Apr 6, 2022·edited Apr 6, 2022

You know what would go a long way towards answering a lot of these questions, like long covid and more? If everyone's medical records were kept in longitudinal consolidated databases, that can be aggregated, searched with algorithms to spot trends and correlations, etc.

Why don't we have that? In significant part because of overblown privacy fears that get the cost-benefit analysis wrong, loading up the cost side with vague, theoretical, hypothetical fears and dismissing likely concrete benefits.

The government is too hobbled and bureaucratic to get it done, though the recent interoperability rules for medical records are a big step towards making it possible for private companies to do it. Since the government can't/won't do this itself, it should get out of the way and focus on removing barriers and helping private companies do it responsibly, such insurance companies and vertically integrated IDNs. There's an enormous public health payoff if this can get done.

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Apr 6, 2022·edited Apr 6, 2022

In the beginning of the pandemic, NIH issued a few NOSIs (Notice of Special Interest) for proposals on broad questions of SARS-CoV-2, including molecular biology and etiology. These dried up within a couple of months, even before their expiration as the small amount of money allocated was already spent. Now the only NOSIs are around downstream effects of COVID, messaging to underserved populations, and the like - nothing on biology or new treatments: https://grants.nih.gov/grants/guide/COVID-Related.cfm#active

In 2020, I submitted an R21 (two-year grant for exploratory research - $275k) to NIH on one of the SARS-CoV-2 proteins, for which we had a couple of publications already. It wasn't funded with the feedback being "there's already too many people working on this". Totally fair on the merits, but you might have thought in the first year of the pandemic that NIH would have wanted more people turning their research to SARS-CoV-2.

Talking to others, mine was a common experience. A collaborator had already developed a promising small-molecule inhibitor that not only worked in vitro against the virus, it even worked in a small humanized mice trial. They submitted an R01 (typical 5-year NIH research grant - ~$2m) proposal, which was not funded with typical stock criticisms.

Now, I don't want this to come off as a "woe is me" post; this isn't to say that my or my collaborator's proposals should have been funded no questions asked! But it's not just us. Having been on the other side of the equation, reviewing proposals for NIH in the last year, I can say there was no special attention paid to COVID-related proposals (if anything, it was more like an eye-roll at yet another one).

Maybe this is kind of self-serving, but it seems a bit tragic to me that after spending trillions of dollars to manage and mitigate the effects of COVID, we can't shake loose even a few billion for basic research.

Addendum: I have defended NIH before as the best way to decide what projects should be funded, and I still contend it's significantly better than the private grants that a lot of people are fond of. My complaint is that the high-level decision makers (e.g., Congress) didn't really prioritize SARS-CoV-2 research.

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"the government agencies whose job is to hand out the grants are so ossified that it’s hard to wish they had billions more to play with"

FWIW this seems to be true across the agencies, not restricted to the healthcare related shops. You've written a lot about the need for the agencies to be more pragmatic and nimble, less process- and precedent-bound. I would very much love to see a post on how they could fix this, on a practical level.

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Apr 6, 2022·edited Apr 6, 2022

Pharma scientist here, who bridges R&D and CMC functions.

In addition to insisting upon a proven benefit for any drug product or treatment, the FDA is all about investigating and controlling risk. This is good.

Test: 1) Think about all the times the FDA got it right. 2) Now think about all the times the FDA missed something.

You probably scratched your head the first time I asked you to think, and you could come up with some examples for the second time, all of which make you skeptical about “big pharma” and the utility of the regulations in place to protect consumers.

What’s going to happen if the FDA misses something, and a drug product that is not efficacious, or a drug product that is unsafe, reaches the market? The FDA will require more proof of safety or efficacy in the future. The regulatory burden increases, the complexity of the studies needed to show safety and efficacy increases, the cost increases. More risks to patients might be caught before the product rolls out (that is good!) but now we have built a very slow and expensive apparatus for making sure we catch those risks in advance. Many incentives push toward MORE complexity, more testing, and slower rollout.

I’m not sure how to undo that, or if we should try. I like the idea of taking compounds that are proven safe and testing their efficacy for other indications — you could lop off a whole host of safety requirements with such an investigation. Agree with Matt Y that the government would be the ideal funder of such studies.

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I'm retired from the biopharma industry and put out a daily newsletter on COVID during most of 2020, stopping when the first vaccines were authorized for experimental use late in the year. I was equally frustrated by the slow pace at NIH and they should have done more to harness the vast clinical trial networks in the US. Most of the early intervention trials were quickly designed and up and running in the UK (first to show the benefits of steroid treatment). NIH had experience in both the HIV/AIDs and cancer areas where they set up large multi-center networks some of which are still up and running (I wrote up a white paper on how this could be adapted to COVID research). This has to go down as a failure even though there are NIH efforts that are ongoing right now.

