METADATA last updated: 2026-03-10_105731 file_name: _archive-combined-files_reg-articles-misc_45k.md category: regulatory subcategory: reg-articles-misc gfile_url: **FLAGGED - TBD user-facing Google-hosted public file URL** words: tokens: CONTENT # _archive-combined-files_reg-articles-misc_45k (5 files, 44,561 tokens) # 6,354 _AI_fda-eua-covid-retrospectives_post2022_report.md METADATA last updated: 2026-02-26 RT initial creation file_name: _AI_fda-eua-covid-retrospectives_post2022_report.md file_date: 2026-02-26 title: FloodLAMP FDA EUA COVID-19 Retrospectives and Criticisms -- Post-2022 Research Report category: regulatory subcategory: reg-articles-misc tags: EUA, diagnostics, FDA, COVID-19, retrospective, oversight, policy-critique, pandemic-preparedness source_file_type: md xfile_type: NA gfile_url: https://docs.google.com/document/d/1NS-w0RRsCFNLmdCXj0qEnpuSAPoZwuSOVVZjPjoM7AM xfile_github_download_url: https://raw.githubusercontent.com/FocusOnFoundationsNonprofit/floodlamp-archive/main/regulatory/reg-articles-misc/_AI_fda-eua-covid-retrospectives_post2022_report.md pdf_gdrive_url: NA pdf_github_url: NA conversion_input_file_type: NA conversion: NA license: CC BY 4.0 - https://creativecommons.org/licenses/by/4.0/ tokens: 6354 words: 2992 notes: Created by ChatGPT 5.2 Pro Extended during archive preparation. **NOT HUMAN VERIFIED - MAY CONTAIN ERRORS** Research report on retrospectives and criticisms of the FDA's EUA process during COVID-19, focusing on post-2022 publications from government oversight agencies, legislative bodies, NGOs, professional associations, and academics. Key source documents: FloodLAMP project description and reg-articles-misc archive bundle. summary_short: Research report identifying post-2022 retrospectives, evaluations, and criticisms of the FDA's Emergency Use Authorization (EUA) process during COVID-19, covering government oversight reports (HHS OIG, GAO, FDA), legislative responses, NGO and professional association critiques, and academic analyses, with archive-ready metadata for each source. CONTENT ## Prompt (Verbatim) I do a thorough research report on retrospectives and especially criticisms of the FDA's EUA process during the COVID-19 pandemic. This is for an archive project that's provided in the project description. I'm providing a few example files that I'm including in the archive and I'm looking for more reports like these and particularly ones that have come out since the end of the pandemic, since the end of 2022. The Booz Allen report was prior to the Omicron surge so there's a severe test shortage of testing then. These could be from any official government sources such as the FDA but also look for them from independent nonprofits or NGOs related to pandemic preparedness and response and then also from academics. Okay, do this and then, you know, organize the report well and provide the output as a markdown file that I can download where the content in the markdown file starts with heading number two. Okay, do it. **Files included in context window:** - project-description.md - _archive-combined-files_reg-articles-misc.md ## Prompt (Cleaned) Do a thorough research report on retrospectives and especially criticisms of the FDA's EUA process during the COVID-19 pandemic. This is for an archive project described in the project description. I'm providing a few example files included in the archive and am looking for more reports like these, particularly ones that have come out since the end of the pandemic (since the end of 2022). The Booze Allen report was prior to the Omicron surge, so there was a severe shortage of testing then. These could be from any official government sources such as the FDA, but also look for them from independent nonprofits or NGOs related to pandemic preparedness and response, and from academics. Organize the report well and provide the output as a markdown file where the content starts with heading level two. **Files included in context window:** - project-description.md - _archive-combined-files_reg-articles-misc.md ## Retrospectives and Criticisms of the FDA Emergency Use Authorization Process During COVID-19 *(Archive-oriented research report; emphasis on post-2022 publications)* ### How to use this document This report is designed for an **archive / curation workflow**: - It identifies **post-2022 retrospectives, evaluations, and critiques** of FDA's Emergency Use Authorization (EUA) process during COVID-19--especially for **diagnostic tests**, but also vaccines and therapeutics. - For each candidate source, it provides (a) a short annotation, (b) the main "EUA process" critique or lesson, and (c) suggested archive metadata (tags + a filename pattern) so the item can be added to a folder like `reg-articles-misc`. ### Baseline context (already in your example archive bundle) Your examples (e.g., the FDA-commissioned Booz Allen independent assessment, plus an FDA overview report) are valuable "baseline" sources because they cover: - **Early-to-mid pandemic test EUA operations** (triage, templates, staffing, postmarket monitoring, outreach) - **Policy volatility / guidance churn** and its effects on developers and access - Recommendations that later reappear in official guidance (e.g., validation frameworks; clearer enforcement-discretion triggers) This report focuses on **what came after ~late 2022**, when more formal retrospectives, oversight reports, and "future emergency" guidance began to crystallize. --- ## 1) What "EUA criticism" typically means in COVID-19 retrospectives Across the literature, "criticisms of the EUA process" cluster into recurring themes. These are useful tags and an organizing lens for archiving. ### A. Diagnostics: speed vs. validity under extreme uncertainty Common critique: policies that expanded testing access sometimes **traded off analytic/clinical validity**, increased false results risk, or produced uneven test quality (particularly early serology, and later some rapid antigen test performance debates). ### B. Diagnostics: policy volatility and interagency conflict Common critique: frequent shifts in FDA testing policy (e.g., pre-EUA pathways, laboratory-developed test policies, enforcement discretion) created **confusion and wasted effort** for developers and laboratories. ### C. Transparency, documentation, and public trust Common critique: the public and outside experts sometimes lacked **timely access to the evidence** or internal decision records supporting EUA decisions (especially salient for vaccines). ### D. Postmarket monitoring, revocation, and "variant churn" Common critique: EUA products can become obsolete as the emergency evolves (e.g., variant escape for monoclonal antibodies). Retrospectives examine whether FDA's **revocation / communication mechanisms** kept pace. ### E. Transition planning (EUA --> traditional authorization; end of PHE vs end of EUA declaration) Common critique: stakeholders struggled with what happens when the **Public Health Emergency (PHE)** ends, while **Section 564 EUA declarations** and individual EUAs may continue. --- ## 2) Key post-2022 sources (annotated, archive-ready) ### 2.1 Official oversight and accountability (government) #### A) HHS OIG: FDA's early testing EUA policy adaptation (retrospective with developer survey) **Source:** *FDA Repeatedly Adapted Emergency Use Authorization Policies To Address the Need for COVID-19 Testing* (HHS Office of Inspector General, 2022) **Link:** https://oig.hhs.gov/reports/all/2022/fda-repeatedly-adapted-emergency-use-authorization-policies-to-address-the-need-for-covid-19-testing/ **Why it belongs in this archive:** One of the most direct **post-hoc evaluations** of FDA's test EUA policies--focused on the critical early months (Jan--May 2020) and grounded in FDA documents + interviews + a survey of test developers. **EUA-process takeaways (from the OIG framing):** - FDA used EUA authority to rapidly expand test availability when no test existed; oversight bodies later evaluated how FDA balanced access with quality. - The report explicitly treats **developer experience** (survey results) as evidence about clarity, timeliness, and friction in the EUA pathway. **Suggested archive metadata:** - `tags: [EUA, diagnostics, COVID-19 testing, oversight, OIG, policy volatility, developer experience]` - `suggested_filename: 2022-00-00_HHS-OIG_FDA-Repeatedly-Adapted-EUA-Policies_COVID-Testing.md/pdf` #### B) GAO: testing availability, enforcement discretion, and "policy triggers" (recommendation with later follow-through) **Source:** *COVID-19: FDA Took Steps to Help Make Tests Available; Policy for Future Public Health Emergencies Needed* (U.S. Government Accountability Office, GAO-22-104266, May 12, 2022) **Link:** https://www.gao.gov/products/gao-22-104266 **Why it belongs in this archive:** Although dated 2022, GAO's recommendation directly shaped later FDA guidance: **FDA should define when it begins/ends enforcement discretion for unauthorized tests** in a future emergency. **Core critiques / lessons (EUA-process relevant):** - In COVID-19, enforcement discretion was broadened early, then narrowed; GAO argues future emergencies need **pre-defined criteria** for start/stop. - Frames a governance problem: "emergency flexibility" without a policy framework creates uncertainty and risk. **Suggested archive metadata:** - `tags: [EUA, diagnostics, enforcement discretion, GAO, policy triggers]` - `suggested_filename: 2022-05-12_GAO-22-104266_FDA-Testing-EUA-Enforcement-Discretion.md/pdf` #### C) FDA: final guidance establishing a framework for enforcement discretion during Section 564 emergencies (direct response to GAO-style critique) **Source:** *Consideration of Enforcement Policies for In Vitro Diagnostic Tests During a Section 564 Declared Emergency* (FDA/CDRH, **Final Guidance**, Sep 23, 2025) **PDF:** https://www.fda.gov/media/178123/download **Why it belongs in this archive:** A post-COVID policy artifact that encodes "lessons learned" into a framework: **factors FDA intends to consider** when deciding whether to exercise enforcement discretion for unapproved IVDs during a declared emergency, and when to end such policies. **Core critiques / lessons (EUA-process relevant):** - Treats COVID-19 as an explicit case study for when FDA widened and later narrowed enforcement policies. - Moves the debate from ad hoc decisions --> **criteria** (need, benefits/risks, alternatives, mitigations, re-evaluation cadence). **Suggested archive metadata:** - `tags: [EUA, diagnostics, enforcement discretion, CDRH, guidance, Section 564]` - `suggested_filename: 2025-09-23_FDA_Guidance_Enforcement-Policies-IVD_Tests_Section-564-Emergency.md/pdf` #### D) FDA: draft guidance on validation for emerging-pathogen IVDs during a Section 564 emergency (institutionalizing "validation framework" lessons) **Source:** *Validation of Certain In Vitro Diagnostic Devices for Emerging Pathogens During a Section 564 Declared Emergency* (FDA/CDRH, **Draft Guidance**, Jan 2025) **Landing page:** https://www.fda.gov/regulatory-information/search-fda-guidance-documents/validation-certain-in-vitro-diagnostic-devices-emerging-pathogens-during-section-564-declared-emergency **Why it belongs in this archive:** Post-COVID attempt to standardize validation expectations for future outbreak tests, addressing a central critique from COVID diagnostics: **how to validate quickly without sacrificing reliability**. **Suggested archive metadata:** - `tags: [EUA, diagnostics, validation, emerging pathogens, CDRH, guidance]` - `suggested_filename: 2025-01-00_FDA_Draft-Guidance_Validation-IVDs_Emerging-Pathogens_Section-564.md/pdf` #### E) FDA: "EUA authorities" umbrella guidance (useful legal/regulatory reference for archiving) **Source:** *Emergency Use Authorization of Medical Products and Related Authorities* (FDA, Guidance; updated Sep 12, 2022) **Link:** https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-medical-products-and-related-authorities **Why it belongs in this archive:** Not a critique, but a **canonical post-COVID reference** consolidating EUA authorities, definitions, and related pathways. Helpful "reference spine" for the retrospective literature. **Suggested archive metadata:** - `tags: [EUA, legal framework, FDA guidance, Section 564]` - `suggested_filename: 2022-09-12_FDA_Guidance_EUA-of-Medical-Products-and-Related-Authorities.md/html/pdf` #### F) FDA: statements on "PHE ending" vs "EUA continuing" (transition clarity) **Source:** FDA FAQ, *What happens to EUAs when a public health emergency ends?* **Link:** https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/faqs-what-happens-euas-when-public-health-emergency-ends **Why it belongs in this archive:** Retrospectives often confuse (or critique) the U.S. legal architecture: the **PHE under the Public Health Service Act** can end while **Section 564 EUA declarations** remain in effect and EUAs continue unless revoked/terminated. This FAQ is a canonical clarification. **Suggested archive metadata:** - `tags: [EUA, transition planning, Section 564, PHE, legal framework]` - `suggested_filename: 2023-00-00_FDA_FAQ_EUA-After-PHE-Ends.md/html` #### G) FDA Voices (agency retrospective framing, May 11 2023) **Source:** *Lessons Learned from COVID-19 Are Informing Preparation for Future Public Health Emergencies* (FDA Voices blog, May 11, 2023) **Link:** https://www.fda.gov/news-events/fda-voices/lessons-learned-covid-19-are-informing-preparation-future-public-health-emergencies **Why it belongs in this archive:** While not a critique, it is an official retrospective narrative explaining FDA's view of lessons learned, including how EUAs persist and how FDA expects transition to traditional marketing pathways. **Suggested archive metadata:** - `tags: [EUA, FDA retrospective, transition, communications]` - `suggested_filename: 2023-05-11_FDA-Voices_Lessons-Learned_COVID-19_Preparing-Future-Emergencies.md/html` #### H) FDA testimony: "Preparing for the Next Pandemic" (late retrospective, with diagnostics + EUA process detail) **Source:** Testimony of Dr. Hilary Marston, *Preparing for the Next Pandemic: Lessons Learned and the Path Forward* (FDA, Nov 14, 2024) **PDF:** https://www.fda.gov/media/183533/download **Why it belongs in this archive:** Succinct congressional-facing synthesis of lessons learned across vaccines, therapeutics, diagnostics--useful as an "official capstone" perspective. **Suggested archive metadata:** - `tags: [EUA, testimony, pandemic preparedness, diagnostics, vaccines, therapeutics]` - `suggested_filename: 2024-11-14_FDA-Testimony_Preparing-for-the-Next-Pandemic_Lessons-Learned.md/pdf` #### I) GAO: "public health preparedness" (broader after-action oversight; useful context for EUA reforms) **Source:** *Public Health Preparedness* (GAO-25-106980, June 4, 2025) **Link:** https://www.gao.gov/products/gao-25-106980 **Why it belongs in this archive:** Not exclusively about FDA EUAs, but useful for "higher-level" retrospectives on federal preparedness, where EUA-related testing policy appears as a component of readiness. **Suggested archive metadata:** - `tags: [pandemic preparedness, oversight, GAO, diagnostics ecosystem]` - `suggested_filename: 2025-06-04_GAO-25-106980_Public-Health-Preparedness_Context.md/html/pdf` --- ### 2.2 Legislative / policy responses (useful for "what changed because of EUA criticism") #### J) House Select Subcommittee recommendations (policy critique and reform agenda; note partisan context) **Source:** *Final Report Recommendations* (Select Subcommittee on the Coronavirus Pandemic, U.S. House; Dec 4, 2024) **PDF:** https://oversight.house.gov/wp-content/uploads/2024/12/2024.12.04-SSCP-FINAL-REPORT-RECOMMENDATIONS.pdf **Why it belongs in this archive:** Captures a congressional critique agenda, including positions on how EUA should be used and how guidance / surveillance should work. **Important caveat:** This content is politically situated; archive it as a viewpoint document. **Suggested archive metadata:** - `tags: [EUA, Congress, oversight, policy critique, diagnostics, vaccines]` - `suggested_filename: 2024-12-04_US-House-SSCP_Final-Report-Recommendations_EUA-and-COVID-Response.md/pdf` #### K) PREVENT Pandemics Act (Dec 2022) and test-evaluation provisions (CRS-style explainer) **Source:** CRS-derived explainer, *PREVENT Pandemics Act (P.L. 117-328, Division FF, Title II)* (EveryCRSReport mirror; Aug 15, 2023) **Link:** https://www.everycrsreport.com/reports/R47649.html **Why it belongs in this archive:** Tracks how Congress encoded "EUA lessons" into statutory tools--e.g., provisions around **third-party test evaluation during emergencies**. **Suggested archive metadata:** - `tags: [EUA, diagnostics, legislation, PREVENT Pandemics Act, third-party evaluation]` - `suggested_filename: 2023-08-15_CRS_PREVENT-Pandemics-Act_EUA-Testing-Provisions.md/html` #### L) Third-party EUA review process (implementation-level response to EUA surge / capacity issues) **Source:** Commentary on FDA guidance: *FDA releases final guidance on 510(k) Third Party Review Program and Third Party Emergency Use Authorization (EUA) Review* (Jan 31, 2025) **Link:** https://www.cmhealthlaw.com/2025/01/fda-releases-final-guidance-on-510k-third-party-review-program-and-third-party-emergency-use-authorization-eua-review/ **Why it belongs in this archive:** The COVID EUA surge stressed review capacity; third-party mechanisms are one "capacity valve" that became more salient post-COVID. **Suggested archive metadata:** - `tags: [EUA, review capacity, third-party review, CDRH, process reform]` - `suggested_filename: 2025-01-31_Commentary_Third-Party-EUA-Review_510k-Program.md/html` --- ### 2.3 Professional associations, NGOs, and policy stakeholders (diagnostics focus) #### M) American Clinical Laboratory Association (ACLA): PAHPA feedback referencing EUA experience **Source:** *ACLA Responds to Senate RFI on PAHPA* (Mar 29, 2023) **PDF:** https://www.acla.com/wp-content/uploads/2023/04/ACLA-Responds-to-Seante-RFI-on-PAHPA.pdf **Why it belongs in this archive:** Represents laboratory-sector critique and reform priorities informed by COVID EUA testing experience, especially around LDTs, regulatory clarity, and emergency readiness. **Suggested archive metadata:** - `tags: [EUA, diagnostics, laboratories, ACLA, policy feedback, PAHPA]` - `suggested_filename: 2023-03-29_ACLA_Response_Senate-RFI_PAHPA_EUA-Testing.md/pdf` #### N) Stanford Law policy commentary (LDT/EUA governance debate remains unresolved) **Source:** *FDA policy reform for in vitro diagnostics and laboratory develop tests remains in limbo* (Stanford Law, Aug 3, 2023) **Link:** https://law.stanford.edu/2023/08/03/fda-policy-reform-for-in-vitro-diagnostics-and-laboratory-develop-tests-remains-in-limbo/ **Why it belongs in this archive:** Concise synthesis of the post-COVID LDT governance limbo--useful for connecting EUA-era controversies to broader regulatory reform debates. **Suggested archive metadata:** - `tags: [EUA, diagnostics, LDT, policy analysis, Stanford]` - `suggested_filename: 2023-08-03_Stanford-Law_LDT-Policy-Reform-Limbo_Post-COVID.md/html` --- ### 2.4 Academic and independent analyses (diagnostics and broader EUA governance) #### O) Legal/academic deep dive on COVID test regulation and EUA policy shifts **Source:** Gibbs & Javitt, *Test of Emergency* (PDF posted Jan 2023; law/policy analysis of COVID testing regulation and FDA EUA policy shifts) **PDF:** https://hpm.com/wp-content/uploads/2023/01/Test-of-Emergency-Gibbs-Javitt.pdf **Why it belongs in this archive:** Detailed narrative of the "zig-zagging" testing policy environment and its impacts--useful for historians and regulatory analysts. **Suggested archive metadata:** - `tags: [EUA, diagnostics, LDT, legal analysis, policy volatility, COVID testing]` - `suggested_filename: 2023-01-00_Gibbs-Javitt_Test-of-Emergency_COVID-Testing-EUA-Policy.md/pdf` #### P) Laboratory-developed tests (LDT) reform literature (post-COVID diagnostic governance debate) **Source:** Miller (2024), *FDA's proposed rule for the regulation of laboratory-developed tests* (Journal of Clinical Microbiology) **Link:** https://journals.asm.org/doi/10.1128/jcm.01488-23 **Why it belongs in this archive:** Connects COVID-era diagnostic shortcomings and policy debates to the post-COVID push to formalize oversight of LDTs--an adjacent but important "EUA aftermath" topic. **Suggested archive metadata:** - `tags: [EUA, diagnostics, LDT, regulation reform, peer-reviewed]` - `suggested_filename: 2024-00-00_Miller_FDA-Proposed-Rule_LDTs_Post-COVID-Diagnostics-Governance.md/html/pdf` #### Q) CRS explainer on FDA's LDT proposed rule (policy overview; good for non-lawyers) **Source:** CRS-derived explainer, *Regulation of Laboratory-Developed Tests: FDA's Proposed Rule* (Apr 8, 2024) **Link:** https://www.everycrsreport.com/reports/IF12628.html **Why it belongs in this archive:** Compact background and timelines; useful as a "bridge document" between COVID testing failures/EUA debates and LDT rulemaking. **Suggested archive metadata:** - `tags: [EUA, diagnostics, LDT, CRS, oversight]` - `suggested_filename: 2024-04-08_CRS_IF12628_LDT-Proposed-Rule_Context-from-COVID.md/html` #### R) Federal Register (public inspection PDF): LDT rulemaking text referencing COVID emergency enforcement guidance **Source:** *Medical Devices; Laboratory Developed Tests* (Public Inspection PDF, Apr 29, 2024; Doc. 2024-08935) **PDF:** https://public-inspection.federalregister.gov/2024-08935.pdf **Why it belongs in this archive:** Primary-source regulatory text that situates emergency enforcement guidance (e.g., for COVID/mpox IVDs) within FDA's broader IVD oversight posture. **Suggested archive metadata:** - `tags: [EUA, diagnostics, LDT, Federal Register, enforcement discretion]` - `suggested_filename: 2024-04-29_Federal-Register_2024-08935_LDT-Rule_Public-Inspection.pdf` #### S) Academic/legal discussion of vaccine EUA controversy (example post-2022 scholarly record) **Source:** Sax (2024), *COVID-19 pediatric vaccine authorization, FDA ...* (PubMed Central article) **Link:** https://pmc.ncbi.nlm.nih.gov/articles/PMC11034974/ **Why it belongs in this archive:** Captures a scholarly framing of why vaccine EUA decisions generated controversy; useful for the "EUA and trust" thread. **Suggested archive metadata:** - `tags: [EUA, vaccines, pediatrics, controversy, scholarly analysis]` - `suggested_filename: 2024-00-00_Sax_COVID-19-Pediatric-Vaccine-Authorization_EUA-Controversy.md/html` #### T) HHS/ASPE: clinical trial enterprise lessons learned (where EUA acceleration intersects with trial design norms) **Source:** *COVID-19 Pandemic Lessons Learned for the Clinical Trial Enterprise* (HHS ASPE, 2024) **PDF:** https://aspe.hhs.gov/sites/default/files/documents/3a0c88cdfc78c03d50043088da18ec4e/Clinical-Trial-Lessons-Learned.pdf **Why it belongs in this archive:** While broader than EUA, it's useful for documenting how "emergency" timelines (including EUA endpoints) pressured trial infrastructure and standards. **Suggested archive metadata:** - `tags: [EUA, clinical trials, pandemic preparedness, HHS, lessons learned]` - `suggested_filename: 2024-00-00_HHS-ASPE_Clinical-Trial-Enterprise_Lessons-Learned_COVID.md/pdf` --- ### 2.5 Postmarket corrections, revocations, and transparency disputes (for historical completeness) #### U) Diagnostic EUAs revoked (example of postmarket quality control) **Source:** CDC Laboratory Alert, *FDA Revokes EUAs for Six SARS-CoV-2 In Vitro Diagnostic Devices* (Mar 26, 2024) **Link:** https://www.cdc.gov/locs/php/messages/2024/2024-03-26-fda-revokes-euas-for-six-sars-cov-2-in-vitro-diagnostic-devices.html **Why it belongs in this archive:** Useful exemplar of how EUA oversight continues after authorization--revocation as a corrective mechanism. **Suggested archive metadata:** - `tags: [EUA, diagnostics, revocation, postmarket monitoring, CDC LOCS]` - `suggested_filename: 2024-03-26_CDC-LOCS_FDA-Revokes-EUAs_SARS-CoV-2-IVDs.md/html` #### V) Therapeutic EUAs revoked as variants made products ineffective (news record) **Source:** Reuters, *US FDA revokes authorization for four COVID antibody drugs* (Dec 23, 2024) **Link:** https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-revokes-authorization-five-covid-treatments-2024-12-23/ **Why it belongs in this archive:** Documents the practical lifecycle of therapeutic EUAs amid variant churn; relevant to critiques about how quickly EUA status must adapt to changing evidence. **Suggested archive metadata:** - `tags: [EUA, therapeutics, revocation, variants, postmarket]` - `suggested_filename: 2024-12-23_Reuters_FDA-Revokes-EUAs_COVID-Antibody-Treatments.md/html` #### W) Transparency / FOIA litigation about vaccine EUA decision records (news record) **Source:** Reuters, *FDA must disclose more COVID-19 vaccine records, US judge rules* (Dec 6, 2024) **Link:** https://www.reuters.com/legal/government/fda-must-disclose-more-covid-19-vaccine-records-us-judge-rules-2024-12-06/ **Why it belongs in this archive:** Captures a central "EUA criticism" theme: the perceived gap between emergency decision-making and later transparency expectations. **Suggested archive metadata:** - `tags: [EUA, vaccines, transparency, FOIA, trust, litigation]` - `suggested_filename: 2024-12-06_Reuters_FDA-Vaccine-EUA-Records_Disclosure-Order.md/html` --- ## 3) Crosswalk: Which sources speak to which critique themes? | Theme / critique area | Especially relevant sources to archive | | --- | --- | | Diagnostics: evidence standards and validation under time pressure | OIG (2022); FDA Draft Validation Guidance (2025); Gibbs & Javitt (2023) | | Diagnostics: enforcement discretion start/stop triggers | GAO (2022); FDA Final Enforcement Policies Guidance (2025) | | Policy volatility / clarity for developers | OIG (2022); Gibbs & Javitt (2023); ACLA (2023); House SSCP Recommendations (2024) | | Postmarket monitoring, revocation, and communication | CDC LOCS (2024); Reuters revocation coverage (2024); FDA enforcement policy framework (2025) | | Transparency and trust (especially vaccines) | Reuters FOIA litigation coverage (2024); scholarly discussions like Sax (2024) | | Transition planning (PHE ends; EUAs may persist) | FDA FAQ on EUAs after PHE; FDA Voices (May 11 2023); FDA testimony (2024) | | "EUA surge" capacity and process design | Booz Allen baseline (2021); third-party EUA review mechanisms (2025); FDA guidance modernization (2022--2025) | | | | --- ## 4) Practical archiving guidance (FloodLAMP-style) ### Suggested filename convention Use a consistent format for easy sorting: `YYYY-MM-DD__.