I want to discuss with you the possibility of removing the placebo arm in clinical research trials. I’m Dr. Jeff Kingsley and welcome to another edition of Riding in Cars with Researchers. The Japanese government just announced that they will be releasing a guidance document sometime around April of 2021, regarding how you would be able to submit data for regulatory approval there, while using what’s called real-world evidence in place of a placebo arm. So let’s discuss this concept and what all of these things mean.

Let’s start with real-world evidence. Real-world evidence is exactly what it sounds like. It’s not a research trial in the traditional sense. It’s real patients, with their real diagnoses, and all of their concomitant medications, going about their regular lives, and the collection of data on, “what does that look like?”. And so real-world evidence allows you to get a sense of how an investigational product, or how a given disease state really looks outside of a research trial. Remember inside of a research trial, we’re selecting very specific types of patients, patients who have type two diabetes, but haven’t had cancer within the last five years, haven’t had a heart attack in the last 12 months. The real world is a different place. In the real world, type two diabetics have had heart attacks recently and have had a cancer diagnosis. So when you have had those things happen, how does it change how medicines are processed in your body? How does it change your symptomatology? That’s what real-world evidence is all about.

Now let’s talk ethics. Anytime you can do something without a placebo, you should. Anytime you can run a research trial without a placebo, you should run a research trial without a placebo. We have with the advent of electronic healthcare records, access to immense amounts of data on real-world patients. And that data could be leveraged and validated, and then be used as the comparator arm. Let’s pretend you were going to do a 300 patient type two diabetes trial with a 50/50 randomization of your investigational agent versus placebo on the background of standard of care. You have to put 300 patients in your trial. If you could use validated real-world evidence data, then you could run your trial and only have to enroll 150 patients, and those 150 could entirely be in the investigational arm of the study. And you would use the validated real-world evidence data as your comparator. You would know the results of your comparator before even starting your research trial. You would know what the comparator arm shows in terms of its values of the primary endpoint, secondary endpoint before you even began your research trial. Your research trial would enroll faster and cost far less than the way we run research today.

Now let’s poke some holes in it: where can’t you do this, where can you, and where is it a little bit gray? Well, you can’t do it with COVID-19. I wish you could, but you can’t. Why? Well, if I took a data set of patients around the nation who got COVID-19 and went to the hospital or were treated outpatient, and what symptoms did they have, and what side effect profiles did they have? Did they get the standard of care? Did they not get anything? I could get that dataset, but then I choose a site in Columbus, Georgia as one of my sites for the investigational product. And let’s say Columbus, Georgia is a hotspot and has loads of COVID-19 positive patients. Well, my trial is going to have a big difference in demographics between my investigational arm and my comparator arm.

Let’s talk about where it certainly would work. Type two diabetes is probably a great example where you really could do this, where you could use real-world evidence as to your comparator arm. Type two diabetics are expected to be seen at least once every quarter, so there’s an immense amount of data on type two diabetics: what medicines they’re on their various treatments and their side effects, and a recent and frequent acquisition of data. So that’s an area where you probably really could use that paradigm.

Where should we be doing it? Well, certainly on rare disease. Rare disease is an example where there are insufficient patients in the world to be able to adequately do our trials. That’s a great example where you could make your trials more successful by using this paradigm.

And let’s talk about where it gets a little gray. Let’s use hypercholesterolemia. Your cholesterol is influenced not only by your genetics but also by your diets. Over the course of time, the diet changes. It changes in any individual, but think about the globe, or a region like the Mediterranean, or a country like America. Diets change over the course of time. So you could do a comparator arm of real-world evidence data and validate it, but maybe it’s only valid for a certain amount of time. I don’t know how long – five years, perhaps? Perhaps for a five-year period, you could still trust that your real-world evidence data is indicative of what historically would have been a placebo arm. But perhaps every five years, you would have to redo a real-world evidence study and revalidate that arm for use.

It’s a complicated concept. And it’s a leap of faith for the industry to start thinking, “could we do this?” But something that I always say is just because something’s hard, doesn’t mean you shouldn’t do it. You should do it because it’s the right thing to do. If we have enough real-world evidence data that we could leverage to eliminate placebo arms, no matter how hard it is, we should do this. We should take on that challenge. My thought for the day. I wish you the best.

Thanks for riding along!

Send me topics you want me to talk about at jeff.kingsley@centricityresearch.com!

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