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Lisa McCorkell

Nature named Lisa McCorkell one of the top ten difference makers in science in 2022.

The NIH’s RECOVER Initiative is in a strange place. It’s gone through most of its $1.15 billion nest egg without producing anything of note and its critics abound.

It does have its supporters. Steven Deek at UCSF called RECOVER “a great success“, and other researchers at the 2023 Keystone Conference on long COVID sang its praises. Plus, it should be noted that NIH was forced to do something unprecedented with RECOVER when it tried to birth a new field of exploration almost overnight. That can’t have been easy and it invariably meant that a lot of people who knew nothing about post-infectious illnesses and neglected conditions like dysautonomia would end up in leadership positions.

Plus, studies are not produced overnight – even in the best of times, they take quite a bit of time to finish and get published. The ‘give RECOVER another year to show its chops’ theme, though, is starting to get a little old.

Without the 500 million dollar infusion RECOVER recently got from the Biden administration, RECOVER appears to have faced the almost unthinkable possibility of shutting its 80 clinical sites and research efforts.

Given how much the long-COVID and the ME/CFS and other post-infectious disease communities have been relying on the RECOVER Initiative to provide answers, I was eager to get Lisa McCorkell’s take on what’s going on over there.

THE GIST

  • Main Takeaway – In its current iteration, the $1.15 billion RECOVER Initiative is not going to solve – or even come close to solving – long COVID.
  • The NIH’s RECOVER Initiative is in a strange place. It’s gone through most of its $1.15 billion nest egg without producing anything significant of note and its critics abound. While it does have its supporters, without the 500 million dollar infusion RECOVER recently got, RECOVER appears to have faced the almost unthinkable possibility of shutting its 80 clinical sites and research efforts.
  • Given how much the long-COVID and the ME/CFS and other post-infectious disease communities have been relying on the RECOVER Initiative to provide answers, I was eager to get Lisa McCorkell’s take on what’s going on over there.
  • Lisa co-founded the Patient-Led Research Collaborative (PLRC) and sits on several RECOVER committees. The Nature journal named Lisa one of the top ten people who shaped science in 2022.
  • I asked Lisa what she thought RECOVER’s strengths and weaknesses were.
  • Sshe felt RECOVER’s strengths included its small extramural research effort, a fairly good job at enrollment, and having a long-term observational study. RECOVER’s weaknesses included putting so many of its resources into the observational study, not prioritizing what patients want to see in the clinical trials, and few, if any, resources devoted to hypothesis testing (other than the $40 million outlay in the beginning).
  • I thought the RECOVER Initiative’s highest priority task would have been to create multiple biomarker-based research and clinical criteria for long COVID. Thus far, large pharmaceutical companies have mostly sat long COVID out, in part because they don’t have the good criteria they need to run their hugely expensive clinical trials. One could argue that the lack of a biomarker is the single greatest factor keeping long COVID from moving forward. So I asked her about that.
  • Lisa said, “the way RECOVER was initially designed will probably not allow it to uncover abnormalities that could be used as a biomarker”. Whoa! A look at RECOVER’s protocols for its observational study indicated that she was right. RECOVER is spending most of its money on assessing factors that aren’t relevant to the biggest long-COVID subset – the ME/CFS-like subset.
  • Except for a small amount of funding (@3%) RECOVER devoted to outside studies 2 1/2 years ago, RECOVER doesn’t appear to be doing the in-depth pathophysiological research needed to find biomarkers.
  • Over time, RECOVER should be winnowing down and adding to its testing protocols as it learns what’s relevant and what’s not. Yet two and half years later, the testing protocols have remained set in stone. It seems inevitable that a great deal of funding will go to producing negative results.
  • RECOVER also doesn’t appear interested in taking advantage of the rapid advances occurring in long-COVID research. It could be providing yearly funding opportunities, but it hasn’t funded any outside studies in the past 2 ½ years – it’s way behind the 8-ball there as well.
  • Given what we know, it appears that RECOVER was always going to need much more money and time to fulfill its goals. A big question, though, is why, given the inability of the biggest long-COVID research effort on the planet to produce anything significant, anyone would want to give it more money.
  • I had to ask a terrible question given how much hope had been invested in RECOVER, not just for long COVID but for diseases like ME/CFS. “Should RECOVER continue? Lisa – said she hoped it would – that there is value in continuing the observational research, but that she felt there needs to be changes. She was happy to see RECOVER get its recent $515 million lifeline but felt more patient involvement was needed in choosing the clinical trials, and that RECOVER should be engaged in more high risk-high reward research – and more pathobiology studies.
  • Then came an incredible assertion given the RECOVER Initiative’s largesse: In its current state, she does not believe that RECOVER is going to lead to the solution for long COVID.
  • With RECOVER soon to chew through its billion-dollar-plus wad without producing anything significant, some hard questions surely need to be asked. The office the Biden administration created almost a year ago (The Office of Long COVID Research and Practice) which has oversight authority on RECOVER and other programs, appears to be a paper tiger. Its website doesn’t list the Office’s director, its staff, the kind of oversight it’s doing, its progress reports, or even how to contact it.
  • Citing many issues with long COVID’s long-term prospects (no long-term funding, lack of infrastructure support) and concerned how long the momentum long COVID has will last, in October, Lisa McCorkell and Michael Peluso (UCSF researcher) published an article, “Long COVID research risks losing momentum – we need a moonshot“, in Nature.
  • The Moonshot Initiative asks for a billion dollars a year for ten years in funding from the NIH. Note that NIH spent 3.3 billion dollars this year on a disease (HIV/AIDS) that has effective treatments and afflicts about a third as many people as long COVID. The increase in funding the Office of AIDS Research at the NIH ($659 million) requested for next year is significantly more than the federal government is spending on long COVID this year.