` Examples: - `2025-09-23_FDA_CDRH_Guidance_Enforcement-Policies-IVD_Section-564.pdf` - `2022-11-00_HHS-OIG_FDA-EUA-Policies_COVID-Testing.pdf` ### Suggested tags (consistent across documents) Recommended tag vocabulary for this topic: - `EUA` - `diagnostics`, `IVD`, `LDT`, `vaccines`, `therapeutics` - `enforcement discretion` - `validation`, `evidence standards` - `policy volatility`, `guidance churn` - `postmarket monitoring`, `revocation` - `transparency`, `FOIA`, `trust` - `pandemic preparedness`, `after-action`, `lessons learned` - `review capacity`, `third-party review` --- ## 5) Notes on completeness and next steps This report emphasizes **high-signal, archive-worthy** documents that either: 1) directly evaluate FDA's EUA decision-making during COVID-19, or 2) codify lessons learned into post-COVID policy and guidance (2023--2025). If you want to deepen the **academic** slice further, a next pass could focus on: - peer-reviewed analyses of vaccine EUA evidence standards and advisory committee process; - comparative analyses (FDA vs EMA/UK MHRA emergency pathways); - empirical studies of EUA revocations, postmarket signals, and communications. # 649 _context-commentary_regulatory-reg-articles-misc.md METADATA last updated: 2026-03-01 RT file_name: _context-commentary_regulatory-reg-articles-misc.md category: regulatory subcategory: reg-articles-misc words: 430 tokens: 649 CONTENT ## Context This subcategory collects a small number of higher-level reports and assessments related to FDA oversight of COVID-19 diagnostics. Unlike other regulatory subcategories in the archive that focus on specific FloodLAMP interactions with the FDA (submissions, correspondence, townhalls), these files are third-party or government-produced documents that provide broader perspective on the EUA process and diagnostic test validation during the pandemic. The three documents are: - **Booz Allen Hamilton Independent EUA Assessment** (`2021-10-08_FDA Report - EUA Assessment by Booze Allen.md`): An FDA-commissioned review of CDRH's COVID-19 test EUA response, covering how the FDA used templates, guidance updates, triage, and deprioritization to manage thousands of submissions. It includes priority recommendations around IT systems, staffing models, and a validation framework for future emergencies. This report predates the Omicron surge and the severe testing shortages that followed. - **FDA's Work to Combat the COVID-19 Pandemic** (`2022-07-01_FDA Report - FDAs Work to Combat the COVID-19 Pandemic.md`): A broad FDA overview summarizing cross-center actions on vaccines, therapeutics, diagnostics, supply chain, inspections, and regulatory science, with data current as of April 2022. - **Phillips and Dinakar Proposal** (`2021-01-18_Phillips and Dinakar - A Proposal for Increasing the Speed of Validating SARS-CoV-2 Diagnostic Tests.md`): A paper proposing three extensions to the EUA process for accelerating diagnostic test validation: structured (machine-readable) EUA data submissions, distributed FDA-directed CLIA-led validation, and building an open synthetic patient clinical specimen panel. In addition, an AI-generated research report (`_AI_fda-eua-covid-retrospectives_post2022_report.md`) was created during archive preparation to identify post-2022 retrospectives, evaluations, and criticisms of the FDA's EUA process. That report catalogs sources from government oversight agencies (HHS OIG, GAO, FDA), legislative bodies, NGOs, professional associations, and academics, and may serve as a starting point for readers interested in pursuing the broader literature on EUA reform and pandemic preparedness policy. ## Commentary TThe Phillips and Dinakar proposal for structured, machine-readable EUA data submissions resonated with FloodLAMP's own experience navigating the EUA process. The idea that submissions could be standardized in a way that accelerates FDA review, reduces ambiguity for developers, and enables computational analysis of submission data is the kind of practical, systems-level reform that would likely have compounding benefits across future emergencies. More broadly, the potential for AI to improve FDA processes around diagnostic test evaluation, guidance development, and emergency response has been a recurring theme throughout this archive (see commentary on the FDA townhalls subcategory and the open-EUAs subcategory). The scale and complexity of the COVID-19 testing response — thousands of EUA submissions, rapidly evolving guidance, variant-driven obsolescence — represent exactly the kind of problem where AI-assisted workflows could meaningfully reduce friction and improve outcomes. # 8,418 2021-01-18_Phillips and Dinakar - A Proposal for Increasing the Speed of Validating SARS-CoV-2 Diagnostic Tests.md METADATA last updated: 2026-03-05 by BA file_name: 2021-01-18_Phillips and Dinakar - A Proposal for Increasing the Speed of Validating SARS-CoV-2 Diagnostic Tests.md file_date: 2021-01-18 title: Phillips and Dinakar - A Proposal for Increasing the Speed of Validating SARS-CoV-2 Diagnostic Tests category: regulatory subcategory: reg-articles-misc tags: source_file_type: pdf xfile_type: NA gfile_url: NA xfile_github_download_url: https://raw.githubusercontent.com/FocusOnFoundationsNonprofit/floodlamp-archive/main/regulatory/reg-articles-misc/2021-01-18_Phillips%20and%20Dinakar%20-%20A%20Proposal%20for%20Increasing%20the%20Speed%20of%20Validating%20SARS-CoV-2%20Diagnostic%20Tests.NA pdf_gdrive_url: https://drive.google.com/file/d/1JNV1qjtI2poNYGCp89FMRv1oNxOSpuBo pdf_github_url: https://github.com/FocusOnFoundationsNonprofit/floodlamp-archive/blob/main/regulatory/reg-articles-misc/2021-01-18_Phillips%20and%20Dinakar%20-%20A%20Proposal%20for%20Increasing%20the%20Speed%20of%20Validating%20SARS-CoV-2%20Diagnostic%20Tests.pdf conversion_input_file_type: pdf conversion: AI license: 3rd Party tokens: 8418 words: 4928 notes: summary_short: Phillips and Dinakar's proposal paper (v0.1.9, January 2021) recommends three extensions to the FDA's EUA process for accelerating validation of SARS-CoV-2 diagnostic tests: structured (machine-readable) EUA data submissions, distributed FDA-directed CLIA-led validation leveraging existing laboratory expertise, and building an open synthetic patient clinical specimen panel to reduce dependence on limited clinical samples for test validation. CONTENT ***INTERNAL TITLE:*** A Proposal for Increasing Speed of Validating SARS-CoV-2 Diagnostic Tests Alexander James Phillips †, Karthik Dinakar ‡ † Center of Complex Interventions, ‡ Massachusetts Institute of Technology Correspondence to ajp@centerofci.org v0.1.9 - 2021 Jan 18th ## SUMMARY Rapid access to diagnostics for emerging high priority pathogens is of great importance from a clinical, public health and economic point of view. Currently in the United States there are several technological, regulatory and organisational improvements that might be adopted for the COVID-19 and future pandemics. In this article, we suggest a proposal for increasing the speed of validating SARS-CoV-2 diagnostic tests, suggestions include: a structured (machine readable) EUA data submission process, distributed FDA directed CLIA led validation, and building an open synthetic patient clinical sample panel. This document is a work in progress, containing some ideas which may be of value to consider and implement. We welcome you to add your name to this proposal or make a contribution of any size and scope. This concept and paradigm will be of utmost importance for pandemics of diseases more prone to the emergence of new mutant strains that evade current diagnostics and vaccines. ## CONTENTS 1 The Opportunity and Goals - 1.1 Diagnostic tests are powerful tools, we need rapid access to them - 1.2 We need trustworthy knowledge of diagnostics performance - 1.3 Emergency Use Authorisation, United States Code 2 The Current Situation - 2.1 Initial response time - 2.2 EUA backlog delays tests coming to market - 2.3 Heterogeneous quality of test performance data - 2.4 No guarantee of accurate test performance data - 2.5 Quality control and reference materials 3 Possible Extensions to Current Validation Process - 3.1 EUA minimum structured data - 3.2 FDA directed CLIA led validation - 3.3 Synthetic clinical specimen panel challenge - 3.3.1 Current strategy: waiting for infections to get specimens to validate against - 3.3.2 New strains are harder to counter - 3.3.3 Underpowered validation: Clinical specimen edge cases - 3.3.4 Routes to characterised viral material for reproducible validation of diagnostics - 3.3.5 Synthetic patient specimen panel - 3.3.6 Potential advantages of a synthetic patient specimen panel 4 Request for Comment 5 Revision History ## 1 THE OPPORTUNITY AND GOALS ### 1.1 Diagnostic tests are powerful tools, we need rapid access to them Well characterised diagnostic tests for diseases are powerful tools to help clinicians, public health and policy makers treat patients, and lessen the burden of communicable diseases on communities. In situations of newly emerging serious infectious diseases, rapid access to diagnostics tests is of utmost importance. Diagnostic tests allow clinicians to better treat their patients. Population screening allows public health officials to help trace and break chains of infection and find asymptomatic individuals. In conjunction with policy makers providing support, this allows for test, trace and isolate public health programs to reduce or eliminate community transmission [4]. ### 1.2 We need trustworthy knowledge of diagnostics performance As important as the test itself is clear and trustworthy knowledge of the tests performance characteristics. Although we do need tests "that work", it's important that we know how well tests work, which includes the uncertainty of those metrics describing the test's performance. One of the objectives of the VITAL Act (Verified Innovative Testing in American Laboratories) of 2020 is to "ensure that laboratory-developed testing procedures are accurate, precise, clinically-relevant" [23, 22d]. In other words, it is necessary for an initial validation to be performed for each new diagnostic test and for that initial validation to be well characterised and consistent to allow comparison between different tests. ### 1.3 Emergency Use Authorisation, United States Code The United States Food and Drug Administration (FDA) oversees the Emergency Use Authorisation (EUA) process, including that for COVID-19 related medical devices [6]. The criteria for the issuance of EUAs are stated in Act 21 U.S.C. §§ 360bbb-3(c)(1-5) [30]. Included is the legal and binding duty to ensure: the known and potential benefits of the product, when used to diagnose, prevent, or treat such disease or condition, outweigh the known and potential risks of the product, taking into consideration the material threat posed and that there is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition This thought piece does not disagree with these objectives and criteria; it raises the question of whether and how we might fulfil these requirements but do so more quickly. ## 2 THE CURRENT SITUATION ### 2.1 Initial response time Crucial to the early access to diagnostics was the timely and accurate publication of the SARS-CoV-2 genome [34]. This enabled high complexity CLIA labs and commercial manufacturers to respond quickly; both in the production of the tests ready for EUA submission and in the quality control material necessary to begin reproducible measurement and validation of test performance. Many elements of our molecular pathology diagnostic response to this pandemic have been exceptional. The rapid speed at which diagnostics were made ready by molecular pathology laboratories was on par with the 2009 H1N1 pandemic [18, 22b]. However the FDA's EUA process initially significantly slowed efforts to deploy these tests. Without these tests, samples were sent to central public health labs which limited the scale of testing and slowed down the test to result time. Both testing capacity and responsiveness are crucial factors in getting ahead of outbreaks and containing them through public health counter measures. This lack of testing and responsiveness also limited clinicians and policy makers in treating and providing scientific, data driven leadership [17]. The FDA responded to these challenges and updated their guidance to accommodate more risk [5c]. This was a crucial leadership decision that will surely be reflected upon and copied for future infectious disease outbreaks. ### 2.2 EUA backlog delays tests coming to market Over the following months, almost 1 new diagnostic test was given EUA status per day [15]. The FDA simultaneously grew their diagnostics review team from 25 to 100 (as of mid October [10]) with many more support staff. Despite these admirable efforts there remains a backlog of new diagnostic tests awaiting FDA review for EUA [11b, 10]. This backlog delays companies from bringing their test to market. This delay has a negative effect on our collective ability to leverage all supply chains and technologies as quickly as possible and bring them to bear against this new infectious disease. In hindsight this backlog and associate delay, along with many other shortcomings outside of the FDA's EUA process [8, 21] may be shown to have had a significant negative effect on the ability of the United States to effectively respond to the pandemic. ### 2.3 Heterogeneous quality of test performance data As previously stated, rapid access to tests with trustworthy evaluation of test performance is a fundamental requirement. Although many tests have now attained EUA, the quality of the documentation and validation of these tests is heterogeneous [28]. This characteristic has persisted since the beginning of the outbreak, is a large source of uncertainty for laboratory staff and managers making decisions about which test to purchase, and increases the burden needed to validate a new diagnostics test. The information heterogeneity shows itself in many forms, the first of which being information in EUAs. Some EUAs are thorough and concise with all the necessary information present. On the other extreme are EUAs that lack crucial information, have errors, or reference data that does not exist. The clearest example of this are primer sequences which although requested by the FDA are only present in 34% of submissions dropping to 5.8% of the most frequently used tests [28]. This is important information given the range of mutations which have been found to negatively impact test performance [13, 32, 2]. Performance degradation might have occurred in other tests and is unlikely to have been detected in all cases. Inclusion of primer / probe sequence information might increase the ability of laboratory, public health and others to be more proactive in the face of new mutant viral strains [29b]. ### 2.4 No guarantee of accurate test performance data Finally the current EUA process does not ensure the validation results reported are reproducible. In several instances [14, 3b] widely used diagnostic test were assessed and a significant difference was found between the limit of detection (LOD) reported in the EUA and that which the investigators measured using their own reagents and protocol. These are not isolated incidences and the sensitivity of diagnostics given by its LOD is important for effective public health Test Trace Isolate (TTI) programs [1]. As mentioned previously, in several cases the EUA process has not guaranteed disclosure of some essential attributes of diagnostic test characteristics. Similar to the previously cited example where LOD reported in EUAs was not reproducible, several EUAs also report LOD with non SI units of TCID50 ml⁻¹ [28]. This prohibits investigations to reproduce the claimed performance characteristics. The lack of information or guarantees about the performance of diagnostics tests has transferred the cost of validation to the labs adopting the tests [22c, 20d]. Various open and closed networks of laboratory staff have taken up the role of sharing important test performance information. It would be powerful if there was an open, structured data repository of diagnostic test performance data. Similar to Wikipedia, lab staff could contribute verification / validation data of diagnostic test performance; benefiting other labs, in return benefiting from data submitted by other labs and collectively benefitting the patients they serve. Whilst such a community of lab staff and shared data store would be of great aid to a public health emergency, most labs are primarily driven by commercial pressures and would not be expected to contribute towards such a collective effort despite benefitting from it. ### 2.5 Quality control and reference materials Viral positive control materials were produced early on and are now widely available. Providers include a range of commercial and government sources [7]. Viral material includes positive clinical specimens, naked RNA, virus like particles, live virus and inactivated virus. ## 3 POSSIBLE EXTENSIONS TO CURRENT VALIDATION PROCESS These proposals revolve around 3 main themes. Firstly, the merits of defining a minimum set of required data for a diagnostics EUA and doing so in a structured form. Secondly, utilising the validation work already done by some of the high complexity CLIA laboratories around the United States. Thirdly, combining existing quality control materials to provide a representative and extensible panel of synthetic clinical specimen challenges for tests to pass. We hope these suggestions aid further discussion around new models of validating tests, potentially helping bring tests to market sooner, both during this pandemic and any future pandemics. ### 3.1 EUA minimum structured data The normal submission process for a new diagnostic tests accumulates thousands of pages and takes years [26b]. The EUA process instead requires only tens of pages and should take days to complete. This might enable labs and manufacturers to legally distribute their test within days and meet the urgent need for diagnostics to contain and aid treatment of SARS-CoV-2. Some tests awaiting review and approval by the FDA have taken over a hundred days and counting. This has largely been due to the volume of testing required which has stimulated a large market response. The correspondingly large volume of submissions has saturated the FDA's capacity to review new submissions in a timely fashion. As mentioned previously the FDA has been exemplary in their continual adaptation and responsiveness. Expanding their team by many factors [10], reducing and refining the minimum set of information required for EUAs and providing multiple template EUA documents [12]. These templates have aided manufacturers, laboratories and others in their EUA submission process by helping to ensure the minimum information is included. And secondly may have aided the FDA reviewers by providing a more standardised form of EUA submission which makes comprehending and reviewing the EUAs a faster process. For the same EUA submission type, for example "Molecular Diagnostic Template for Commercial Manufacturers", each EUA submission should contain the same types of data. However despite the templates provided there is still significant heterogeneity in the data [28]. Adopting a tool to enforce structured data upon submission for an EUA might aid both the companies in ensuring all the necessary fields are completed, and the reviewers in checking the data. There are many providers of such tools such as TypeForm, Microsoft Forms, etc. These off the shelf solutions are cheap, secure, fast to configure and reliable. The structured data they take in could then be provided as is or additionally used to automatically populate the templates mentioned earlier. The applications for structured data are many but at a minimum might allow laboratories looking for a new test to more easily compare and search across the available EUA data. The structured data might also aid the FDA's internal processes, allowing for better prioritisation, communication with and tracking of applicants. _Flowchart diagram showing the EUA process from test manufacturers through FDA review to approval and publication of EUAs/IFUs. Solid red boxes indicate where structured data could be employed at the submission, initial review, and laboratory use stages. Dashed boxes indicate downstream processes and workflows—such as prioritisation, clarification requests, and cross-EUA comparison—that may be aided by the presence of structured data._ **Figure 1:** Locations in the current EUA process where structured data may be employed (solid red boxes) to expedite and enable related processes and workflows (dashed boxes) by ensuring data is present, formatted consistently and easier to parse, prioritise and compare against other EUAs. IFU: Instructions For Use documentation may form part of the package inserts. Adapted from FDA's SHIELDx presentation [25]. SHIELDx (Systemic Harmonization and Interoperability Enhancement for Lab Data) program's stated goal is to "Describe the same test data the same way". ### 3.2 FDA directed CLIA led validation The requirement of an EUA for a Laboratory Developed Test (LDT) has recently been lifted by the FDA [16b]. Whilst there may have been a component of political pressure, this in part is due to the depth of expertise of the directors and staff in the nation's ~2,500 high complexity CLIA laboratories subspecialising in virology (~127,000 high complexity CLIA laboratories as of 2011 [33b] of which 2% subspecialise in virology [33c]). The LDT EUA rescission has allowed many hundreds of laboratories to legally begin immediate use of their LDTs for diagnosis. In conjunction with the LDTs they have developed and validated, many laboratories have and will continue to increase their testing capacity by evaluating and purchasing commercial test manufacturers equipment and reagents. It has already been highlighted that expert validation work of newly purchased diagnostic tests is being conducted by the purchasing labs [22c], as is required by CLIA regulations [27b]. Taken together this validation work may collectively be being conducted with a much broader range of acceptable sample types. This is important as it has the potential to contain a sufficient number of specimens to be representative of the population of specimens and avoid being a statistically underpowered validation of a diagnostic test. Secondly this work is inherently aligned