Infusion confusion: the rollout of mAbs for COVID-19 could be chaotic
Operation Warp Speed is leaving critical aspects of mAb deployment to overwhelmed state and local governments
Operation Warp Speed is leaving critical aspects of mAb deployment to overwhelmed state and local governments.
FDA could soon grant emergency use authorization to one or more COVID-19 monoclonal antibodies. Rather than being celebrated for creating lifelines that could keep hundreds of thousands of Americans out of hospitals, the announcements may mark the start of yet another round of pandemic pandemonium.
Effectively deploying mAbs will require the kind of creative thinking and tight coordination across the healthcare system that have helped South Korea and other countries tame COVID-19 — and that are largely absent in the U.S.
The U.S. government’s Operation Warp Speed, Regeneron Pharmaceuticals Inc. (NASDAQ:REGN), Eli Lilly and Co. (NYSE:LLY) and other biopharma companies have been scrambling to increase manufacturing capacity, but if COVID-19 mAbs are as effective as their sponsors hope and the experience of high-profile recipients suggests, supply is certain to fall far short of demand in the U.S. and especially in other countries.
The first problem, however, will be creating safe sites for patients to receive infusions without endangering others.
“There are a lot of ideas out there about how to administer antibodies, but a plan hasn’t come together yet,” Mark McClellan, director of the Duke-Margolis Center for Health Policy, told BioCentury. “There is no strategy that assures broad access, that assures that people who can benefit the most are likely to be treated, or to figure out who can benefit the most given the limited evidence and data likely available at time of EUA.”
There is a need for urgent action, said McClellan, who served as FDA commissioner and CMS administrator in the George W. Bush administration. “We have to act very fast to prevent the distribution and access problems from worsening inequities” that are already a hallmark of COVID-19 in the U.S.
McClellan serves on the boards of Johnson & Johnson (NYSE:JNJ) and Cigna Corp. (NYSE:CI).
The disparities in outcomes by race, ethnicity and income seen so far in the U.S. have been largely “driven by the risk of contracting COVID, combined with a higher incidence of co-morbidities in those groups,” McClellan said.
The U.S. is on track to exacerbate those inequities by layering on differences in care, McClellan warned. “We now are in a position where disparities in outcomes from COVID could get substantially worse. Issues of distribution and administration [of therapies] are primed to be aligned with risks of contracting COVID and higher comorbidities.”
“Getting patients to sites where they can be treated will be the rate-limiting step.”
Unlike the case for most therapies, COVID-19 mAb manufacturers will not be responsible for distributing them.
Two companies — Regeneron and Eli Lilly — have announced that they have filed applications for EUAs for COVID-19 mAbs.
FDA could issue the EUAs as early as next week, Paul Mango, HHS deputy chief of staff for policy, told reporters Friday.
Regeneron has sold its entire production capacity of about 300,000 doses through the end of 2020 to the U.S. government and is discussing with Warp Speed a contract for additional sales. Lilly has announced that it is negotiating a similar commitment.
Operation Warp Speed is procuring mAb doses, but it is not undertaking the kind of massive effort to distribute them that it is putting in place for vaccines. The U.S. government has promised to ensure that once vaccines are authorized or approved, it will rapidly make access possible for every American who wants to be vaccinated.
Warp Speed plans to treat distribution of mAbs in a manner similar to the way it has deployed Veklury remdesivir, Janet Woodcock, head of therapeutics at Operation Warp Speed, told BioCentury. The U.S. government will hand off distribution and allocation to the states.
“With remdesivir there is a pro rata allocation to states based on hospitalization,” Woodcock said. “Something similar will be used here. The allocation plan is being worked out very carefully.”
As with Veklury, it will be up to state health departments and local governments to determine, within the bounds of the EUA or BLA, how to get mAbs to individual patients. “If there were an EUA, it would be up to cities and health departments to work together” on plans for administering a COVID-19 mAb, Woodcock told BioCentury.
Woodcock has temporarily stepped away from her position as director of FDA’s Center for Drug Evaluation and Research and is not involved in regulatory decisions about COVID-19 therapies.
Creating safe places to administer mAbs isn’t an insurmountable problem, but it will take a concerted effort on the part of governments and providers. Given the increasing numbers of infections and hospitalizations, and the confidence government leaders have expressed in mAbs — at the debate on Oct. 22, President Donald Trump reiterated his belief that Regeneron’s REGN-COV2 had “cured” him — there will be little patience for a slow rollout.
If and when FDA issues EUAs for COVID-19 mAbs, setting up infusion facilities and “getting patients to sites where they can be treated will be the rate-limiting steps,” at least for an initial period, Woodcock told BioCentury.
