TOGETHER Trial on Ivermectin: Did the Gates Foundation Fund It?

There have been questions as to the funding of the TOGETHER trial by the Bill and Melinda Gates Foundation. And how could there not be, when in 2020, Ed Mills, the Principal Investigator of the trial, said in an interview that…

The majority of the time I work for a company called Cytel, where I design clinical trials, predominantly for the Bill & Melinda Gates Foundation

Now, to be fair, it is clearly stated in all relevant materials that the Bill and Melinda Gates Foundation (henceforth Gates Foundation) funded the initial run of the TOGETHER trial in 2020. That run produced a spectacularly underpowered Hydroxychloroquine trial that got chalked up as a “negative” trial, though most other “effective” drugs would also have failed in the same setup. We’ve talked about underpowered trials before, so I won’t delve deeper.

While it is not the mark of an unbiased trial to have your main funding source making statements like these for the drug you investigate, while you are investigating it:

Journalist: What about the conversation around hydroxychloroquine, which the White House has promoted despite its repeatedly being shown to be ineffective and, in fact, to cause heart problems in some patients?

Bill Gates: This is an age of science, but sometimes it doesn’t feel that way. In the test tube, hydroxychloroquine looked good. On the other hand, there are lots of good therapeutic drugs coming that are proven to work without the severe side effects.

…at least it was clearly marked that the Gates Foundation indeed funded that stage of the TOGETHER trial.

The 2021 studies

The problem is about the 2021 epoch of the trial, which initially investigated fluvoxamine, metformin, and ivermectin. The Gates Foundation is not mentioned as a funder in the metformin, fluvoxamine and ivermectin publications themselves, nor in the presentation given on August 6, 2021, presenting initial results for those drugs, or in the fluvoxamine preprint. Those outputs name only FastGrants and Rainwater Foundation in their funding statements.

Full disclosure: I have, from time to time, discussed various matters—including the TOGETHER trial—with high-level people at both FastGrants and Rainwater CF. Everything I have seen from them tells me they are led by people who genuinely want to help repurposed generic drugs succeed in the market and have no interest in funding trials to produce negative results. This doesn’t mean they are without their biases, but who is? In the context of the pandemic, however, both of these organizations gave “no strings attached” funding to the TOGETHER trial, leaving the investigators with a free hand in how the trial was run.

Examining the Evidence

The involvement of the Gates Foundation is far less clear. From the McMaster press release published in early February 2021, while the trial was ongoing, the Gates Foundation certainly seems to be in the mix:

The study is funded in part by the Bill and Melinda Gates Foundation and Fastgrants, a collaboration of technology philanthropists.

Also, versions 2 (dated March 25, 2021) and 2.1 (dated May 5, 2021) of the TOGETHER master protocol mention BGMF as a funder, though later versions do not.

The master protocol attached to the TOGETHER metformin publication, as well as a version published in Gates Open Research mentions the Gates Foundation as the main supporter of the trial:

Grant information: The TOGETHER Trial is supported by the Bill and Melinda Gates Foundation [INV-019641]. Overall trial infrastructure is also supported by the Rainwater Foundation, with additional funding support from FastGrants for current evaluations of trial interventions. Future evaluations of interventions may be supported by other funding organizations. The funders have no role in the conduct, interpretation, or dissemination of the study findings

The Mysterious Dr. Rayner

Craig Rayner is the researcher who responded to the original in-vitro ivermectin for COVID-19 publication by Caly et al. to indicate that

Even with most generous assumptions for clinical translation, the in vitro IC50 is > 9-fold and >21-fold higher than the day 3 plasma and lung tissue simulated Cmax respectively, following a high dose ivermectin regimen of 600 μg/kg dose daily for 3 days.

The original authors responded to Rayner, and explained that the mechanism of action they were suggesting did not depend on concentration as much as Rayner implied, but the meme that ivermectin cannot reach antiviral concentrations in humans was born, and we’ve been hearing about it ever since.

It was strange, then, to see Dr. Rayner as an investigator in TOGETHER for ivermectin. If he did not believe the drug could work, why did he participate in a trial that was investigating whether the drug works? The principle of clinical equipoise dictates that trials should be run only when the investigators have genuine doubt as to which course of action is best. Rayner’s position on ivermectin has been consistent throughout the pandemic: It doesn’t work, because it can’t work.

Then we get to the clue that started me going down this rabbit hole: in a correspondence in The Lancet about fluvoxamine and fluoxetine, we see this fascinating little note:

MGD, EBD, FB, CRR are employed by Certara. Certara scientific support into the TOGETHER study was funded by the Bill and Melinda Gates Foundation.

Let’s unpack this: CRR is Craig R. Rayner. In fact, he became the corresponding author of the ivermectin publication in NEJM in February 2022—a few weeks before its publication—replacing principal investigator Ed Mills, who was the original corresponding author, since November 2021. MGD, EBD, FB are Michael G. Dodds, Eileen B. Doyle, and Fran Brown, respectively. All four work for Certara, which has received considerable amounts from the Gates Foundation, to the tune of seven digits:

NEJM Conflicts of Interest Disclosure

When you read the declaration in the ivermectin publication as published in the New England Journal of Medicine, it is consistent with the fluvoxamine and metformin papers:

What if we look into those disclosure forms that the TOGETHER authors submitted to the New England Journal of Medicine?

We see that when it comes to the disclosure by Craig Rayner, for every funding entity he lists, and there are many of them, there is a clear note that the funding is not related to the TOGETHER trial or ivermectin. Every entity, that is, except for… the Bill & Melinda Gates Foundation:

What’s more, while the conflicts list of Ed Mills also mentions the Gates Foundation, it makes clear that that funding was not related to the TOGETHER trial. As such, the implication is abundantly clear, and consistent with the note in the Lancet: the work of Craig Rayner, who is the corresponding author in the ivermectin paper for the TOGETHER trial, was funded by the Bill and Melinda Gates Foundation. In other words, Bill and Melinda Gates Foundation contributed funds towards the ivermectin portion of the TOGETHER trial.

Here he is, one of the two frontmen when the results of the TOGETHER trial on ivermectin were presented to the NIH Pragmatic Trials Collaboratory:

Meanwhile, the trial website does not mention Gates Foundation funding at all:

Then again, using the wayback machine, we can see that until September 13, 2021, Gates Foundation was cited as a funder of the trial:

It really seems that the outputs that are later than the August 2021 generally omit the Gates Foundation, while the ones before then, mention it as a funder. Outputs during the August/September 2021 are mixed. Given that the biggest portion of the trials was before that period, it really seems like there was some Gates money going towards the trial, money that was not clearly declared in the publications, perhaps as a strategic communication choice.

Conclusion

While the trial has gone to significant lengths to present an image of not being funded by the Bill and Melinda Gates Foundation in its 2021 incarnation, the early materials from that period say otherwise. In addition, the most straightforward interpretation of the disclosures by corresponding author Craig Raynor is that funds were contributed towards the trial by the Bill and Melinda Gates Foundation throughout.

If so, we are forced to ask the question of why that fact was obscured in official trial materials, and not properly reported in the various publications that came out of it. As with most scandals, it’s not the crime that is the biggest concern, but the coverup.