to the interests of patients, society, laboratories, regulators and test manufacturers by avoiding the potential unconscious bias of diagnostic manufacturers as they validate their own test. As previously suggested [20b], there is an obvious opportunity to leverage this expert validation work being conducted by CLIA labs. What follows is a potential model the FDA could design, implement and coordinate in this and future pandemics: 1. A prospective supplier seeking an EUA sends a number of copies of the machine (a minimum of 3, preferably more) and sufficient reagents (e.g. for 1000+ tests each) to the FDA along with their submission of structured data describing the test, its performance characteristics as assessed by the manufacturer, claimed capabilities, etc. 2. Separately, for free or a fee, laboratories make themselves available to the FDA to review the EUA and validate machines. This is a task all have already had to do during this pandemic and seems prudent to harness this significant capacity of distributed talented work 3. The FDA can conduct their own evaluation of the machine whilst also sending the draft EUA, a machine, and reagents to a random subset of available laboratories. Optionally a reference panel (see "Synthetic clinical specimen panel challenge" below) can be sent as well. Amongst other potential benefits a reference panel would enable harmonising results between laboratories 4. The initial standard sets of validation data, including positive viral materials used, comparator test, etc. are uploaded to a centralised database 5. Any significant discrepancy between laboratory validation results are resolved 6. The company is authorised for a particular set of EUA performance characteristics 7. Only then can the submitting company know which labs are in possession of their test machine and may offer them to buy it This is one potential model for the distributed initial validation of diagnostics for emerging, high priority pathogens. It is coordinated by the FDA and uses the existing legislation but leverages the latent, capable and eager talent of our molecular pathology laboratories. _Flowchart diagram showing test manufacturers submitting EUAs along with machines and reagents to the FDA, which then distributes them to randomly selected available CLIA laboratories for independent validation. The laboratories conduct CLIA-led validation and report results back to the FDA for review, leading to approval and publication of EUAs/IFUs._ **Figure 2:** Potential model leveraging validation work being performed in CLIA laboratories to maximise speed, volume and accuracy of authorising emergency diagnostics. IFU: Instructions For Use. ### 3.3 Synthetic clinical specimen panel challenge #### 3.3.1 Current strategy: waiting for infections to get specimens to validate against When a new pathogen emerges the availability of clinical samples to test with is very limited. This limitation slowed down the effective development and validation of much needed new diagnostics for COVID-19 pandemic. (todo: find and cite paper reiterating benefits of international sharing of specimens) Our current strategy is to wait for sufficient new infections to get sufficient samples needed for multiple labs, commercial manufacturers and government agencies to all develop and validate their diagnostics tests. If not addressed, this strategy will slow down the response to the next pathogen or strain that emerges. Secondly the threshold for which diagnostics tests must overcome to show clinical efficacy was 20 and is now set at 30 positive patient samples. During the early stages of a pandemic, when testing is most important to control spread, there are insufficient samples which makes this barrier insurmountable. #### 3.3.2 New strains are harder to counter In later stages of a pandemic that is under control there will also be insufficient samples. If there are many new infections, such as the United States and other countries like the United Kingdom are experiencing coming into the winter of 2020, there is a different problem, namely the increased infections, increases the chance of mutations rendering existing diagnostics less effective [13, 32, 2]. This is an identical, if not harder, scenario to contend with than at the outset of a pandemic. It is harder because there will be many infections from existing strains which makes identifying appropriate samples for testing against more challenging. Simultaneously, in the early phase of a new strain spreading, there will be a very low absolute and relative number of specimens for which to validate tests against. #### 3.3.3 Underpowered validation: Clinical specimen edge cases Finally, the validation of new diagnostic tests is conducted using a random but small set of samples from clinical specimens. This is likely to be statistically underpowered whilst also likely not including many or any of the significant edge cases a diagnostic test would preferably be able to correctly deal with. Edge cases such as a concurrent infection with pus, elevated mucin levels, blood, or for saliva samples, the presence of food, or acidity from orange juice etc. Some EUAs, often submitted during periods of relatively low disease prevalence, used contrived samples based on repeating tests on the same clinical sample, further limiting the range of samples the test is validated for. Other EUAs have been given based on samples of RNA in solutions of stabilizing buffer RNA Diluent P which although likely justifiable given the circumstances, would seem to have significant room for improvement to meet US Federal Regulations calling for samples used (in proficiency testing) to "mimic actual patient specimens when possible" [31]. #### 3.3.4 Routes to characterised viral material for reproducible validation of diagnostics In the absence of a national or international standard of SARS-CoV-2 material the FDA has made available a reference panel of samples [9]. This material is an important step and one called for previously to enable the standardisation of diagnostic test sensitivity [20c]. In the context of the current pandemic, wider and early access to such a control material would enable a more robust characterisation of diagnostic tests between different laboratories, machines, and batches of reagents and consumables. As this material is still restricted to the diagnostics tests which have received EUA an alternative approach is the use of commercially available control materials [7]. As these are not yet benchmarked a harmonisation study being prototyped by JIMB is underway [19]. The results from this important work should allow the use of commercial control materials to yield commutable results of diagnostics test sensitivity. This study is predicated on the quality control material being homogenous and consistent with one batch. #### 3.3.5 Synthetic patient specimen panel With the FDA reference panel, or an open source panel constructed from harmonised commercial viral material it would then be possible for multiple testing labs, and or by the FDA or another organisation like FINDDX [24]. to conduct independent and comparable validation of diagnostic sensitivity. If an open source list of ingredients for each of the reference panel specimens were made available, then over time it could be improved to more closely represent clinical specimens and extended to cover more edge cases. For example the inclusion of blood, mucin, a simulated concurrent bacterial infection and other interfering components and pharmaceuticals could be included in an extended reference panel. _Timeline comparison diagram showing two parallel processes. The current process proceeds from pathogen isolation through sequencing, test development, waiting for community prevalence to rise, collecting sufficient clinical specimens, conducting test validations, and finally granting EUAs for widespread deployment. The proposed process using a synthetic specimen panel bypasses the need to wait for clinical specimens by spiking a pre-made panel with inactivated viral material, enabling earlier test validation and EUA granting. The diagram indicates that the time saved would result in avoided community infections._ **Figure 3:** How the use of a pre made clinically relevant synthetic patient specimen panel spiked with inactivated viral material may allow more rapid validation of diagnostics. Based on the assumptions that rapid access to diagnostics aids public health test, trace and isolate interventions to curtail community transmission and secondly that limited clinical samples delayed validation of new diagnostics. #### 3.3.6 Potential advantages of a synthetic patient specimen panel Confronted with a new pathogen, or a mutant of an existing pandemic pathogen, it might be much faster to spike new synthetic or inactivated viral material into such a reference panel than wait for sufficient patient specimens to validate a diagnostic test. Such a panel would also offer the opportunity to include all the edge cases such a test should be able to handle. 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In: *The Journal of Molecular Diagnostics* 22.8 (Aug. 2020), pp. 968–974. doi: 10.1016/j.jmoldx.2020.06.003. [link](https://doi.org/10.1016/j.jmoldx.2020.06.003); (b) [annotation](https://hyp.is/94iqCB9_EeuQCNcJXiV1IA/www.jmdjournal.org/article/S1525-1578(20)30360-3/fulltext); (c) [annotation](https://hyp.is/gTHBhB6_EeudDw8HxXC_sg/www.jmdjournal.org/article/S1525-1578(20)30360-3/fulltext); (d) [annotation](https://hyp.is/0rG_vCgrEeuRumtNauILPw/www.jmdjournal.org/article/S1525-1578(20)30360-3/fulltext). [23] Rand Paul. "VITAL (Verified Innovative Testing in American Laboratories) Act of 2020". Mar. 2020. [link](https://www.congress.gov/bill/116th-congress/senate-bill/3512/text). [24] "SARS-COV-2 diagnostic performance data". [link](https://finddx.shinyapps.io/COVID19DxData/). [25] "SHIELDx - Harmonizing Standards Application to Accelerate Innovation". [link](https://mdic.org/wp-content/uploads/2020/02/SHIELD-Harmonizing-Standards-Application-to-Accelerate-Innovation.pdf). [26] (a) Jeffrey Shuren and Timothy Stenzel. "Covid-19 Molecular Diagnostic Testing — Lessons Learned". In: *New England Journal of Medicine* 383.17 (Oct. 2020), e97. doi: 10.1056/nejmp2023830. [link](https://doi.org/10.1056/nejmp2023830); (b) [Traditional vs EUA annotation](https://hyp.is/WHCaiigbEeudVUcdtkaPAw/www.nejm.org/doi/10.1056/NEJMp2023830). [27] (a) "State operations manual, Appendix C. Survey procedures and interpretive guidelines for laboratories and laboratory services, §493.1253". 2017. [link](https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_c_lab.pdf); (b) [New test annotation](https://hyp.is/V6fXvinMEeur7c_bYPXtXQ/www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_c_lab.pdf). [28] "Structured SARS-2 diagnostic data". [link](https://interventions.centerofci.org/pub/structured-sars-2-diagnostic-data). [29] (a) "The SARS-CoV-2 genome: variation, implication and application". Aug. 2020. [link](https://royalsociety.org/-/media/policy/projects/set-c/set-c-genome-analysis.pdf); (b) [annotation](https://hyp.is/9tlYGB6uEeuYWEOCIUY17Q/royalsociety.org/-/media/policy/projects/set-c/set-c-genome-analysis.pdf). [30] "Title 21-FOOD AND DRUGS, CHAPTER 9-FEDERAL FOOD, DRUG, AND COSMETIC ACT, SUBCHAPTER V-DRUGS AND DEVICES, Part E-General Provisions Relating to Drugs and Devices, §360bbb–3. Authorization for medical products for use in emergencies". [link](https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title21-section360bbb-3&num=0&edition=prelim). [31] "Title 42 Public Health, Chapter IV Centers for Medicare & Medicaid Services, Department of Health and Human Services, Subchapter G Standards and Certification, PART 493 - LABORATORY REQUIREMENTS, Subpart I - Proficiency Testing Programs for Nonwaived Testing, 493.901 Approval of proficiency testing programs, (b)(1)(ii)". 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[link](https://doi.org/10.1309/LMPGOCRS216SVDZH); (b) [Claimed approximate number of CLIA-certified high-complexity laboratories in the US](https://hyp.is/GRQ0PFsGEeuZRYtChYD_7w/academic.oup.com/labmed/article/44/2/163/2657801); (c) [Percentage of labs with subspecialty in virology](https://hyp.is/Yha9RFsGEeurKYsSWIH69g/academic.oup.com/labmed/article/44/2/163/2657801). [34] Y.-Z. Zhang et al. "Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1, complete genome". 2020. [link](https://www.ncbi.nlm.nih.gov/nuccore/MN908947.1). ## 5 REVISION HISTORY - v0.1.9 - 2021 Jan 18th - Integrate feedback, gratefully received from Dr Alex Greninger, University of Washington School of Medicine. - v0.1.8 - 2020 Nov 25th - Add 3 figures - v0.1.7 - 2020 Nov 23rd - Typesetting polishing and readability - v0.1.6 - 2020 Nov 19th - Typesetting polishing - v0.1.5 - 2020 Nov 19th - Author affiliations - v0.1.4 - 2020 Nov 19th - Add summary - v0.1.0 - 2020 Nov 17th - First public version # 20,803 2021-10-08_FDA Report - EUA Assessment by Booze Allen.md METADATA last updated: 2026-03-05 by BA file_name: 2021-10-08_FDA Report - EUA Assessment by Booze Allen.md file_date: 2021-10-08 title: FDA Report - EUA Assessment by Booze Allen category: regulatory subcategory: reg-articles-misc tags: source_file_type: pdf xfile_type: NA gfile_url: NA xfile_github_download_url: https://raw.githubusercontent.com/FocusOnFoundationsNonprofit/floodlamp-archive/main/regulatory/reg-articles-misc/2021-10-08_FDA%20Report%20-%20EUA%20Assessment%20by%20Booze%20Allen.NA pdf_gdrive_url: https://drive.google.com/file/d/13-zuJBhVAxgYMoiFMYajWIkbo8xxAzJ_ pdf_github_url: https://github.com/FocusOnFoundationsNonprofit/floodlamp-archive/blob/main/regulatory/reg-articles-misc/2021-10-08_FDA%20Report%20-%20EUA%20Assessment%20by%20Booze%20Allen.pdf conversion_input_file_type: pdf conversion: gdoc markdown license: Public Domain tokens: 20803 words: 14900 notes: summary_short: The FDA/Booz Allen Hamilton “Emergency Use Authorization Assessment — Final Report” summarizes an independent review of CDRH’s COVID-19 test EUA response, including how FDA used templates, guidance updates, triage/content screens, and deprioritization to manage thousands of EUA and pre-EUA submissions while prioritizing tests that increased capacity and access. It describes FDA’s validation approach (including the SARS-CoV-2 molecular reference panel and postmarket monitoring via adverse event reporting, removal lists, warning letters, and safety communications) and highlights extensive outreach tools such as town halls, FAQs, and email inboxes. It also presents Booz Allen’s priority recommendations — improving IT systems for EUA workflows, creating a systematic staffing/surge model, and developing a framework for validating diagnostics for emerging pathogens during future public health emergencies, along with FDA’s stated agreement with these priorities. CONTENT FDA PERSPECTIVE ***INTERNAL TITLE:*** Emergency Use Authorization Assessment — Final Report ## Introduction During the prior six declared public health emergencies under section 564 of the Federal Food, Drug, and Cosmetic Act, the FDA has used its emergency use authorization (EUA) authority to authorize diagnostic tests developed by commercial manufacturers and laboratories. The EUA process provides critical flexibility and expedites access to tests during emergencies. The EUA process enabled COVID-19 tests to be developed, validated, authorized, and deployed in weeks rather than months to years, as may be the case of the more rigorous evidentiary standard required outside of a public health emergency. To date, the FDA has authorized approximately 400 tests and home collection kits and granted emergency use authorization or full marketing authorization for over 1,700 medical devices, including tests, PPE, ventilators, and other devices for diagnosing, preventing, or treating COVID-19. ## Background In March 2021, Booz Allen Hamilton was selected by the FDA to conduct an independent assessment of the FDA’s Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization (EUA) response. Booz Allen Hamilton reviewed primary documents and conducted internal and external stakeholder interviews to evaluate the FDA’s response and develop recommendations for improvement. To further address current and future public health needs, the FDA’s Center for Devices and Radiological Health (CDRH) is sharing Booz Allen Hamilton’s independent assessment. For an overview of the recommendations from the independent assessment, along with CDRH’s perspectives and steps we have taken or plan to take to address the feedback, see Emergency Use Authorization of COVID-19 Tests: Independent Assessment of the FDA’s Response. The FDA agrees with the three priority recommendations identified by Booz Allen Hamilton that are presented in the independent assessment. Booz Allen Hamilton recommends that the FDA: • Optimize the IT system to account for EUA processes • Develop a systematic approach (a strategy and plan) for allocation and tracking of staff during public health emergencies (PHE) • Develop a framework for how to conduct validation of diagnostic tests for emerging pathogens in the setting of a declared PHE **Priority Recommendations to Support the EUA Process** **Recommendation: Consider ways to optimize the IT system to account for EUA processes** • From March 2020 to present, CDRH took several steps to identify IT system needs to improve tracking of EUA requests. In parallel CDRH has been working to streamline EUA processes. • Further, CDRH initiated a Digital Transformation Initiative, launched in Fiscal Year (FY) 2016, which is ongoing. This initiative is focused on providing better IT infrastructures, technology solutions, and data to help both internal and external stakeholders across all regulatory programs**.** The Digital Transformation Initiative: o Will improve tracking and data for several program areas, including EUAs, over the next two to three years. o Will help CDRH be more agile and address pressing IT challenges and stakeholder needs during a public health emergency. o Is made possible by funding first received from Congress in FY 2019 to support CDRH’s Digital Transformation Initiative. **Recommendation: Consider developing a systematic approach (a strategy and plan) for allocation and tracking of staff during public health emergencies (PHEs).** CDRH is undertaking efforts to proactively prepare for future situations by focusing on how to identify staffing needs and deploy staff to the “right place at the right time” by: • Outlining a blueprint for an Emergency Response Process that will provide guidelines for information sharing, staff mobilization, and operational flexibility with the goal of engaging the right people at the right time in future emergencies. • Starting a process improvement effort to address how ‘Surge Capacity’ is defined and managed in a standardized way across the Center. • Using a resource pool of qualified contractors to support various activities, including EUA review activities on an ‘as-needed’ basis to address the demands of the PHE. In addition to identifying ways to manage resource needs, CDRH is exploring ways to simplify and streamline the EUA process. For example, the use of review templates reduced the number of manufacturer submission pages and focused on what was the most important data to submit to the FDA. This helped FDA review staff work more efficiently given the staffing challenges. The Center will continue to develop strategies to improve its ability to increase capacity for future PHEs. **Recommendation: Consider developing a framework for how to conduct validation of diagnostic tests for emerging pathogens in the setting of a declared PHE.** CDRH’s experience with COVID-19 tests highlights the need for a common legislative framework to help ensure that all tests are accurate and reliable, regardless of whether they are developed in a laboratory or by a commercial manufacturer and regardless of whether there is an emergency. CDRH plans to: • Engage with test developers to speed the availability of future *in vitro* diagnostic (IVD) devices, including establishing: o Generic templates for commonly anticipated pathogens that may be adapted for potential future outbreaks. o A framework for conducting appropriate validation under different circumstances. • Continue strengthening communication strategies and tools that have proved effective during the COVID-19 PHE. Further, CDRH suggests that the U.S. government consider: • Working with international partners to establish a plan for sharing clinical specimens as soon as a public health threat emerges. • Establishing the capacity to independently evaluate test performance before outbreaks occur so that independent evaluation can be performed quickly during an outbreak. **For more information:** • Emergency Use Authorization of COVID-19 Tests: Independent Assessment of the FDA’s Response **Deliverable 15:** **Emergency Use Authorization** **Assessment – Final Report** CONTRACT NO. HHSF223201510027B ORDER NO. 75F40121F19043 ## CONTENTS EXECUTIVE SUMMARY ........................................................................................................ 3 1. ASSESSMENT BACKGROUND AND OBJECTIVES .................................................................. 4 2. METHODOLOGY .............................................................................................................. 5 3. ASSESSMENT FINDINGS .................................................................................................. 6 3.1 Approach to development, review, and authorization of COVID-19 tests .......................... 6 Policy developed to address COVID-specific challenges .................................................... 6 Stakeholder perspectives and lessons learned .................................................................. 9 3.2 Approach to process improvements and review times ...................................................... 9 Implemented process changes to keep pace with evolving needs and increasing submission volume .......... 9 Various factors impacted review times over the course of the public health emergency ...................... 12 Stakeholder perspectives and lessons learned .................................................................. 18 3.3 Approach to test validation, postmarket actions, and evaluation of real-world test performance .......... 18 Validation and use of reference panel to demonstrate performance ........................................ 18 Using real-world evidence to confirm test performance ..................................................... 20 Stakeholder perspectives and lessons learned .................................................................. 22 3.4 Approach to communication with requestors, clinical community, and the public .............................. 22 Established multiple communication channels .................................................................. 22 Stakeholder perspectives and lessons learned .................................................................. 25 4. BEST PRACTICES AND PRIORITY RECOMMENDATIONS .................................................... 26 5. APPENDIX .................................................................................................................... 28 5.1 Glossary .................................................................................................................. 28 --- List of Figures Figure 1-1. Key Actions in FDA’s Response to Development and Authorization of COVID-19 Tests ................. 5 Figure 3-1. Submission Templates Published ....................................................................................... 9 Figure 3-2. Percentage of OHT7 Working on COVID-19 ....................................................................... 12 Figure 3-3. Authorized IVDs During Previous PHEs ............................................................................ 13 Figure 3-4. EUA Authorizations and Acknowledgements by Month .......................................................... 13 Figure 3-5. Number of IVD EUA Requests Received by Month ................................................................ 14 Figure 3-6. Review Times of Original EUA Requests (Authorized and Declined to Issue or Denied) .............. 15 Figure 3-7. Review Times of Authorized and Acknowledged EUA Requests (Originals and Supplements) ....... 16 Figure 3-8. Review Times of Original Molecular EUA Requests from Laboratories (Authorized and Declined to Issue or Denied) .... 