The Trial Design Spectrum, Vaccines and More - Brendan Buckley

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It's time to get Totally Clinical. Today, I'm joined by Brendan Buckley. Ted Cruz, chief medical officer Brendan has over 40 years experience in academic clinical practice as a physician. He also chairs the board of the leading Irish research charity Fighting Blindness and as a member of the board of breakthrough cancer research now recently.

Brendan wrote a blog about the wide spectrum of trial design from so-called mega trials, especially good for vaccine development and more conventional trials that were best for personalized medicine. Today, Brendan talks to me about these different types of trial designs, as well as why you can trust the vaccine is safe and much more. Welcome, Brendan. The pandemic has inspired worldwide interest in clinical trials, yet few people know the differences between trial phases and the types of trials that are out there.

In your blog, you talk about the wide spectrum of clinical trials. Could you elaborate a bit on this? Certainly, clinical trials range from very small trials at the first time that a drug is used in so-called phase one, maybe involving 20, 30, 40 people all the way out to trials that require Tens of thousands of people. For example, with the recent COVID vaccine, field trials and the designs of these vary considerably depending on what phase of the drug development is being investigated.

For example, 1 May be attempting to develop a drug for a relatively small number of people who may have a rare disease. Or maybe a rare subset of a more common disease like, say, breast cancer in certain cancers, for example. Drugs are designed to address really specific mechanisms that may only be present in a small subset of those with the disease. And these are called personalized medicines.

They're targeted at molecules and processes which are within the tumor that may only be present in 1% or 2% of people with the overall disease and of necessity. These trials can only recruit small numbers of people and may need to do it in lots of centers and even in lots of countries to recruit the trial quickly enough. And often, these may comprise only a couple of participants at the other end of the spectrum. There are huge trials that may require 15, 20 30,000 participants.

And these typically occur towards the end of the development of a medicine. We're very familiar with the vaccine studies that have been happening over the last year, in which many Tens of thousands of people are inoculated with the vaccine. And then we see how many of them got COVID. And how many of them were protected by the vaccine.

So it's easy to see why these types of trials are ideal for vaccines. Do you have any other examples of drugs that are suited to huge trials? There are other trials as well. So, for example, a new diabetes drug has got to show that it prevents heart attacks and strokes and to do these trials quickly enough.

You need about 15, 20,000 participants to show the effect and to do it in a reasonable timescale. There is a more complicated example than these are studies which involve the use of many drugs. Sometimes these drugs are ones that were very familiar with them. We're trying to repurpose them.

The WHO solidarity trial took a variety of well-known, well-established treatments for other conditions to see whether they could be helpful in treating patients with COVID. And what solidarity did was to compare all of these to each other and to no treatment at all or to standard treatment. And it was rapidly able to determine that, in fact, none of these drugs worked. So, you know, the really high profile example was hydroxychloroquine, which was the one that Donald Trump was very active in promoting at one stage.

So these trials are particularly useful in quickly recruiting very large numbers of people to answer a very simple question might this drug work or not, particularly in the situation where we need to find that answer very early on, we can't afford delay. I imagine there'll be more and more interest in these larger type trials as people become more aware of them how they're designed, as they're specifically good for vaccine trials. I think the commentary, which is out there in the press and in social media about the development of vaccines and the very rapid development in particular unprecedented maybe shaving 90% of the time scale of some of these agents.

That commentary has really raised the profile of clinical trials in people's minds. And I think, you know, even people who are averse to vaccines. One would hope that in establishing their reverse positions, at least they're reading about clinical trials, even if they form a judgment about them that isn't accurate. They at least have read about them and are aware of them.

What would you say to people who are worried about the vaccine? They will say that the full testing phase isn't over until 2023. A lot of these people will need a lot of reassurance in terms of these trials. Could you explain a bit more about why they managed to get the results they did so quickly?

I completely agree that it's appropriate for people to be concerned and to question and to read as much as they can about this issue, where there is a huge mass medication process going on across the world. And in my case, I was very happy to receive this vaccine as quickly as possible. But the reason for speed? Is twofold.

One is that the cost of development of vaccines has been guaranteed by governments, and that is almost never the case with normal drug development. So in the past, for example, the vaccine for measles might take years to develop, but it's being developed at commercial risk and financial commercial risk. Biopharmaceutical company in COVID governments guaranteed that cost. The second piece is what we call white space in the normal development of a medicine.

There are often long periods of delay, while results of earlier studies are being done over and argued about. And then one goes off and tries to finance the next phase. And so forth. So between the end, say, of a phase I study and the commencement of a phase two study, there may be four six months of delay.

While debate occurs within the company as to how they'll proceed with the next phase and then how they design the next bit with the vaccines, that white space has been taken out completely so with the vaccine development. What has happened really is that studies have been done very quickly on small numbers of people phase two to see whether the vaccine caused an immune response. And once they were able to see the immune response, they launched immediately into the big phase three field trials in which they vaccinated Tens of thousands of people. And because there was so much COVID out there, a high enough proportion of people were exposed to COVID to show whether the vaccines worked in a short timescale.

