Pharma giant AstraZeneca voluntarily paused the trials of its COVID-19 vaccine, which was in phase II/III after one of its participants developed adverse reactions.
The New York Times reported that it was likely that the participant reported symptoms of inflammation in the spinal cord(transverse myelitis). Whether these symptoms are directly linked to the time the participant was inoculated with the vaccine is not yet clear.
The vaccine was one of the front runners in the race to find a COVID-19 vaccine after their Phase I/II trial findings were published in the Lancet in July. These findings showed that none of the 543 participants had adverse reactions.
Dr N. Kumarasamy, Chief & Director, VHS-Infectious Diseases Medical Centre said it is important to find out if the neurological effect of transverse myelitis happened after inoculation of the vaccine.
While it might be possible that this was not related to the vaccine or the patient might have been given a placebo, it is important to find out the exact cause before further trials are conducted, said Dr Kumarasamy.
"There are reports that some of the vaccines can produce certain types of neurological disorders. But whether it remains true for this vaccine, it is yet to be seen," said Dr Kumarasamy.
He also added, "But more research needs to be done on the cause for the safety of trial participants who are included in future trials."
The full transcript of the interview can be read below.
Govindraj Ethiraj: Hello and welcome a patient who was part of COVID-19 vaccine trials, phase three triggered a global shutdown after she experienced neurological symptoms with a rare but serious spinal disorder reports have said now this obviously seems like a setback for the vaccine programme for COVID-19. But we yet don't know the details. And of course, we're trying to find out what this means in the larger context of the race for the vaccine, which is obviously gathering steam. The larger question also is what does this tell us about vaccine trials and should we understand them a little better to know the context in which this particular shutdown may have happened and remember, there are many trials going on at the same time in different phases. As you know, there are three phases of vaccine trials after which they could potentially come into the market to discuss this. I'm now joined by Dr. N. Kumarasamy chief and director of infectious diseases Medical Centre at the voluntary health services or VHS Hospital in Chennai. He's also the director and site leader for the Chennai antiviral research site of the US National Institutes of Health. Dr. N. Kumarasamy, Thank you very much for joining us. So give us a bit of background first. I mean, you know, this, this sudden shutdown of the vaccine trials obviously caused a lot of fear. I think the fear is not just that we will not get the vaccine in time, but the fear that a vaccine can cause an adverse reaction, which can obviously harm people.
Dr. N. Kumarasamy: Right, you know, thank you for inviting me.
to this very important programme. And then, you know, as we all know that, you know, everyone on the race to find a cure for COVID or to prevent the perfect vaccine for i1, so more than hundred different vaccines are in the pipeline.
They are in the preclinical, or the phase one, phase two, and few of them will be in you know, phase three clinical trials with at least three good candidates. So being entered into the based on the previous phase to assess.
Now before we talk about these adverse events, how vaccine development happens, first there is the preclinical phase where all this happens in the lab, where we're trying to identify the candidate.
And also, the interim search happens with the vital particles or with the actual data particle, enough to know how you can elucidate the immune response to particularly this virus. Once the candidate is developed preclinically, then it's been tested in of course, and it goes to a lot of toxicology testing, in animals and before it is tested in a small number of people in phase one, trying to understand whether it is tolerable or is it safe.
These trials are done on a smaller number of people.
And based on that, then phase two trials happen, which will have anything from a hundred to 200 people where it's not mainly to prove the efficacy of the vaccine, but it's mostly into these against safety tolerability.
In a short time, you know, those safety studies don't go on for a longer time, you know, it can happen, anything from you know, six weeks to six months, but now, it's a pandemic situation, and things are happening so quickly.
And even Russell Serbin extrapolator, we're not waiting for the real endpoint. And based on all those, this historical evidence in the last six months, now, there are a couple of candidate vaccines which have been moved out of phase two, where the results have shown they have been safer and stimulating immunogenicity, so that means that it is stimulating your immune response to fight against this virus.
So that means if these products are given to someone as an injectable, those individuals who have been vaccinated with these vaccines developed a substance called antibodies to fight against this COVID-19 virus if they have been exposed to. So following this principle now that they have developed these large phases three trials, they have developed not only just to study the safety, tolerability and immunogenicity, which has already been done in phase two, but more from inefficacy. So, here is all done in a group of people where they vaccinate and have studied against a placebo, where it grew where they want to see the vaccine, but they still receive something as an injection, which will look similar like a vaccine, but that is not a vaccine, you know, it can be a novel solution.
So these are usually the phase three trials. Best that and again, the phase three trial the primary endpoint is always efficacy, but there will be a lot of other secondary endpoints which have also been studied as part of the phase two trial, on the safety, tolerability and you know, any type of vaccine-related reactions.
So when we do these vaccine trials, especially from my background, I've been involved as a principal investigator and doing TB vaccine studies and TB vaccine development and as well as for HPV vaccine, Human Papillomavirus vaccines.
