Elie Hassenfeld: [00:00:00] Hey everyone, this is Elie Hassenfeld, GiveWell's co-founder and CEO. Today we're going to talk about a randomized control trial for preventative malaria medication that we're supporting in Malawi. I think this is a really interesting case study of GiveWell's grantmaking for a few reasons. First and foremost, it is helping us make progress on one of our biggest goals, which is doing work that can put us in a position to allocate funds more cost-effectively in the future.

We've supported preventative malaria medication for a long time, directing more than a hundred million dollars in total over the last two years. That's mostly been in West Africa. This trial is looking at East Africa, and it could open up a significant amount of additional cost-effective room for more funding for us to support. And so it's enabling us to be in a position to do better work in the [00:01:00] future.

We're gonna get pretty into the weeds in this conversation, but it is a really good illustration of the way that GiveWell's research process works. How we think through a potential grant decision, how we think about the case for a grant, the potential case against the grant, how we think about cost-effectiveness, and how we importantly combine quantification with subjective qualitative judgment to make good decisions in our grantmaking.

I'm really excited about this grant because I think it is an area where GiveWell is filling a major gap that exists in the malaria space. There is a lot of money going to malaria, but notwithstanding that, there are still research needs like this one, a large randomized control trial for preventative medication in Malawi, in East Africa, that's falling through the cracks and other funders are, you know, for one reason or another, not supporting. And so I'm really glad that [00:02:00] GiveWell is in a position to be able to support this important work because of what it will do for our future grantmaking, and then hopefully also, you know, in addition, build the knowledge base so that other funders, other actors like governments, can use this information to support better malaria programming around the world.

And so, we're gonna talk about that today and really get into it. And so I'm joined today by John Macke, a senior researcher on our malaria team. Hey, John, before we dive in, can you just share a little bit about your background?

John Macke: Yeah, sure. I'm John. I am a senior researcher on our malaria team, where I lead our malaria cross-cutting research function. I've been at GiveWell for a little bit under three years at this point. And on this malaria cross-cutting research team, what we do is we try to answer tricky questions that cut across our malaria research. We also look into funding research, which is something that we're going to talk about today. And we're also interested in sort of new [00:03:00] areas for malaria interventions beyond things like insecticide-treated nets and chemoprevention, which have constituted the bulk of our malaria grantmaking in the past.

Elie Hassenfeld: Can you give an example of a cross-cutting question that comes up, you know, across different malaria grants? I mean, malaria's a huge part of our giving portfolio, and so what are the kinds of questions that you're often asking and trying to answer?

John Macke: Sure. So I guess one thing would be like really basic, how many people are dying or getting infected with malaria each year in a given location?

So obviously that's whatever kind of grants you're going to make, you're going to want to know, how many people are suffering, what's the burden of disease. That would be sort of one cross-cutting question.

Elie Hassenfeld: Great. That's really helpful. So, let's dive in. You know, we're talking about this big randomized control trial focused on seasonal malaria chemoprevention. Why don't you just walk us through to start what it is and why it's important.

John Macke: Yeah, so this trial is called, the short name is the [00:04:00] CHAMP Trial. That's C-H-A-M-P. It's an acronym for CHoice of Anti-Malarial drugs for chemo Prevention. And basically this is an around 7,000-patient trial of different drugs that could be used for seasonal chemoprevention.

Specifically, this trial would be in Malawi, would be in children under the age of five. And you know, there are six different possible combinations of chemoprevention drugs that they could receive. And we'll monitor, you know, based on which drugs they receive, or potentially placebo, how likely it is that they get malaria, that they end up being hospitalized. The goal there is to see what the effects of these different drugs are.

Elie Hassenfeld: We've supported seasonal malaria chemoprevention for a long time. So what question is this trial trying to answer, what's not known that this could teach us?

John Macke: So there's a couple different questions. I guess [00:05:00] one piece of helpful background here, you know, this trial in Malawi that's in southeastern Africa, we think there's a really strong evidence base for seasonal malaria chemoprevention in West Africa. In southern and eastern Africa, it's a bit more complicated. So I have to get a little into the weeds here, but there's sort of three different drugs that we're looking at in this trial, and then combinations of them. One of them is called sulfadoxine-pyrimethamine. Another is amodiaquine, and the third is chloroquine. The short names for those are SP, AQ, and CQ. This drug SP, there's widespread resistance to it in eastern and southern Africa. And that's the most common drug used in seasonal malaria chemoprevention, or most common pair, is to use SP and AQ. We know in West Africa, or we think that SP works pretty well and AQ works likely very well.

