Two monoclonal antibodies have received emergency use authorization (EUA) by the U.S. Food and Drug Administration. Bamlanivimab (produced by Eli Lilly) and casirivimab/imdevimab (produced by Regeneron) were both approved in November 2020 as treatment for outpatients with COVID-19 and mild to moderate symptoms. The two drugs were studied in 2 different clinical trials in which each was compared to placebo with a primary outcome being detectable viral load on the days following treatment. Both drugs showed a reduction in viral load compared to placebo. But the clinically important findings were in secondary outcomes of need for subsequent hospitalization and duration of symptoms. Both drugs reduced the duration of symptoms from 6 days to 5 days. Both drugs also significantly reduced the need for hospitalization. Four subjects taking the combination drug casirivimab/imdevimab required subsequent hospitalization compared to 10 subjects taking placebo. In the other study, 3 subjects taking bamlanivimab required hospitalization versus 10 subjects taking placebo. This was great news to hospitals facing a surge of COVID-19 patients that threatened to overwhelm hospital and ICU beds.
The FDA-approved indications were for outpatients (including patients in the emergency department that were planned to be released and not admitted to the hospital) with documented COVID-19 infection and not requiring supplemental oxygen (or an increase in normal oxygen flow rates if already on oxygen). Patients must have had symptoms for less than 10 days. In addition, patients must have at least one of the following risk factors for severe COVID-19 infection:
- BMI ≥ 35
- Chronic kidney disease
- Immunosuppressive disease or taking immunosuppressive medication
- Age ≥ 65
- Age ≥ 55 AND either cardiovascular disease, hypertension, or chronic respiratory disease
- Age 12-17 AND either BMI ≥ 85th percentile for age/gender, sickle cell disease, heart disease, neurodevelopmental disease, medical-related technological dependence, or chronic respiratory disease (including asthma)
The challenge for hospitals and outpatient practices is how to identify those patients with COVID-19 who fit the criteria, create a safe location for the infusions to be given, and then get patients in for their infusions within 10 days of symptom onset. These are enormous logistical challenges. We had less than a week to prepare from the time the FDA approved the medications until Ohio began distribution of the drug. We received our first shipment of the drug on a Monday afternoon and were able to have our first patient get infused 90 minutes later. Here is how we did it at our hospital.
Identify A Location For Infusions
Most hospitals have an infusion suite that can be used for chemotherapy to treat cancer or biologic drugs to treat autoimmune diseases. These areas are unsuitable to treat patients with COVID-19 because of the need to keep COVID patients far away from immunosuppressed patients. Ideally, the monoclonal antibody infusion location should be close to the hospital (for pharmacy, nursing, and physician support) and should have its own entrance so that patients with COVID do not have to walk through public hallways in the hospital. The area has to be large enough to accommodate the projected demand (on our busiest day so far, we treated 38 patients). We elected to use the auditorium at our hospital since it is large enough to handle up to 24 patients in the area at a time and has a separate entrance directly to the parking lot.
The Role Of Infection Control
Once we identified a suitable location, we had to be sure that it would be safe for patients and for the healthcare staff. Our infection control team checked the air flow in the auditorium and we were pleasantly surprised that the number of air exchanges in the room per hour was higher than our bronchoscopy suite! The floor was carpeted so we had our facilities team install a solid floor covering. We needed to have a separate entrance for healthcare staff that was different than the patient entrance so we put up a temporary wall in the auditorium lobby so that staff could enter through the hospital corridors and we could keep masks, gowns, and gloves in the staff entrance, away from the patient entrance.
The Role Of Information Technology
Next, we had to ensure that there was computer access so that healthcare staff in the infusion suite could chart in the electronic medical record. This required augmenting our wireless signal strength in the auditorium. We had to create a separate monoclonal antibody infusion location in the electronic medical record for the purposes of scheduling and charting. We created an order set for an “E-consult to COVID monoclonal antibody infusion” so that physicians and other providers could order the infusion.
The Role Of Pharmacy
When we received our supply of the drugs from the State of Ohio, we had to have a location to store and re-constitute the medication. Our hospital pharmacy was ideally suited for this since they already do this on a regular basis for inpatient medications. We assigned oversight to the pharmacist who also oversees our regular outpatient infusion center since she was experienced in the logistics of infusion drug preparation and delivery.
The Role Of Nursing
Nursing represents the most staff-intensive component of the program. There has to be registered nurses experienced in placing IV catheters and in administering IV medications. There needs to be other staff who can check vital signs and assist with throughput; for example, outpatient medical assistants (MAs), inpatient patient care assistants (PCAs), or licensed practical nurses (LPNs). Because our infusion center needed to be up and running less than a week after the FDA made the approval announcement and because it was anticipated that the infusion center would be temporary (only lasting for a few months), we could not just go out an hire nurses and PCAs dedicated to the infusion location. Instead, we drew from nurses currently working in other locations within the hospital or ambulatory sites; we paid a lot of overtime.