 

The Lisa McCorkell Interview

(Lisa’s answers are in italics. Everything else is by me.)

“In its current state, I do not believe that RECOVER is going to lead to the solution for long COVID.” Lisa McCorkell

A person with long COVID, Lisa co-founded the Patient-Led Research Collaborative (PLRC). A patient representative who sits on the study design committee and a publication subcommittee, and has been a co-author of a few of RECOVER’s papers, Lisa has some insights into what’s going on in this immense initiative. Nature named Lisa one of the top ten people who shaped science in 2022.

Strengths

The RECOVER Initiative’s strengths – observational trial, small amount of pathobiological funding; weaknesses – pretty much everything else (clinical trials, pathophysiology).

RECOVER’s Strengths and Weaknesses

I asked Lisa what she thought RECOVER’s weaknesses and strengths were.

  • Strengths: She thought RECOVER’s strengths included its pathobiology studies and the extramural research RECOVER has funded. RECOVER has also done a fairly good job at enrollment. It was also a good idea to have a long-term observational study.
  • Weaknesses: RECOVER’s weaknesses included putting so many of its resources into the observational study, not prioritizing what patients want to see in the clinical trials, and few, if any, resources devoted to hypothesis testing (other than the $40 million outlay in the beginning).

Research and Clinical Criteria (???)

I would have thought that RECOVER’s highest priority task would have been to create multiple biomarker-based research and clinical criteria for long COVID. Thus far, large pharmaceutical companies have mostly sat long COVID out, in part because they don’t have the good criteria they need to run their hugely expensive clinical trials. One could argue that the lack of a biomarker is the single greatest factor keeping long COVID from moving forward. I hadn’t seen anything from RECOVER on this critical task, though, and I asked Lisa about it.

Lisa said the National Academy of Sciences has been tasked with creating a “working definition” for long COVID for the US government. Lisa noted that RECOVER did take preliminary stab at identifying subsets that was published in the Journal of the American Medical Association.

A 2022 working definition that was developed emphasized that long-COVID contains different entities, each with different biological causes. Since then, two workshops and a questionnaire have been completed by various stakeholders. Three-quarters of the respondents (and 9 out of 10 patients, patient organizations, and/or caregivers) agreed that the definition should include “severe impacts on normal daily activities”. At some point (date undetermined), the Committee will produce a letter report that includes new definitions for long COVID.

THE RECOVER Study – That study assessed almost 10,000 people. Using only symptoms, it plucked out 3 ME/CFS-like subsets and one non-ME/CFS-like subset. Note how PEM and fatigue predominate in the ME/CFS-like subsets, which were broken down into brain-fogged and gut/dysautonomia subsets – which would likely be found in ME/CFS as well.

  • Non-ME/CFS – loss of or change in smell or taste (100%)
  • ME/CFS – fatigue/PEM – PEM (99%) and fatigue (84%)
  • ME/CFS – Brain fog – brain fog (100%), PEM (99%), and fatigue (94%)
  • ME/CFS – gut/dysautonomia – fatigue (94%), PEM (94%), dizziness (94%), brain fog (94%), GI (88%), and palpitations (86%).