In East Africa, [00:06:00] it seems pretty likely that SP doesn't work as well. We have genetic evidence in the malaria parasite that basically it has these mutations that make it unlikely that SP would work as well. But we don't know sort of exactly how well it works. There hasn't been a recent trial of chemoprevention using SP in children. So that's one question is, like, how well does this SP drug work? How well does the combination of SP and AQ work?

Another thing that we're interested in that we'll learn about is the third drug I mentioned, chloroquine, that's not currently used in chemoprevention or treatment. Historically it was used in treatment, but resistance developed, and that was 20 or 30 years ago. Now they haven't been using it. And there's some suggestive evidence that the resistance may have waned. So the other thing we're learning, and on the one hand we're kind of asking, should we be worried that SP or SPAQ doesn't [00:07:00] work? And then on the other hand we're saying with chloroquine, is there a chance that does work and that that does prevent malaria, especially in eastern and southern Africa?

Elie Hassenfeld: We have a program that has strong evidence in West Africa, but in a different region there is some evidence of resistance to the drugs and we don't really know what will work. And so the question is, can we determine an effective drug regimen that would enable us to deliver this very cost-effective program to people who will benefit from it. And, I guess without this evidence, we don't feel like we have good enough reason to support this program—this program meaning some form of preventative malaria medication through some combination of these drugs in southern and eastern Africa.

John Macke: I think that's right. I mean, I think there are limited contexts where we're supporting it right now, but without stronger evidence on these questions, we wouldn't be confident scaling that up.

Elie Hassenfeld: And so talk about that. Like what do we know so far? How does that give us [00:08:00] confidence to support it in some contexts? And why do we need more to go further?

John Macke: So for SPAQ, the main seasonal malaria chemoprevention combination, we have a couple—well, we have many trials in West Africa and a couple trials in eastern or southern Africa, specifically we have them in Uganda and Mozambique.

Those trials didn't test sort of every combination of drugs. They tested SP and AQ together versus a placebo. They generally found relatively strong results. I don't have the numbers off the top of my head, but pretty effective results. There are a couple drawbacks that make us somewhat hesitant to just scale immensely.

One is that there were some attrition issues in the trials, or in at least one of them. So what that means is that we weren't able to follow up with everyone that we initially reached in the trial. I think that makes us worried [00:09:00] that, you know, maybe that we can't fully trust the treatment effect estimate that we got.

The other thing that we don't know from that trial, or from those, is we didn't test SP by itself. Part of the reason you give two drugs, for treatment or prevention, is that it's harder for the parasite to sort of randomly stumble onto resistance to two things at once. And so we don't know what's generating the protective effect. And the reason that's concerning is it could be the case that SP is doing nothing and then this other drug AQ is sort of doing all the work. In the short run, that's kind of fine if it works really well.

The thing that's concerning is that in a lot of countries, AQ is a backup drug that's used for malaria treatment. And if we're giving, effectively, amodiaquine (AQ) sort of monotherapy, the SP isn't really doing anything, we would worry that that would more quickly select for resistance to AQ. That would be bad [00:10:00] because it would reduce our options for malaria treatment and prevention. So that's the other benefit of this, is learning how much SP is contributing helps us understand how concerned we should be about this potential evolutionary pressure we're putting on amodiaquine.

Elie Hassenfeld: Got it. So there's some evidence that demonstrates, suggests, that running this preventative malaria medication program in southern or eastern Africa is effective. There's some issues with the trials via attrition, there's the possibility of, I guess, accelerating resistance more than we would like. How does that then feed into the decision to support the program to some extent?

John Macke: Yeah, I mean, I think it's hard. It's a challenge. I mean, I guess why do you support it at all? Chemoprevention has really huge benefits, right? Like, let's say that, again, I don't remember the exact numbers, but these drugs work really well, maybe say we thought they reduced malaria by 50% in the people who received them.

