Following the declaration of a public health emergency for monkeypox on August 4, 2022, the Secretary of U.S. Department of Health and Human Services (HHS) invoked an Emergency Use Authorization (EUA) for diagnostic tests as of September 7, 2022. This allows the U.S. Food and Drug Administration (FDA) the availability to expand testing options for monkeypox via the emergency use pathway. In support of HHS, the FDA issued its policy on monkeypox tests to guide laboratories, commercial manufacturers and FDA staff on submitting documentation to the FDA for EUA device approval.
For this latest policy, the FDA is inviting experienced test developers with high manufacturing capacity to notify the FDA of their intent to submit an EUA request by October 13, 2022. The FDA will respond to the email notice of intent with an “invitation” to submit the EUA or provide other advisement. The government organization intends to prioritize the review of EUA requests for:
- High throughput testing technologies
- Tests with at-home specimen collection
- Rapid diagnostic tests
To provide further insight for in vitro diagnostic (IVD) test developers, this review provides a side-by-side comparison of the COVID-19 and monkeypox FDA policies, identifying the critical similarities and differences in the FDA requirements for the EUA pathway.
A National Response Needed to Contain the Monkeypox Outbreak in the U.S.
While the monkeypox national emergency may not pose the same level of public health risk as COVID-19 (Table 1), the declaration of a public health emergency allows a coordinated national response to contain the outbreak before it becomes more widespread. Such a response supports disease surveillance, makes public health emergency funds available and ensures timely and equitable access to testing, vaccines, and treatment.
Table 1. Disease, Transmission and Impact to Public Health
| COVID-19 | Monkeypox |
| Respiratory illness (Coronavirus Disease 2019) caused by novel coronavirus (SARS-CoV-2) | Zoonotic viral infection (transmitted to humans from animals) caused by Orthopoxvirus (similar to variola virus) |
| Transmitted in the air | Transmitted by close skin-to-skin contact |
| Can be contagious even without symptoms. | Is not contagious until the infected person is symptomatic |
| Presents as a respiratory illness | Presents as skin rash/lesions (easier to identify) |
| Isolation to contain the outbreak requires symptomatic, exposed, and asymptomatic considerations | Containment requires isolation of infected symptomatic individuals |
| No available vaccines at the time of declaration | Two effective vaccines available at the time of declaration (although in short supply) |
| Critical illness and deaths with strained hospital and essential worker resources | Painful but not typically a critical illness with an added burden on healthcare facilities/providers |
| Insufficient testing capabilities – at the start of the PHE, only 150,000 tests were shipped from CDC to state laboratories3 | Insufficient testing capabilities – at the start of the PHE, only 8,000 tests per week1 available via the Laboratory Response Network (67 labs) |
FDA’s Policy Encourages the Development of Tests from Commercial IVD Manufacturers and High-Complexity CLIA Labs with Specific Guidance on LDTs, Home Specimen Collection Kits and Rapid Diagnostic Tests
In both the COVID-19 and monkeypox public health emergency situations, the FDA cites rapid detection of cases and a wide availability of diagnostic testing as critical to control the spread of COVID-19 (rapid spread and severe illness) and monkeypox (contagious infection) diseases (Table 2).
The FDA differentiates applicants as either high-complexity CLIA-certified laboratories (where the tests are lab-developed tests (LDTs) or IVD test manufacturers intending to commercialize through the EUA, 510(k) or premarket submission pathways. While the FDA may exercise enforcement discretion over high complexity CLIA certified lab tests, the discretion assumes the test and/or test modification is CLIA validated. The CLIA-certified lab must notify the FDA within five (5) days of offering the appropriately validated test. This enforcement discretion does not apply to at-home tests, home specimen collection or any testing outside a high complexity CLIA-certified lab.
In addition, the FDA does not intend to object to using CLIA-validated, high complexity lab serology tests* offered in academic medical center settings where the test results foster research from the available serology test data.