So in the course of three or four months, it was possible if you vaccinated 20,000 people that a few of these got COVID or were protected from COVID by the vaccine. So again, the huge number of people in the population with the disease, the extent to which it was spreading and very large numbers enabled the results to be obtained in a very short timescale. There were absolutely no corners cut. So if you compare very big studies, for example, the example I gave earlier of a new diabetes drug that might take five or six years to conclude, but the event rate, the number of endpoints that would occur in a study like that is quite small.

If you compare the designs and the reports of conventional, very large studies with the vaccine ones, you see that they're identical. The vaccine ones were able to happen very quickly because there was so much COVID in the community. And so many people were vaccinated that it was possible to see what was going on. Yeah, that makes sense.

So I imagine this is why regulatory authorities were granted approval so quickly. Now, the reason that regulatory agencies granted a provisional approval was that they realized that it was going to take time to see really, really rare adverse events. So adverse events that might occur in one in a million people. And that's again normal if we do a clinical trial that even takes 50,000 people on it.

You're not going to see adverse events that occur one in a million times very reliably. So it's normal in the course of medicine development, that safety becomes clearer and clearer as time goes by and the medicine is out there in the real world being used by millions of people. So I have no reservations about the speed with which vaccines have been developed. In fact, they've been developed in exactly the same way as any other medicine, with the exception of taking up the White space, the guarantee of funding.

But the design is precisely the same, and it's the high rate of COVID in the community enabled us to see whether the vaccines were working or not. Fortunately, they were working. Moving on, talk a bit more about your blog. You refer to the rather aptly named octopus trial for multiple sclerosis.

The first multi arm, multi-stage or MEMS trial for progressive MS in the world. You've also got a special interest in octopus. Could you tell us a bit more about this? Well, I have a sentimental interest in this area.

In parts of my former life, I was very interested in medicines that change cholesterol metabolism and my interest, particularly within these. Relation to their prevention of heart disease, but one of the so-called statin drugs very widely used to lower cholesterol and to prevent heart attack. One of the statin drugs simvastatin we know crosses from the blood into the brain, and some of its action is known to damp down excess inflammation. So multiple sclerosis occurs when inflammation is occurring inside in the brain and spinal cord, and damage and scarring occurs as a result of the inflammation.

So you get Ms So there was a suggestion, particularly from animal studies, that simvastatin might help with multiple sclerosis. And I attempted, in fact, to set up a clinical trial to see whether this was the case. It was impossible to fund, unfortunately, and this is almost 20 years ago, and it's not surprising that it was difficult to fund because the drug was very much a heart disease drug at the time and getting people interested in it. This is the brain was pretty difficult, so I was very glad to see that the investigators of the trial had done some work in this respect.

And I believe that simvastatin and some other drugs that they're trying in this trial, which are being repurposed from other indications, may be very helpful. The really nice thing about trials like octopus, in which there are multiple arms, hence the name each arm representing the treatment with one drug. And then there are multiple stages because when drugs are being shown not to work, you can stop using them. Or if they work really well, you've got a result.

Also, they must know a lot about the safety of these drugs already. Is that right? What you're really doing is you're standing on the shoulders of the developers of these drugs for other indications in which they're now on the market and widely used prescribed standing on those shoulders and seeing whether one can reach into a new disease and repurpose the drug for the benefit of people with that condition. So I shall be watching the octopus trial with considerable interest if we think about the types of trials you've talked about how quickly different cohorts need to be enrolled.

Medicines drops reintroduced, et cetera. Tekrar seems so perfectly suited to these types of trials. Could you discuss a bit more about his versatility when it comes to these larger trials, and obviously as well the more conventional type traditional trials? Let's take two extremes a personalized medicine trial in which there may be 200 or 300 people enrolled, but they're in 30 countries across the world.

Communication really quickly and accurately is very important with these, and it's more difficult because they're so diffusely spread. So tecra is very good at enabling these people to have access to the very most accurate information instantly, and it allows them to communicate back and forth with experts who are working at the sponsor. So, for example, if I'm doing a personalized medicine trial in Taiwan and I have a question about the protocol, I can look it up instantly on tekrar. And we know that people spend on average only about 40 seconds looking because it's so instantly available.

Equally, if I have a question that isn't answered in the protocol, but I want to talk to the sponsor about our communication system allows that to be securely done. When you go to the other end of the spectrum, for example, like a trial like octopus, a multi stage adaptive trial design. Again, these trials change quite a lot. There isn't a single protocol that carries all the way through from beginning to end, with only small changes.

So what would such a trial like octopus, for example, be like without the types of technology we have available today? Doing something like octopus in pre-check roadways, I guess, would have involved a lot of emailing a substantial delay in people picking up their emails, emails, going to people's Gmail accounts that are not terribly secure and that stand out and very little tracking of whether somebody has received a message or not. And even worse than that, communications like Whatsapp or by SMS messenger are a nightmare because. It's very difficult to put those communications together into the trial master file at the end so that a regulator, if they're doing an inspection, can see that appropriate communications and actions have followed each other.

So technical turns out all of these problems and whether there are a couple of patients in the trial or 50,000 in the trial. It works just the same because it's just a great communications tool and provides instant access to expertise, all of which is tracked and auditable. Thanks, Brendan, for chatting with me today and explaining to our audience more about trials, vaccines and how tech crew works at the end there. And that's your dose of Totally Clinical for all the listeners out there.

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