If that's the case, sort of, [00:11:00] in these countries where there's, yeah, like we're not sure how strong the evidence is, but we think it probably does something, we're a little worried about resistance. You're sort of trading off, like on the one hand, you're probably saving lives right now. It's not that expensive of a drug. The adverse events are not on the same scale as the malaria reduction benefits. You're saving lives right now.

On the other hand, this resistance, it could cause more problems in the future. There could be other ways we could set up the chemoprevention program, like other drugs we could use that would put less pressure on resistance and, sort of, have a lower chance of future harm. So it's a really hard trade off. We spend a lot of time thinking about how to try to quantify this, but I think just like sort of qualitatively that's the big thing. Like we think you can probably save lives with this right now. You're trading that off against all the other things you could do and the potential for long-term [00:12:00] drawbacks.

Elie Hassenfeld: Yeah. So I'm kind of curious how you would describe the past decisions and the decision we're making now about how much to support this program in East and South Africa. Because one framing might be, you know, we've done our best to synthesize all the information that exists and come up with an estimate of the cost-effectiveness of the program in different contexts.

And then, and here's where the fork occurs, we're supporting it in all the places where our quantitative estimate shows that it is sufficiently cost-effective to be above our cost-effectiveness threshold. That's kind of path A, and then path B might be, we are not supporting it in every place where our quantitative estimate says that it is cost-effective because we are capping our support because of these qualitative factors.

We know that there's this major question about increased resistance and you know, we find that very hard to quantify and so therefore we're, you know, essentially like capping support while funding this trial, so we get better information as soon as we can to move forward. I [00:13:00] mean, maybe something else, but those seem like the two different ways to understand the decision making framework you described.

John Macke: Yeah, I think that's right. I guess I would say closer to what you described as option B. We're probably capping it a little bit because we have these qualitative concerns. I don't know, if you open up our spreadsheet, there are lines in the spreadsheet where we say, like, this is how much we're going to haircut our cost-effectiveness because of resistance concerns. This is how much we're going to adjust effectiveness because of these issues with the trials. And so like it's in the spreadsheet, but I think if we took that super literally, my guess is that there are probably other places where we might consider scaling it up, where it looks a little bit above the bar and we're probably pumping the brakes on that because like with this trial, if we learn chloroquine works really well and we're less worried about putting resistance pressure on it because it's never used in treatment. We think sort of [00:14:00] qualitatively it might make more sense to wait two years and scale that, then scale a different set of drugs and then go through all the effort of making a change and convince people to do a new program.

Elie Hassenfeld: Yeah, and I think it's just a really interesting illustration of some of the way that we work, which is we're doing a lot to quantify as much as we can. Like you said, we even have estimates for each of the uncertainties and how much we think they affect the bottom-line cost-effectiveness estimate.

But then I guess we just know that we really have no idea what those—I mean, we do our best to come up with those numbers, but don't really know what they should be. And there is this, I don't know, like subjective judgment that's applied at the end that says like, does this actually make sense? And then I think it sounds reasonable to me. Just trying to reach a compromised position about the prudent way to move ahead in the face of a significant amount of uncertainty.

John Macke: Yeah. I think that's right.

Elie Hassenfeld: So, John, at the beginning of the conversation you mentioned that there are 7,000 children in this trial, and I think it would just be helpful to give some sense of like, is that a lot, is that not a lot? How does that compare to other studies? And how should we think [00:15:00] about the scale of what's happening here?

John Macke: Yeah. So the short answer is, it's a lot. I think this will be the largest individually randomized trial of chemoprevention drugs ever. There are some studies which are called cluster randomized, where maybe you randomize entire villages or districts of an area, and those may have more people in total. But in terms of individually assigning a large group of children to different groups, this is I think the largest trial of chemoprevention drugs ever. You might ask, why such a big trial? And I think there are like a couple benefits we get out of that, that I, yeah, I'm happy to talk about that.

Elie Hassenfeld: And I think in particular, like what are the benefits of the large trial and, to the extent it is part of the same answer, like thinking about the trade off of like smaller versus larger trial where clearly smaller trial is less expensive, so more money to spend on delivery of program rather than research. And so interesting to, if you could share the key benefits of the larger trial and how they are worth the [00:16:00] additional money.

John Macke: Yeah. So I'll start with the benefits,. and then I'll try and kind of give the framework for how I think about the trade off between both doing a trial at all versus just giving people drugs. But also, the size of the trial.