Table 2. FDA Policy Scope and Applicability
| COVID-19 | Monkeypox |
| No FDA cleared test at start of PHE2
Critical need for validated tests |
FDA cleared test for non-variola orthopoxviruses, including monkeypox, developed by the Centers for Disease Control and Prevention (CDC). Policy focus on specific testing needs |
| False positive test results delay accurate diagnosis/treatment and impose unnecessary isolation; false-negative results impact treatment decisions and could lead to additional exposures and disease spread | |
| Initial priority review on high complexity CLIA lab tests (high sensitivity PCR) | Priority Review as of September 7, 2022:
· High-throughput tests (detection of monkeypox specifically or for non-variola orthopoxviruses) · Tests with home specimen collection · Rapid diagnostic tests |
| Shifted to home collection, Point-of-Care (POC), and at-home tests to increase capacity, and serology testing to understand the immune response | · From experienced developers with high manufacturing capacity
· That inform FDA of intent to submit an EUA required within 30 days of September 7, 2022 |
| Diagnostic Test Validation Templates:
· Molecular · Molecular Home Specimen Collection · Antigen · Molecular and Antigen Home Use Test · Supplement for Screening with Serial Testing |
Diagnostic Test Validation Templates:
· Summary template with recommendations for analytical and clinical validation testing · Comprehensive template with study design considerations and fill-in-the-blank responsive text Molecular Only (FDA plans to provide additional templates) |
| · Serology (as a measure of adapted immune response) template
· Serology with Neutralizing Antibodies template |
*Serology tests cannot be used to diagnose or aid in the diagnosis of an active infection and are not tests of immunity |
| Serology testing (detection of antibodies) is not for use to diagnose active infection or as a measure of vaccine immunity | |
FDA Intends to Prioritize EUA Requests from Experienced Test Developers
Test developers intending to submit an EUA for monkeypox tests are required to notify the FDA by email and include the types of information noted by FDA in Section 4 of the Policy. The FDA will respond to inform developers whether they intend to prioritize the review of the manufacturer’s proposed test. FDA suggests manufacturers apply to the National Institutes of Health (NIH) Independent Test Assessment Program (ITAP) if they have monkeypox tests intended for use at the point of care or for home testing while high-complexity CLIA-certified testing is the current FDA EUA priority. More information about that program is available at Independent Test Assessment Program (ITAP) | National Institute of Biomedical Imaging and Bioengineering (nih.gov).
Table 3. Molecular Diagnostic Test Requirements
| COVID-19 | monkeypox |
| Test developers should monitor new and emerging viral mutations and variants that could impact molecular test performance on an ongoing basis | Test developers should include a highly conserved monkeypox virus target (i.e., a target in a portion of the genetic code not restricted to a specific monkeypox virus variant) or a non-variola Orthopoxvirus target as part of a multiple target test |
| · Limit of Detection (spiking quantified virus)
· Inclusivity · Cross-reactivity/Interference · Sample Stability · Clinical Evaluation |
|
| Summarized strategy to monitor new and emerging viral mutations and variants that could impact molecular test performance | |
| Comparator must be high sensitivity FDA-cleared or EUA-authorized RT-PCR assay with chemical lysis step followed by solid phase extraction of nucleic acid | |
| Multiple authorized comparator tests at current state in PHE | 1. Quest Diagnostics monkeypox Virus Qualitative Real-Time PCR – EUA 9/7/2022
2. CDC has FDA-cleared tests in the Laboratory Response Network (LRN) as well as: · Quest Diagnostics · Mayo Clinic Laboratories · LabCorp · Sonic Healthcare · Aegis Science |
| Respiratory samples or saliva from symptomatic and asymptomatic populations. | Human skin lesion material (Contact FDA for other sample types to discuss validation strategy) from symptomatic populations. |
| Clinical performance evaluation: prospective, blinded, randomized clinical agreement (30 + and 30 – natural clinical samples**) with 95% PPA and NPA for all specimen types. | |
| All IRB and ICF rules (in 21 CFR 50, 56, and 812) apply to prospective sample collections from human subjects. | |
| Collect Standard of Care (SOC) sample before research samples. Randomize sampling order for candidate and comparator test unless two distinct anatomical sites are used for testing. | |
| Under an EUA, certain sections of the 21 CFR Part 820 Quality System Regulation (QSR) requirements may be waived for an authorized production during the duration of the EUA. However, FDA recommends that test developers follow comparable practices as much as possible, even if such requirements are waived. | |
** “If no prospective or retrospective specimens are available for clinical performance evaluation, the use of contrived specimens may be acceptable for initial authorization, with additional clinical testing of positive natural clinical specimens provided as a condition of authorization. Note that the FDA recommends that each contrived clinical specimen should consist of a unique individual natural clinical matrix sample (i.e., each contrived specimen should be made by spiking quantified material into a human skin lesion material specimen that is negative for monkeypox virus).” 5,6
“It looks like the FDA is balancing the monkeypox public health risk with a strategic and responsible approach to manage the quality and numbers of EUA requests,” commented Sonia Lecce, NAMSA’s EUA Regulatory subject matter expert. “The FDA is clearly identifying priority tests as high throughput, rapid tests and home specimen collection, and they intend to prioritize submissions from experienced developers with high manufacturing capacity. Experienced test developers will likely have a previous U.S. FDA clearance, a quality management system and/or a market history of fully regulated product submission to the agency,” Lecce concluded.
