already a very rare recourse in the country. The hospital couldn’t become just another general quarantine facility. Pakistan currently has 4000 ventilators for a gigantic population of 220 million. So the best contribution this facility could offer was to convert their wards into ventilated beds and help the country already burdened healthcare infrastructure, especially critical care.

Another big factor that caused hindrance in the research projects was the availability of very few modern labs. The Shaukat Khanum Cancer Hospital has a molecular pathology lab which is very scarce in tertiary healthcare setups in Pakistan. This lab soon became one of the only three reference labs nationwide that were initially validating the kits and performing COVID-19 diagnostics. As the pressure mounted, they needed more space and resources. Hence, the basic sciences lab in the hospital soon became part of the diagnostic lab, and the research associates were trained to become part of the molecular pathology team and provide assistance. The reallocation of staff enabled them to handle the enormous number of COVID-19 tests that were coming their way during the initial phase of the pandemic in Pakistan. This ultimately caused basic science research to be halted. The facility had to reschedule many elective surgeries, which meant that newly diagnosed patients had to wait longer for their surgeries. Many patients among them were part of the cross-sectional studies. The newly diagnosed patients were either referred to other centres that were already performing surgeries or used oral chemotherapy, which was certainly not a gold-standard for the particular disease. Although the surgeries were resumed once it was safe for the patients as well as the healthcare providers, that short period of time was certainly a challenging period for Dr. Hassan, her team, and her patients. However, she and her team learned a lot in this short time. They adapted and developed a quick ethics review process that offered speedy but robust reviews of research. This improved the communication and coordination between institutes who were previously not that collaborative in the country. They succeeded in achieving a collaborative hub of clinical trial sites that were able to work together.

The use of telemedicine as an alternative was another great experience for Dr. Hassan. She points out that the central statistical monitoring and remote monitoring will be the future. It will not only bring down the cost but play a big role in shaping the future of even non-COVID research.

Though there were challenges and difficulties, they got to learn some great lessons. Unlike the initial phase of the pandemic, the researchers and healthcare providers now have actual experiences that can guide them forward.

A question to Elissa Prichep: Have you got a bit more insight into the innovations that could be implemented in the future? What help might this provide and any associated risks or difficulties that we might need to try and overcome?

Elissa started by commenting on the active clinical trials in the oncology space. She mentions that there are 12,000 such trials. She states that a phase-3 clinical trial costs around 20 million dollars. Thinking in this context, Elissa put forward the following concerns:

1) Which projects will be restarted quickly, and which will be delayed?
2)What type of projects will not have the funds to proceed in terms of future clinical trials as well as current clinical trials in oncology?
3) What type of data from the ongoing trials will be acceptable, since we’ve witnessed data gaps, particularly to regulatory agencies?
4) Will we see some kind of forced-move towards flexibility in the adaption of clinical trial approaches?

She then went on to comment on how some of this may accelerate approvals in areas of significant need. Elissa talks about what the data gaps will do to drive advancements in clinical trials from a technology perspective. She comments on a growing area that is related to the internet of things called the internet of bodies. It is about wearables, ingestibles, and implantables that record human data and human activity. These have now started to be incorporated into clinical trials, and we will potentially see an increase in their use based on the experiences that have now been had through COVID. It is not super straightforward; there are issues around standards. How these technologies collect data and are there minimal standards around that is still unclear. And whether the information coming from these IOB devices can be compared with each other? She highlighted issues with privacy and comments on whether the data is kept and protected. She then goes on to talk about how we are seeing a convergence between devices that are used in the medical space, which are highly regulated and those devices that are in the consumer wearable space. She predicted that these areas of tech are soon going to merge. But for now, there are different regulatory bodies that tend to oversee these types of technologies at different levels of regulations. There is a need for expanded or modified policies related to how that data is treated. She mentions that GDPR already addresses human biometric data, but HIPAA, at this point, does not do so.

A question to Professor Richard Sullivan: In terms of trials that are ongoing, whether we’ve got a bit more information on how the ongoing studies were carried on? How were they changed? What sort of different assessments were done? Were there different treatments administered? What actual changes to the ongoing studies had to be implemented on a quick basis?