Summarizing data produced to date about mAbs, Woodcock told reporters at an Oct. 9 briefing that trials of the mAb products from Regeneron and Lilly show that “giving antibody early in the course of the disease rapidly helps in clearing the virus from the body” and shortens the duration of symptoms.
“What Regeneron found,” Woodcock said, “was that the main effect is in people that by their assay were seronegative — in other words, they hadn't started making their own antibodies to the virus. What Lilly found was that their intervention appeared numerically, although it was not a primary endpoint, to decrease the number of hospitalizations of patients who receive the antibody compared to placebo.”
In addition to identifying and equipping locations where patients can be safely infused, to turn mAbs into tools that can bend the curve of the pandemic, it will be necessary to overcome cultural and economic barriers.
Americans have been bombarded for six months with instructions to isolate themselves if they have COVID-19 symptoms. To receive treatment with mAbs, symptomatic patients and their caretakers will have to be persuaded to leave their homes.
The U.S. government will have to find a way to make good on President Trump’s promise that mAbs will be provided at no out-of-pocket cost.
As with any product allocated from the national stockpile, there will be no charge for the mAbs. It will, however, be necessary to pay substantial costs for the infusion procedure.
While private insurers can be persuaded to drop copays, the White House and CMS are still working to find a way around rules that would force Medicare beneficiaries to pay hundreds of dollars in administration costs.
Those costs could be higher if providers agree to collect data that could be critical to learning which patients benefit most from mAbs.
The first EUA requests for COVID-19 mAbs are targeting patients with moderate to severe symptoms who have not been hospitalized.
While it will be up to FDA to determine the indication, mAbs are likely to be reserved for patients with moderate to severe disease who are at the greatest risk of requiring hospitalization in the absence of treatment, Woodcock said.
“Data made public by Lilly and Regeneron indicate that a large number of people [on mAb trials] got better on their own,” Woodcock noted, “so a heroic effort to infuse everyone who tests positive may not be worthwhile.”
In a commentary published in the Wall Street Journal, former FDA commissioners Scott Gottlieb and Mark McClellan estimated that “at least 12,000 of the new Covid cases each day would be indicated for the drug[s] based on age and risk factors, even if there’s no further surge of infection.”
Demand for mAbs would be reduced but not eliminated by widespread adoption of vaccines. Vaccines will not be 100% effective in all subpopulations and uptake will not be complete, so there will be a continuing need to treat cases of COVID-19.
Location, location, location
The most likely setting for administering mAbs to COVID-19 patients who haven’t been hospitalized will be hospital emergency rooms and hospital outpatient facilities, said Mango at the Oct. 9 briefing.
Emergency rooms are not, however, equipped to serve a large influx of symptomatic COVID-19 patients or to provide them beds and care for the one to three hours required to complete an infusion and monitor for adverse effects. Even if ERs had room to administer infusions, given the risk of infection, they are one of the last places that should be welcoming infectious COVID-19 patients.
There are infusion facilities operating all over the country, primarily serving patients who need intravenous treatments for cancer or autoimmune diseases — people who must be protected from exposure to infectious diseases. The need to isolate infectious patients will make it challenging, or possibly impossible, to safely infuse large numbers of COVID-19 patients at these facilities.
Large hospital systems could dedicate an entire infusion facility to treating COVID patients, or convert observation units, McClellan said. He and Gottlieb have also suggested that FDA consider including language on mAb EUAs that would allow home healthcare nurses to provide the infusions.
Woodcock says it should be possible to set up infusion centers in non-traditional settings such as hotel ballrooms. “Were one of the EUAs to be granted, there are many sites capable of administering an IV infusion,” she told BioCentury.
It would be necessary to assemble a team, including a physician to oversee the infusions, one or more nurses to handle the procedure, and someone to handle billing. Beds, infusion pumps, and rescue medicines to help patients who experience adverse reactions would also be needed.
Another possibility, especially to serve patients in rural areas who live long distances from cities where infusion centers are likely to be located, is to create mobile facilities similar to the mobile blood donation RVs the Red Cross operates.
In addition to the patient who is being treated, facilities will have to accommodate whoever accompanies the patient. That caregiver will need to be treated as if he or she is infected with COVID-19.
While all of this is doable, it won’t happen instantly, especially in the middle of a raging pandemic.
“The U.S. healthcare system is going to have to pick this up and do it,” a senior HHS official told BioCentury.
The problem with leaving it to local medical systems is that the places where the therapies are most needed, locations where the outbreak is peaking such as those in the Midwest states, are in crisis mode and are too overwhelmed to efficiently set up a new kind of service, the official, who did not want to be identified because they are not authorized to speak to the media, said.
The decision to push critical aspects of mAb deployment onto states that are ill-prepared could create a chaotic situation.