So when we do all these clinical trials, there are individuals who develop certain adverse events. Again, when we do these vaccine trials, these are rejections. Now when you do this injection for someone, people will complain about pain, everybody gets a payment, something is perfect. You know that itself is in practice and it goes even and there could be some itching and reaction of the vaccinated site. The area can be red and swelled and that also can be captured as an adverse event.
And some individuals developed a fever. When someone develops an immune response, body start stimulating the immune response and starts developing antibodies, they can develop a fever, some people develop mild dizziness following their immune response and some of them develop flu-like symptoms. They can have fever and symptoms like running nose. This is because they are injecting something and your body's reacting to that and as a result, you develop these, you know, flu-like symptoms. All these reactions are all captured as are those events.
Govindraj Ethiraj: The one that we are currently talking about was that was something beyond these symptoms, which are known to be prevalent.
Dr. N. Kumarasamy: So these are the rules events that are being captured as part of vaccines trails. So other than these, these are all vaccine-related, we know that that is there anything happens to this individual also been captured, for example, someone who fostered and they have been vaccinated. The next two weeks, they fell down there a fracture at the hospital that's also been captured as an adverse event, or someone who develop chest pain and heart attack, you've been captured, some deliver severe diarrhoea, they are hospitalised or someone developed some sort of a new neurological problem as discussed in this particular case. In this particular phase three in a vaccine all have been captured as humans, again in this grade, grade one, grade two, grade three grade four, usually in any clinical trials either drug trial vaccine trial, grade one and grade two usually resolve on its own, when you stop that or you take the source of the symptomatic things, but grade three and grade four, they are very symptomatic or something. Their lack of normality happens when you do these vaccines, we always do a variety of biochemical tests starting from liver function tests, kidney function, haemoglobin and various other safety tests we do, if it gets altered beyond certain level also we call grade three in grade four, then we stopped that particular intervention. So, we are doing this individual. So, this all has been created. And once it's all graded, you know, researchers what they do is when these adverse events happen, they will always do what is called cash reality, you know, where it is later to this vaccine or something, you know, anybody can do a heart attack not necessarily because of this vaccine. So, they try to link this. So, when it is very severe, always kill all these real causes of harm, then we attribute it could be directed to vaccine now, particularly, you know in vaccine trials in phase three, we recruit individuals for all normal, healthy volunteers, they have no disease, they don't have any problem perfectly fine. So it's important to restrict inclusion criteria.
So, when we before we vaccinate if they develop something, the first thing always come to mind is related to the vaccines. So, before you know we achieve or whether it is due to the vaccine, you know, some other costs.
So, I think here, this particular vaccine phase, AstraZeneca in collaboration with Oxford, which is a little shocking on hearing this news that one individual developed neurological manifestation, which is a cause of serious concern, and that you're producing transverse myelitis. There are reports coming up there are certain types of vaccines can produce this. Now, I do not know whether it is related to this particular vaccine . The disorder which again, is a work in progress by the investigators and by the data safety monitoring board.
I think till that time, the investigators and as well as the sponsors decided that they should call this trial, trying to find out whether it was really related to the vaccine, or, you know, it is later to go forward. And I say it's a huge setback. But on the other hand, it happens, in many clinical trials, and as well as in vaccine studies, I think we need to wait for more evidence on this. Also, as rightly said, then now it has been released to the public that discussed these issues. So this is a serious concern now among the volunteers to participate in future vaccine studies, you know, will their persons will come will disband to be safe and do that, I think this now,
the first thing is now these investigators and the data safety monitoring board of this particular study,they have clearly come up with an answer which I'm sure they will do what they're doing now, whether it is really due to vaccines or that particular individual or any other issue which causes the condition.
Govindraj Ethiraj: You said that in the past there has been a link between some vaccines and spinal disorders, right. And that's why there was maybe more concern in this particular case.
Dr. N. Kumarasamy: Yeah, not necessarily spinal or neurological, there are reports that some of the vaccines can produce certain types of neurological disorders.
Govindraj Ethiraj: There seems to be a pattern here, otherwise why would these trials be brought to a halt? Is it a normal adverse reaction?
Dr. N. Kumarasamy: I think I think now in the safety of the future study participants who are going to enter, I think the investigators did the right thing to try and identify the reason before they move forward.
But again, at this time,we do not know whether it is just an incidental finding, or is due to the vaccine. I think we need to wait for more information from the study team.
Govindraj Ethiraj: In other trials that go on what is the point at which a trial is brought to a halt? Obviously, because it's COVID we all know about it, but I'm sure there are many other trials going on where there could be similar responses and is that common then?
Dr. N. Kumarasamy: So as I said earlier, during any trials, any clinical trial either drug trial or vaccine trial, there are various angles even happens like pain and itching.
