Emergency Use Authorization and Enforcement
FDA Response to COVID-19 – Extracorporeal Circuits
COVID-19 can trigger acute respiratory failure and/or acute cardiopulmonary failure. Long-term (≥ 6 hours) extracorporeal membrane oxygenation (ECMO) can be an important tool for treating patients. EUA and enforcement policy applies to extracorporeal circuit devices that are intended to pump blood or oxygenate blood, but do not apply to devices intended only for carbon dioxide removal, as they may not oxygenate blood at clinically meaningful levels.
Extracorporeal Blood Purifications (EBP) EUAs
The EUA request process for ECMO or cardiopulmonary bypass devices are not significantly different from the request processes for other devices. Open to devices that are not legally marketed in the US, FDA recommends including general information on the manufacturer and specific product. Evidence of regulatory clearance or approval in appropriate regions and conformity to FDA recognized standards, general and device specific, are expected, especially quality system requirements such as 21 CFR 820 or ISO 13485.
At the time of writing, FDA has issued four (4) letters of authorization for extracorporeal blood purification (EBP) devices. Both devices are intended to be used to reduce pro-inflammatory cytokine levels to prevent or ameliorate a cytokine storm as a result of COVID-19. Patients 18 years of age and older admitted to the ICU with confirmed or imminent respiratory failure is the intended use population for both devices. Both devices reduce inflammatory cytokines through adsorption. The CytoSorb device is able to be integrated into a number of extracorporeal circuits including ECMO and continuous renal replacement therapy machines. The other authorized devices, Spectra Optia Apheresis System and the oXiris Set device, use plasma separation and filtration to adsorb inflammatory cytokines. The final EBP device, Seraph 100 Microbind Affinity Blood Filter, filters whole blood of pathogens and various inflammatory mediators via affinity adsorption. Letters of authorization indicate that 21 CFR 820 requirements have been waved with respect to design, manufacture, packaging, labeling, storage, and distribution of the authorized devices in accordance with the EUA. Note that these requirements are only waived under the letter of authorization and not included in the enforcement policy guidance released by the FDA. This indicates 21 CFR 820 requirements are to be met for request of EUA, while not enforced under an EUA.
Conditions of authorization align for the devices and can be expected for future devices as well. “Authorized labeling” to be included with the devices are Fact Sheets for healthcare personnel and patients, and instructions for use devised with and authorized by the FDA under terms and conditions of the EUA. Consultation and concurrence with the Division of Renal, Gastrointestinal, Obesity and Transplant Devices (DHT3)/Office of GastroRenal, ObGyn, General Hospital and Urology Devices (OHT3)/office of Product Evaluation and Quality (OPEQ)/Center for Devices and Radiological Health (CDRH) is required for changes to labeling, fact sheets, components, materials, and software. Furthermore, the letters of authorization are specific to authorized labeling, components, and materials so these changes require changes to the scope of authorization that may be requested with additional consultation from DHT3/OHT3/OPEQ/CDRH and the Office of Counterterrorism and Emerging Threats (OCET)/Office of the Chief Scientist (OCS)/Office of the Commissioner (OC).
In union with other EUAs, all records associated with the EUAs are to be retained and made available for inspection. Adverse events are to be reported to the FDA. Distribution information including number and specific location of devices is to be maintained. All promotional material is to be aligned with labeling and indicate that devices are not cleared or approved by the FDA to treat patients with COVID-19 and authorized only for the duration of the declaration of emergency.
ECMO Enforcement Discretion
FDA does not intend to object to limited modifications to the indications and design of FDA-cleared or approved ECMO devices and cardiopulmonary bypass devices. FDA is choosing to waive premarket requirements, the 510(k), and premarket approval application (PMA) supplement for changes or modifications within the scope of the guidance. Waiver of the 510(k) or PMA supplement apply in the case that changes or modifications to not create an undue risk. Circuit devices often incorporate multiple components, it is best practice that compatibility between components is considered. Changes to indications, such as a cardiopulmonary device for long-term use in an ECMO circuit, or design, such as component changes due to supply chain disruption, are not believed by the FDA to create undue risks. However, changes to components that affect flow-rate or gas transfer/exchange create unacceptable risk and do not fit within the scope of the discretion policy.
All changes to devices should be indicated in labeling (and noted that changes are not cleared or approved by the FDA) and be designed, evaluated, and validated under FDA recognized standards. All changes are to be documented in their device master record and change control records. This information is to be made available to the FDA for inspection upon request.