This was a nice start and showed what RECOVER, with its large sample sizes, can produce, but we’re still stuck on symptom-based subsets and biological biomarkers are needed. It wasn’t until biological biomarkers were found in HIV that treatments showed up in spades.

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A Long-COVID Biomarker?

“… a biomarker, which is something we really need in the clinic to confirm diagnosis, provide an objective way to follow patients under treatment, and help develop effective treatments.” Eric Topol on long COVID

A biomarker that would galvanize the field and rapidly propel it forward would be, one would think, where RECOVER, with its immense resources and huge sample set, should shine – and perhaps one day it will – but not now. I asked Lisa why RECOVER hasn’t given us a biological biomarker yet.

Lisa said that the way RECOVER was initially designed will probably not allow it to uncover abnormalities that could be used as a biomarker.

That was a stunner.  A look at the adult observational study protocols RECOVER’s spending the vast bulk of its funding on, though, suggests that unless something is going on we don’t know about, Lisa was right. The biggest long-COVID initiative isn’t even close to producing what is long COVID’s perhaps greatest need.

The latest observational study protocols (June 2023) suggest that if long COVID is like ME/CFS – and studies suggest that around half of long-COVID patients have something very similar to ME/CFS – the observational studies may simply be reinventing the wheel – and only a small portion of it, at that.

Old bicycle

With regard to the ME/CFS-like subset, RECOVER appears to be reinventing the wheel – and not very much of it. (Image from Wikimedia Commons – Library of Congress)

Of the dozens of tests done, only perhaps the (limited) coagulation tests, the skin and muscle biopsies, the tilt table, gastric emptying, the CPET, an MRI, and lastly – the invasive exercise test which was added last year – appear to pertain to the ME/CFS-like group of long-COVID patients. The blood tests – our best chance to find a biomarker – seem likely to be completely unrevealing. The fact that so few ME/CFS relevant tests were included suggests that ME/CFS findings didn’t heavily inform RECOVER’s protocols.

Over time, as RECOVER understands what’s useful and what isn’t, it should be both winnowing down and adding to its testing protocols. One would hope it would know by now, for instance, what tests not to give its ME/CFS subset, yet two and half years later, the testing protocols have remained set in stone. The addition of the invasive exercise test in June of last year – as welcome as that is – is the only substantial change in RECOVER’s testing protocols that I could find. It seems inevitable that a great deal of funding will go to producing negative results.

It appears that RECOVER, in its current iteration, was never intended to dig deep into the pathophysiology of long COVID. While it did pour $37 million into outside pathophysiological studies, it’s rather damning that Lisa picked out this small slice of its funding (3.2%) for praise. One wonders how much we would know about long COVID, if instead of pouring $40 million into its pathophysiological studies, RECOVER had put $200 million into them?

RECOVER also doesn’t appear interested in taking advantage of the rapid advances occurring in long-COVID research. It could be providing yearly funding opportunities, but it hasn’t funded any outside studies in the past 2 ½ years – it’s way behind the 8-ball there as well.

RECOVER’s big ace in the hole is the massive blood, urine, and tissue samples it’s been collecting that could feed research into long-COVID pathophysiology for years. That will, of course, require RECOVER funding deep pathophysiological studies – something the Initiative has shown little interest in doing.

No one knows exactly what’s going on with RECOVER – and it would be very, very nice to be wrong about it – but one wonders if RECOVER’s creators expected it to be where it is now. One must conclude they probably did. Maybe their timeline was off a bit, but once RECOVER decided it would spend a very small amount of funding on pathophysiological studies, and the bulk of its money on huge but quite limited observational studies we were always going to end up here; RECOVER was always going to need much more money and time to fulfill its goals.

Maybe that was the plan. The problem is that RECOVER doesn’t look right now like it deserves that money. It appears to lack creativity and flexibility, and perhaps worst of all, it doesn’t appear to have paid much attention to the easiest part – getting up to date on the other post-infectious diseases. It looks more like the conservative NIH that people have complained about for years than a dynamic initiative that’s up to taking on long COVID.

Time will tell. Hopefully, RECOVER will surprise us yet.

A Terrible Question

Terrible question

It was a terrible question to ask: “Should RECOVER even continue?”

I asked Lisa a terrible question that I never thought I would ask. As an ME/CFS/FM patient who’d counted on RECOVER to blaze a path forward for my disease, this question came hard. I asked if she believed RECOVER should continue?