16 Figure 3-9. Review Times of Original Molecular EUA Requests from Commercial Manufacturers (Authorized and Declined to Issue or Denied) .. 17 Figure 3-10. Review Times of Original, Authorized, Molecular EUA Requests (Commercial Manufacturers and Laboratories) with Overlay of Number of IVD EUA Requests by Month ............................................. 17 Figure 3-11. Distribution of Original Molecular EUA Requests by Decision (Commercial Manufacturers and Laboratories) .............. 18 --- List of Tables Table 2-1. Assessment Objectives ........................................................................................................ 5 Table 3-1. Overview of Policies Outlined in Guidance to Expand Access to for COVID-19 Tests .................... 7 Table 3-2. Overview of Umbrella EUAs for COVID-19 Tests .................................................................... 7 Table 3-3. Use of Individual and Umbrella EUAs .................................................................................. 8 Table 3-4. Stakeholder Perspective on the Approach to Development, Review, and Authorization of COVID-19 Tests ................. 9 Table 3-5. COVID-19 Test Prioritization Factors .................................................................................. 10 Table 3-6. COVID-19 Test EUA Breakdown by Decision ......................................................................... 14 Table 3-7. Stakeholder Perspective on the Approach to Process Improvements and Review Times ................................. 18 Table 3-8. Molecular Diagnostic Reference Panel Results ...................................................................... 19 Table 3-9. EUA Postmarket Actions .................................................................................................... 21 Table 3-10. Collaborations to Evaluate the Potential Application of RWE During a PHE ............................................ 21 Table 3-11. Stakeholder Perspective on the Approach to Test Validation, Postmarket Actions, and Evaluation of Real-world Test Performance ..................................................................................................................... 22 Table 3-12. Stakeholder Perspective on the Approach to Communication with Requestors, Clinical Community, and the Public .......... 26 Table 4-1. Best Practices Identified by Booz Allen to Support the EUA Process ...................................................... 26 Table 4-2. Priority Recommendations Identified by Booz Allen to Support the EUA Process .......................................... 26 Table 5-1. Glossary of Abbreviations and Acronyms .............................................................................. 28 ## EXECUTIVE SUMMARY In March 2021, Booz Allen was selected by the U.S. Food and Drug Administration (FDA) to conduct an independent assessment of the Agency’s Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization (EUA) response. Booz Allen reviewed primary documents and interviewed internal and external stakeholder to evaluate FDA’s response and develop recommendations for improvement. FDA has played a critical role in our nation’s response to the COVID-19 public health emergency (PHE). As medical devices, particularly diagnostic tests, are the first line of defense against an emerging outbreak, the Center for Devices and Radiological Health (CDRH) was the first FDA Center to review EUA requests that were authorized under the Agency’s authority to issue EUAs in this PHE. The number of device EUA requests granted by FDA were well above the total number of EUAs granted for all previous PHEs combined. The current pandemic has driven a need for medical devices, including tests and more, that has far exceeded what was experienced in prior PHEs. This assessment focuses on the EUA process for COVID-19 tests, how the Agency prioritized processing of EUA requests, review times, accuracy/reliability of the COVID-19 tests, a comparison of FDA’s response to prior PHEs, and requestors’ perspectives. Throughout the course of the PHE, FDA modified the EUA process to respond to the increased volume of submissions. The findings outlined in the report identify key actions FDA took in their response to COVID-19, including the following: • **Requestor Support:** Published three guidance documents and developed ten submission templates, and continuously updated these to maximize development of and facilitate access to COVID-19 tests with flexible policies. • **Review Prioritization:** Established factors to prioritize review of EUA requests, including test capacity, accessibility, and supply chain considerations, to focus review time on the most impactful requests based on the state of the pandemic. • **Process Improvements:** Developed and implemented process improvements to operationalize prioritization factors and improve review efficiency, including a front-end triage, content screen, and deprioritization process. • **Review Volume:** Reviewed and closed out over 2,000 EUA-related submissions, including Original EUAs and Supplements as well as over 1,000 Pre-EUAs as of April 2021\. • **Authorization:** Authorized a total of 360 Original EUA requests and 452 EUA Supplements for *in vitro* diagnostics (IVD) as of April 12, 2021\. • **Real-World Evidence (RWE) Generation:** Established collaborations focused on gathering and analyzing Real World Data (RWD)/RWE to enable data sharing, harmonized data standards, reporting, and data collection. • **Communications and Outreach:** Hosted over 50 Town Hall sessions and webinars; posted over 300 Frequently Asked Questions (FAQ); stood-up a 24/7 hotline; created a central mailbox to help requestors accelerate submissions by providing frequent feedback; and developed educational testing resources for health care providers. • **Test Performance Transparency:** Created three informational websites addressing test performance (molecular reference panel website, serology test performance website, and viral mutations impacts website); sent out Warning Letters and Safety Communications; and collaborated with the National Cancer Institute (NCI) for independent evaluation of certain performance characteristics of serology tests. The recommendations presented in this report incorporate lessons learned and stakeholder perspectives and serve as a summary of actions for the Agency to consider as they continue to serve on the frontline in response to current and future public health needs. ## 1\. ASSESSMENT BACKGROUND AND OBJECTIVES Booz Allen evaluated the Center for Devices and Radiological Health’s (CDRH) Emergency Use Authorization (EUA) process for Coronavirus Disease 2019 (COVID-19) tests. Specifically, we performed a comprehensive analysis of how the Agency prioritized the processing of the EUA requests, review times, accuracy/reliability of the COVID-19 tests, a comparison of the U.S. Food and Drug Administration’s (FDA) response to prior public health emergencies (PHE), and requestors’ perspectives. FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. On January 31, 2020, the Secretary of the Department of Health and Human Services (HHS) declared a PHE related to COVID 19\. On February 4, 2020, pursuant to Section 564 of the Federal Food, Drug, and Cosmetic Act (FD\&C Act), the Secretary of HHS provided FDA with the authority to grant EUAs for *in vitro* diagnostics (IVD) to detect and/or diagnose COVID-19. EUA authority helps strengthen the nation’s public health protections by facilitating the availability and use of unauthorized medical products, or unapproved uses of approved medical products, during PHEs. An EUA request for a test can be issued when, among other things, FDA determines based on the totality of scientific evidence, that there is a reasonable belief that the test may be effective in diagnosing patients, and the known and potential benefits outweigh the known and potential risks, rather than waiting to grant full marketing authorization when it has reasonable assurance that the product is safe and effective. FDA recognized the need to quickly detect the spread of COVID-19, and the first EUAs issued were for COVID-19 tests in February 2020,1,2 allowing them to be deployed much quicker than under traditional premarket pathways. FDA faced criticism over public perceptions that surrounded COVID-19 testing ranging from the amount of time to development and availability, to the validity of tests. However, there were underlying reasons for these challenges including supply chain shortages of materials needed to develop and perform tests, unprecedented EUA volume, and inexperienced test developers. Prior to the declaration of the PHE, FDA took actions to advance development of diagnostic tests to control the emergence and spread of COVID-19. To support early engagement with EUA requestors, FDA began proactively coordinating EUA related activities including the development of voluntary EUA review templates, interactive review with requestors, policy development, initiating the development of reference materials, and external communications. Such initial efforts required internal coordination across the Center and were made possible by policies and procedures put in place during prior PHEs. In January 2020, FDA reached out to requestors with previous EUA experience to solicit interest in development of a COVID-19 test. In addition, FDA reached out to requestors with existing authorized tests for similar viruses to ask that they conduct analyses to determine whether their tests could be used to detect COVID-19. Figure 1-1 outlines the key actions FDA took to provide guidance and flexibility to test developers, communicate regularly with EUA requestors, implement prioritization and efficiency efforts, and develop tools and templates. **Figure 1-1. Key Actions in FDA’s Response to Development and Authorization of COVID-19 Tests** _Horizontal timeline spanning January 2020 through April 2021, with milestone markers organized across four action categories — Created Multiple Pathways & Notification Process, Established Communication Channels, Implemented Prioritization & Process Efforts, and Developed Tools & Templates — plus HHS Actions, showing key dates such as the PHE declaration (1/31), mailbox establishment (2/20), Town Hall launch (3/2), and content screen implementation (11/30)._ \* FDA first posted notice of template availability on its website on 1/27/2020. See Figure 3-1 for additional EUA template milestones. \*\* Policies A through D are outlined in FDA’s “Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency.” See Table 3-1 for descriptions of each policy. ## 2\. METHODOLOGY In this assessment, Booz Allen used quantitative and qualitative data analysis, as well as stakeholder interviews, to evaluate CDRH’s response to COVID-19. This independent assessment focused on the EUA process for COVID-19 diagnostic tests and how the Agency prioritized the processing of the EUA requests, review times, accuracy and reliability of the COVID-19 tests, a comparison to prior PHEs, and requestors’ perspectives as outlined in Table 2-1. There are a variety of different types of tests (i.e., molecular, antigen, and serology) and each are used for different purposes. Molecular tests are preferred for diagnosis and are the primary focus of this report. The goal of the assessment is to evaluate FDA’s response, better understand challenges, and propose potential recommendations for consideration. Booz Allen gathered quantitative and qualitative data from CDRH points of contact, internal and public-facing documentation, and stakeholder interviews. These data were used to develop the findings and recommendations in this report. **Table 2-1. Assessment Objectives** | Assessment Objective | Description | |---|---| | Prioritization | Evaluate how the Agency prioritized the processing of EUA requests and actions taken to facilitate the development, validation, and authorization of COVID–19 diagnostic tests, including:
• Modified processes and policies including postmarket monitoring
• Communications and interactions with EUA requestors
• Triage process
• Process improvements | | Review Times | Evaluate Agency review times for EUAs over the course of the pandemic and assess causes and challenges | | Accuracy and Reliability | Report on the accuracy and reliability of diagnostic tests, particularly real-world, postmarket performance | | Comparative Response | Evaluate how the Agency’s response to EUAs for COVID-19 tests compares to prior PHEs | | Requestor Perspectives | Evaluate EUA requestor perspectives of what has worked well compared to previous PHEs and what can be improved | || ## 3\. ASSESSMENT FINDINGS Booz Allen evaluated CDRH’s COVID-19 response, including actions to facilitate the development, validation, and authorization of COVID-19 diagnostics. For each report section, we describe the approach taken by CDRH, how these actions compare to those during previous PHEs, and challenges and successes noted by stakeholders. ### 3.1 Approach to development, review, and authorization of COVID-19 tests **POLICY DEVELOPED TO ADDRESS COVID-SPECIFIC CHALLENGES** **Created Notification Process to Provide Flexibility** To help accelerate the development and availability of COVID-19 tests, CDRH issued guidance3 on February 29, 2020\. This guidance described a policy for diagnostic tests developed by Laboratories certified to perform high complexity testing under the Clinical Laboratory Improvement Amendments (CLIA), Policy A, shown in Table 3-1. The guidance described a unique notification policy to address the urgent need for diagnostic tests by allowing developers to offer certain tests prior to submitting their EUA request and while their EUA request was under review. The notification process established in February called for laboratory developers to: validate their test, notify FDA of their intent to offer tests, include a statement in the test report that the test was not reviewed by FDA, submit an EUA request containing test performance data within a reasonable period of time (e.g., 15 days), and confirm results for the first five positive and first five negative clinical specimens with an authorized test. Where this notification process is used, FDA explained it did not intend to object to the use of these tests. Through an update on March 16, 2020, CDRH developed more policies to provide flexibility for additional circumstances, types of developers, and types of tests, shown in Table 3-1. Policy B allowed state authorities to take responsibility for authorizing tests developed by Laboratories certified under CLIA that meet the CLIA regulatory requirements to perform high complexity testing in their state; Policy C extended the notification process to Commercial Manufacturers of diagnostic tests, including antigen tests, and recommended that manufacturers publish performance characteristics of their test on their website; and Policy D outlined FDA’s intent not to object to marketing of serology tests from Commercial Manufacturers or Laboratories who validate their test, notify FDA of the intent to offer the test, and include statements in the test report indicating the test has not been reviewed by FDA and should not be used to diagnose or exclude severe acute respiratory syndrome coronavirus 2 (SARS-CoV-24) infection. The March 16, 2020 update also broadened flexibility to modifications of authorized tests. Under this update, FDA stated that it did not intend to object to High Complexity Laboratories using a modified version of an already authorized test without a new or amended EUA request, provided that the modification was validated with a bridging study.5 In addition, FDA did not object to immediate implementation of modifications to EUA-authorized tests from any manufacturer where validation data supporting the modification had been submitted to FDA while FDA conducted its review. Policy D was intended to accelerate the availability of serology tests to advance the scientific community’s study and understanding of COVID-19, but a concerning number of notified serology tests demonstrated poor performance and some tests were marketed with misleading claims. In response, CDRH updated their policy on May 4, 2020 to reflect that EUA requests were expected for serology tests from Commercial Manufacturers within 10 days of notification to ensure that claims and performance were independently assessed. CDRH established a notification list following the initial publication of the guidance6 and published a public removal list7 to provide transparency and address questions on the status of tests following the May 4th update. If the requestor does not submit an EUA request within a reasonable period of time, or CDRH identifies significant problems with a test, CDRH would intend to remove the test from the notification list and take additional actions, as necessary. **Table 3-1. Overview of Policies Outlined in Guidance to Expand Access to for COVID-19 Tests** | Policy | Date Introduced | Date Updated | Developer | Test Type* | Key Point | |---|---|---|---|---|---| | Policy A | February 29, 2020 | N/A | High Complexity Laboratories | Molecular | Notification process created
EUA request expected within 15 days | | Policy B | March 16, 2020 | N/A | High Complexity Laboratories | Tests for COVID-19 | States could take responsibility for authorizing tests from High Complexity Laboratories
EUA not expected | | Policy C | March 16, 2020 | N/A | Commercial Manufacturers | Molecular and Antigen | EUA request expected within 15 days
Notification process was extended to Commercial Manufacturers | | Policy D | March 16, 2020 | May 4, 2020 | Commercial Manufacturers and High Complexity Laboratories | Serology | Following May 2020 revision, EUA request became expected within 10 days for Commercial Manufacturers but not for High Complexity Laboratories | || \*Excluding at-home testing and specimen collection On March 31, 2020, CDRH used another novel mechanism created earlier in the pandemic, the Umbrella EUA, to further streamline the authorization process for certain tests, shown in Table 3-2. This mechanism creates efficiency by allowing FDA to quickly authorize multiple similar devices under pre-specified conditions of use. By using the same Letter of Authorization and fact sheets, CDRH can eliminate layers of review while maintaining the same standards for authorization as the individual device. The first Umbrella EUA for tests allows FDA to authorize multiple molecular-based tests developed and performed by Laboratories certified under CLIA to perform high complexity tests under a single EUA. **Table 3-2. Overview of Umbrella EUAs for COVID-19 Tests** | Date Introduced | Date Updated | Developer | Test Type | Key Point | |---|---|---|---|---| | March 31, 2020 | N/A | High Complexity Laboratories | Molecular | Eligible tests may be added to the Appendix of the Umbrella EUA | | April 28, 2020 | Revoked July 21, 2020 | Commercial Manufacturers | Serology | Eligible tests that have been independently validated may be added to the Appendix of the Umbrella EUA^8 | | April 20, 2021 | N/A | Developers of Certain Authorized Molecular Diagnostic Tests | Molecular | Amends the authorization of certain previously authorized tests to include pooling and serial screening (i.e., pooled specimens for screening asymptomatic individuals when used as part of a serial testing program) | || Table 3-3 illustrates the number of requestors with tests authorized in an Umbrella EUA as of May 21, 2021\. FDA authorized 38 molecular Laboratory Developed Tests (LDT) under this mechanism, representing approximately 14% (38/281) of all authorized molecular tests. On April 28, 2020, less than a month after creating the Umbrella EUA for molecular LDTs, CDRH subsequently issued an Umbrella EUA for serology tests. The Umbrella EUA for serology tests was revoked on July 21, 2020 given concerns that the scope of the Umbrella EUA was too restrictive of the test performance and claims. Instead, FDA authorized Individual EUAs for these tests since this allowed for broader indications and scopes of authorization, individualized conditions of authorization to address any issue unique to a specific test, and more streamlined EUA amendments such as additional uses that would not fall under the Umbrella EUA. **Table 3-3. Use of Individual and Umbrella EUAs** | Test Type | EUA Type | Number of EUAs Issued* | |---|---|---| | Molecular test | Individual | 243 | | Molecular test | Umbrella | 38^9 | | Antigen test | Individual | 25 | | Serology test | Individual | 79 | || *\*As of May 21, 2021* **Continued to Update Policy to Address Evolving Needs** CDRH continues to adjust authorization policies and make updates when appropriate. For example, on March 16, 2021, CDRH published a new supplemental template that outlined a streamlined path to authorization for COVID-19 tests for screening with serial testing. Approximately two weeks later, FDA issued the first five authorizations for serial screening tests, including non-prescription tests for fully at-home use. In April 2021, FDA issued a pooling and serial testing umbrella amendment10 that streamlined the approach to adding pooling and serial screening claims to certain authorized tests. An emerging need identified by requestors was guidance on transitioning an EUA-authorized test to a full marketing authorization under traditional pathways (e.g., De Novo, 510(k)). FDA discussed this topic and lessons learned from past PHEs at a February 2020 workshop hosted by the Medical Device Innovation Consortium (MDIC) and announced plans in November 2020 to develop a draft guidance on transitioning COVID-19 tests authorized under EUA. On March 17, 2021, one test received a full marketing authorization via the De Novo pathway, which established special controls and opened the 510(k) pathway for other COVID-19 molecular tests. **Developed Templates to Streamline Submission Process** CDRH developed voluntary templates to support developers with EUA requests, as was done in prior PHEs (e.g., Zika virus). Ten EUA templates were developed to support various test types and developers,shown in Figure 3-1. The templates help organize the EUA request and outline recommendations for the submission package. In addition, the templates provide specific recommendations on analytical and clinical validation (e.g., number of clinical specimens recommended for evaluation). These templates also form the basis for CDRH’s internal review memos, streamlining the review process as well as the submission process. The templates were initially available upon request, which allowed CDRH to track who was developing tests and provide this information to government partners such as the Biomedical Advanced Research and Development Authority (BARDA). On February 29, 2020, the same day that FDA issued guidance, FDA made the template available on its website to support its new notification policy. As CDRH gained experience with reviewing EUA requests for specific test types and noticed certain information was commonly missing in submissions, they revised the templates to include more specific details about test validation. Templates were revised a total of 11 times as of April 12, 2021\. These templates also expanded over time to address different testing scenarios that increased access and availability of testing. **Figure 3-1. Submission Templates Published** _Horizontal timeline spanning January 2020 through April 2021, showing publication and update dates for ten EUA submission templates covering molecular diagnostics, serology, antigen, home specimen collection, and non-laboratory-use test types for both Commercial Manufacturers and Laboratories._ **STAKEHOLDER PERSPECTIVES AND LESSONS LEARNED** To help inform current and future public health needs, Table 3-4 outlines stakeholder perspectives and lessons learned on the approach to development, review, and authorization of COVID-19 tests. Stakeholders included a mix of experienced/inexperienced firms, small and large companies, multiple technologies and Laboratories as well as Commercial Manufacturers, and developers with varied previous EUA experience. **Table 3-4. Stakeholder Perspective on the Approach to Development, Review, and Authorization of COVID-19 Tests** | Focus Areas | Key Takeaway and Lessons Learned | |---|---| | Policy | • All stakeholders noted that the templates were helpful resources and often requested additional ones for different test types and developers.