The Role Of The Doctors
To ensure that the monoclonal antibody treatments were being used appropriately, we needed to have a process for review of the referrals. Rather than having primary care physicians order the infusion directly, we created an order in our electronic medical record for “E-consult for COVID monoclonal antibody infusion”. One of the pulmonologists became the designated consultant and he reviews each patient to be sure that the FDA-approved inclusion criteria are met. This was simplified by structuring the electronic medical record order for the consult to require that the ordering physician check boxes for the various inclusion criteria, such as age ≥ 65 or diabetes.
In addition, Medicare requires physician oversight whenever infusions are performed. Fortunately, in January 2021, Medicare loosened the requirements from “direct supervision” to “general supervision”. With direct supervision, a physician must be physically on-site in the building while infusions are being administered. With general supervision, the physician merely needs to be available by phone or video conferencing and does not need to be physically in the building. Since I am in the hospital most of the time, I became the designated physician supervisor – on those days that I am seeing patients in the outpatient clinic area, one of the hospitalists is my back-up, in the event that a patient must be seen in-person for medical attention.
The Role Of The Legal Department
There are several compliance issues that we needed to address and fortunately, our legal department was able to provide immediate assistance to ensure that the infusion referral process was compliant with everything from the “general supervision” issue to physician referral. For example, it was recommended that a physician or other provider who has a pre-existing relationship with the patient be the one to contact the patient to inform them of their COVID diagnosis and determine if the patient wanted to be referred for treatment. In addition, we needed to register the auditorium with the state department of health as an outpatient treatment location.
Setting Up The Work Flow
We notified physicians at our medical center of the availability of the monoclonal antibody infusion suite and how to order a referral. However, we immediately found that many patients were self-referring to get their COVID-19 tests and so those test results did not necessarily get routed to a physician’s electronic medical record inbasket. Furthermore, many tests were ordered by surgeons, gastroenterologists, or other proceduralists as part of the patient’s pre-procedure evaluation and those results also did not get routed to a primary care practitioner. Therefore, we needed a way to identify patients with a positive COVID-19 test, determine if those patients meet the FDA approved indications, and then notify the appropriate physician or advanced practice provider that one of their patients meets criteria.
Once again, our information technology staff had an answer. They created an app within the electronic medical record that identifies all of the positive COVID-19 tests each day and then stratifies patients based on the number of FDA-approved risk factors for infusion. We do 500 – 1,000 COVID tests each day at our medical center and on some days, we can have more than 100 positive tests so the ability of the app to identify those patients who may be eligible was vital. When we first began our infusion center, I would run the app several times a day to identify eligible patients and then send a message to those patients’ primary care provider or other physician in our medical system alerting them and giving them instructions on how to order the e-consult. As our process evolved, we now have one of the pharmacists who works in the general internal medicine division and another pharmacist in the family medicine department take responsibility for positive tests ordered by physicians or providers in those departments. I now just review those patients whose tests were ordered from another department/division.
Once the order for the e-consult is placed, my colleague reviews the consult and then enters an orderset for the infusion. That order goes to the pharmacy where a pharmacist reviews the orders and contacts the patient to schedule their infusion. We can generally get the patient infused within 24 hours. Patients are told to park in the parking lot adjacent to our auditorium/infusion suite and call a number that one of the infusion nurses answers. The patients are then directed where to enter the suite and are placed in a reclining chair. Nurses then do a nursing assessment, check vital signs, start the IV and administer the drug. The FDA requires that the infusion be given over 60 minutes and further requires that the patients be observed for 60 minutes after completing their infusion. Once the patients leave, the nurses route the electronic medical record encounter to me for review, supervision attestation and encounter closure. We operate the COVID-19 infusion suite daily from 8 AM to 5 PM, Monday through Saturday.
The medication is provided by the State of Ohio so there is no medication charge. The infusion can be billed under code M0239 (bamlanivimab) or M0243 (casirivimab/imdevimab); both are reimbursed by Medicare at $310.
Is It Making A Difference?
As of the day this post was written, we have given 442 infusions in our COVID-19 monoclonal antibody infusion suite. Statistically, this has prevented 31 COVID hospitalizations at our medical center and helped to reduce the strain on hospital resources from the current surge in patients. In addition, we have developed a similar process for our emergency departments so that patients with COVID meeting infusion criteria can be infused with monoclonal antibody and released from the ER. When an outbreak of COVID happened at a nearby nursing home this month, we partnered with the nursing home staff so that we gave infusions at the nursing home so that those residents did not need to be transported to our hospital’s infusion center. All told, we estimate that these efforts have prevented 50-60 hospitalizations in the past 1 month.
Winning the war against COVID-19 will not be done by any one intervention. It takes social distancing, face masks, hand hygiene, availability of testing, isolation of infected people, prompt initiation of treatment, and widespread vaccination. A monoclonal antibody infusion program is just one of these interventions but one that will pay off with reduced hospitalizations and lives saved.
December 20, 2020