In 2021, the National Institutes of Health (NIH) launched its ambitious nearly $2 billion RECOVER Initiative, dedicated to finding the root causes of and possible treatments for Long Covid.
Solve played a critical role in securing the preliminary $1.25 billion in funding for the program, and Solve representatives continue to serve on many advisory, authorship, and oversight committees for RECOVER.
RECOVER has published nearly 80 papers and collected millions of data points with more work still underway, but only recently has responded to public pressure to focus on therapeutics and treatments. The launch of RECOVER-Treating Long COVID (RECOVER – TLC), a new program to develop and initiate additional Long Covid clinical trials, is backed by $500 million to find new ways to treat patients with Long Covid.
In September, the NIH held a three-day workshop at its campus in Bethesda, Maryland, to discuss the path forward for RECOVER-TLC. In this blog series, we’re summarizing the workshop in its entirety.
Read our coverage of Day 1 here.
Read our coverage of Day 2 here.
RECOVER-TLC: DAY 3
The last day of the workshop focused on how RECOVER-TLC plans to move forward. The morning session started with perspectives from agencies (in the US and Europe) that handle regulating and approving clinical trials: the FDA (in the US) and the European Medicines Agency (EMA, in Europe).
What do regulators think about Long Covid clinical trials?
Food and Drug Administration (FDA)
Dr. John Farley, from the Center for Drug Evaluation and Research at the FDA, spoke about how the FDA views and helps Long Covid clinical trials. He explained that the FDA not only makes sure that new drugs work and are safe, but also helps researchers to develop these new drugs. The FDA also helps to decide whether established drugs can be repurposed for Long Covid. The FDA is now actively helping new clinical trials for new and repurposed interventions for Long Covid.
From the FDA’s perspective, clinical trials on Long Covid face unique challenges because many key things the FDA looks for when evaluating drugs are hard to do in Long Covid interventional trials. For example, to approve a drug for a disease, the FDA needs researchers to understand in detail what goes wrong in that disease. But we still have much to learn about the details of what goes wrong in patients with Long Covid. The FDA also wants investigators to be certain that clinical trial participants have the disease in question (or will probably get that disease). But we have no definite way to tell whether someone has Long Covid, or whether they have a disease that looks like Long Covid. The FDA also asks that researchers have solid evidence that an intervention works better than placebo or better than the usual way of treating a disease.
But many Long Covid clinical trials lack placebo treatments. And we have no established way to treat Long Covid, with which to compare new interventions. Finally, the FDA wants researchers to measure clearly and reliably how much interventions improve how patients feel, function, or survive. But we sorely lack biomarkers to measure improvements among patients with Long Covid. For these reasons, clinical trials of Long Covid have special difficulties meeting the FDA criteria for new drugs.
Dr. Farley explained how the FDA thinks we should design future clinical trials to show Long Covid interventions are safe and effective. Primarily, the FDA wants researchers to focus on the things that matter the most to patients—how patients most want to improve.
“It turns out that what is really bothering the patient and what is really bothering the doctor can be radically different things.”
— Dr. Janet Woodcock, Principal Deputy Commissioner, FDA
Researchers must also be able to measure how much interventions improve these things. To measure improvements in things that matter the most to patients, clinical trials should measure patient-reported outcomes to tell how patients are feeling and functioning. Patient-reported outcomes are aspects of patients’ health reported directly by patients, without modification or interpretation by anyone else. In this spirit, the FDA held a public meeting in the spring of 2023 to hear how patients with Long Covid most want to improve; to help the FDA better weigh risks and rewards for new Long Covid interventions; and to help researchers launch patient-approved clinical trials.
Dr. Farley also recommended that early on, observation trials should find the most reliable ways to measure patient-reported outcomes. Once observational trials show the best ways to measure these outcomes, then interventional trials can use these methods to test drugs. What the FDA doesn’t want, he said, was a late-stage interventional clinical trials trying a new, unproved way to measure a patient-reported outcome. By then, it would be too late to tell whether that method worked. He also recommended that smaller clinical trials collaborate to share participants (making more participants available for all small trials) and use funds and resources more effectively.
