The COVID-19 Pandemic triggered the U.S. Food and Drug Administration’s most widespread use of the Emergency Use Authorization (EUA) Pathway in response to a single threat. The FDA managed EUA applications for a range of devices, including blood purification products, infusion pumps, personal protective equipment (PPE), respiratory assist devices, ventilators and other therapies and vaccines to meet public need. All the same, the FDA Center for Devices and Radiological Health (CDRH) put the hardest, longest and most intensive work into reviewing EUA applications for COVID-19 diagnostic tests. The result was a shift in how the FDA, MedTech manufacturers and CROs conduct work, which is still in place today.
How successful was the EUA in addressing the public need for reliable COVID-19 tests?
In September 2022, The U.S. Department of Health and Human Services (HHS) Office of Inspector General (OIG) released a review of the FDA response to the COVID-19 public health emergency, specifically the EUA abbreviated pathway to market for diagnostic tests. The focus of the review was FDA EUA activity in the first half of 2020, but includes commentary and feedback on the FDA’s own independent assessment and of their COVID-19 response (Booz Allen Hamilton).
The FDA’s self-evaluation of their COVID-19 response is consistent with OIG observations and commentary. Analogous to these evaluations are CRO experiences and lessons learned worth mentioning in context, below.
1) The FDA was met with the challenge to ensure the public had access to quality tests. COVID-19 testing is critical to disease surveillance, as a metric for containing transmission, and for individual and public health care and treatment. In their efforts to meet demand for COVID-19 testing, the FDA had an “all comer” experience with test developers that included a wide range of laboratory and product development experience. Of survey respondents, only 28 percent had any prior FDA submission process experience; the FDA recognized a requirement for a very different level of support for inexperienced applicants compared to manufacturers who had previous regulatory submission experience.1
Likewise, many laboratory and device test developers sought CRO support for COVID-19 clinical validation studies. Business entrepreneurs forming partnerships with U.S. and OUS equipment manufacturers required expert strategic consulting to manage study implementation, timelines and cost expectations. Novice test developers struggling with funding had to pace their test development and validation with their bank accounts. Excluding those who had no experience at all, we can identify two types of test developers with different testing and application experience: one group from laboratory environments regulated by CLIA, and the other from medical device manufacturing regulated by FDA.
Moreover, in several cases NAMSA observed that Clients had a very limited understanding of clinical trial regulations, human subject protection, informed consent and data integrity. In response, we became the experts in FDA EUA requirements and disease prevalence, protocol writing, sourcing clinical samples, and adapting our SOPs and process controls to align with EUA as an abbreviated pathway to test authorization.
NAMSA’s Teams attended FDA Town Hall Meetings and translated valuable information for our Clients. We committed to FDA FAQs and “templates” as the most current source of truth when communicating FDA EUA requirements. And, we used the CDRH email option frequently for queries or validation to ensure confidence in Client communications. With these tools and adjustments, we could offer clinical validation support that was smarter and more efficient than clinical investigations intended for a full regulatory submission 510(k) clearance or Pre-Market Approval (PMA).
2) The FDA also used different approaches to ensure test availability while being mindful of assay quality in the face of test component shortages, labile infection prevalence and volumes of applications that strained their resources. The FDA Microbiology Division, for example, saw EUA requests rise from roughly 100 per year, to 100 per month during the height of the pandemic.1 Ultimately, the FDA sees an opportunity to optimize IT systems to better manage logistics such as tracking applications, understanding review status and supervising staff allocation.
Likewise, all of us working to deliver best-in-class global MedTech solutions felt a dramatic pandemic work shift associated with lockdowns, quarantines, research site closures and limited access to clinical study teams and site documents. In response, we also became the experts in “virtual” clinical trials management, remote monitoring, and secure methods to share and transfer critical and confidential documents.
When the FDA shifted priority to Point of Care (POC), home use and Over the Counter (OTC) tests, we found clinical sites with simulated home environments, mastered the quick reference instruction (QRI) and stood fast to clinical validation testing in the hands of the intended user in the intended use environment.
Just like the FDA, NAMSA designed Case Report Forms (CRF) and database templates and created clinical implementation workflow by a standardized “logistical recipe for success.” We leveraged our people, our tools and processes, and our pandemic expertise in ongoing collaborations with clinical sites and the National Institutes of Health supporting Covid-19 diagnostic test validation.
3) The OIG cited a key takeaway in their report:
“…FDA repeatedly adapted its approach to how it used EUAs to address Covid-19 testing challenges and to expedite access to tests. However, these efforts to increase test availability sometimes came at a cost to test quality.”1
Most notably, early in the pandemic declaration, the FDA permitted qualified laboratories to perform COVID-19 testing with prior notification, expecting that these labs would provide test validation data within 15 days of notification. Subsequently, several laboratory-developed tests (LDTs) had performance problems. In an evaluation of 125 EUA requests from laboratories, Shuren & Stenzel (NEJM, 2020) report 82 device applications with design or validation problems.2 Many EUA submissions were low quality with missing or inadequate data to meet FDA standards to reasonably demonstrate the tests’ effectiveness. The expected “shorter” review period for an EUA application was at risk each time the FDA was asked to review an inadequate submission.
For test developers, the EUA opportunity is/was extremely time-sensitive causing a rush of “ASAP” CRO work. It has been said, “when everything is ASAP, nothing can really be ASAP…there’s no real planning involved”.4 The “real planning” most important to a successful clinical validation is product and protocol clinical readiness. Test quality concerns may be innate to EUA policies and not solely the result of FDA adaptations and efforts.