Observational trials are also incredibly useful. I was part of the industry group that developed and funded an exploratory approach to the use of observational data from medical records to look at both drug safety and efficacy. We involved FDA in the planning of this and, not wanting to get into all the gory details, it successfully morphed into a large multi-national group. The Observational Health Data Sciences and Informatics (or OHDSI, pronounced "Odyssey") program is a multi-stakeholder, interdisciplinary collaborative to bring out the value of health data through large-scale analytics. They mobilized quite early in the pandemic and set up an number of good research protocols to look at a variety of interventions. As commentator Allan Thoen notes below, these kinds of research protocols can be useful in ongoing work.

I don't know whether one can put up web links in the comments section. there is a very good YouTube video up on the TOGETHER Trial by 'Biotech and Bioinformatics with Prof Greg' Google will be your friend if you want to watch it. It's a good description of new trial designs. Such designs are being used by industry and Matt should have been more clear on this.

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As someone who has done clinical research, there really is a huge burden on individual scientists. We have to secure funding, develop protocols, get it all through IRB, do enrollment, write and submit to journals in hopes of being accepted for publication, etc. Just tons of veto points. Industry-sponsored research is easier because the company helps do much of this stuff even if the only direct financial support is in-kind (i.e., not making you pay for their trial product). I think we have over learned the ethical failures of past research by creating a vetocracy that's creating its own potential harm. (Sound familiar?)

There really should be projects that are "nationally approved" so that individual clinicians don't have to deal with the local administrative barriers. Just need to have a patient sign a premade consent form, the doc follows the protocol, and data is directly accessed by the central agency (or delegated research team) via the EMR.

Most patients are treated without being OFFERED to participate in research, much less a prospective study, so enrollment takes much longer or we just end up with a bunch of underpowered pilot studies that never develop further. I want to actually participate in more research but it's just too hard to get off the ground, especially since it may not even be publishable and our clinical load is perpetually at burnout levels.

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I’ve spent 20 years working on how to get medical evidence into practice faster and I think you are understating the impact of the Republican party’s decision to adopt anti-science/anti-public health as a core principle. Before 2009, this was something that could be openly discussed. Now it’s confined to the Democratic Party and is seen as too wonky and risky to spend a lot of political capital on. If Democrats had enough power to push through multiple objectives, I think we could do something about the ossification fairly quickly. But not as long as every attempt at public health is blocked and turned into an attack by Republicans.

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Probably a third of the discussions that take place here boil down to “state capacity is important and it’s near-impossible to cultivate when one side refuses to.”

Sucks, but there’s nothing to be done about it at the federal level. Get back to me when MN, CO, or VA is willing to do some trailblazing.

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One of the things that makes long Covid so difficult to study right now is that we don’t really have a good case definition which makes it difficult to recruit patients. There was one good quality study that found that the only symptom that was more common in people who had had the virus vs those who had not was loss of smell. That study was probably not large enough to detect rarer syndromes like the post viral syndromes we have with other viruses an almost certainly occur with this virus. Still, it suggests that the estimates that 10% of Covid cases lead to long Covid are a massive overestimate. I’d say that’s actually a good thing.

One of the problems with a lack of high-quality science is that low quality science ends up being used when estimating the incidence of stuff like long Covid. Some of the studies with high estimates of long Covid don’t have a control group, which is really important because the pandemic had massively disrupted the lives of everyone and that will affect everyone’s health status. Others do not confirm that the people in the study have actual evidence of Covid infection (positive pcr test, antibodies, T cell response) in order for them to be included in the long Covid group. And the NIH should be demanding that the science it funds is high quality because otherwise we waste time on stuff that has little chance of working.

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Apr 6, 2022·edited Apr 6, 2022

I am 100% on board with the sentiment that the clinical trial could and should have been done faster and it is a tragedy that more hasn't been done.

I think there are a few extra facts that might add some nuance to the situation:

1) The NIH did in fact have around 6 (non-vaccine) platform trials as part of its ACTIV trial research program (and associated ACTT trials). But they are largely too small and too slow.

The best known output of this is in the ACTIV-2 trial (outpatients) which by itself tested around half a dozen monoclonal antibodies under a common protocol so that results could be compared and the trials could be supported by NIH.

The biggest disappointment is the ACTIV-1 trial (hospitalised patients). Basically all the hospitalised patient recommendations come from the UK RECOVERY trial which has randomised ~44,000 patients and figured out dexamethosone helped by mid-2020. ACTIV-1 has (I think?) randomised around 3,000 which may be quite underpowered to detect small but important impacts on mortality.

Most hope is for the ACTIV-6 trial, which is the US govt trying out a structure like the ones you've promoted here. Started way too late, but they actually have 2 different doses of ivermectin (probably won't work but good to really put a nail in this coffin) and also fluticasone and fluvoxamine (much better chance of working and are cheap).


2) The PANORAMIC trial in the UK may be the fasting enrolling therapeutic trial in recent history and has a jaw-dropping ~22,000 patients randomised to Merck's antiviral (molnupiravir) and has done this over the past 4-5 months. This is already around 10 times the size of Merck's original controversial trial! It could give a much cleaner answer than the original trial did. Interestingly, the trial protocol includes a pre-specified 'economic analysis' as well to basically figure out if giving these antivirals to less at risk (50s and vaccinated) people is worth it to the NHS.