Govindraj Ethiraj: I mean something like this something of this nature is a neurological
Dr. N. Kumarasamy: So since it is a serious concern about the neurological system. I think till we try to understand whether it is definitely not related to vaccines, and I think the ideal thing is to halt this trial and try to identify all the possible reason before it is restarted, If it is new to the vaccine, which Do not know.
Govindraj Ethiraj: So is this adequate precaution? If you look at other trials, wherever they happen, is it adequate precautions as being taken by halting trials? Is it more than adequate precaution? Or what's the nature of response from your understanding?
Dr. N. Kumarasamy: It was sudden news, really shocking, because we all want a vaccine. You know, after seeing the phase two results of this, we thought that this will make it as one of the front runner has covered a lot of other vaccine development in progress.
So, but on the other hand, when you see such an event, so I think now, I think what the investigators and the sponsors do the right thing to try to find out, at least it is not the real cause of the vaccine to move forward because that is a very important; one as a safety concern, and also the confidence of future volunteers. So to say that, you know, you're just not due to the vaccine. I think, you know, that type of answer should come from these investigators and for the strategy.
Govindraj Ethiraj: And that's an important point. I mean, obviously future volunteers would be very, so you talked about the placebo being injected, and you know, so could this be a placebo? So I'm assuming somehow from the train of thought that is not unlikely to a placebo?
Dr. N. Kumarasamy: Yeah, it's quite possible because it is a randomised, blinded, clinical trial. So the investigators do not know whether the particular participant received a placebo or, you know, really the intervention vaccine product. I think now they're halted. Now, they've now unblinded this, because here comes the data safety monitoring board, they would have been invited to to review this data. And they work very closely with the statistical and their analytical team and do the unblinding in of this particular participant and if it is a placebo they will come up and say that "Okay, there is no cause of concern."
But if it is a new vaccine, then they will try to look into the cashew already to this. I think currently, it's all happened in the last 24 to 36 hours, I think, yeah, I assume whatever I said is currently happening, I think they will not be able to move on completely this blanket thing to everybody. So you get a confounder. So there is a small group of DSMB they meet and do that. And they will advise a study team to continue or interrupt I think that's going to be that so probably in the next 48 hours.
Govindraj Ethiraj: Last question, Dr. N. Kumarasamy so it's not clear to me from the outside, so who calls a halt to trials and in situations like this, is it the people who are conducting the trials? Is there someone regulating it? And obviously, different countries are involved here? How does that work? What's the oversight?
Here's what Anita Chauhan, head of Sakhi centres of Vatsalya foundation, an NGO that works to provide low cost sanitary napkins told us
Dr. N. Kumarasamy: So when we do a clinical trial by the investigators, they are part of an institution. So, it goes through their own institutional ethical committee, they review the study and use all the approval before they do the study. And once that approval happens, only they can initiate the study, before that, it also goes through other country regulations. For example, in India, it also goes through the drug control of India, you know, before it goes to the ethics committees, that the proper approval, whether this particular product can be tested in India then goes to these ethics committees. So, the minute when an adverse event happens, the investigators of that particular institution, within 24 hours, report to the own ethics committee, as well as to the drug control of India dcgi here in India, and as well as the sponsors. And once it is been informed about this particular incident that happened, then the ethics committee immediately takes a decision and as well as the sponsors, and as well as the regulators here DCGI. All together take a decision that whether the study should be immediately halted. The first thing happens is usually when you see an unwanted thing they say, okay, don't do no new enrollment, what our participant you're already enrolled, continue the same way like in the similar protocol, but don't do no new enrollment that's currently happened here. I won't use the word altered from the trial. The trial is ongoing. You know, they have already vaccinated a very large number of people in different parts of the world. And they are not continuing, they are already vaccinated. They are continuing the study procedures where there are Red Cross happening over a period of time and for safety and as well as for the efficacy of it. But what they were called is they're not doing a new enrollment. This happens in many studies. I think now how quickly since it is now in a pandemic situation, everyone on the running race for the vaccine, and how quickly all those able to solve it before they move forward with this product.
Govindraj Ethiraj: Right. N. Kumarasamy thank you very much for joining us. And thank you also for your insights and I'm sure we'll get back to you as we continue to look for a vaccine for COVID-19 Thank you so much.
Dr. N. Kumarasamy: Yeah, one other thing before we sign off is, I think this is very important, to identify what is the real cuase because it's also important to build confidence among the future volunteers not only for this vaccine study, there are several vaccine trials in the pipeline.
I think the minute when these investigators and the sponsors find the real answer stating what could be the possible cause will also you not have confidence for the future volunteers to participate in at this time. We also need volunteers to participate in these clinical trials. To move forward, to build the confidence of these volunteers, I think we need good answers, good reviews by the data safety monitoring board investigators and by the sponsors to the public.
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