Pertaining to product clinical readiness, a declaration of a national pandemic permits the FDA to waive otherwise-applicable Good Manufacturing Practice (GMP) requirements, as applied to medical devices, “these are referred to as Quality System Regulation requirements” (21 CFR § 820).5 This allows a shortcut around design controls limiting the opportunity for thoughtful design, testing against a specification, and discovery and mitigating problems related to design. This acquiescence is necessary to expeditiously meet the critical need for diagnostic tests while noting laboratorians are valuable test developers regulated differently and not subject to GMP. Introducing assays that are barely engineering prototypes into clinical performance testing created real-life quality concerns about tests that:
- Had inadequate QC procedures
- Had unclear or complex instructions – tests that performed well “at the bench” failed in the hands of the intended user
- Failed performance criteria
- “Missed” low positives
As it relates to protocol clinical readiness, EUA products benefit from a lower level of performance to demonstrate they may be effective compared to the requirement for reasonable assurance of safety and effectiveness for fully regulated products. For example, with labile prevalence, the study protocol target N to achieve 30 positive cases became a moving target and when the “case count” was low, the timeline and cost of a clinical validation study was proportionate to the “priceless” value of fresh samples.
Setting a performance target is necessary to establish what the tests can provide, but might be short of the assurances needed to demonstrate quality. Using a minimum 30 positive test results with at least 80 percent agreement to a comparator as the acceptable performance metric without a pre-specified protocol target N allowed some latitude that potentially dilutes performance data and adds to test quality concerns:
- Enrolling 100 people to get 30 positive tests but <80% PPA could be “fixed” by enrolling more subjects until enough positive tests agree with the comparator test to achieve the acceptable PPA.
While not necessarily directly related to test quality, the law of supply and demand played out in a fundamental interplay of pandemic variables that drove up the cost of performing the clinical studies:
- Sample scarcity
- Manufacturer competition for clinical sites
- Increased demand for research personnel otherwise re-allocated to patient care
- Competition for supplies, reagents, comparator assays
Ultimately, a protocol is dependent on recruitment. When OTC COVID-19 tests became readily available, there were more people testing at home and fewer people seeking healthcare for non-threatening illness, thereby depleting the number of potential clinical trial volunteers.
As of November 15, 437 test and sample collection devices are authorized by the FDA. The COVID-19 public health emergency has been extended to at least January 11, 2023 with no 60-day advance notice of “an end” from the Biden Administration. The test developers persevered. CROs persevered. The FDA persevered, and hindsight now informs future considerations moving forward and for the “next time.”
The OIG notes:
“Balancing the need for test availability with test performance amidst an unprecedented pandemic was difficult for the FDA to navigate. No roadmap existed to achieve that balance, so the FDA made calculated decisions that prioritized testing availability. This meant that poorly performing tests reached the market, although how many were ultimately used or the impact on public health remains unknown.”1
In addition to logistical recommendations for better preparedness (assess and revise FDA guidance for EUA submissions, develop a suite of templates for emergencies involving novel pathogens, optimize submission tracking, improve resources for test developers), the OIG offers two strategic suggestions:
a) Establish formal communication channels with the lab community, and
b) Work with federal partners to coordinate a national testing strategy.
Common to both of these strategies is an emphasis on “collaborative relationships:”
- With the Centers for Disease Control (CDC) and the lab community to establish communication protocols
- With NIH and CDC to consolidate and standardize validation at one or more sites
- To potentially “pre-certify” labs for emergency test development
- To potentially include contracting with BARDA (The US Department of Health and Human Services (HHS) Biomedical Advanced Research and Development Authority) and qualified test manufacturers who could support and scale test development during a pandemic
NAMSA is a trusted partner already involved with these collaborative leaders and there is more we are learning together about COVID-19, and now the Monkeypox Pandemic response.
Tracking the course of a pandemic is a collaboration of expert data analysis looking at viral epidemiology, outbreak statistics, severity indexes (public health and social measures in place such as masks, school and business closures, restricted gatherings, domestic and international movement/travel restrictions, etc.), along with standard metrics such as number of reported cases, hospitalizations and deaths. While new COVID-19 variants emerge, the diagnostic testing response capabilities seem to have scaled with the public health threat. In fact, the FDA has issued at least 42 EUA revocation letters in response to manufacturer requests noting:
a) This test (RT-PCR) is discontinued and testing continues under another FDA EUA
b) The test is no longer: in distribution, on the test menu, conducted under the EUA or is commercially supported
These manufacturers indicate the tests are no longer in demand and the public needs are being met with other FDA EUAs. This is good news for everyone going into 2023.
If you would like to learn more about NAMSA’s COVID-19, including on-demand webinars, white papers and other blog posts, please visit: https://namsa.com/resources/covid-19-resources/.
How Can NAMSA Help?
At NAMSA, our European regulatory team can help guide you through this complex regulatory environment and help determine the correct regulatory pathway for your IVD product. We not only understand how to accurately interpret the complicated regulatory challenges that IVD manufacturers sometimes face, but we also help you simplify the development and implementation of effective development strategies. Whether supporting IVD regulatory assessments and submissions, developing IVDR compliant technical files, designing and managing clinical trials or building ISO 13485:2016 and 21 CFR part 820 compliant quality systems… we’ve got you covered.
To learn about NAMSA’s full suite of IVD services and solutions, including IVDR compliance planning, please visit: https://namsa.com/services/ivd/. Or, if you’re ready to set up a complimentary consultation, get in touch with one of our IVD experts here: https://namsa.com/namsa-expertise/subject-matter-experts.
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.