Professor Jeremy Nel, Co-principal Investigator of the South African Solidarity Trail
Moderator: Tian Johnson
Complied by: Anna Matendawafa – with inputs from Wilfred Gurupira & Maaza Seyoum
Webinar Recordings & Supplementary Materials:
Date: 06 August 2020
Professor Jeremy Nel obtained his MBChB at the University of Cape Town. He also obtained a diploma in Tropical Medicine and Hygiene from the Royal College of Physicians in London, UK. He recently completed a Transplant Infectious Diseases fellowship at the University of North Carolina, Chapel Hill, USA. He’s also the Co-principal investigator of the South African Solidarity Trail.
Professor Jeremy Nel introduced civil society advocates to the Solidarity trial, an international clinical trial which they are using to help find an effective treatment for COVID-19 launched by WHO and partners. The trial compares various drug options against the standard of care to assess the relative effectiveness against COVID-19 in patients in multiple countries. The Solidarity trial aims to rapidly discover whether any of the drugs being tested slow disease progression or improve survival.
It is an international randomized trial of additional treatment for COVID-19 in hospitalized patients who are all receiving the local standard of care
Livingstone Tertiary Hospital Charlotte Maxeke Johannesburg Academic Hospital King Edward VIII Hospital Dr George Mukhari Academic Hospital Addington Hospital FAM-CRU Tygerberg Academic Hospital Inkosi Albert Luthuli Central Hospital Groote Schuur Hospital ,University of Cape Town Steve Biko Academic Hospital Military Hospital Helen Joseph Hospital Universitas Hospital Chris Hani Baragwanath Academic Hospital Pelonomi Hospital Walter Sisulu University
QUESTIONS AND ANSWERS
*This section contains a transcribed account of the Question and Answer Session
What work has the trial done to ensure beyond Community Advisory Boards(CABS) that communities are engaging with Solidarity that is happening in their neighborhood, and if not, how do you envision what Helen described as almost a new learning process for us as civil society to rethink community engagement in the context of this particular, the way Helen characterized a unique trial?
Thanks very much, so to confirm what you have asked, we have over 40 countries participating in Solidarity. The protocol is developed by the WHO executive committee. Hence, it is central; the protocol has to be identical across all sites in every country, so as you rightly said, there isn’t any right to change the protocol. At least in any meaningful sense, we have added other monitoring layers, two of which we were allowed to, but it has to remain constant in terms of the core protocol. So yeah, that is one of the challenges of this sort of trial is that it’s very, we are not able to change the core protocol the other thing, of course, is the pandemic scenario where you know, this is happening during lockdown were it’s not only challenging but potentially dangerous and potentially even unethical to go into communities and in a way that we would typically do, in terms of severe community engagement structures this sort of method of doing it electronically and on zoom, offers some way around that in the sense that it’s a way to engage without, you know, while still being socially distant but it does as I’m sure you will be the first to appreciate Tian, it does limit as well. Whenever you have this sort of thing, it’s only a subset of the community who will log on to a Zoom meeting, and it makes it very difficult to sort of have a detailed community engagement with it. It’s also tricky because it is limited in the scope of what community engagement can achieve other than information sharing, which is vital clearly and the ability to answer concerns and address as many concerns as raised. So, we have dealt with, you know, by really engaging as broadly as we can imagine by this, but you know, we are happy to take suggestions, I mean, and I think that we are all learning in this kind of way. This is really difficult, COVID-19 pandemic, lockdown type scenario; you know how you engage more broadly outside of Zoom meetings with community advisory boards and community leaders elsewhere.
Could you unpack the general consenting process of a hospitalized patient? And then in the second instance, the ethical implications of a next of kin providing consent?