I think the two benefits of doing a really large trial are that there are a couple sort of hard questions that you need a lot of, a high sample size to answer. One is, does this drug SP, does it have even a moderate anti-malarial effect? So we know that there's resistance to the drug. The last two trials of, I think, intermittent preventive treatment in East Africa that I've seen—the last two large ones—found effects that they couldn't statistically distinguish from zero. There was a big margin of error on that. Like it could have had a 30% effect, could have had no effect at all. That's important because SP is like a really cheap drug, really easy to give. If it has even a moderate [00:17:00] anti-malarial effect, it could easily be cost-effective.

By having a large trial, we should have sort of the statistical power to detect if there's, say, even a 15 or 20% effect of SP on malaria. We think that's sort of about the threshold we would want to know if it's likely to be cost effective, and also give us a sense of how concerned to be about this resistance. That's one benefit of the larger trial.

I think the other benefit is for amodiaquine and chloroquine, we should get a sense not only of whether they reduce malaria infections and also hospitalizations with malaria. So, averting deaths in young children is like ultimately the main benefit we think we get from most of our malaria programs. People listening may or may not know this, but death is not a very common outcome and it's not usually something we're able to study and trials. And in fact, usually we're extrapolating measured benefits on malaria infections to say, okay, if it reduces [00:18:00] malaria infections by 50%, our best guess is that it might reduce malaria deaths by 50%.

Elie Hassenfeld: And the basic reason for that, that you said, just to highlight it, is that death is such a rare event that a trial would have to be like absolutely massive to be able to see that effect clearly.
John Macke: Yeah. Especially cause-specific death of malaria.

Elie Hassenfeld: In some sense, it's a major uncertainty that just undergirds the estimates we're making about cost-effectiveness. Because if you're basing it on infections alone, well, if the relationship between infections and death is not what you expect, then you could be getting things very wrong.

John Macke: Yeah, exactly. So like the type of thing you might be concerned about is, possible in theory, I guess, that SMC prevents most cases, but the sort of case that breaks through is like a really bad case.

And you know, this trial, we, I think we are going to measure deaths, but we don't have that much power. It's not a primary outcome. But hospitalizations for malaria are something that'll be a primary [00:19:00] outcome of this study, and we should be able to detect, in general, if, well, one, do we get a reduction in hospitalizations from doing AQ and CQ? And then, two, is that reduction in hospitalizations, you know, broadly similar in magnitude to the reduction in infections? So, having that additional piece of evidence it's helpful to us, you know, in the context of SMC, but I also, I think more broadly.

Elie Hassenfeld: Yeah. I mean, it's really helpful. There's a lot of other questions I could ask about the trial, but I wanna shift gears a bit and focus on how it could influence our work in the future. You talked about the key research questions that we're trying to answer, and those questions could affect other malaria, you know, actors, funders in the malaria space, governments, et cetera.

But, you know, primarily like when we do this, we think about the effect on our own future decision making. And so, yeah, what do you see as the potential outcomes for this study and how they would affect our future work?

John Macke: Yeah, I think there are several. One thing I think we could find out, related to [00:20:00] SP, is like this has basically no effect. We're pretty confident this has no effect.

I think the way that would affect future work, or like our sort of thoughts about the space: one, I think that it would make us less optimistic about doing SP monotherapy really anywhere in eastern and southern Africa. So there are some countries in eastern and southern Africa where they're distributing this SP drug by itself to young children. And it's possible that it has no effect. I think if we found that out, we probably would not fund it, and we probably would want to advocate to other people funding this or policy makers that this might not be the best use of funds. That's one possibility.

On the flip side, we could find out that this works better than we expected, and I think there's something like 50 million children that would be eligible to receive perennial chemoprevention with SP. And that would be something we could consider funding at a high level, and it could be highly cost-effective if it works.

Elie Hassenfeld: Yeah. Do you have any sense of just [00:21:00] like the numbers on that, like if there are 50 million children who could potentially receive this program if it's cost effective—obviously it depends on how effective and formulation which affects costs—but you know, just some ballpark of the kind of additional funding that you could imagine us providing in a world in which this is at, I don't know, different levels of effectiveness.

John Macke: Yeah, yeah. I think very rough ballpark might be like, if say that SP had a, I don't know, a 25% or 30% effect, I think you could probably spend a hundred million dollars a year on it, and then sort of scaling down as you imagine lower levels of effectiveness.