• Stakeholders appreciated FDA’s efforts to gather feedback on the templates.
• Some stakeholders noted changes in the guidances were hard to follow. For example, there was confusion regarding some of the nuanced CLIA laboratory certifications and the state-based authorization processes listed in Policy B.
• Stakeholders identified the need for guidance on transitioning an EUA-authorized test to full marketing applications (e.g., De Novo, 510(k)).
• Stakeholders provided input on ways to communicate and incorporate continuous improvements to the templates. For example, stakeholders indicated that definitions (e.g., low positive sample, high sensitivity) were not the same across the templates, causing some stakeholders to refer to multiple templates to determine all information needed. | || ### 3.2 Approach to process improvements and review times **IMPLEMENTED PROCESS CHANGES TO KEEP PACE WITH EVOLVING NEEDS AND INCREASING SUBMISSION VOLUME** **Developed CDRH-specific Standard Operating Procedure to Define Roles and Enhance Review Efficiency** Prior to the COVID-19 pandemic, the FDA had in place an Agency-wide Standard Operating Procedure (SOP) for EUAs used during previous PHEs. CDRH has followed this SOP from the beginning of the outbreak. As part of CDRH’s 2018-2020 strategic priorities, CDRH had engaged in a process improvement effort for all major business processes, including for CDRH’s portion of the EUA process. These efforts were still ongoing when the pandemic began and did not take into consideration a scenario in which the volume of EUA requests approached that seen during the COVID-19 pandemic. In the Spring of 2020, CDRH determined that a more detailed Center-level SOP was needed to manage COVID-19 EUA requests due to the higher volume of EUA requests compared to prior PHEs and to reflect CDRH-specific processes put in place during the COVID-19 PHE (e.g., electronic submissions through the public inbox). Taking into consideration the lessons learned from the 2019 business process improvement effort and experience with EUA requests in the COVID-19 pandemic, CDRH implemented a CDRH EUA Pilot Process SOP on July 10, 2020 to more clearly outline CDRH staff roles and responsibilities and consistent processes to follow for EUA review in CDRH. **Developed Prioritization Factors and Implemented Processes to Address Growing Backlog** At the beginning of the pandemic when there were relatively few diagnostic tests authorized, the Center’s priority was to rapidly increase the availability of tests, which meant that every test was a priority. CDRH staff were able to interact closely with most developers, including requestors who submitted incomplete requests and those who had little to no prior experience with EUAs or FDA. As the number of tests available and in development increased and the state of the pandemic changed, the early levels of interaction were unsustainable and necessitated the development of prioritization factors shown in Table 3-5 to best utilize the available CDRH resources for the public health need. Prioritization factors were implemented internally and discussed at weekly Town Halls in Spring 2020\. In the context of tests offered through the notification policies described above, FDA focused on tests for which an initial review identified performance or safety concerns. In such cases, FDA made it a priority to work with the developer to address the concerns or stop testing. In early October 2020, factors FDA considers in prioritizing review of EUA requests were posted on FDA’s website12 through Frequently Asked Questions (FAQ) and further discussed during the weekly Town Hall sessions. CDRH identified a series of process improvements to support prioritization and efficiency, which are described below in the next sections. **Table 3-5. COVID-19 Test Prioritization Factors** | Factors | Description | |---|---| | Increases Testing Capacity | Tests for which there is a capacity for large-scale manufacturing, distribution, or processing (e.g., high-throughput tests, high product volume tests), or that reduce reliance on limited testing supplies (e.g., saliva-based tests) | | Expands Test Accessibility | Tests with increased availability or convenience because of where they can be performed (e.g., Point-of-care (POC) tests, home collection devices, at-home tests) | | Reduces Real-World Performance Concerns | Tests that were being offered under a notification policy and for which FDA identified performance concerns | || **Implemented Process Changes** In Fall 2020, CDRH introduced a number of process changes to try to address the growing backlog of EUA requests and help focus Center resources. These changes included alignment with the structure of CDRH’s standard review processes for other regulatory submissions. In addition, updates to the pilot SOP enabled reviewers to more efficiently deal with incomplete submissions (i.e., close files with requests for information), allowing them to focus on submissions with complete information that could move quickly through the authorization process. If files were closed with requests for information, requestors could provide the requested information in response for FDA to review. *Front-End Triage* Beginning in Fall 2020, CDRH instituted a front-end triage and prioritization process for all EUA requests to help focus Center resources on tests that were deemed to have a significant impact on the PHE, such as those that would increase testing accessibility or capacity. Staff use this process for all Pre-EUA and EUA requests soon after they are logged into CDRH’s IT systems and assigned a Lead Reviewer. Given the substantially higher submission volume received during this pandemic compared to prior PHEs, having a formal set of prioritization factors was necessary to evaluate the potential scope and urgency of each request. *Deprioritization Processes* To complement the front-end triage process, CDRH introduced streamlined mechanisms to quickly Decline to Issue tests that had significant validation problems and Decline to Review low-priority files such as those that were highly manual, low-volume tests. Prior to implementation, CDRH processed all negative decisions for tests as Denials, which were issued by the FDA Chief Scientist. These deprioritization processes (i.e., Decline to Issue and Decline to Review), introduced in Spring 2020 and streamlined for IVDs beginning in October 2020,13 was designed to allow CDRH to more easily process these files when requests were not a priority (or were deemed to not have an impact on the PHE), did not have sufficient information to evaluate whether they met the EUA criteria, or had validation or performance issues (and were not being offered under a notification policy). In the case of low-priority tests (e.g., because they were low throughput or low manufacturing capacity), CDRH would Decline to Review the file and close it, communicating the decision and reason why to the requestor. Alternatively, for priority tests with critical deficiencies (e.g., inadequate or missing performance data) that the requestor was unable to resolve in a reasonable period of time, CDRH would Decline to Issue the EUA, notifying the requestor and providing them with a list of deficiencies that had been identified. Requestors could choose to address the outstanding concerns in a follow up to the submission. Both options provided a mechanism for reviewers to focus on relatively high-priority (i.e., high-impact) and comparatively complete EUA requests that were going to make an impact on the PHE. Following HHS’s August 2020 statement14 announcing its updated policy that FDA would no longer require premarket review of any LDTs (including those for COVID-19) absent rulemaking, CDRH Declined to Review over 200 LDT EUA requests in October. Given that LDTs could be marketed without an EUA and also the high volume of other EUA requests, this action allowed CDRH to focus valuable resources on priority tests that could not be offered without FDA review and authorization (e.g., home collection tests, POC tests, multi-analyte panels). *Supply Chain Monitoring* Beginning early in the pandemic, global manufacturing and distribution supply chains experienced strain, especially in response to demand increases, which had a substantial impact on certain medical devices. Recognizing this, FDA proactively reached out to medical device companies in February 2020 to monitor the supply chain for signs of shortages. Provisions in the Coronavirus Aid, Relief, and Economic Security (CARES) Act (enacted March 2020\) further strengthened the Agency’s early response by providing FDA with new statutory authority to require manufacturers to notify FDA about changes in the production of certain devices to mitigate public health impacts of shortages. In addition, CDRH established a Medical Devices Shortages Mailbox for manufacturers to report interruptions, shortages, and discontinuances of devices critical to the pandemic, and additionally conducted outreach to other U.S. government agencies, trade groups, hospital systems, and non-profit organizations to determine supply and demand issues. Leveraging this network, FDA identified 11 shortages related to testing, which are published on their website. As the pandemic progressed, CDRH began to operationalize the information gathered from its monitoring network. Supply chain issues were discussed during daily huddles to inform current review priorities. The CDRH Office of Strategic Partnerships and Technology Innovation (OST) also played a key role in supply chain activities by initially providing analysis of products flagged by review teams as possibly experiencing a supply shortage. Eventually, both the analytical process and the output data from it were formally incorporated into CDRH’s overall EUA review process in the form of a consult service (part of the front-end triage process) and internal shortage dashboard, complementing the public-facing shortage list, enabling CDRH to prioritize submissions experiencing supply chain issues. For example, information obtained by OST informed CDRH’s response to nasal swab shortages, allowing CDRH to pivot and prioritize tests that used saliva specimens. *Review Tracks* In Fall 2020, CDRH developed two review tracks for EUA requests: an Express Track and Standard Track. Tests eligible for the Express Track included those for which there was a critical need (e.g., no alternatives available, including other EUA authorized devices) or the subject device is significantly better in terms of improved performance or safety compared with the alternatives. This allowed the most impactful devices to be reviewed not only first, but more quickly as each track had its own review milestone goals. Generally, files on the Express Track are not closed with requests for information but instead information is requested interactively. The goal is for the review team to make recommendations within 30 days. Files on the Standard Track follow a similar review process, although these submissions are lower in the queue, may be closed with requests for information if additional information is needed that cannot be provided in a timely manner, and have a longer final recommendation goal (i.e., 60 days). Regardless of the review track, recommendations from the Office of Health Technology 7 (OHT7) for authorization or denial are sent to the Office of the Chief Counsel (OCC) and the Office of Counterterrorism and Emerging Threats (OCET) for review, and OCET provides the final sign off on such decisions. Decisions to Decline to Issue an EUA are signed off by OHT7. *Content Screen and Closing with Requests for Information* CDRH observed that some EUA requests frequently lacked information that was recommended in publicly available documents (e.g., EUA guidance or templates). As a result, the Center implemented a content screen in Fall 2020\. Occurring after the front-end triage and prioritization process, these screens follow a checklist to determine if various criteria are met, including administrative (e.g., the submission is written in English and a description of the product and its intended use) and technical requirements such as the inclusion of a device description and performance data (e.g., evaluation using clinical specimens). These screens were implemented to identify EUA requests with sufficient information for review that could quickly move through the EUA process as well as requests with major issues that could not be addressed quickly. In such cases, FDA closed the files with requests for information, which the requestor could provide in an amended submission. By reducing the need for lengthy back-and-forth interactive review of submissions missing basic information, this provided staff with the opportunity to focus their time reviewing high-impact devices with complete submissions. Of the Original IVD EUA requests CDRH received since implementing the content screen, about two-fifths (144/357) of the files did not pass the content screen (as of April 23, 2021). Ultimately, CDRH intends to use the results of these content screens, noting specifically which information is most frequently being missed or requirements not followed, to inform an update to the interactive review templates, emphasizing and clarifying CDRH’s expectations. **VARIOUS FACTORS IMPACTED REVIEW TIMES OVER THE COURSE OF THE PUBLIC HEALTH EMERGENCY** **Allocation of Staff to Support COVID-19 Response** As the PHE progressed, CDRH continued to receive a high volume of EUA requests, regular workload continued to accrue, and inexperienced EUA requestors required extensive support from FDA. These challenges led FDA to develop processes to refocus resources from lower impact EUA requests to higher impact EUA requests. Additional reviewers were allocated to help address the COVID workload and support the response. Some came from within OHT7, but CDRH also leveraged reviewers from other offices and hired term employees. The specialized nature of IVD scientific expertise and regulatory experience limits how quickly a large volume of staff can be quickly or easily trained in this area. Training of reallocated staff requires time from the IVD specialists which pulls them away from review work. **Figure 3-2. Percentage of OHT7 Working on COVID-19** _Bar chart showing the monthly percentage of OHT7 staff working on COVID-19 from April 2020 through March 2021, with values rising from around 62% in Spring 2020 to 84% by February–March 2021._ *excludes Division of Radiological Health and Division of Mammography Quality Standards The number of staff conducting review of COVID-19 tests fluctuated throughout the pandemic. In Spring 2020, CDRH directed some reviewers of other medical devices from other offices to focus on COVID-19 work. In Fall 2020, additional IVD reviewers performing non-COVID-19 work were shifted to focus on review of COVID-19 tests. Figure 3-2 shows a representative piece of the larger picture, showing the percentage of OHT7 staff (excluding the Division of Radiological Health and Division of Mammography Quality Standards) working on the COVID-19 response.16 These data include review and non-review work, but they do not indicate the percentage of a *person’s time* dedicated to COVID-19. Data were not available for contractors or staff from other Offices of Health Technology (OHTs) or Centers who provided OHT7 with assistance in the review of COVID-19 tests. Reallocating staff and resources from product areas less impacted to those with increased submission volume presents a trade-off in meeting other priorities, even with others picking up extra non-COVID-19 work to support the response. This has resulted in review delays for non-COVID-19 work, and CDRH is declining to review IVD pre-submissions that are not related to COVID-19, companion diagnostics, a breakthrough designation, or significant public health impact. **Submission Volume Surpassed All Prior PHEs** As of April 2021, CDRH reviewed and closed out over 2,000 EUA requests, including Original EUAs and Supplements (i.e., requests for revisions to previously authorized tests), Authorizing or Acknowledging 812 requests as of April 12, 2021\. Acknowledged decisions reflect files where CDRH concurs with changes in Supplements or Amendments that do not require an update to the Letter of Authorization (e.g., addition of a new laboratory instrument, extraction method, or sample type). Supplements that result in changes to the Letter of Authorization are reauthorized by OCET and include changes that commonly involve new indications such as home collection or screening. The number of Original Authorized EUA requests (360) dwarfs the number of tests authorized during all previous PHEs combined (Figure 3-3). Figure 3-4 shows the trends in authorization by month. In addition to these authorized tests, several tests had submitted notification to FDA and were marketing their tests while FDA reviewed their EUA requests. This substantially increased the volume of available tests, particularly in Spring 2020. **Figure 3-3. Authorized IVDs During Previous PHEs** _Bar chart comparing the number of authorized IVDs across seven PHEs, with prior emergencies ranging from 1 to 20 authorizations each, dwarfed by COVID-19's 360 authorized Original EUAs._ *IVDs includes serology, molecular, and antigen tests. Prior PHE values represent authorized devices. COVID-19 value represents authorized Original EUAs. Data as of April 12, 2021. **Figure 3-4. EUA Authorizations and Acknowledgements by Month** _Bar chart showing monthly EUA authorization and acknowledgement counts from February 2020 through March 2021, with separate series for all test types and molecular-only, peaking at 104 total authorizations in September 2020._ *Includes authorized Original EUAs and Supplements. Time is month FDA made decision, not month submitted. Data as of April 12, 2021. Table 3-6 shows a breakdown of decisions made on EUA requests, both for all COVID-19 test types (i.e., including molecular, serology, and antigen) as well as molecular diagnostics in particular since they represented the majority of CDRH’s files reviewed. As of April 12, 2021, 2,133 EUA requests were closed out. Of these, 61% (1,294) were molecular diagnostic tests, 29% (623) were serology and 9% (199) were antigen tests. Molecular IVD EUA requests were split evenly between Commercial Manufacturers and Laboratories, with more Original requests than Supplements. Overall, molecular tests were Authorized or Acknowledged more and Denied/Declined, Withdrawn, or Closed with Requests for Information slightly less frequently than all tests combined. While only a small percentage of molecular tests were either Denied or Declined to Issue due to concerns with the EUA request (e.g., regarding test validation), CDRH Declined to Review a larger proportion of low-priority files (e.g., low-volume tests) that were deemed to have a smaller impact on the PHE. Withdrawn files were done so at the request of the requestor for a variety of reasons (e.g., after receiving deficiencies from FDA or utilizing the flexible policy that does not require an EUA when bridging to an authorized test). **Table 3-6. COVID-19 Test EUA Breakdown by Decision** | Decision | Description | All EUA Requests for COVID-19 Tests n (% of Column Total) | Molecular EUA Requests n (% of Column Total) | |---|---|---:|---:| | Authorized or Acknowledged | • Action taken to authorize Original EUA requests and Supplements for changes requiring reissuance of the Letter of Authorization (reauthorization)
• Action taken to acknowledge EUA Supplements for changes that do not require changes to the Letter of Authorization | 812 (38%) | 642 (50%) | | Closed with Requests for Information | • Action taken to close an EUA request when additional information is needed to support authorization, but it is not readily available; the EUA request may be reopened at a later date if the requestor submits the additional information | 233 (11%) | 109 (8%) | | Declined to Issue or Denied | • Action taken to close an EUA request with critical deficiencies that the requestor is unable to resolve in a reasonable period of time | 280 (13%) | 83 (6%) | | Declined to Review | • Action taken to close EUA requests that are a low priority without complete review | 460 (22%) | 315 (24%) | | Withdrawn | • Action taken to close EUA requests when the requestor voluntarily withdraws their request | 348 (16%) | 145 (11%) | | Total* | | 2,133 | 1,294 | || *\*Data as of April 12, 2021* Figure 3-5 shows the trend of all files submitted in that month, including Original EUA requests and Supplements, as well as 1,070 Pre-EUA requests. This includes all files received each month between March 2020 and March 2021, including those that have been closed and those that remain under review, and represents the total number (3,672) of COVID-19 IVD submissions for CDRH to review. This demonstrates a large influx in the early months of the pandemic with sustained numbers throughout the Summer, then leveling out in the Winter. As submission volume grew, CDRH pivoted to focus efforts on authorizing tests that would make the largest impact on public health, as described in Section 3.2. **Figure 3-5. Number of IVD EUA Requests Received by Month** _Stacked bar chart showing monthly IVD EUA request volumes broken down by Pre-EUA, Original EUA, and Supplement requests from February 2020 to March 2021, peaking at 554 total submissions in April 2020 and declining to around 150–200 per month by Winter._ * These include Pre-EUA requests as well as requests for Original EUAs and Supplements: all test types and all developers. Time is the month submitted, not the month FDA began active review. Data as of June 9, 2021. † In February 2020, there were 21 Pre-EUA requests and two Original EUA requests received. **Trends in Review Time** As shown in Figure 3-6, review times for denied EUA requests were initially much higher than for authorized EUAs, which reflects the many layers of review in the denial process. CDRH implemented its Decline to Review and streamlined Decline to Issue processes for IVD EUAs in October 2020 (as described above), which deprioritized a large volume of low-priority tests and tests with validation or performance concerns, reducing burden on staff and allowing them to focus on high impact submissions. Review times for authorized tests steadily increased during the Fall months, corresponding to the high volume of requests received. In addition, EUA requests for tests available through the notification process were not as highly prioritized as others which were not already in use, unless the triage revealed performance or safety concerns. Review times for authorized tests ultimately decreased and then remained steady throughout the Winter as process improvements were implemented (e.g., content screen, closing incomplete files with requests for information), Center staff were reallocated, and the number of new requests submitted each month began to decrease. Median review times may increase as more files are closed out. **Figure 3-6. Review Times of Original EUA Requests (Authorized and Declined to Issue or Denied)** _Bar chart showing median review times in days by month submitted (February 2020–March 2021) for authorized versus declined/denied Original EUA requests, illustrating that denial review times were initially much higher (peaking at 186 days) before dropping after streamlined deprioritization processes were introduced in October 2020._ *These are EUA Originals: all test types and all developers. Time is the month submitted, not the month FDA began active review. Data as of April 12, 2021. Review times for authorization/acknowledgement of Supplements compared to Originals were relatively fast in the early months of the pandemic, during which there were relatively fewer Supplements received. As developers began to modify their tests (e.g., using saliva as a specimen type, seeking authorization for at-home collection or POC settings for use in asymptomatic patients), review times for both types increased. Although Supplements made up only one-third of EUA requests reviewed for COVID-19 tests, Figure 3-7 shows that Supplements can take as long (if not longer) to review than Original EUA requests. While some Supplements included changes in the device use (e.g., at-home collection or POC settings), others included changes to add instruments, extraction methods, or indications for sample pooling and screening. Validating these changes can involve new clinical and analytical studies, similar to or beyond that of the Original Authorization. Many of these changes were implemented immediately upon submission of validation data to FDA under CDRH’s modification policy. As a result, many Supplements were not high priorities for review. **Figure 3-7. Review Times of Authorized and Acknowledged EUA Requests (Originals and Supplements)** _Bar chart comparing median review times for Original versus Supplement EUA requests by month submitted (February 2020–March 2021), showing that Supplements could take as long as or longer than Originals to review, with both peaking in the Fall 2020 months._ *These are EUA Originals and Supplements: all test types and all developers. Time is the month submitted, not the month FDA began active review. Data as of April 12, 2021. Figure 3-8 and Figure 3-9 show how review times for Original molecular EUA requests varied by month, broken down by decision and manufacturer type. Similar to observations presented in Figure 3-6, denials initially took much longer than authorizations for both Laboratories and Commercial Manufacturers, although review times for requests from Commercial Manufacturers tended to be longer compared to those from Laboratories, except during the Summer months. The decrease in review times for tests approaching Fall 2020 highlights the impact the streamlined Decline to Issue process had on review times.This could possibly be explained by the higher number of tests from Laboratories submitted early in the pandemic and certain Laboratories’ relative inexperience in preparing EUA requests. Review times for authorized tests were initially longer for tests from Laboratories than those from Commercial Manufacturers, although they began to converge in the Summer and then the trend reversed in the Fall and Winter months. **Figure 3-8. Review Times of Original Molecular EUA Requests from Laboratories (Authorized and Declined to Issue or Denied)** _Bar chart showing median review times for Laboratory-submitted Original molecular EUA requests by month (February 2020–March 2021), with authorized test review times ranging from 1 to 73 days and declined/denied times spiking to 216 days in July 2020 before dropping sharply after the streamlined Decline to Issue process was implemented._ *These are EUA Originals: Molecular tests from Laboratories. Time is the month submitted, not the month FDA began active review. Data as of April 12, 2021. **Figure 3-9. Review Times of Original Molecular EUA Requests from Commercial Manufacturers (Authorized and Declined to Issue or Denied)** _Bar chart showing median review times for Commercial Manufacturer–submitted Original molecular EUA requests by month (February 2020–March 2021), with authorized test review times rising from 1 day in February to a peak of 100 days in October 2020, and declined/denied times peaking at 255 days in May 2020._ *These are EUA Originals: Molecular tests from Commercial Manufacturers. Time is the month submitted, not the month FDA began active review. Data as of April 12, 2021. Figure 3-10 shows a subset of the graph above, comparing review times of Original EUA requests from Commercial Manufacturers and Laboratories that were authorized while overlaying the number of submissions (regardless of test type or decision) submitted in each month. The figure demonstrates the large number of new submissions received each month, particularly at the beginning of the pandemic. The number of EUA requests submitted peaked at over 550 in April, declining into the early Summer, and then becoming relatively stable in October. **Figure 3-10. Review Times of Original, Authorized, Molecular EUA Requests (Commercial Manufacturers and Laboratories) with Overlay of Number of IVD EUA Requests by Month** _Dual-axis chart with grouped bars showing median review times for authorized Original molecular EUA requests from Laboratories and Commercial Manufacturers, overlaid with a line showing total monthly IVD EUA request volume peaking above 550 in April 2020._ *Review Time bars are EUA Originals: Molecular tests. Volume line includes Pre-EUAs as well as EUA Originals and Supplements: all test types and all developers. Time is the month submitted, not the month FDA began active review. Data as of April 12, 2021. Figure 3-11 shows that a greater percentage of Original EUA requests from Commercial Manufacturers were authorized (37%) compared to those from Laboratories (25%). In addition, requests from Commercial Manufacturers were Declined to Issue or Denied (15%) at a higher rate than those from Laboratories (3%). The Decline to Review rate for Laboratories (48%) is higher compared to Commercial Manufacturers (22%) because as the pandemic progressed, LDTs were deprioritized in October 2020 following HHS’ statement on LDTs. **Figure 3-11. Distribution of Original Molecular EUA Requests by Decision (Commercial Manufacturers and Laboratories)** _Grouped bar chart showing the percentage of Original molecular EUA requests by decision type — Authorized (25% Labs, 37% Commercial), Declined to Issue or Denied (3% Labs, 15% Commercial), and Declined to Review (48% Labs, 22% Commercial) — highlighting the higher deprioritization rate for Laboratory-submitted requests following HHS's October 2020 LDT statement._ *These are EUA Originals: Molecular tests. Data as of April 12, 2021. **STAKEHOLDER PERSPECTIVES AND LESSONS LEARNED** To help inform current and future public health needs, Table 3-7 outlines stakeholder perspectives and lessons learned on the approach to process improvements and review times. **Table 3-7. Stakeholder Perspective on the Approach to Process Improvements and Review Times** | Focus Areas | Key Takeaway and Lessons Learned | |---|---| | Process and Review Times | • Stakeholders shared positive feedback about interactions with review teams and their dedication to providing support throughout the EUA process.