European Medicines Agency
Dr. Marco Cavaleri then explained how the EMA (the European counterpart of the FDA) regulates new interventions to treat patients with Long Covid. Dr. Cavaleri is head of the Public Health Threats Department and the chair of the Emergency Task Force at the EMA.
Many of the EMA’s responses to Long Covid are like those of the FDA. The EMA helps researchers design and conduct clinical trials to test interventions and to make sure that patients have a say in how new treatments are scored.
Dr. Cavaleri said European clinical trials on Long Covid also struggle with knowing which patients to include, telling whether an intervention is working, and knowing what matters the most to patients (and therefore, what to measure). Dr. Cavaleri emphasized that defining Long Covid was immediately valuable for clinical trials. With a clear definition, we know which patients to include and which to exclude. Here in the US, the definition of Long Covid produced by the National Academies of Sciences Engineering and Medicine has greatly changed how we treat patients and how insurance companies and government agencies allocate money to address this disease, as summarized by Solve.
One unique part of Dr. Cavaleri’s presentation was how the EMA focuses on not only clinical trial data to understand Long Covid, but also real-world data. Real-world data includes data from electronic health records, insurance files, and wearable devices (like Apple watches or Fitbits). These data are usually more heterogeneous than data from clinical trials. But real-world data can uniquely show how interventions help many people in everyday settings, not only patients who meet inclusion and exclusion criteria and are carefully watched in clinics. Another new idea from Dr. Cavaleri was that the EMA wants to develop interventions that treat patients with Long Covid more than interventions that prevent the disease. (In contrast, many clinical trials in the US focus on interventions that prevent Long Covid.)
Panel discussion
Ms. Lisa McCorkell, co-founder of the Patient-Led Research Collaborative, kicked off a panel discussion on what we should do next to launch patient-centered clinical trials of Long Covid. Ms. McCorkell said we should follow in the footsteps of clinical trials that work. Several successful trials were discussed. The ACTIV clinical trial is a model for how to inject a spirit of urgency and collaboration into a study. The HIV/AIDS Clinical Trial Network and the CURE ID initiative are examples of how to deeply engage patients. The RECOVER-TLC clinical trials are also doing great work with their agent submission portal (Box 4).
Ms. McCorkell recommended that RECOVER trials recruit patients and caregivers to review portal submissions. Patients and caregivers should also have a say in how interventions are chosen from these submissions. What a researcher considers a reasonably safe intervention may differ from what a patient considers safe, and patients’ opinions should count more than they currently do.
Ms. McCorkell said we need both small clinical trials that explore new interventions, and large ones that rigorously test leading candidates. We need both trials that validate patient-reported outcomes, and those that search for biomarkers to more fairly measure outcomes. (Here, Ms. McCorkell especially emphasized post-exertional malaise.) We need clinical trials both for new drugs and for repurposed ones. And we need a single-minded agency (perhaps a new NIH office devoted to studying infection-associated chronic conditions) that will fund these trials. This agency could also fund trials for interventions suggested by patients, through the agent submission portal, that are not chosen for moving forward.
Ms. McCorkell said that clinical trial researchers should understand that Long Covid has traumatized many patients. Thus, clinical trials should offer patients results quickly. Researchers should also offer interventions to patients assigned to placebo groups, so these patients also have a chance to benefit from treatments. In short, patients should get something out of taking part in trials—whether it be treatments, knowledge, or financial compensation. This is especially important because patients with Long Covid often join studies at great personal expense. Even if a trial produces information (and no treatment), patients can use this information to better understand their disease.