Test developers have until October 13, 2022 to notify FDA of their intent to submit an EUA request
How Can NAMSA Help?
Test developers interested in submitting an EUA request to the FDA for monkeypox testing should contact NAMSA as soon as possible. NAMSA’s team of qualified IVD Clinical Research and Regulatory experts are available to assist you with your EUA strategy, letter of intent, EUA labeling, pre-submission, clinical trial support, template compilation and EUA submission review. Register your inquiry with us today at: http://www.namsa.com/locations-contact/.
Or, request a complimentary consultation today by visiting: https://namsa.com/namsa-expertise/subject-matter-experts/
Sources:
- Gostin,L. and Hodge, J. (2022, August 2nd). Monkeypox: National Emergency Declaration & Powers. The O’Neil Institute. https://oneill.law.georgetown.edu/monkeypox-national-emergency-declaration-powers/#:~:text=Reported%20monkeypox%20cases%20in%20the,symptoms%2C%20fatigue%2C%20rash)
- S. Department of Health and Human Services (HHS). (2022, July 15). HHS orders additional vaccine, increases testing capacity to respond to monkeypox outbreak. https://www.hhs.gov/about/news/2022/07/15/hhs-orders-additional-vaccine-increases-testing-capacity-to-respond-to-monkeypox-outbreak.html
- Centers for Disease Control (CDC). (2020, February 6). Shipping of CDC 2019 Novel Coronavirus Diagnostic Test Kits Begins – Distribution of CDC Diagnostic Test Kits Will Expand Laboratory Capacity to Detect 2019-nCoV. https://www.cdc.gov/media/releases/2020/p0206-coronavirus-diagnostic-test-kits.html
- S. Department of Health and Human Services (HHS), Food and Drug Administration (FDA), and Centers for Disease Control (CDC). (2021, December 15). Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised)* Guidance for Developers and Food and Drug Administration Staff. https://www.fda.gov/media/135659/download
- S. Department of Health and Human Services (HHS), Food and Drug Administration (FDA), and Centers for Disease Control (CDC). (2022, September 7). Policy for Monkeypox Tests to Address the Public Health Emergency Guidance for Laboratories, Commercial Manufacturers and Food and Drug Administration Staff. https://www.fda.gov/media/161443/download
- Food and Drug Administration (FDA). (2022, September 7). Template for Developers of Molecular Diagnostic Tests for Monkeypox. https://www.fda.gov/media/161448/download
Wendy Schroeder, RN, BSN, CCRC/PM, CRCP
Wendy Schroeder has been involved with research and clinical trials for more than 20 years, and has a deep understanding of in vitro diagnostics (IVDs) and companion diagnostics (CDx). She has served as a key company stakeholder in the implementation of an in-house contract research organization (CRO) infrastructure for a commercial laboratory moving bench IVD science into clinical validation studies and launching a biorepository of blood samples with annotated clinical data. Wendy has provided research operations oversight for commercial laboratories (Caris Life Sciences, Ashion Analytics) and IVD manufacturers (VisionGate, Inc.) as well as at hospital and clinical sites. Wendy holds a Bachelor of Science in nursing degree from Arizona State University (Tempe, AZ). She is a certified Research Coordinator and Project Manager (ACRP) and a certified Research Contracts Professional (MAGI). She has been an invited speaker and author of peer-reviewed journal publications on molecular diagnostics (MDx), clinical trial billing and IVD/Laboratory Developed Test (LDT) regulatory matters.