• Stakeholders relied on direct communications with review teams for updates. Stakeholders shared that they frequently asked about timelines for follow up with reviewers, information on review times, and contacted other groups at FDA (e.g., EUA mailboxes) if they did not hear back from them.
• Stakeholders noted that response times were faster in the beginning and as volume increased, interactions became less frequent.
• Stakeholders asked frequently about prioritization factors, which FDA later posted on their website and discussed during the weekly Town Hall sessions. | || ### 3.3 Approach to test validation, postmarket actions, and evaluation of real-world test performance **VALIDATION AND USE OF REFERENCE PANEL TO DEMONSTRATE PERFORMANCE** **Developed Flexible Validation Process to Establish Performance** During preparation of EUA requests, requestors must validate their test by conducting a series of studies that demonstrate the product may be effective. These include both analytical studies, for example determining the smallest concentration of virus the test can detect and differentiating between other pathogens, and clinical evaluations, focusing on the real world ability of the test to detect the virus in human samples. CDRH provides recommendations for these studies in guidance, which incorporates each of the ten EUA templates, although developers may propose alternative study designs as long as they adequately demonstrate that the test is accurate and reliable. Based on experience with prior PHEs, CDRH anticipated some challenges related to test validation. For example, understanding that clinical specimens are difficult to find early in an outbreak, the January 2020 template provided flexibility to validate tests with contrived specimens instead. Contrived specimens can be made with either genetic material taken from the virus itself or from synthetic genetic material matching the virus. FDA later saw that validation with certain types of contrived specimens masked performance issues for some tests. FDA coordinated (with other U.S. government agencies) shipment of viral material (produced by culturing the virus in a laboratory) to developers working on tests in February 2020\.18 Subsequently, FDA authorized 59 COVID-19 diagnostic tests based on validation data using contrived samples between February and May.19 However, validation with contrived samples is not as robust a validation study as those performed with clinical specimens; as availability of both standardized commercial samples and natural clinical specimens increased, CDRH recommended in a May 11, 2020 policy update that developers obtain and use these for validation. **Developed Reference Panel to Assess Comparative Performance** Recognizing the limitations of the type of validation that can reasonably be accomplished early in an outbreak, CDRH has developed reference panels for this and prior PHEs. Reference panels are composed of common, independent, and well characterized reference material that allow for a more precise comparison of the analytical performance of different molecular IVDs.20 CDRH began collaborating with the Center for Biologics Evaluation and Research (CBER) on development of a reference panel for SARS-CoV-2 molecular diagnostic tests in January 2020\. The team obtained viral material when it became available in February 2020\. The reference panels and accompanying protocol for evaluation by test developers became available on May 27, 2020\. More than 1,000 reference panels were produced for SARS-CoV-2 compared to approximately 80 produced for Zika virus, reflecting the difference in scale between the PHEs. Starting with the first authorization in February 2020, CDRH established conditions of authorization requiring requestors of all authorized EUAs to submit their test’s performance data on FDA-recommended reference materials. Once the reference panel was available, FDA contacted all developers with EUAs to request they evaluate the reference panel per the established condition of authorization. Results were submitted as EUA Supplements and are made available on FDA’s website, allowing comparisons across tests. Once final results were released by CDRH, requestors updated their labeling information with the new performance data and the Supplements were closed. Results were first posted on FDA’s website on September 15, 2020 and last updated in December 2020 (Table 3-8). As of this date, three-quarters of developers either had data currently under review or published on FDA’s website 21 (147/195); just under one-fourth (48/195) had either not provided shipping information or returned data, or had presented uninterpretable data, although no EUAs have been revoked for these reasons. **Table 3-8. Molecular Diagnostic Reference Panel Results** | Reference Panel Results Status | Number of Tests* | |---|---:| | No shipping information | 17 | | Data not returned | 26 | | Data uninterpretable | 5 | | Under interactive review | 21 | | Data published | 126 | | Total | 195 | || *\*All data as of December 2020 update* Development of the molecular reference panel differed from the approach to the evaluation of serology tests, which involved a collaboration beginning in April 2020 with the National Institutes of Health’s (NIH) National Cancer Institute (NCI). One difference in approach was that developers ran the molecular reference panel themselves, but serology tests were sent to NCI so the government could conduct its own evaluation against a standard set of samples. Similar to the molecular reference panel approach, results from the NCI evaluation of serology tests and underlying validation data are made publicly available on FDA’s website22 and openFDA,23 which allows test developers to compare their in-house data to the validated results of other developers’ tests, provides additional information to clinicians, and promotes increased transparency to the public. The partnership with NCI represents a collaborative model that could streamline data analysis and improve the response to future PHEs. **USING REAL-WORLD EVIDENCE TO CONFIRM TEST PERFORMANCE** **Established Postmarket Reporting Requirements to Support Monitoring** CDRH has had to strike a balance between timely access to tests and assurance of real-world test performance. The EUA process allows FDA to authorize tests with less data than typical review pathways, which underscores the importance of postmarket monitoring. Allowing for this type of process underscores the need for reporting mechanisms. The primary way CDRH is able to monitor trends in performance is through the established postmarket reporting requirements communicated to requestors under conditions of authorization in the Letters of Authorization. Requestors are required to have appropriate processes in place and, pursuant to Code of Federal Regulations Title 21 Part 803 and the conditions of authorization, to track and report to FDA adverse events (AEs), including any occurrence of false results (i.e., false positives, false negatives) or any significant deviations from established performance characteristics. Many of the requestors already had and used existing mechanisms in place to report results, which is standard practice for medical devices. It is unclear how well EUA requestors and their authorized Laboratories are complying with the reporting requirements at this time. For example, authorized Laboratories are required to collect information on test performance and report it to FDA through the designated email inbox CDRH-EUA-Reporting@fda.hhs.gov. As this is a non-traditional reporting mechanism, not all Laboratories have processes in place to do this reporting. EUA requestors are also required to comply with labeling requirements under FDA regulations, and document where and how many tests have been distributed. In some instances, CDRH required postmarket studies as a condition of authorization in an attempt to provide requestors with some flexibility with their pre-authorization data package (e.g., requiring prospective clinical study when contrived samples were used for validation). The additional data and study requests, which include performing the reference panels as outlined in the previous section, are included in the Letter of Authorization and in some cases also outlined in the EUA templates. **Conducted Postmarket Surveillance and Enforcement Activities** Device manufacturers, including those of diagnostic tests, must follow certain conditions of authorization once their products are marketed such as reporting malfunctions and AEs. Surveillance allows FDA to monitor these incoming data and determine what actions, if any, need to be taken in assessing tests’ real-world test performance by reviewing information submitted to identify network signals, evaluate potential risks to the public, and conduct follow up investigations when necessary. These reports contain data from a variety of sources including: (1) Medical Device Reports (MDRs), mandatory AE and device malfunction reports from manufacturers; (2) MedWatch, FDA’s voluntary device safety reporting program for health care providers and consumers; (3) Medical Product Safety Network (MedSun), CDRH’s mandatory AE reporting system for hospitals and other health care facilities; and (4) publicly available reporting mailboxes (e.g., CDRH-EUA-Reporting@fda.hhs.gov). As of May 2021, over 6,000 MDRs have been reported for COVID-19 tests, each including information about the device, who reported it, and the problem experienced (e.g., false positive/negative). CDRH reads incoming reports daily and conducts weekly analysis to identify potential trends or emerging safety issues. As more COVID-19 tests were authorized, CDRH observed a steady increase in report submission starting in Summer 2020 (between 650 and 1,050 reports per month); to handle the increase in volume, the Center reallocated resources from other areas and implemented process improvements (e.g., automating part of the data entry process to summarize MDRs). Surveillance efforts can lead to postmarket actions (e.g., EUA revocation, removal from the notification list, Warning Letters issued). Many of these postmarket activities pertain to serology tests and were informed by real-world performance identified by CDRH’s surveillance activities. A breakdown of all the actions and communications taken by CDRH as of June 11, 2021 during the PHE are summarized in Table 3-9. **Table 3-9. EUA Postmarket Actions** | Postmarket Action/Communication | Description | Number^24 | |---|---|---:| | EUA Revoked | The criteria for issuance are no longer met or other circumstances make such revocation appropriate to protect the public health or safety. | 3^25 | | Notification Removal List – Laboratories with Diagnostic Tests | Diagnostic tests developed by Laboratories and offered under the notification policy that may have significant problems that cannot be addressed in a timely manner and should no longer be used. | 2 | | Notification Removal List – Commercial Manufacturers with Diagnostic Tests | Diagnostic tests developed by Commercial Manufacturers and offered under the notification policy that may have significant problems that cannot be addressed in a timely manner and should no longer be used. | 18 | | Notification Removal List – Commercial Manufacturers with Serology Tests | Serology tests developed by Commercial Manufacturers and offered under the notification policy that may have significant problems that cannot be addressed in a timely manner and should no longer be used. | 266 | | Warning Letters | Letters sent to developers that have adulterated or misbranded products related to COVID-19. | 36 | | Letters to Health Care Providers | Letters sent to health care providers about safety concerns and recommendations for medical devices used in health care facilities. | 7 | | Safety Communications | FDA posts Medical Device Safety Communications to describe FDA’s current analysis of an issue and contain specific regulatory approaches and clinical recommendations for patient management. | 4 | || One of the postmarket actions taken is the revocation of an EUA. This has resulted primarily due to the criteria for issuance of authorization no longer being met (e.g., the known and potential benefits of the product no longer outweigh the known and potential risks, such as due to poor performance) or the availability of adequate approved alternatives(e.g., as a result of subsequent premarket authorization through 510(k) clearance, De Novo classification, or PMA approval). For example, two EUAs for serology tests for COVID-19 have been revoked. CDRH notified the requestors of poor performance issues between the NCI evaluation of serology tests and the clinical and analytical data submitted with their applications. The requestors were provided an opportunity to provide information to refute FDA’s findings. Once a decision was made to revoke the EUA, the requestor was notified via letter and notice of the revocation was published in the Federal Register. This process thereby removes the ability of the test to be legally marketed and further informs the public of FDA’s intent to take strong action against poor-performing tests. The previous PHEs also had a small number of tests revoked due to performance issues: one antigen test for Ebola and one molecular test for Zika virus. **Collaborated on Real-World Evidence Generation** CDRH participated in various collaborations focused on gathering and analyzing real-world data (RWD) and real-world evidence (RWE) to help inform its COVID-19 response. Table 3-10 describes ongoing collaborations with stakeholders from the medical device industry, academia, non-profit organizations, and other U.S. government agencies that seek to better understand how to use data to improve testing quality and incorporate data into evaluation of COVID-19 diagnostic and antibody tests to better inform population testing strategies and understand patterns of disease transmission. **Table 3-10. Collaborations to Evaluate the Potential Application of RWE During a PHE** | Collaboration | Partners | Research Objectives | Anticipated Outcomes | |---|---|---|---| | Systematic Harmonization and Interoperability Enhancement of Lab Data (SHIELD) | Federal agencies, industry, Laboratories, Electronic Health Record vendors, standards developers, academia | Promote harmonized application and implementation of diagnostic data standards | Enable rapid data sharing between different data sources to facilitate evaluation of RWD/RWE | | Diagnostic Evidence Accelerator | Reagan Udall Foundation, Friends of Cancer Research | Encourage collaboration and development of data linkages within the research community, critically discuss findings from different data sources, and develop key research questions that multiple teams can address simultaneously | Provide actionable information on specific populations and highlight individual risk factors for patients, improve the understanding of disease to tailor public health interventions and strategies to mitigate risk, identify supply chain issues, and provide RWE of test performance | | Informatics-driven real-world analysis of SARS-CoV-2 serologic response and IVD accuracy | Yale University-Mayo Clinic Center of Excellence in Regulatory Science and Innovation | Correlate diagnostic test results with clinical disease using RWD to better understand serologic results | Address questions about the COVID-19 immune response, including how long patients remain infected, the accuracy of serology test methods over time, formation of antibodies, and how long an individual may be immune after infection^27 | || **STAKEHOLDER PERSPECTIVES AND LESSONS LEARNED** To help inform current and future public health needs, Table 3-11 outlines stakeholder perspectives and lessons learned on the approach to test validation, postmarket actions, and evaluation of real-world test performance. **Table 3-11. Stakeholder Perspective on the Approach to Test Validation, Postmarket Actions, and Evaluation of Real world Test Performance** | Focus Areas | Key Takeaway and Lessons Learned | |---|---| | Postmarket Performance | • Stakeholders had questions regarding expectations for test validation and the degree of flexibility in the validation recommendations.
• Stakeholders noted it was helpful to talk through validation study options with reviewers during the Pre-EUA process.
• Stakeholders had many questions around Supplements and Amendments, with common themes including asymptomatic testing, pooling, and at-home/POC validation expectations.
• Stakeholders noted that molecular reference panel was a helpful tool; however, some had technical issues running the panel. Commercial Manufacturers expressed concerns about not having a reference panel until May 2020. International EUA requestors indicated challenges receiving the reference panel.