Professor Richard Sullivan stated that the clinical trials that continued during the pandemic were highly heterogeneous and done on a very distinct centre-by-centre risk-assessment. Early phase clinical trials couldn’t be shut down as these were the only route for any potential treatment for the patients. However, the trials which continued in certain centres were shut in other centres because the staff was either furloughed, move elsewhere, or because the overall risk in that particular centre for COVID-19 was considered to be too high. So what we witnessed was that within one single multi-centre trial, some centres continued while other centres shut down.

Professor Sullivan talks about the dramatic changes in what has been the standard of care for many of the patients. These include hyper-fractionated radiotherapy regimens and chemotherapy drugs that were not used before, such as enzalutamide, a hormone-sensitive prostate cancer drug. He emphasised on the fact that changes in the standard of care and adapting to the new scenarios once we restart those clinical trial, will be very complicated. He then goes on to talks about the practices that need to be continued even after the COVID situation is over. There is no need to bring patients in as much as we have been doing in the past. He talks high of central data verification. But then, on the other hand, he is a firm advocate of multi-centre and multi-armed clinical trials with cancer patients. And performing biological add-on studies with increasingly complicated regimens, different approaches like zero-window opportunity studies in a setting where we are able to take multiple biopsies, able to image them and keep a very tight eye on them.

Professor Sullivan talks about how he struggles with the tension between the safety security of patients within COVID-19 and making sure that these patients sill have access to clinical trials in the future. He talks about how age and comorbidities are still significant risk factors for SARS-CoV-2. He then comments on how people are talking about tightening the inclusion-exclusion criteria and how it is a retrograde step. He talks about how we got to have a lot more complexity, heterogeneity, and honesty with the patients. Regulatory bodies and the sponsors to get through this pandemic and ensure all those trials resume and even start new ones. He states that currently, there are no new trials in development.

A question to Professor Bondarenko: Do you think there is a lot of missing data? Do you think the trials that are still running will be able to provide useful data, or do you think that it is going to be an issue moving forward as some of the trials running currently won’t be able to reach the outcomes that they’re trying to access?

Professor Bondarenko mentioned that he was too worried about the missing data and contacted his colleagues regarding this issue at different sites in various countries around the globe. He mentioned that the information he received was different from different areas. He then goes on to say that personally, missing data was not a big issue for him. He states how they have developed a site management system that is accessible from his cellphone and other devices. He mentions that missing data was not a problem for him. Professor Bondarenko emphasises the idea that we may be willing to work effectively and have a desire to achieve goals. But the main question is, how is it possible? How must we train? And how we must be ready for it?

He states that this management system took five years to develop and was tested in clinical trials. We tested medical drugs as well as site management principles with the idea to ensure
high quality. He then goes on to talk about what the system needs to be able to do. The system needs to have the ability to plan all kinds of activities, control the performance of all activities, and procedures automatically like scanning QR codes and receiving performance reports. The system generates high-quality medical records according to the scheduled procedures. These records and events must be followed as they are pre-planned and controlled. The other most critical function of such a management system is to automatically relay information to the data managers. This ensures quick data transfer from medical records to eCRF. He then mentions the need to accurately calculate finances and prepare invoices that will reflect on what has been done. This will help to establish an efficient payment system that will help in-time payments. He then emphasises the need to incorporate the remote monitoring ability in the management system, especially during current times. He mentions that their monitors were able to check everything remotely, and when the cities open up from lockdown, monitors visited the sites and compared the data, it was found that remote monitory showed very good results and everything was in check. Professor Bondarenko states that automatic and remote monitoring can dramatically reduce the cost of clinical trials. He also talked about the automatic transfer of the data, which was collected on-site to the eCRFs. He and his team conducted field tests and concluded that this system works. Professor Bondarenko mentions that he is looking for other people around the work who are on the same page as him and want to decrease the cost of running clinical trials by innovating the procedures involved in conducting such trials.

He closes his address with repeated mentions of how eager he is to find a colleague who shares his philosophy of conducting clinical trials. He even tries to share his email id by holding a piece of paper to the camera. He was very passionate and firm on changing the strategy for conducting clinical trials and want to revamp the traditional philosophy that predominates clinical trial conduction.