Elie Hassenfeld: Right. And so the basic thought here is that we're spending approximately $7 million on this trial. And then that has the possibility of opening up much, much larger annual funding needs in a very cost-effective area that we could fill.

And then beyond that, there are just these major questions that would affect [00:22:00] GiveWell's funding specifically, but just whether it's good policy to be delivering SP on a regular basis or not. Like this trial could answer that question and in some sense, that's an additional benefit or potential benefit that comes out of doing this work: creating additional knowledge that helps other actors behave more cost-effectively.

John Macke: Yeah, I guess the way I think of it at the sort of highest level is like we're spending around $7 million on this trial. Our bar is let's say around $5,000 per life saved. So we want the outcome of this to be that we sort of on the margin save an additional 1,400 lives because of it. And yeah, maybe that's through us finding, you know, another $25 million in annual seasonal chemoprevention funding that costs $4,000 to save a life instead of $5,000, or maybe it's by influencing these other actors.

Elie Hassenfeld: You know, when we fund direct delivery of programs, the timeline from funding to impact is fairly short because we get money and then eventually the organization uses it to deliver a program and those effects, [00:23:00] for a program like this, accrue very quickly. With a trial, it takes much longer for the trial to take place, to be run, for the results to come in. And then what is the timeframe in this case from, you know, today, we're recording this in January 2026, toward getting results back from the trial and then being able to make decisions based on those results.

John Macke: So the trial should go in the field, I believe December of this year. It'll be in the field for five months. And so by spring 2027, most of the sort of main results data will have been collected. The authors will run some analyses. Maybe three to six months before we get an opening read. So we would hopefully have a read on sort of how this went by the middle to late 2027, and then could start factoring that into grants we would make for seasonal chemoprevention, perennial chemoprevention at that time. I guess then the people would sort of receive the [00:24:00] marginal drugs from the grants we made maybe in late 2028 or going into 2029. So like two or three years, hopefully.

Elie Hassenfeld: You know, one question that all of this begs for me is why isn't anyone else funding this trial? You know, it's like the whole setup is we have these big questions that affect so many different aspects of malaria delivery. Billions of dollars go to malaria programming. You know, why is GiveWell the funder that has to stand up for the $7 million for this trial? Why isn't someone else stepping in, and how do you think about that?

John Macke: First of all, if anyone is listening to this who would like to fund these trials, like I think you should because I think it's a good trial. The sense I've gotten from talking to the PIs on this trial is that maybe it falls in like a little bit of a weird gap. The things they mentioned were like the combination of three things. One, it's a large trial, some funders [00:25:00] just don't have $5 million, $10 million to spend on one trial. Chemoprevention isn't really a novel thing anymore. It's not a new malaria vaccine or it's not a new sort of mosquito killing technology that's never been tried before. So some funders are more interested in things that feel more novel or cutting edge. And then the last thing that I heard is that it's a pretty simple trial. We're going to randomize drugs and give combinations to people to see how well they work. Some funders want to see a more methodologically ambitious thing. So those are the things I've heard from them, and I think that aligns with what I've seen as sort of gaps in the space more generally.

Elie Hassenfeld: Yeah. Well, great. Thanks, John.

John Macke: Thanks, Elie.

Elie Hassenfeld: Hey everyone, it's Elie again. I hope you found that conversation interesting and useful. I think it really illustrates the ways in which GiveWell's work has expanded over the last several years [00:26:00] to new areas.

You know, not only funding the direct delivery of needed programs, but also research into those programs; how we think through the question of what programs and research to support; how to trade off between supporting additional research versus just doing more program delivery; and how this research support that we're providing, we hope, enables us to deliver more funding cost-effectively in the future.

If you wanna help, you can do that via our Top Charities Fund. Among our top charities is Malaria Consortium's seasonal malaria chemoprevention program. That's the program that we were discussing in this conversation. Our Top Charities Fund [00:27:00] supports that program and others that prevent illness and death among young children. If you're interested in supporting a wider range of GiveWell grantmaking, like the research that we discussed in this program, you can do that via our All Grants Fund, which gives us more flexibility in how we respond to the needs that we see around the world.

Thank you again for listening, for supporting GiveWell, and for caring about doing the most good we can together. I really appreciate it.