• Experienced stakeholders leveraged postmarketing reporting processes they already had in place. | || ### 3.4 Approach to communication with requestors, clinical community, and the public **ESTABLISHED MULTIPLE COMMUNICATION CHANNELS** **Established Weekly Town Halls for EUA Requestors** In March 2020, CDRH started to host weekly, hour-long Town Hall meetings as an opportunity for OHT7 Leadership, including the OHT7 Director, to provide updates and answer questions for test developers. By the end of April 2021, CDRH had hosted 53 Town Halls that have been well attended (\>40,000 attendees to date). Transcripts, slides, and recordings of the Town Halls are posted to the FDA’s website, typically within one week after being recorded. The Town Halls are ongoing and provide an opportunity for test developers to have an open dialogue on EUA policies and guidance, tools and resources (e.g., Templates, FAQs, CDRH mailboxes), validation and postmarket performance procedures, test development recommendations, review time expectations and prioritizations. For example, when new policies and policy updates have been announced, such as new or updated guidance documents and EUA templates, FDA has responded to stakeholder questions and concerns about policy implementation. OHT7 Leadership provides specific feedback and directs requestors to reach out to the EUA template mailbox or their reviewer for details on highly technical questions. For example, in response to requestor questions on validation, OHT7 Leadership provides insight into analytical and clinical validation expectations including the number of positive samples developers are expected to evaluate while explaining that these expectations may be dependent on specific details of the test, which may not all be apparent in the brief discussion on the Town Hall. In addition, OHT7 uses the Town Halls as a platform to provide information on CDRH’s review and prioritization processes and test development recommendations. For example, FDA began to encourage development of POC and at-home tests in Summer 2020, and also encouraged the development of multi-analyte panels to prepare for the upcoming flu season. Similarly, OHT7 Leadership has discussed in the Town Halls the significance and limitations of serology tests, and the focus on different types of tests at different stages in the pandemic. **Created Central Mailbox for Inquiries** CDRH developed a public-facing email inbox to collect questions from EUA requestors and requests for submission templates, which provided CDRH an opportunity to track the pipeline of interested requestors. In addition, EUA requestors could submit electronic submissions through the mailbox, COVID19DX@fda.hhs.gov, starting February 20, 2020 as opposed to mailing physical submission packages to the Document Control Center. Mailboxes are also a primary way of obtaining feedback from requestors, enabling CDRH to identify communication or expectation gaps and informing future Town Hall topics and template revisions. Between March and May 2020, CDRH received over 120,000 emails to the COVID19DX@fda.hhs.gov inbox. By October 2020, there were over 170,000 inquiries. CDRH deployed two dedicated full time employees and other part-time staff to triage and respond to inquiries, process submissions, and filter submissions to the appropriate contact. The questions received related to how to submit an EUA request, specific data requirements, and how enforcement policies outlined in guidance apply to a specific test. CDRH quickly established additional mailboxes enabling more specialized information to be quickly directed to various stakeholders. By May 2020, CDRH had an EUA template mailbox for Pre-EUA questions, template inquires and general questions about COVID-19 tests, a fraud mailbox to report false labeling, and a SHIELD mailbox for insight into data harmonization and the SHIELD program. As with prior emergencies, CDRH also used mailboxes for external stakeholders (e.g., hospitals, group purchasing organizations) to report shortages in diagnostic test supplies and other supply disruptions. **Developed FAQs and 24/7 Hotline** CDRH established several additional mechanisms for communicating with EUA requestors, including a 24/7 phone hotline to communicate expectations for test developers, information related to shortages and alternative supplies, and issues related to safety and test performance. In addition, CDRH posted FAQs on the FDA website to educate EUA requestors on the development and performance of COVID-19 tests. Over 300 FAQs have been posted so far across nine websites (i.e., Notifications and Emergency Use Authorizations, Removal Lists of Tests that Should No Longer Be Used and/or Distributed for COVID-19, Test Development and Review, Test Settings, Test Uses, Test Supplies, 3D Printed Swabs, COVID-19 Related Test Data and Reporting, and Serology/Antigen Tests). The FAQs are updated as needed and include other resources for test developers. For example, FDA has published an interactive Testing Supply Substitution Strategies resource that includes validated supply alternatives that Laboratories can use to continue performing testing when there is a supply issue with some components of a molecular test. As information needs evolved, FDA added websites to cover topics including scientifically valid alternative testing supplies during shortages28 and pooling strategies. **Communicated Surveillance Information to Developers and Health Care Providers Through Multiple Channels** In addition to using surveillance efforts to inform postmarket actions, FDA also communicates information about tests and test performance in a variety of ways. These communications convey information on tests’ real-world performance trends to EUA developers, the clinical community, and the general public. FDA communicated this information through Letters to Health Care Providers, Safety Communications, other press releases, weekly Town Halls, and updates to FDA’s website. Letters to Health Care Providers and Safety Communications are similar communication mechanisms used to provide information about test issues, potential impacts on performance, and recommendations on how these tests should be used. Seven Letters to Health Care Providers have been issued as of June 11, 2021\. The first Letter to Health Care Providers was published on April 17, 2020 on the use of serology tests. These letters are posted to the FDA website in addition to being sent to the health care community. Each one provides background information, recommendations, FDA actions taken, mechanisms for reporting additional problems, and additional information such as linking to the EUA, appropriate FDA websites, and updates on instructions. Safety Communications are similar but are targeted at the general public. Four have been issued as of June 11, 2021\. Both Letters to Health Care Providers and Safety Communications are intended to inform the appropriate audiences on trends to watch for and instruction updates. FDA has closely tracked the potential impact of emerging viral mutations on COVID-19 test performance by routinely comparing the genetic sequences of each new mutation to the target sequences of currently marketed tests. FDA has publicly posted the tests whose performance could be impacted by SARS-CoV-2 viral mutations, along with general information for clinical laboratory staff and health care providers on the potential for false negatives. As of June 11, 2021, FDA has identified four molecular diagnostic tests for COVID-19 potentially impacted by SARS-CoV-2 mutations.30 FDA has also issued guidance for test developers to evaluate the potential impact of emerging and future viral mutations on COVID 19 tests for the duration of the COVID-19 PHE. There are a variety of examples where CDRH’s surveillance efforts have detected trends using real-world performance and communicated accordingly. For example, CDRH quickly determined there were inaccuracies with the Abbott ID Now POC tests based on the AE reports received. As a result, CDRH was able to alert the public through a press release and the clinical community through a Letter for Health Care Providers, and to work with Abbott to update the Instructions for Use, all within a month of the test’s Original Authorization. Another example involves Becton, Dickinson and Co (BD) SARS-CoV 2 Reagents for the BD Max System test, which was granted authorization in April 2020\. Analysis of real-world performance data showed a false positive rate of about 3%. CDRH worked with BD to identify the issue and address it through updates to labeling and the Factsheet for Health Care Providers. CDRH also issued a Letter to Health Care Providers on July 7, 2020 alerting them of the potential for false positives and recommending positive results be confirmed with an alternate authorized test. FDA maintains lists on their website of previously notified tests that should no longer be used and that have been removed from the lists of notified tests. A test may be placed on the removal list for a variety of reasons: (1) failure to submit an EUA request in a reasonable amount of time as outlined in guidance; (2) poor test performance or inadequate validation; and (3) voluntary withdrawal of the EUA request by the requestor. FDA expects that tests on this list will not be distributed unless and until an EUA is issued for the test. This process may also facilitate the withdrawal of poor-performing tests from the market. The vast majority of tests on the removal lists are serology tests, which may be a reflection of serology developers taking advantage of the notification policy to a greater extent than commercial developers of diagnostic tests (i.e., antigen and molecular). To address an influx of firms marketing fraudulent tests with false or misleading claims, FDA issued Warning Letters to companies for adulterated and misbranded products related to COVID-19. Warning Letters are issued when FDA finds that a manufacturer has violated FDA regulations (e.g., poor manufacturing practices, unsubstantiated claims). These Warning Letters are published on FDA’s website and provide information on the tests and the company that produced it.33 These companies are provided 48 hours to explain how they have addressed their violations. The first Warning Letter for a COVID-19 test was issued on June 10, 2020, and a total of 36 Warning Letters have been issued, as of June 21, 2021, for firms offering violative COVID-19 tests.34 19 of the firms that were issued Warning Letters have ceased marketing of their violative COVID-19 tests. The public is encouraged to submit tips of potential fraud through the appropriate channels like the Fraud Email and Office of Criminal Investigations. FDA stated that it has provided companies with regulatory flexibility but would not tolerate fraud or conduct that puts the health of Americans at risk. **Communicated with the Public Through Various Mechanisms** FDA used a variety of communications to increase transparency and understanding of the EUA process. Since January 27, 2020, FDA has issued press releases,36 often daily, with the latest information on COVID-19. These releases cover topics such as key authorizations, descriptions of policy decisions, safety concerns, and guidances. In addition to these press releases, FDA has provided updates through other communication channels. For example, Dr. Jeff Shuren, Director of CDRH, published an article 37 on the “FDA Voices” page on July 21, 2020, describing FDA’s ongoing work to support diagnostic test accuracy and availability. Similarly, FDA published three medical device consumer updates related to COVID-19,38 translated into five other languages, which describe regulatory terminology, potential for fraudulent products, and testing basics. FDA has supplemented these resources with videos and infographics to further clarify information. FDA has developed communications to promote transparency of real-world test performance to further bolster confidence in the EUA process for COVID-19 diagnostic tests. CDRH publicly posts reference panel results for COVID-19 molecular diagnostic tests on FDA’s website,39 allowing for direct comparison of available tests’ performance for the public. Similarly, results from NCI’s validation studies on serology tests were made public,40 which provides the opportunity to see the objective performance of each test. FDA also shared lessons learned with the public through multiple avenues, including peer-reviewed publications on molecular diagnostic tests41 and antibody tests,42 blog posts of expert opinions on CDRH’s strategy to facilitate COVID-19 test development and authorization,43,44 and a report of FDA’s analysis of South Korea’s COVID-19 response. **STAKEHOLDER PERSPECTIVES AND LESSONS LEARNED** To help inform current and future public health needs, Table 3-12 outlines stakeholder perspectives and lessons learned on the approach to development, review, and authorization of COVID-19 tests. **Table 3-12. Stakeholder Perspective on the Approach to Communication with Requestors, Clinical Community, and the Public** | Focus Areas | Key Takeaway and Lessons Learned | |---|---| | Communications | • Stakeholders shared that frequent communications were beneficial. Specifically, stakeholders found the Town Halls very informative, appreciated the opportunity to ask questions, and often had representation at the meetings to bring back information to their teams.
• Stakeholders leveraged the FAQs and other FDA websites often, many of the EUA requestors kept them bookmarked to frequently check for updates.
• Stakeholders appreciated the convenience of electronic EUA requests and hoped that electronic submissions would be implemented permanently.
• Some stakeholders noted technical issues with file type and size constraints when submitting their EUA request electronically.
• Stakeholders indicated the need for greater clarity on certain issues, specifically: (1) when a change to the test requires filing an EUA Supplement; (2) how to get authorized; and (3) updates to templates since it likely impacts development programs. | || ## 4\. BEST PRACTICES AND PRIORITY RECOMMENDATIONS Booz Allen identified areas where CDRH could build on lessons learned and successful improvements as well as priority recommendations to further strengthen the EUA process. We observed best practices, outlined in Table 4-1, that CDRH should continue to leverage as well as areas for additional improvement to further strengthen and optimize the EUA process. **Table 4-1. Best Practices Identified by Booz Allen to Support the EUA Process** | Focus Area | Best Practices | |---|---| | Best Practices | • Rapid updates to guidance and policy regarding different test types and developers, allowing CDRH to strike a balance between urgent need for tests and assurance of test performance
• Use of publicly available templates to provide guidance on the EUA requests and continue to gather feedback from stakeholders on the templates
• Factors to prioritize submission review, including test capacity, accessibility, novelty, and supply chain considerations, to focus review resources on the most impactful requests
• Development and required use of a reference panel for assurance of performance
• Collaboration on validation and performance testing; generation and evaluation of RWD; and supply chain monitoring
• Hosting Town Halls to communicate interactively and frequently
• Electronic submission to facilitate the process for EUA requestors | || Table 4-2. outlines priority recommendations that would allow FDA to capitalize on its previous success, enhance current processes and procedures, and facilitate the next steps to strengthen FDA’s public health infrastructure to respond to future PHEs. **Table 4-2. Priority Recommendations Identified by Booz Allen to Support the EUA Process** | Key Observation | Priority Recommendation | Intended Impact | |---|---|---| | Precise tracking of new review metrics was encumbered by the IT system, which is not optimized to account for updated EUA processes | Consider ways to optimize the IT system to account for EUA processes | Fully automate submission and tracking of EUA requests (e.g., linking Pre-EUA to EUA; lags while awaiting additional information from requestors; lags due to backlog or priority designation) to provide more comprehensive picture of review time from EUA submission to decision for review efficiency, performance monitoring, prioritization, process improvements, and workload management | | The approach to staff allocation was difficult to systematically quantify and analyze, making it difficult to determine what events or criteria triggered shifts in staff and how shifts were coordinated to address the triggering event or criteria | Consider developing a systematic approach (i.e., strategy and plan) for allocation and tracking of staff during PHE | Quick determination of staffing needs and deployment of the right staff to the right place at the right time to maximize review efficiency. Identification of most likely areas for future PHEs (e.g., emerging infectious diseases) and development of process for cross-training to prepare a subset of staff in those areas in the event of a PHE | | There was limited understanding in the test developer community on how to appropriately validate a diagnostic test | Consider developing a framework for how to conduct validation of diagnostic tests for emerging pathogens in the setting of a declared PHE | Earlier access to appropriate, effective diagnostic tests | || ## 5\. APPENDIX ### 5.1 Glossary **Table 5-1. Glossary of Abbreviations and Acronyms** | Abbreviation or Acronym | Definition | |---|---| | AE | Adverse Event | | BARDA | Biomedical Advanced Research and Development Authority | | BD | Becton Dickinson | | CBER | Center for Biologics Evaluation and Research | | CARES | Coronavirus Aid, Relief, and Economic Security | | CDRH | Center for Devices and Radiological Health | | CLIA | Clinical Laboratory Improvement Amendments | | COVID-19 | Coronavirus Disease 2019 | | EUA | Emergency Use Authorization | | FAQ | Frequently Asked Question | | FD&C Act | Federal Food, Drug, and Cosmetic Act | | FDA | Food and Drug Administration | | HHS | Health and Human Services | | IDE | Investigational Device Exemption | | IO | Immediate Office | | IVD | *In Vitro* Diagnostic | | LDT | Laboratory Developed Test | | MDIC | Medical Device Innovation Consortium | | MDR | Medical Device Report | | MedSun | Medical Product Safety Network | | NCI | National Cancer Institute | | NIH | National Institutes of Health | | OCC | Office of the Chief Counsel | | OCET | Office of Counterterrorism and Emerging Threats | | OHT | Offices of Health Technology | | OHT7 | Office of Health Technology 7 - In Vitro Diagnostics and Radiological Health | | OPEQ | Office of Product Evaluation and Quality | | OST | Office of Strategic Partnerships and Technology Innovation | | PHE | Public Health Emergency | | POC | Point of Care | | RWD | Real-World Data | | RWE | Real-World Evidence | | SARS-CoV-2 | Severe Acute Respiratory Syndrome Coronavirus 2 | | SHIELD | Systematic Harmonization and Interoperability Enhancement of Lab Data | | SOP | Standard Operating Procedure | || **About Booz Allen** Booz Allen Hamilton has been at the forefront of strategy and technology for governments, and not-for-profits across the globe. Booz Allen partners with public and private sector clients to solve their most difficult challenges through a combination of consulting, analytics, mission operations, technology, systems delivery, cybersecurity, engineering, and innovation expertise. With international headquarters in McLean, Virginia, the firm employs more than 22,600 people globally and had revenue of $5.41 billion for the 12 months ended March 31, 2016\. To learn more, visit BoozAllen.com. (NYSE: BAH) © 2021 Booz Allen Hamilton Inc. # 6,335 2022-07-01_FDA Report - FDAs Work to Combat the COVID-19 Pandemic.md METADATA last updated: 2026-03-05 by BA file_name: 2022-07-01_FDA Report - FDAs Work to Combat the COVID-19 Pandemic.md file_date: 2022-07-01 title: FDA Report - FDAs Work to Combat the COVID-19 Pandemic category: regulatory subcategory: reg-articles-misc tags: source_file_type: pdf xfile_type: NA gfile_url: NA xfile_github_download_url: https://raw.githubusercontent.com/FocusOnFoundationsNonprofit/floodlamp-archive/main/regulatory/reg-articles-misc/2022-07-01_FDA%20Report%20-%20FDAs%20Work%20to%20Combat%20the%20COVID-19%20Pandemic.NA pdf_gdrive_url: https://drive.google.com/file/d/1--FKbp2c_Q5mUbbm7qg04VCmbKaUEDmL pdf_github_url: https://github.com/FocusOnFoundationsNonprofit/floodlamp-archive/blob/main/regulatory/reg-articles-misc/2022-07-01_FDA%20Report%20-%20FDAs%20Work%20to%20Combat%20the%20COVID-19%20Pandemic.pdf conversion_input_file_type: pdf conversion: megaparse license: Public Domain tokens: 6335 words: 4827 notes: summary_short: The FDA “Work to Combat the COVID-19 Pandemic” overview (data current as of April 2022) summarizes FDA’s cross-center actions on vaccines, therapeutics, diagnostics/devices, supply chain resilience, inspections/fraud enforcement, and regulatory science. It highlights scale and mechanisms such as EUAs and postmarket monitoring, expanded data infrastructure and real-world evidence efforts, device/test oversight and communications, and initiatives to prevent shortages and intercept fraudulent or contaminated products. It also notes crosscutting research and equity-focused work intended to strengthen preparedness for future public health emergencies. CONTENT ***INTERNAL TITLE:*** FDA’s Work to Combat the COVID-19 Pandemic July 2022 ## Introduction On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic. The pandemic has caused unimaginable harms, with over 1,000,000 American lives lost to the disease. These two years have also seen unprecedented progress in pandemic preparedness across the U.S. government, particularly at the U.S. Food and Drug Administration. The FDA continues to build on the foundation of scientific rigor, thoughtfulness, and adaptability in rising to this challenge. The agency is deeply appreciative of Congress’ support to ensure the American public’s access to medical products they need to diagnose, treat, and prevent COVID-19. The FDA is responsible for monitoring the continued performance, safety, availability, and effectiveness of the COVID-19-related products on the market now, as well as in the years to come. To accomplish this long-range mission, the FDA is hiring and training new talent, building large data infrastructure and analytic capacity, modifying processes, and developing new partnerships. These efforts improve the resiliency of the agency and the health of Americans, responding to the COVID-19 pandemic and preparing for future crises such as public health emergencies, supply chain disruptions, geopolitical changes, and natural disasters. This document outlines much of the broad range of work the FDA is undertaking to combat the COVID-19 pandemic and prepare for future emergencies. ## Contents Vaccines ........................................................................................................ 3 Pharmaceuticals ............................................................................................. 4 Devices, including Tests and Personal Protective Equipment .............................. 5 Resilient Supply Chains .................................................................................. 7 Advanced Manufacturing and Innovation ............................................................. 9 Inspections, Investigations, Imports, and Fraud ............................................... 11 Crosscutting Research .................................................................................... 13 ## Vaccines Vaccines save lives by preventing disease, hospitalizations, and deaths. Given the COVID-19 public health emergency (PHE), development timelines for COVID-19 vaccines were shortened without compromising safety and effectiveness standards. The FDA’s Center for Biologics Evaluation and Research (CBER), in close partnership with industry and governmental partners, facilitated the needed scientific studies and manufacturing process validations to support this timeline. CBER issued an Emergency Use Authorization (EUA) for the first COVID-19 vaccine within eight months of the declaration of a PHE and licensed the first COVID-19 vaccine within two years, less than 100 days from the Biologics License Application submission. Typical vaccine development and approval can take 10 years or longer. Over 570 million doses of vaccines have been administered in the U.S., and 82.2% of the American public over age five has received at least one dose of a vaccine per CDC data. After authorization, CBER tracks the safety and performance of these vaccines in the real world. Even very large clinical trials are sometimes too small to detect extremely rare side effects and may not be designed to learn about the efficacy of a vaccine in certain groups, like patients with cancer. Real World Evidence (RWE) is the analysis of anonymous health information for millions of people collected through multiple sources such as electronic health records, insurance claims, reports, and public health databases. The FDA uses RWE and multiple other tools to detect potential safety issues early and mitigate them, as well as to answer critical questions around vaccine effectiveness, duration of protection, impacts of variants and mutations, and more. CBER conducted 24 research studies in FY 2020 and 2021 which have produced more than 58 publications,° with wide-ranging implications for evaluating antibody and vaccine effectiveness, relevant for COVID-19 and for future vaccine development and regulation. **The FDA has:** * Issued EUAs for three vaccines, two of which are authorized for the population age 6 months and up. * Approved two vaccines. * Reviewed over 1,300 EUA amendments to authorized COVID-19 vaccines. * Held nine advisory committee meetings regarding COVID-19 vaccines. * Issued five draft, updated, or final guidances, related to COVID-19 vaccines. * Continually reviewed and updated EUAs to include authorizations for boosters, immunocompromised people, and other special circumstances. * **The Vaccine Adverse Events Reporting System (VAERS)** relies on healthcare providers, vaccine recipients, and parents of vaccine recipients to send in reports of their experiences. CBER received 812,147 VAERS reports in FY 2021 relating to the COVID-19 vaccines, a 1,488% increase over the FY 2020 reports. * **The Biologics Effectiveness and Safety System (BEST)** and the Centers for Medicare & Medicaid Services data systems are tracking 16 potential rare adverse reactions in data representing 120 million people. The FDA detected four such potential reactions (pulmonary embolism, acute myocardial infarction, immune thrombocytopenia, and disseminated intravascular coagulation) and issued a protocol and public communication. ## Pharmaceuticals Treatments are crucial for saving lives from COVID-19 infection. Congress established a process called Emergency Use Authorization (EUA) to make appropriate treatments available to patients as quickly as possible during PHEs when certain criteria are met. The FDA’s Coronavirus Treatment Acceleration Program (CTAP) uses multiple methods to expedite development of treatments including targeted guidance, communications, and interdisciplinary teams to assist drug sponsors with trial design and data submissions. The FDA has been closely monitoring data from multiple sources to rapidly identify emerging potential safety issues associated with drugs and biologics used to treat or prevent COVID-19. These include safety issues that may not have been captured in a clinical trial, or those that arise from the misuse or off-label use of these products. The FDA can use this information to revise EUAs including updating the authorized Fact Sheets; communicate with the public, health care professionals, and other stakeholders; or act against fraudulent products. To accomplish this, the FDA uses two main systems: * The FDA Adverse Event Reporting System (FAERS), enables healthcare professionals, consumers, and manufacturers to submit adverse event reports, medication error reports and product quality complaints. In 2021, the FDA launched a new COVID-19 EUA FAERS Public Dashboard to provide the public with easy access to COVID-19 EUA products adverse event data. * The FDA Sentinel System and other Real World Data (RWD) systems, which assess potential safety signals in health records, insurance claims, and other RWD. The FDA enhanced these systems in response to the COVID-19 pandemic to include new electronic health records data and to increase the speed of signal detection. This supports the FDA's efforts to characterize the natural history of COVID-19 and to better understand the use and performance of drugs and biologics used to treat or prevent COVID-19. As of June 1, 2022, Sentinel completed 62 COVID-19 related analyses in the Sentinel Distributed Databases and associated electronic health record sources. 