It’s an excellent question. So the ability to enroll hospitalized patients in many sorts of trials is vital. In COVID-19, its especially important because people who don’t require hospitalization generally don’t require treatment, you know, in the sense that you can take Panadol if you have a fever. Still, you don’t require antiviral treatment. You don’t require Dexamethasone or things like that because you will be fine, so the landscape for intervening in COVID-19 is limited to people who are hospitalized for at least for the vast majority of cases. So that’s why it’s essential to be able to research hospitalized patients. Of course, it’s not unpresented because many types of research occur in hospitalized patients. However, in things like HIV and TB, we are unfortunate that we can enroll most of the outpatients because the patients’ population is much more well. So, in terms of what happens with hospitalized patients, we have very experienced trial teams running these projects, which apply to the highest ethical standards about this sort of thing so the patient will be. So firstly, we make sure that the patient is not in obvious distress or anything like that. We try not to enroll people until they are a bit more stable, so you can imagine the sort of person who might be on an oxygen mask who is otherwise feeling okay on that oxygen mask. So that’s the sort of patient we are trying to enroll. We are not trying to enroll people who are in kind of medical distress because that’s really, that would raise all sorts of other issues which we don’t want to sort of traverse. So this is a patient who is doing okay but requires hospitalization, they get given an information sheet. They make sure that they are first very competent on their own, in one of the languages we offer. So we go through the consent process in the local language, depending on the site. Most sites have the ability to have counselors and people who enroll and are fluent at least three languages. We make sure that the patient is articulate in one of those languages, and if there is a language barrier, then again, that’s somebody we can’t consent. We shouldn’t be consenting because, also, the patient must understand. There is an information sheet they go through, and they talk to the patient about the trial; they assess whether the patient is willing to enroll in this trial once they understand more about the trial and what’s required. They do a test of comprehension in other words; they make sure the patient understands what’s going on and towards the end, and only really towards the end of that process, that process may take 20minutes or 30minutes even longer potentially to make sure that all the questions that patient has answered, are answered and then if the patient is willing to engage in the trial beyond that point. Then they get the go-ahead and randomize that patient to one of those arms. Still, it’s quite a lengthy process like I said, its very experienced trial teams involved, and a lot of information given to the patient in some accessible way. Remember, the information sheet goes through the ethics board to make sure that it is comprehensive and understandable to ensure that it’s not too detailed in using too much jargon. That’s aimed at y people, re getting the information that they need. It’s only really at the end of that point when the patient is satisfied, and they understand everything about the trial, and they have no more questions and are willing to proceed and go ahead and randomize beyond that. The patient is free to say no at any stage. We are selective of who we choose; we don’t choose people who are too medically unwell. We worried about the ability to sort of meaningfully consent because someone who is desperate and very severely ill is perhaps not the best frame of mind to be enrolling in the trial. Thanks, Tian.
Does this adaptive design allow you to add drugs not in the original protocol should studies elsewhere suggest an efficacy signal?
So it’s a good question. We certainly can’t add drugs ourselves that are not on the protocol, but WHO can add on to the list. That would be, you know, protocol amendment and we go through all the various regulatory approvals again, so that’s certainly something that they consider, so that’s they can remove arms or add arms. We can’t decide to add on our drugs at the local level in terms of the study. But remember that Solidarity also does work around whatever the standard of care is that’s really essential because that means that we can ensure that whatever the background drugs are that worked, something like Dexamethasone is a good example which I’m sure you are all familiar with really does help people on oxygen. You know it’s not a problem for anyone to be on Dexamethasone in Solidarity, unlike some other trials which you can’t do, you only take trial drugs. Solidarity works around whatever standard of care is; if the standard of care changes and improves, that’s brought on board to Solidarity, but we can’t do that in terms of adding drugs to study them. WHO may decide to do that and in which case, we go through all regulatory approvals to make sure that’s okay on our side
How does planning for success and adequate rollout in all of these trials look like and what does that involve, as well how do you feel civil society should influence that part of the process?
Sure, so in terms of the success, just that our National coordinator is on the call. She will be hopefully smiling, and hopefully not crying in the background. But it’s an enormous logistics issue to get 15 different sites across the country up and running. I’m not aware of another trial in South Africa that has done that anytime recently in terms of the scale and the breadth. If we were doing say 15 sites in Gauteng, it would be a lot easier because you would have one ethics board to go through. Still, we deliberately decided to make sure all corners of the country are covered, but that made it a lot more difficult logistically. So, it’s a massive process in getting approval from the hospitals. In terms of getting approval from the sites, the hospitals’ ethics boards fall under the provinces and the South African Health Products Regulatory Authority (SAHPRA) overall, so at least four sets of approvals are required. Lots of training for the staff and the pharmacists to make sure that they understand the protocol, here as the best practices. Lots of training for the doctors and the study doctors and the study nurses to make sure that they are doing all the right stuff, so it’s an enormous amount of planning that goes into this. And then, of course, getting and dispensing the drugs because you know we get them from WHO for the most part, and we send them out to trial sites. So now those are huge logistics issues, there is a lot of planning that comes into it, in terms of trying to make it rolling it out. In terms of the drugs, they should, so we get them from WHO, and we ship them to Wits, our Hr offices, and send them to sites as they need it. So, there is a lot of planning and logistics that go around at the back of this, and I think it’s something, even though we anticipated it would be difficult it caught us a bit off guard in terms of its scope. And then in terms of kind of community, you know, how to involve communities. So I think Solidarity is a bit different, as we mentioned, because of the protocol’s fixed nature. Still, I think one key thing is that when we do have Solidarity findings in any direction, in other words, if we find this drug works or it works in this way or that way, or it doesn’t work, then we would need to drop it. I think that’s a critical point in which community engagement becomes vital because it’s essential. The value of these trials is a direct proportion to the ability to spread the knowledge that’s gained from these trials. And you know, we can spread within the medical community. Still, we want the whole community, not just the medical community, but the communities around each of these sites and beyond to get as much information as soon as we know anything. I think that’s a critical kind of inflation point that I would want to see us work on when there are Solidarity changes, which explains why and to get that information to the communities and empower them. So we have seen, for example, Dexamethasone that the messaging hasn’t been all that great, you know, it’s not clear, do you take only in hospital , do you take it outside hospital or who benefits and who doesn’t,and that’s something within Solidarity that if the drugs change and if we get answers on them that we really want to make sure that the communities are aware of this possible and we are happy to fill in the question for as long as it takes and as much as we can to ensure that information is spread as broadly as possible .
