Hello and welcome to another edition of Riding in Cars With Researchers. I was reading some research news today and the FDA just released a new guidance on improving enrollment of diverse patient populations into clinical research trials. So it’s time we take up this topic and talk about it.
We need to improve diversity in clinical research trials. What we’re going to talk about today is (1) what diversity is (which is much more complicated than you would think), and (2) we’ll talk about three strategies that you can implement to help improve diversity in clinical research trials.
What is Diversity
It’s daunting. It’s bigger than you would think! In the news, we typically equate diversity conversations to race. Diversity usually means white, black, Asian. Diversity usually is simplified as a race conversation. It’s not. Diversity in a healthcare sense is your genetics, but diversity is also your metabolic rate, your other medical conditions, the other medicines that you happen to be taking, how well you’re sleeping, what you eat.
Think about it. Isn’t it reasonable to assume that a medication, a biologic or a medical device, is going to behave differently in somebody of one genetic background versus another? Isn’t it reasonable to understand that it’s going to behave differently in somebody with one set of other diagnoses versus someone else? One person who is taking 20 concomitant medicines (simultaneous different medications) versus somebody else who’s taking none. What about somebody who’s a meat eater or versus somebody who’s a vegetarian?
Diversity in Clinical Research Trials is Complicated
You’ve heard me discuss diversity in the past. We have a medical, scientific, and an ethical obligation to look for diverse populations. What I’m discussing right now is more of the medical reasons, the scientific reasons. We have an obligation to do research on diverse patient populations to understand how that drug, biologic, or device is going to work in those very different patient populations.
But we also have an ethical obligation. It is unethical to do research on one patient population and then frankly, extrapolate, and assume that it’s going to work the same in a different patient population. We are being far too simplistic on how we look at this today. A friend of mine identifies as black. If you ask her her race, she would readily say she’s black. Her genetic background shows that she is 51% of African descent and 49% of European descent. A drug, biologic, or device is going to work differently in her then it would have in patients of other backgrounds. We have an obligation to tackle this.
What are the three things that we can do? We’re going to discuss three things that we can do to help tackle this: (1) Inclusion/Exclusion (I/E) criteria; (2) adaptive trial design, and (3) alternate recruitment strategies
Inclusion and exclusion criteria are actually designed to reduce diversity. We don’t think about it that way, but that’s their purpose. Their purpose is to select very specific patient populations and, in effect, reduce diversity. We’re selecting for patients that aren’t taking many different medications, but when the drug gets regulatory approval and is on the market, in fact, it will be used in patients with many, many different medications being used at the same time. Our I/E criteria selects patients who don’t have multiple different medical conditions and yet, when it gets FDA or regulatory approval, it will be used in those patients that weren’t included in the research data set.
Tufts University’s Center for the Study of Drug Development has been speaking out against all of our I/E criteria for many, many years now and the FDA is now saying the same thing. FDA is now saying we have to get better.; we have to reduce inclusion and exclusion criteria. One of the ways we can do that is by stopping the behavior of cutting and pasting the I/E criteria we used in a Phase 2 trial into a Phase 3 trial. In the Phase 2 trial, we had less information about the safety of the drug in patients with renal insufficiency, for example, a mild impairment of your kidney function. We have more information by the time we get to a Phase 3 trial design, but all too often we simply cut and paste. The Phase 3 trial could be designed with less stringent renal criteria in its I/E criteria. That’s an example of things we can do to loosen I/E criteria. Now that’s normal trial design – Phase 2, Phase 3, as if it’s static.
Adaptive Trial Design
Now let’s talk about how you get study awards and I categorize it in three ways. It’s all really marketing, but there’s really three things: relationships, databases, and your differentiation. I’ve talked about differentiation a lot in Riding in Cars With Researchers episodes.
Adaptive trial design has been around for many, many years. Our industry has been very slow to adopt adaptive trial design. You can think of adaptive trial design as micro protocols. You’ve got a Phase 2 protocol and when you finish that and the data looks good, you proceed to a Phase 3 protocol. Adaptive trial design is to design a trial that can have smaller changes as you’re collecting data. Imagine a 3000 patient trial where you have one set of inclusion and exclusion criteria, one set of randomization strategies, but when you hit the thousand patient mark, there’s going to be an interim analysis. And based upon that analysis, if we’re seeing a great signal that this patient population is responding and that there’s great safety in, for example, renal parameters, then by prior design, the I/E criteria loosens around the renal parameters and perhaps, in fact, the randomization strategy adjusts into the patient population that is responding the most favorably. That’s what adaptive trial design is. It gives you the ability to make small adaptations as you’re getting smarter as opposed to large swaths of data. You do an entire Phase 2, you do an entire Phase 3. Adaptive trial design would again help us get more diverse patient populations because as we’re showing safety, we can loosen I/E criteria.
Randomization or Recruitment Strategies
We have to get better than simply looking at our patient practices for potential participants in research trials. The FDA guidance document that came out talked about beginning to market into areas where diverse patient populations are, selectively market into, and they mentioned houses of worship, barbershops, beauty salons, community centers, and selectively recruit so that we are making an active effort to improve the diversity, the true diversity, of the patients going into our research trials.
A Medical and Ethical Obligation
We frankly need to do all of these things. So think about diversity differently in your research trials. Diverse patient populations mean genetic diversity, socioeconomic diversity, dietary diversity, diversity in what the patients look like, all of their diagnoses, all of the medications that they’re on. Diversity is a really complex thing and three strategies we can use immediately is as an industry, we have to get smarter about I/E criteria, we have to accept adaptive trial designs to allow us to get smarter faster, and we have to begin to recruit into diverse patient populations so that we are taking an active role in improving the diversity. Why? Because we have a medical and an ethical obligation to do so.
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