Our ability to reduce mortality is hugely hampered by the slow recruitment of these trials and I hope someone who can do something about it reads your piece and acts.

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A few notes here:

The fact that the NIH has done poorly with their Long COVID study is depressing but unsurprising. Government institutions serve a particular function well, but speed is not their focus (unlike pharma/biotech where every single day a drug is not on the market is costing them money and have vast experience with setting up and running clinical trials). This, unfortunately, is a problem without a simple solution. Who stands to benefit with Long COVID research? We all do, but not one particular company, so there's no profit motive to go fast.

Related to this is how the vaccines were actually developed -- there was a clear need for something to be developed quickly, so hundreds of companies started working on it. Most of them failed! But they were willing to devote the resources to doing so *because of the profit motive at the other end.* Albert Bourla (CEO of Pfizer) received a ton of praise for refusing the government's money to develop their vaccine... but he knew that the payoff would be huge on the other end so it was a worthwhile investment. Pre-pandemic, many companies had small teams (if any) working on things like novel coronavirus drugs/antivirals. A lot of them simply decided it wasn't worth it since there was no guarantee of a buyer on the back end. The system worked because governments were (rightly) willing to pay for the drugs if they were successful.

I strongly recommend this writeup of Pfizer's discovery and development of Paxlovid, which gets to this very point: https://cen.acs.org/pharmaceuticals/drug-discovery/How-Pfizer-scientists-transformed-an-old-drug-lead-into-a-COVID-19-antiviral/100/i3

"What’s more, Pfizer already had a lead in hand. In 2003, researchers at the company developed an antiviral, known as PF-00835231, that could block the main protease of a coronavirus that emerged in 2002 and causes severe acute respiratory syndrome (SARS). But by the time they were ready to test it in patients, the SARS outbreak had been contained. PF-00835231 is structurally similar to a peptide that binds within SARS’s main protease. That binding site in SARS is identical to the one in SARS-CoV-2, so Pfizer researchers thought the molecule could work against the new virus. Tests showed they were right."

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Stuff like this makes me grateful for billionaire philanthropy, and pushes me towards libertarianism. Especially depressing: no other government in the world funds these studies either. Why are all governments broken in the same way? (I am genuinely confused)

Maybe it's not good that the government does all the science funding. It would be an interesting experiment to have some private entities allocate some of the grant money and see what they do differently (e.g. from what I hear, https://fastgrants.org/ has done a good job with money from private philanthropy).

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Or… hear me out:

There was never any good reason to expect ivermectin to have any impact on Covid and it seemed wrong from the start so a trial investigating its efficacy was a waste of time and money. Same with hydroxychloroquine, lopinavir, etc.

There was no clear mechanism of action, no clear theory of why these drugs would be effective, and the people promoting these drugs to the public were scammers and quacks (and ended up running online businesses to prescribe and sell these cheap genetics at huge markups).

Fluvoxamine is a notable exception. Or is it? The suggestion came not from delicensed physicians and podcasters on Facebook and Twitter but from researchers already investigating the drug’s other uses and had plausible mechanisms of action, namely the anti-inflammatory effects through serotonin transporter inhibition and the sigma-1 receptor agonist effects blocking COVID’s use of those receptors. And, indeed, other SSRIs seem to hold similar benefits because they function similarly although research is ongoing.

Do we need a clinical trial (even a fast one) every time someone suggests anything? Are there not ways to evaluate the quality and possible efficacy of a suggested treatment before engaging in the scientific process? Or will we need human challenge trials to prove injecting people with bleach is ineffective?

These alternative treatments were never about finding a better treatment for Covid. They were about ideology and they were about a few opportunists making a quick buck off a desperate and fearful population.

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Regarding the footnote about the FDA requiring proof of efficacy... part of the reason for this is that FDA approvals are based on a relative assessment of benefits (efficacy) vs. harms (safety).

Safety is not a simple binary where all FDA-approved products are proven "safe." The FDA has signed off on the safety of, say, the OTC allergy medications (Claritin, Zyrtec, etc.) and also of cytotoxic chemotherapies. In an absolute sense, the former are obviously MUCH safer than the latter, and, indeed, in most medical settings outside of cancer, cytotoxic chemotherapies would be considered unsafe.

I don't think the idea that the FDA should switch to "safety-only" regulation is crazy, but it would be complicated. Maybe the FDA would need to rate safety on a sliding scale with 1 being "safe enough to market as an OTC allergey med" and 10 being "unsafe in most contexts buy accepable as a cytotoxic chemotherapy."

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Can I just second the sense of the despair about institutions and politics?

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Apr 6, 2022·edited Apr 6, 2022

Bioethicist are to important medical research what environmentalists/housing advocates are to new home construction? They are so caught up in their own bull$hit that they end up doing more harm than good?

And while there’s most certainly a need for them they need less power and less control of policy.

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