Thank you. Colleagues on this call will remember we’ve had discussions around the spread of the COVID-19 within the health care facilities and healthcare-associated infections; how would you manage those infections during the trial infections that occur within a facility or hospital-acquired infections? And I would imagine, would those be any different from how you would treat any other potential patient?
A good question, so there are two aspects, one is the spread of COVID-19 between patients in the trial. So we are obviously enrolling people who already have COVID-19 so they can’t get it. They are not the receiving end of COVID-19 from the hospital, but obviously, a critical aspect there is why we wanted to be so sure about the Personal Protective Equipment(PPE) that does protect the spread. So if you are wearing PPE as the trial nurse or doctor interacting with patients on trial, it protects you as the trial nurse and doctor. Still, it also protects other people and other doctors and other nurses and patients from getting COVID-19, so that’s the kind of crucial aspect of preventing COVID-19 spread from our enrolled people to other patients. And then the other part is the other nosocomial infections. In other words, it’s how it would if while the patient is hospitalized what if they get pneumonia that’s not COVID from another patient that we would treat according to the best standard care we would typically treat as you suggested Tian so, it wouldn’t be different to any other nosocomial pneumonia say treatment. The patient will get the highest standard care they would receive if they got that from any other patient. It’s just worthwhile mentioning again that the Solidarity doesn’t keep people in the hospital longer than they need to medically. So even if the course says 10days of Remdesivir, the patient is well enough by day 4 to go home, they go home. We stop them there in terms of Remdesivir. So, it’s key to make sure they don’t get exposed to the hospital environment for longer than they need to. And that’s important for freeing up hospital beds, but that’s also important for prevention from getting hospitalized acquired infections.
Could you speak to the involvement of people with HIV in the trial so far as potential participants.
Sure, so that’s an excellent question, one of the critical advantages of doing the trial in a country like South Africa is that we want to know what these drugs do in an HIV population. That question is not going to be answered well, along with the rest of the world. So, we do need to enroll people who have HIV and other opportunistic infections. So, HIV is not a contraindication to the trial in that we can enroll HIV positive patients and that like I said, I view it as a strength obviously. So, of course, if they have other reasons with HIV not to be enrolled, such as kidney disease, or bad liver disease, that’s a different story. Still, reasonably well, HIV positive patients can be part of this trial. That’s going to be important because I think we will contribute the most in knowledge about HIV and COVID in Solidarity more than any other participating country.
That process sounds like it is taking from the limited resources of an already limping healthcare force. My question to be clear was more on a successful roll out for when the trials give a positive result as a trial outcome. What specific policy, in terms of drug purchasing and delivery of these products has and what discussions have you had with key people. Could you unpack the role of Pharma in this particular trial. What is the Clinicians Society involvement in all of this and how does it contribute to success?