A question to Dr. Farah Rasheed: What are the changes that you had to implement over in Pakistan to try and keep the trial running and modifying things in order to help patients?

Dr. Rasheed started by appreciating the rich discussion and how it a learning opportunity for her. She shared a brief insight into how COVID had already spread to other areas before it entered Pakistan. So most of the adaptation and preparations were made during this time. She consolidated on Dr. Hassan’s point-of-view regarding the reallocation of resources and COVID-19 affecting clinical trials nationally. She went on to discuss how the behaviour of patients changed toward seeking healthcare. She pointed out the fear factor that plays a significant role in how things turned out. Dr. Rasheed stated that it was a learning process all along; they switched over to telemedicine and adopted accordingly. They learned to use technology more effectively, which ultimately added to the convenience of its users. She emphasises the need to learn and understand how to react and respond if we were to be faced by another worldwide pandemic in the future. The normal has changed and that there are many things that need to be continued as we move forward into non-COVID time. The switch from paper to electronic was among the bigger moves, but here is still room for improvement and optimisation. The pandemic showed that regulatory bodies, ethical bodies, and sites could coordinate and work in a more synchronised and efficient way. So all those beneficial practices learned during the pandemic should not be forgotten or left out once we move forward into a pandemic-free world.

A question to Elissa Prichep: You mentioned the importance of standards if are to optimally exploit the innovation possibilities, what sort of standards were you to, and which of those are most urgently need?

Elissa appreciated the question before following up.

1. Technology Standards: The wearables used in medical space will collect information differently, which can cause variations in the data that is delivered back to the physician.

2. Governance Perspective:

• How is this data being kept private?
• What are patients knowingly consenting to regard the type of data that is being collected from them?
• How long will that data be accessible?
• What other data it might be combined with?
• How will it be used in the future?

3. Institutions:

• If stored by an institution, what security is put into place to ensure protection?
• If the data is shared with another institution, how is the data being secured as it travels?
• Is the other institute following the same governance models, responsibility, and accountability that the parent institution follows?
• Who sets the standards?

These are general areas around the use of data that still need to be addressed across many spaces related to healthcare.

In regard to use wearables and the adoption of technologies, we are still in a learning and coping phase. We are still trying to figure:

• What are the key questions we need to answer?
• What learning can we gather?
• How do we apply those learnings?
• How can these technologies be deployed in a way that is sustainable?
• Will governments, businesses, and other organisations will fund the development of these data infrastructures?
• How will regulatory bodies cope up with the expanded need to review and approve certain things?
• How will the information and its use be de-risked?

Maximum data needs to be de-risked, especially in clinical trials, because they are expensive. Elissa closed her remarks by the following question:

• How will everybody across the value chain be incentivised to start to address the standards of the government’s need as well as the use of that technology?

A question to Professor Sullivan : How do you think the risk of the second wave, which is in the back of everyone’s mind, is influencing? How clinical trials at the moment?
And how clinical trials will be planned and performed in the next few months? What sort of outcomes will we be looking at?

Professor Sullivan stated that behaviour pattern has changed for the patients as well as the clinical community. The notion of the second wave is very much real. The virus is here, and it is here to stay. It will keep sweeping backward and forwards inside our populations until an effective vaccine is rolled out or we achieve some form of herd-immunity, which is even more complicated as we now know that antibody-tests don’t reflect true underlying immunity. This all adds to the uncertainty. There is a far lower risk threshold in surgery. A lot of surgical procedures are being put off. The majority of the high-risk operations that would have been undertaken before are now being pushed out. Not a lot of alternates are seen coming forward. The ones which are suspended, people are questioning whether to restart them at all. This is the mindset in most of the clinical community and the clinical leaders. Then there are people who are bullish or more used to managing risks like those in hematooncology are much better at managing overall risk to patients and making those trade-off decisions with the patients.