Lisa – said she hoped it would – that there is value in continuing the observational research but that she felt there needs to be changes. She was happy to see RECOVER get its recent $515 million lifeline but felt more patient involvement was needed in choosing the clinical trials, and that RECOVER should be engaged in more high risk-high reward research – and more pathobiology studies. In its current state, she does not believe that RECOVER is going to lead to the solution for long COVID.

That’s a pretty damning indictment of a long-COVID research effort that is magnitudes larger than any other. RECOVER’s conservative clinical trials were, with a few exceptions, disappointing and, at times, even a bit bizarre. RECOVER poured a ton of money into low-hanging fruit like cognitive retraining, a behavioral sleep (hypersomnia?) trial, and exercise.

With a minimum of funding, RECOVER could have designed a series of experimental trials that probed drug effectiveness and long-COVID pathophysiology. That’s the exciting, innovative approach one would have hoped RECOVER would have chosen. The answer to why RECOVER hasn’t chosen this pathway might tell us much about why RECOVER is where it is right now.

Oversight? What Oversight?

With RECOVER soon to chew through its billion-dollar-plus wad without producing anything significant, some hard questions surely need to be asked. It doesn’t appear that they are, however. In June 2023 (after quite a delay), the Biden administration created “The Office of Long COVID Research and Practice” which has oversight authority on RECOVER and other programs.

Eight months later, the office’s website consists of links to a bunch of federal reports – none produced by the Office or which have anything to do with it. Neither the Office’s director, its staff, the kind of oversight it’s doing, its progress reports, or even how to contact it have been produced. I had to find out who the Director was (Rachel Levine) using AI Copilot (lol). Secretary of Health and Human Services Xavier Becerra stated that the creation of the Office “solidifies this issue [of Long COVID] as an ongoing priority” of the Biden administration. Right now, it looks more like a paper tiger than anything else.

I’ve been told that the NIH doesn’t care what people outside the Institute think, but I wonder. It’s beholden to Congress for funding and it’s not the only game in town. Complaints about the NIH’s stodginess led to the creation of the Advanced Research Projects Agency for Health (ARPA-H), and other possibilities for long-COVID research (Congressionally Directed Research Funds – Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA) have been discussed).

The RECOVER Initiative was the NIH’s opportunity to show it could rise to the occasion and creatively and effectively deal with a new disease. While the full RECOVER story has not been written it’s not looking good right now. Let’s hope for better news over the next year.

The Moonshot

MOONSHOT

The Long COVID Moonshot aims to provide a billion dollars a year for long COVID and other post-infectious diseases.

We were hoping that RECOVER, with its big bankroll, would light the way for long COVID and other post-infectious diseases. With those hopes fading, advocacy becomes ever more important. Advocacy is particularly critical given long COVID’s uniquely vulnerable situation. As a new disease, it doesn’t have the institutional infrastructure that will enable it to thrive. Absent effective advocacy that helps to build that infrastructure, long COVID risks slowly fading.

Concerned that the momentum long COVID has will not hold, last October, Lisa McCorkell and Michael Peluso (UCSF researcher) published an article, “Long COVID research risks losing momentum – we need a moonshot“, in Nature.

They presented long COVID as the best chance for researchers to “understand, and find treatments for, a chronic illness associated with an infectious disease”. They cited the uncoordinated nature of long-COVID research, the few clinical trials underway, the absence of long-term funding opportunities, and the desire among many to move on from anything COVID-related as reasons to be concerned about the long-term viability of the field.

Noting that long COVID is expected to cost the US economy over 3 trillion dollars over the next 5 years, that up to 2.5 million people in the U.S., and 24 million globally have ME/CFS, and up to 1.9 million people in the U.S. may have had post-treatment Lyme disease, they called for a long-COVID moonshot – a ten-year commitment from the US government to invest at least US$1 billion a year in long COVID and post-infectious disease research.

They also called for the creation of an NIH Office for Infection-Associated Chronic Conditions Research to coordinate research, establish research agendas, and have budgetary authority to fund work on all of these illnesses. (The Solve ME/CFS Initiative is involved in the creation of the NIH Office.)

A billion dollars a year may seem like a lot of money, but consider this: the NIH spent 3.3 billion dollars on a disease (HIV/AIDS) that has effective treatments and afflicts about a third as many people as long COVID. The Office of AIDS Research at the NIH requested a 20% increase in funding for HIV/AIDS this year. That requested increase alone ($659 million) is significantly more than the federal government is spending on long COVID this year.

Let no one think the NIH doesn’t have the money to fund a long-COVID moonshot. Whether it has the will or desire to do so is another matter.

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