Yep. Thanks. That’s a good question. Sorry, I, I think I missed the gist of your first question. So let’s see if I can take a bit of crack at it. So, this trial is different from say, an HIV trial where, in an HIV trial, for example, if you were put up on trial regimen A and it works there is an obligation to make sure that you can access that drug of the trial and that’s what most responsible drug companies do. Even now, the post-trial access to that drug is essential. Remember, this is a bit different in the COVID-19 epidemic where you only require the access to this drug as an individual for that duration, you know the 6-10 days depending on which arm you are. For example, if you get your 6days, there is no benefit to continue with that drug afterward. So really, what post-trial drug access means in this setting is accessing it for other people who are not on trial. Who are on the trial who get their access? So, in that setting, it requires that would mean to potentially millions of people in South Africa as well, and that requires the Department of Health to be on board with that. They are on board, and it’s interesting, for example, for something like Remdesivir in this case. So Remdesivir for the Department of Health is interested in it but seeing that it costs a lot of money, it costs about R7-10,000 per course and the patients at the moment and that we are sure of from the trial that have reduced hospital stay by a few days. The Department of Health doesn’t view that as a good purchase in reeling it out to the rest of the country. However, suppose Solidarity was to show that it reduces mortality; in other words, it saves lives. In that case, the Department of Health will say that they will look very strongly at it again and decide whether it is worth it despite the cost purchasing it for the population. So that’s where Solidarity will interface in the sense that if you find positive or negative results, it really feeds into the level of evidence that the Department of Health requires in terms of the State sector. The private sector is a beast, as you know. If they can purchase these drugs as needed for their use, they are taking a chance in that sense because it’s outside the clinical trial on a monitoring environment. It’s not also clear whether or not these drugs are saving lives. That is what Solidarity is aiming to prove, so it’s a very different beast. So, in terms of the hospital, sorry in terms of the drug company role in this. So with Interferon and the other drugs which were part of The Solidarity before they were dropped now. They are very commonly available drugs, and many generic manufacturers make them and so WHO purchases them and provides them for our sites, so they don’t deal, we don’t deal directly with the drug companies in terms of that. Remdesivir is a little bit of an exception because it’s manufactured only by Gilliard at the moment in terms of the original product. So, WHO has to interface with Gilliard and purchase enough drugs for that purpose? There are possibilities of getting some of the generic manufacturers into the Solidarity that we are looking to make sure that we have enough access within the trial. But so the drug companies don’t have anything to do with the protocol design. They don’t sponsor the trial in any way but obviously, WHO has to interface with them to obtain the drugs themselves. Thanks, Tian. A couple of clinician society, HIV clinician society doesn’t have a direct role in Solidarity. They are supportive of it. But I think they are as interested as anyone in terms of HIV’s effects of HIV in this COVID epidemic, but they’re not directly involved in this trial.
What are your thoughts on Remdesivir before hospital
It’s an excellent question, but you hit the nail on the head. The problem is there is no form of it that’s not given by intravenously, so there is no way of easily accessing therapy for outpatients. As I said, where it becomes challenging because 95%+ of our patients don’t require hospitalization do fine anyway, the benefit of Remdesivir will be limited to quite a small subset of people who would later have been hospitalized. What we do in Solidarity, though, is that we can give it as soon as they hit the hospital doors before they require ICU. Anyone who is admitted even if they have mild diseases, but if they are in the hospital, we are potentially able to get you Remdesivir. If you randomize to that arm, of course, but it’s long before ICU. So I think that benefit is retained, but getting it as an outpatient, I don’t see it any easy way to do that anywhere in the world really because, exactly as you have said, it’s only available really as an intravenous infusion, so it requires a nurse and a drip and things like that which is not something you could do easily at home.
Any remarks or messages to us on the controversy of hydroxychloroquine?
Yeah, yeah, thank you very much. So, it’s unfortunate that it became a bit political and it became a bit political really in the USA, not here. The history of it was one of the drugs that seemed promising in the beginning based on lab data but needed to be tested in actual, in patients in high-quality trials. So, it was one of the drugs that Solidarity was enrolling, was included in its initial protocol. What happened with time was that the initial studies which were not high quality some of them showed benefits some of them did not show benefits and some of them showed harm some of them showed no harm, and that’s the typical problem with not doing, with doing not outstanding quality research you end up with this sort of mess and no clear answer. Trials enrolled people well in the highest quality randomized controlled trials. That was the Recovery Trial in the UK, a sister trial of the Solidarity very similar methods, slightly different drugs, and Solidarity itself. And what happened was the Recovery Trial was the first to enroll enough people to say, based on best quality evidence definitively, it isn’t helping. It didn’t help in terms of saving lives; in fact, there was a suggestion that it might have increased mortality potentially, although that is less clear, but it certainly wasn’t saving lives. It wasn’t protecting you from getting on a ventilator, and it wasn’t saving you any days in the hospital. And then when Solidarity looked at its interim data as well, it showed the same thing as Recovery, so again it wasn’t saving lives, it wasn’t reducing hospital stay, and it wasn’t keeping you out of a ventilator. When you put these two massive trials together, the highest quality of evidence, I think pretty much most clinicians in the world are convinced that this drug unfortunately really doesn’t offer the benefits we hoped it might in the beginning. What’s happened though, of course, is that you’ve got the Trump factor in the USA when he put a lot of press credibility on the line saying this is a wonder drug,well beyond where the evidence was at that stage. It become a bit politicalized there, so you get a lot of pros and cons. I’m confident as a doctor even outside Solidarity, even if I were not in Solidarity. I would say the same thing that I would not recommend it for patients with COVID19. I think that we have good evidence that it doesn’t work and maybe harmful in some cases, so I believe that though the jury is pretty much in on this one, the controversy persists well beyond the evidence, and I think mostly for political reasons.