What about the patients coming forward and willing to participate in the trials in the first place? That is something still completely unknown and will depend on a lot of factors. The way media is currently portraying the situation is complete nonsense. The map that actually counts is hospitalisations and the number of people ITU. It’s not just the general background noise of cases. We need a shift in the way that the fear and the public message around this virus put out there to change behaviour overall. This will require a lot of community leadership as well as clinical leadership to get things restarted, get new trials planned, and they started in the first place. However, it is highly dependent on the centres agreeing to allow those trials to happen. There is still a tremendous amount of uncertainty going forward from here. A lot of people will try and restart trials that were suspended, particularly those important trials which are quite far through at the moment. Quite a few trials are going to fall off the edge and never get restarted. And the new trials that were in design and scheduled to launch this year will be delayed and highly depend on the business of the vaccine.

A question to Dr. Hassan: How do you see issues where patients want to interact with your health services but are afraid? And how do you anticipate it will look next year in terms of how clinical trials will be running? And how will you be able to recruit patients?

Dr. Hassan stated that this pandemic had highlighted our moral responsibility to have a robust dialogue on research. We observed the deficiency in the research system and the research process, including the ethics and the regulatory review process. The flaws in these crucial steps were gravely highlighted in the last few months. Though it is necessary that we adopt technology, it has to be done in conjunction with a dialogue on two critical issues that emerged during the current pandemic. It is only then we can go to our patients and ask them to be part of research. Even though research is a right, it’s greatly altruistic on the part of a cancer patient to offer themselves for clinical trials. After all, its research and they are not being offered direct benefit. It helps us answer the question.

The first critical issue that demands a serious dialogue is:

• The issue of research exceptionalism which surfaced during the current pandemic. It was justified in with the excuse to have quick answers. We saw fallouts of the exceptionalism that was made because there were retractions for hastily made publications and major data integrity issues.

Hence a constructive dialogue needs to take place not only for the sake of second peak or future pandemic but for the research enterprise itself.

• The second part of the dialogue is especially important for LMICs. The centralisation of the ethics review process is crucial. It takes forever to get through with the approval process. It is already being used in Europe now. It actually has the potential to revolutionise the research process more than any other form of tech. Centralisation doesn’t necessarily mean that individual institutes IRBs shouldn’t be developed, or no standards should be created for them. But in a pandemic, there should a process in place that is capable of providing robust and quick review without compromising the actual assessment that is need of the hour.

The biggest challenge while performing research and clinical trials in a public health emergency is negotiating the emerging evidence and its uncertainty. There are a lot of problems with it. Referring to the WHO solidarity trials, when the individual countries started it up, the risk-benefit ratio, the clinical equipoise surrounding the treatment arms, and the clinical uncertainty around treatment options were completely then it is today. We later saw how adaptive trial designs could be, and this again is going to be the future for not just COVID related research but for other global health aspects, including cancer trials. But to reach that point, a major capacity-building overhaul is required, especially in LMICs. If we lack the statistical capacity building, performing adaptive trials will be impossible.

Dr. Hassan then concluded her remarks by highlighting the importance of collaborative platform trials. The oncology trials are crucial for us, and there is a better way to get it done, that is, to perform the trials collaboratively.

Questions from the audience.

Question by Dr Craig Hartford: Could you give us a little more detail about how various research units have reduced the risk of cancer patients acquiring COVID-19?

Professor Sullivan took the question and started by mentioning ruthless and rigorous testing both of staff going in and also patients coming in, and having very standard biosecurity countermeasure in place. Nothing can be called COVID-free because of the asymptomatic shedding and difficulty in latency periods. But what we can do is minimise the potential for being infected. There is a reality in keeping your hospitals clean, your hands clean, cleaning surfaces, and cleaning equipment. Although we’ve known this for a long time, he’s seeing hospitals getting cleaned properly after an awfully long time. This is very important as the right sources with the potential to transmit are being targeted. In addition, practising social distancing and allowing patients to come back and be seen. It does reduce the throughput. He states that their team can’t see the number of patients for the clinical studies they used to be able to see on any given day. This means that any existing trial will take much longer to finish. Most of the protocols being observed across Europe satisfy the standard biosecurity.

Professor Bondarenko adds that some unusual things implemented might end up being effective. The separation of different patients groups was something that helped him and his team to keep the patients protected. Moreover, the exclusion of public transport in exchange for private transportation was also a key change that Professor Bondarenko implemented. He then highlights the use of educative videos that helps patients to be informed and cautious at all times to lower the risks of infection. Another step that he mentioned was to ensure the attending physician contacts the patient he is supposed to see a day later. The physician accesses the patient’s condition over a phone call to ensure they are not showing any symptoms of COVID-19. It helps to lower the potential risk of spreading the infection.