700+ Drug development programs in planning stages 460+ Trials reviewed by FDA 13 COVID-19 treatments currently authorized for Emergency Use 2 Treatments currently approved by FDA for use in COVID-19 Antivirals: > 23 million courses of two types of antiviral pills have been purchased by the federal government for 2022. Millions of doses of an IV antiviral medication have been administered. Antibodies: 7.1 million courses of antibody treatments have been distributed by the federal government. * Treatment: 65-90 % reduction in hospitalization or death depending on the product. * Prevention: 77% reduction in infection in those who cannot respond to vaccinations. ## Devices, including Tests and Personal Protective Equipment Medical diagnostics and other devices are necessary in combatting the pandemic: * Tests allow people to seek early care, get the appropriate medications, quarantine to prevent infecting others, and return to travel and work more safely. * Personal Protective Equipment (PPE) like masks, respirators, and gloves protect against infection. * Other devices, like ventilators and syringes, are needed to treat sick patients. Many of these were in short supply at the beginning of pandemic, so the FDA leveraged the EUA regulatory pathway to make tests and other devices available to patients as quickly as possible while assuring that they are appropriately safe and effective. Many of the manufacturers of these products are new and unfamiliar with the FDA's policies and procedures, which required the FDA Center for Devices and Radiological Health (CDRH) to organize significant outreach to prepare them for regulation. CDRH has hired new reviewers, conducted town hall meetings, created new validation templates and guidances, assembled a software SWAT team, partnered with sister agencies (such as the National Institutes of Health (NIH) and Biomedical Advanced Research and Development Authority) to support development and FDA authorization of devices with novel technologies, and created new review mechanisms. **The FDA has:** * Reviewed > 8,000 EUA device submissions (> 5,000 for tests), which is 100 times more than in any prior public health emergency. * Issued EUAs for >800 devices, 450 of which are for tests, including 19 OTC tests. * Approved/cleared 706 PPE devices, 109 ventilators, and 635 other devices such as infusion pumps and syringes through non-EUA pathways. CDRH managed >400,000 inquiries and interactions related to COVID products, and held 105 town hall webinars for >53,000 participants. The FDA and firms have taken postmarket actions, including EUA revocation and recall for many devices. COVID-19 DEVICE POSTMARKET METRICS 45 WARNING LETTERS ISSUED (2021) 64 DEVICES RECALLED (2021) 263 EUAS REVOKED (COVID-19 PHE TOTAL) 315 TESTS REMOVED FROM NOTIFICATION LISTS (COVID-19 PHE TOTAL) Tracking real-world performance of tests is important for the FDA to be able to continue to make sure that the available tests are working correctly. To accomplish this, test results need to be captured consistently; results for most over-the-counter (OTC) rapid tests and tests performed at a hospital or laboratory are not always structured in the same ways, and do not always align with the systems that store health information from electronic medical records and insurance claims. To solve these issues, the FDA is leading efforts, such as the Systematic Harmonization and Interoperability Enhancement for Laboratory Data (SHIELD), to capture and integrate test data, laboratory data, and patient health data. The FDA is also collaborating with NIH’s Variant Task Force (VTF) program to identify and prioritize tests that can detect circulating variants, assess how current tests perform with new variants, and model the anticipated effect of new mutations on multiple different kinds of tests. Over 630,000 CDRH staff hours have been spent on COVID-19 work in 2020-2021. OTC Tests: Hundreds of millions of COVID-19 tests have already been performed in the U.S., and over are being contracted by the Biden Administration. The FDA focused particularly on the authorizations of 18 home-use tests as they are relatively inexpensive, allow people to stay in quarantine during testing, and provide faster results. A rollout of home-based testing at this scale is unprecedented, and the FDA's experience regulating novel technologies during this pandemic will facilitate a fast and robust response to a future crisis and to emerging variants. ## Resilient Supply Chains COVID-19 highlighted vulnerabilities in the medical supply chain. Supply chain disruptions == for products like ventilators, pharmaceuticals, active ingredients, and PPE were already beginning to occur before COVID-19 cases were identified in the U.S. As demand increased, stockpiling occurred globally, and manufacturing was disrupted. Although the agency has intervened where possible to mitigate medical product shortages, responding to the massive shortages complicated by the pandemic has required establishing new or much more comprehensive programs, focused on three areas: * Monitoring and visualization of supply, demand, and the availability of supplies by integrating data from a wide variety of sources, such as active ingredient manufacturers, product manufacturers, distributors, suppliers, and end-users like hospitals and pharmacies. * Prediction of products at risk of shortage using statistical methods and artificial intelligence. * Prevention or mitigation of shortages with evidence-based strategies such as enforcement discretion; expedited review of manufacturing supplements, generic drug applications, or premarket devices; and requesting that manufacturers identify alternative suppliers, redistribute stock, or increase manufacturing. * The programs developed are expected to be beneficial for preventing future shortages including in other emergencies like natural disasters (hurricanes and winter storms), labor disputes, and shipping disruptions. ### PHARMACEUTICALS * CDER’s Drug Supply Chain Surveillance System is being developed to provide enhanced insight into the drug supply chain—from active ingredient suppliers to clinical settings such as hospitals and pharmacies. This system will utilize existing as well as new data sources to identify early signals that may indicate shortages so they can be prevented and mitigated. o CDER was able to work with manufacturers to prevent 482 potential shortages in 2020-2021. Consequently, there was no increase in the number of shortages: 46 in 2019, 43 in 2020 and 38 in 2021. o CDER accomplished this in part by expediting review and approval of > 1,300 manufacturing supplements and > 100 generic drugs. For example, starting in April 2020, there were shortages of Cisatracurium, a necessary medication for some patients on ventilators with dangerously low oxygen levels. The FDA identified this shortage and expedited the review of a generic version of the drug to increase supply. CDER also issued temporary guidances on compounding to allow for a wider array of compounding formulations to address certain supply disruptions. ### VACCINES AND BIOLOGICS * CBER’s shortages program was able to work with manufacturers to prevent 34 potential shortages in calendar years 2020 and 2021. CBER accomplished this, in part, by expediting review and approval of 17 biologics license application supplements and 15 lot release submissions for CBER-regulated products. ### ANIMAL DRUGS * The FDA Center for Veterinary Medicine (CVM) Animal Drug and Manufacturing System is launching in 2022 and will generate reports with necessary data for the analysis of potential animal drug shortages, which have more than tripled during pandemic. ### DEVICES * CDRH’s new Resilient Supply Chain Program (RSCP) program aims to develop and apply state-of-the-art supply chain intelligence to predict and prevent supply chain shortages. CDRH has implemented the reporting authority that requires manufacturers to report the shortage of certain medical devices utilizing a newly created webform, and actively maintains a medical device shortage list. In addition, CDRH has integrated internal and external data sources for supply chain analysis and modeling to inform shortage mitigations. o The RSCP has performed outreach to >1000 manufacturers in 12 countries to perform impact assessments and inform mitigation strategies. o CDRH has performed hundreds of shortage assessments on PPE, COVID-19 testing supplies and equipment, ventilators, and other related device shortages, and has provided evidence- based data to support both regulatory and non- regulatory mitigations. For example, CDRH, in partnership with the Biomedical Advanced Research and Development Authority and the U.S. Department of Defense, helped to coordinate a series of military airlifts of millions of testing swabs during a severe shortage. ### IMPORT IMPROVEMENTS * The FDA Office of Regulatory Affairs is investing in import modernization with our partner government agencies. For example, FDA continues to work with U.S. Customs and Border Protection to refine existing data interfaces and with the U.S. Postal Service to develop a data exchange to better track and target international mail. These efforts should enable more effective efficient legitimate trade, while intercepting potentially harmful products before they enter the U.S. ## Advanced Manufacturing and Innovation The COVID-19 pandemic has revealed that most existing manufacturing systems, which depend on a limited number of facilities fed by long and complex global supply chains, can be disrupted by delays, shortages of raw materials, contamination events, or other disturbances. In some cases, this can lead to shortages of much-needed medical products. Advanced manufacturing is a set of manufacturing technologies and principles that can allow for products to be manufactured in a new or innovative way, such as novel technological approaches that permit production through a distributed network of smaller plants capable of responding in an agile and adaptable way to supply chain threats. Advanced manufacturing techniques can help protect against emerging threats, public health emergencies, natural disasters, and economic supply chain shifts by: * Matching supply to meet demand by creating agile and high-throughput production systems that can scale to respond to new threats and changes in demand. * Improving supply chain resilience by integrating independent operations end to end so that a single plant can depend on fewer input sources and is thus less susceptible to shortages. * Creating cost-effective small-footprint plants that may make the manufacture of medications, including those for rare diseases, more financially viable and may lead to cost savings for consumers. * Increasing product quality, manufacturing, consistency, and output through improving process design and process controls that can detect non-conforming materials in real time. There are multiple production techniques that could be considered “advanced,” and there is explosive growth in the development of new techniques. Evaluating and regulating advanced manufacturing is complex: the array of different manufacturing techniques is vast, many technologies are designed to be adapted to changing circumstances, and the amounts of data collected can be staggering. Yet, the potential of these technologies is extraordinary, and the FDA has a critical role in facilitating this innovation with respect to medical product manufacturing. * For **pharmaceutical manufacturing**, the chemical reactions and purification steps to make active ingredients typically occur in different rooms, different plants, different companies, or even different countries. The blending, weighing, compressing, and coating of a pill may occur somewhere else altogether. There are many advanced manufacturing techniques in development to integrate these steps, incorporate real-time quality controls, and transform physical plant infrastructure. During the pandemic, CDER and CBER partnered to launch the Center for the Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals. The FDA has conducted COVID-related research projects exploring active pharmaceutical ingredient manufacturing processes, smart data analytics for product quality, techniques to make monoclonal antibodies, and more. addition, the FDA has increased its support of targeted research, testing, and training in advanced manufacturing technologies. * For **vaccine manufacturing**, messenger RNA (mRNA) vaccines leukemia, asthma, and two have emerged as a powerful platform technology. These critical drugs needed during vaccines have several advantages: the vaccine antigen can COVID-19. be redesigned relatively easily to target new diseases or new variants and can be simpler to manufacture. Still, they present several new unique manufacturing challenges, such as the need for suitable delivery vehicles (for example lipid nanoparticles), very cold storage, and reliance on specialized materials (reagents). Production of these, and other vaccines, may benefit from several advanced manufacturing techniques. For example, distributed manufacturing in decentralized or mobile units could allow vaccines to be produced near the site of distribution, reducing the cost and risks of transportation. CBER is working to launch a demonstration project for mRNA vaccine manufacturing which will focus on best practices in integrated and continuous vaccine manufacturing. This work is relevant for multiple vaccines, including influenza, COVID-19 variants, and other pathogens. * For **medical device manufacturing**, new robotics, additive manufacturing (also known as 3D printing), and digital design tools can allow changes in a manufacturing process in response to a new need. Robotics and design tools can also be used to reconfigure a device to be able to use anew part without any loss of effectiveness. CDRH has invested in the Medical Device Information Analysis and Sharing Initiative to integrate data from patients, providers, payers, device manufacturers and regulators to understand “blind spots” in product safety and manufacturing quality that can be improved with advanced manufacturing techniques. CDRH also initiated two programs to work directly with manufacturers on “proof-of- concept” manufacturing technologies, called the Advanced Manufacturing Technology Clearinghouse and the Voluntary Improvement Program. The FDA is a global leader in advanced manufacturing regulation, supporting the development of two International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines on continuous manufacturing and Manufacturing using cell lines. CDER held > 150 meetings with drug manufacturers and approved 15 applications and supplements, which use new technologies (e.g., continuous manufacturing and 3D printing) to manufacture products _used in the treatment of cystic fibrosis, HIV/AIDS, breast cancer, leukemia, asthma, and two critical drugs needed during COVID-19. One CDRH and industry collaboration reduced technology implementation time from 18 to eight months, resulting in a reduction in non-conformances of 45% and projected savings of $30 million. **The Ventilator Digital Twin Project.** A digital twin is a model of all the objects, people, designs, processes, and systems involved in the creation of a complex device. This allows one to virtually “try out” a new technique. The Ventilator Digital Twin can model the impact of disruptions like social distancing or parts shortages on ventilator production and come up with solutions. ## Inspections, Investigations, Imports, and Fraud Inspections and examinations of firms, manufacturing facilities, and imported products, are a critical component of the FDA’s strategy to protect the public from harmful or fraudulent products. The need for these field activities, which are led by ORA in partnership with the relevant centers, only continues to grow. As one example, the number of imported medical product lines increased by 42% in FY 2015-2021, including a 9% increase during pandemic (FY 2020-2021). The pandemic brought about additional unique challenges: * Inspections were initially significantly limited due to travel bans and risk to personnel, though mission critical inspections were continued throughout. * Accelerated growth in the vaccine industry necessitated new inspection programs. * Online marketplace revenue grew from $360 billion in 2019 to $768 billion in 2021, including ~$56 billion in health products, increasing the potential for fraudulent online activities. To **facilitate inspection activities**, the FDA is initiating a new inspection planning system that will be more efficient, transparent, and adaptable to changing needs. This will help prioritize high-impact inspections such as those for facilities manufacturing COVID-19 vaccines or ingredients used in multiple critical products, as well as the inspections needed for clinical trials of COVID-19 drugs. The FDA is also developing new approaches to inspect firms utilizing novel advanced manufacturing techniques. To **identify fraudulent products**, ORA has begun a proof of concept using handheld, field-deployable, fraud detection tools including Raman Spectrometers (Progeny) and counterfeit detection devices (CD5). Additionally, ORA is standing up 2-person satellite laboratories at selected international mail facilities. These hand-held devices and satellite laboratories can be used to analyze the chemical composition of a product to verify authenticity and detect potential contamination directly on site. The ORA’s Forensic Chemistry Center experts can then review this field-generated data in real time. If successful, one or more of these pilots could allow field staff to decide about admitting an imported product much faster than if they need to send samples to a fixed laboratory and wait hours or days for a result. This could reduce the time it takes for the FDA to intercept fraudulent products, expedite legitimate trade, and potentially promote mitigation of supply chain issues. **The FDA has:** * Identified > 1,706 fraudulent and/or unapproved medical products related to COVID-19. * Issued > 219 warning letters to companies and individuals selling unproven products and >70% of recipients took voluntary action in response. * Identified 340 contaminated hand sanitizers (see Box 4). * Continued mission-critical inspections throughout. * Reinvigorated a system to conduct > 1,400 domestic and > 500 foreign remote assessments. * Conducted domestic inspections at standard operational levels since October 2021. * Resumed foreign facility surveillance inspections in March 2022. **Combatting False Marketing:** The Genesis II Church of Florida falsely marketed a chlorine dioxide formulation, a bleach-like disinfectant, as a treatment for a range of conditions including COVID-19. The FDA sent a joint warning letter with the Federal Trade Commission, which the manufacturer defied. The FDA then successfully pursued in court a temporary restraining order, a preliminary injunction, and, ultimately, a permanent injunction, which enjoins the manufacturer from labeling, holding, or distributing the product. The FDA launched a data system to track and flag online sales of potentially fraudulent COVID-19 related products. To **prevent harm to consumers and animals from violative or fraudulent products**, the FDA takes multiple different actions. Illustrative examples include issuing consumer warnings about unapproved and unauthorized products distributed with fraudulent claims to treat or prevent COVID-19 in humans and animals; alerting healthcare providers on how to identify fraudulent PPE; and pursuing regulatory actions to stop the production, importation, distribution, and use of potentially harmful products like contaminated hand sanitizers. **Combatting Fatal Contamination:** The FDA noted 2,660 cases of poisonings reported to the National Poison Data System’, including 18 confirmed deaths, from ingestion of contaminated hand sanitizers. The FDA saw a sharp increase in hand sanitizer products from Mexico that were labeled to contain ethanol (also known as ethyl alcohol) but, among other concerns, tested positive for methanol contamination; 84% of the samples of alcohol-based hand sanitizers imported from Mexico analyzed by the agency from April 2020 through December 2020 were not in compliance with the FDA's regulations, and more than half of the samples were found to contain toxic ingredients, including methanol and/or 1-propanol, at dangerous levels. The FDA worked with companies and retailers to recall dozens of violative products. In January 2021, due to safety concerns about alcohol-based hand sanitizers manufactured in Mexico, the agency placed all such products on an import alert, which was the first time the FDA had issued a countrywide import alert for any category of drug product. In addition, as part of the agency’s efforts to protect consumers from potentially dangerous or violative hand sanitizers, the agency published on its website a list of over 250 hand sanitizers that consumers should not use, released a guidance, developed safety toolkits in multiple languages, and issued warning letters. ## Crosscutting Research ### Crosscutting Activities Regulatory science is the science of developing evidence-based tools, standards, and approaches to assess safety, efficacy, quality, and performance of all FDA-regulated products. Much research conducted at the ; . : . FDA is relevant to multiple different products and may involve more than one FDA center or office. The studies below have resulted in more than 60 publications: * Laboratory standards and techniques such as the development of reagents, reference panels, and artificial intelligence (Al) to identify targets for new drug development. * Immunology research including neutralizing antibody studies, cytokine studies, and a model of the interactions between the virus, immune system, and body tissues. * Advanced manufacturing research including an analysis of the current advanced manufacturing landscape, 3D printing pilots, and IT and physical infrastructure plans. * The RWD Research Lab including pilot projects to establish rapid-cycle analytic approaches and foster collaboration on topics such as understanding vaccine effectiveness. * Transmission research including studies on SARS-CoV-2 transmission in food or on surfaces, and algorithms to link maternal and infant data to understand perinatal transmission. The FDA has created translations of FDA health communications in numerous languages, including EUA fact sheets in multiple languages. ### Health Equity Many diseases, including COVID-19, disproportionately impact racial and ethnic minority communities. The FDA Office of Minority Health and Health Equity (OMHHE) launched The Enhance EQUITY Initiative to advance diversity in clinical trials, increase equitable data efforts, and increase understanding of diverse stakeholder perspectives. OMHHE launched The COVID-19 and Health Equity Innovation Award which has funded five studies on topics such as understanding COVID-19 outcomes by different demographic variables, including ethnicity, race, age, and geography among others; racial and ethnic minority participation in COVID-19 clinical trials; and understanding diverse patient perspectives, preferences, and unmet needs. OMHHE also supported four additional COVID-19 research projects. ### Identifying Variants in Wastewater Testing for SARS-CoV-2 in wastewater can indicate a surge one to two weeks before a rise in cases. Wastewater also gives a snapshot of a whole population served by a wastewater system, not just those who get tested. Most of the wastewater surveillance for SARS-CoV-2 tests only small fragments of the virus, which can indicate the quantity of the virus present but unfortunately does not give any indication about the proportion of variants within a sample. The FDA Center for Food Safety and Applied Nutrition’s (CFSAN) existing GenomeTrakr program uses whole genome sequencing to evaluate the genomes of pathogens in the food supply. CFSAN deployed a similar technology to sequence SARS-CoV-2 in > 50 sites in the U.S. geographic regions with high percentages of agricultural and food facility workers, whose health is critical for stability of the U.S. food supply chain. These data can be used to monitor circulating variants and their impact on vaccines, therapeutics, and diagnostics. Furthermore, the analysis software CFSAN developed has been adopted by other partners, including the U.S. Centers for Disease Control and Prevention (CDC). ### Understanding COVID-19 Spread from Animals Approximately 75% of recently emerging infectious diseases affecting humans are of animal origin, including HIV, Ebola, and influenza. Mink, deer, and other animals are known to be reservoirs for SARS-CoV-2. Humans have transmitted SARS- CoV-2 back to animals, including some domestic dogs and cats. Researchers are currently exploring how environmental factors, including ground and wastewater, play a role in viral transmission. Recognizing that the health of people, animals, and the environment is intertwined, CVM is partnering with other government agencies, such as the U.S. Department of Agriculture and CDC, to solidify a One Health approach to the FDA’s human and animal public health work, and the FDA is standing up a One Health Center of Excellence. An example of CVM’s One Health approach is the work being done with other veterinary diagnostic laboratories to identify COVID-19 variants in animal populations and compare them to those in humans. This type of approach is to understanding not just COVID-19, but many other emerging threats, such as antimicrobial resistance.