Participants emphasized that we must meet patients where they are. Some patients are too ill to travel to clinical sites. The people who suffer from Long Covid the most are the same people who have been stigmatized for being of lower socioeconomic classes; for being from rural areas; for being members of racial, ethnic, or LGBTQ+ communities; or for having other preexisting conditions (like other infection-associated chronic conditions). Ms. McCorkell said patient navigators are critical for helping people participate throughout trials. Many in this section supported this idea.
Closing the workshop: What did we learn and what will we do?
On day 1, Dr. Marrazzo told participants that RECOVER-TLC would review everything discussed during the workshop and use that information to better find treatments and cures for patients with Long Covid. Now at the end, she showed several remarkable slides that explained exactly how this would happen. One side of each slide listed what participant discussed; the other, what RECOVER-TLC would do as a result.
Communication and structure
Workshop participants said discussions among diverse groups of people—all committed to helping patients with infection-associated chronic conditions—are incredibly valuable. Thus, Dr. Marrazzo said that RECOVER-TLC would hold regular forums for these groups to keep speaking and collaborating. Every month, RECOVER teams will update patients and community groups about clinical trial progress. And once a year, the teams will have a larger meeting where all groups will review and recalibrate. Workshop participants also said the RECOVER leaders must be more transparent about how they structure the organization and must be accountable for their decisions. In this spirit, Dr. Marrazzo said, the RECOVER initiative will finish the organizational work of finding and recruiting dedicated experts to serve on committees; finding and engaging valuable reviewers; and centralizing leadership at the National Institutes of Allergy and Infectious Diseases.
Selecting clinical trials
Regarding choosing the best clinical trials moving forward, Dr. Marrazzo said RECOVER teams will work with the FDA to define the best patient-reported outcomes to measure and to plan clinical trials that best match the FDA’s criteria for new interventions. RECOVER-TLC will also launch not only larger clinical trials (testing whether well-established interventions work and setting the stage to submit these for FDA approval), but also smaller, exploratory ones (to better understand the disease mechanism and to explore new therapeutic possibilities). RECOVER will also actively manage its portfolio of clinical trials to make sure studies engage a wide range of approaches and include young people as well.
Linking interventions to pathobiology
Dr. Marrazzo returned to recommendations from participants to quickly use the RECOVER-biorepository samples in clinical trials, especially trials on the details of how Long Covid affects patients. To do this, the NIH will at once investigate how best to use these samples to answer the most pressing questions about how Long Covid, the goal being to quickly decide which clinical trials to prioritize next. If necessary, RECOVER will set up a working group (including experts in diverse fields, like neurologists, immunologists, and pediatricians) to kick-start use of biorepository samples for mechanistic studies.
Involving patients
Repeated throughout the workshop, participants said that patients and community organizations must help design and conduct these clinical trials. Patients with Long Covid must have a say in interpreting, discussing, and using clinical trial data. Dr. Marrazzo said that patients will most certainly be a part of all stages of RECOVER-TLC clinical trials. For example, patients will be members of all working groups and committees, including the highest ones. RECOVER-TLC will also establish the Community Engagement Group, which will directly talk with the Executive Committee, help choose the most important interventions to push forward and join all working groups and the Scientific Oversight Committee. Participants also said that healthcare providers lack resources to use results from clinical trials to better care for patients with Long Covid. In response to this, RECOVER may develop and update guidelines for treating patients with Long Covid, which would help healthcare providers use the latest findings.
The packed, three-day workshop showed that RECOVER-TLC is a powerful initiative that engages the best researchers, community advocates, and government agencies. Already, RECOVER-TLC is making substantial progress in treating and curing patients with Long Covid. The initiative is paying attention to what worked and what didn’t work for earlier initiatives. The RECOVER-TLC initiative is also a work in progress. It continually improves as we learn more from researchers about this disease and, especially, as we learn more from patients about how to help them best.
RECOVER-TLC has posted videos of all presentations from the workshop, and more workshops will be coming to update us all on progress with these next steps and with finding treatments and cures.