Question by anonymous: Do you think, as a clinical community, we have more to do and try to encourage people in this era to participate in trails? Given the fear that patients have, how much do you think we should be doing to positively encourage people is that not something that we see ourselves doing?

Elissa Prichep took the question. She mentioned that most of the issues people face are not new to the COVID era. The issue of being able to access clinical trials and diversity in such trials is a prominent problem. As already discussed, how can health system designs be adjusted to increase those opportunities, such as the use of telemedicine? There are opportunities to set up remote labs, which enables patients to not have to travel but puts clinical trials out beyond just academic research centres. Although these require certifications and funding, these are our potential ways to engage a wider diversity of patients in clinical trials. For a large number of patients, clinical trials are a source of hope and a way to access potential live-saving treatments when they have not been able well otherwise. The choice of whether to take up a clinical trial, to stay in one, or to simply avoid everything and stay at home is a very devastating choice both mentally and emotionally for the patient and the family, especially during the COVID-19.

Question by anonymous: Is there any data on how patients in the clinical trials are affected with COVID-19 compared to the general instance?

Dr. Hassan stated that cancer patients who are on active treatment, have comorbidities, and end up catching COVID-19 certainly have a higher mortality rate.

Question for Dr. Rasheed: Do you think you will change cancer research in Pakistan following COVID? Any other specific changes that you envisage?

Question by Dr. Cecilia also for Dr. Rasheed: And what proportion of your trials are academic versus industry trials? And are they many industry trials running and is it something that will change in the future

Dr. Rasheed mentioned that there would be changes in clinical trials post-COVID, inevitably. This situation had both good and bad effects on research in Pakistan. They learned new lessons, but on the contrary clinical trials, were halted and even suspended. They faced recruitment problems. One of the long-term benefits was the clinical trial sites were able to coordinate, which was not the case in Pakistan previously. However, COVID allowed small and individual research groups to collaborate and support each other. Moreover, the national ethics review board and the drug regulatory authority also cooperated and acted fast. She emphasises the importance of keeping the momentum going and build towards a more effective and synchronised research system in the country.

Although Pakistan has had the ability to conduct a commercial trial on a wide scale, due to some internal and some international factors, the country has been unable to tap into its full potential. She then mentioned that there are more academic trials being conducted in her facility. However, there are commercial opportunities for national and international pharmaceutical companies to invest and collaborate on large commercial trials. She also mentioned her team is carrying out an investigator clinical trial, which has limited scope. The main hurdle she and her team faces is the lack of funding and other necessary resources to conduct state-of-the-art commercial trials. But they are confident and believe that when the right opportunity arrives, Pakistan will be able to play a key role in commercial clinical rials as well.

Closing Remarks

Elissa Prichep: She emphasised the need for patients and physicians to find ways of coping with what’s happening right now is very critical. But looking for the potential long-term implications, what can be learned from technology application and data. There has been a discussion on the greater collection and sharing of information with which comes greater concern for data security and data privacy. She then hinted on how the healthcare system design should be able to incorporate patients easily without friction. She highlighted the importance of technology and how it can influence the trial design, especially in the space of oncology. The idea about how data will help in clinical trials and the role of AI and machine learning will be significant moving forward in the space of research enterprise. She strongly believed that technology had provided the means to find answers to questions that were present before COVID but are brought to the forefront after the pandemic and forced people’s hands in trying out these new technologies. She concluded by mentioning that the global community addresses the system inadequacies as we start to move into the next phase of the COVID era.

Dr. Hassan: The pandemic highlighted the issue of misinformation and showed how research could help to tackle this problem effectively. The role of community engagement is just as crucial as the research work itself. Social sciences model of research should be incorporated with the biomedical model of research to better understand the community behaviour and use the biomedical intervention effectively.

Professor Bondarenko: Thanked the whole team and closed the session with the need to improve the management process. He emphasised the need to improve ourselves and our procedures. He beautifully stated that if we work together, we will win the fight and be the CHAMPIONS!