The U.S. Food and Drug Administration (FDA) has issued final guidance on the validation of certain in vitro diagnostic devices for emerging pathogens during a Section 564 declared emergency.
Issued on 10 November 2026, the guidance replaces the draft published on 7 January 2025 and provides manufacturers with a framework for validating diagnostic tests that may be submitted through a pre-EUA or Emergency Use Authorization request during future public health emergencies.
Preparing IVD Manufacturers for Future Emergencies
The guidance is intended to help manufacturers prepare validation strategies for diagnostic IVDs intended to detect emerging pathogens associated with serious or life-threatening infectious diseases.
FDA explains that accurate and reliable diagnostic tests are critical for:
diagnosis;
outbreak tracking;
treatment;
interruption of disease transmission;
management of chemical, biological, radiological and nuclear threats.
The document also reflects lessons learned from the COVID-19 and mpox public health emergencies.
Scope of the Guidance
The guidance applies to certain diagnostic IVDs intended to detect pathogens associated with a serious or life-threatening infectious disease or condition where an applicable Section 564 declaration has been issued.
The recommendations may apply to data submitted through:
pre-EUA interactions;
EUA requests;
certain enforcement discretion policies.
FDA notes that the recommendations are designed to remain broadly applicable to future emerging pathogens and may be adapted depending on the stage and circumstances of an outbreak.
Not All IVDs Are Within Scope
The guidance primarily addresses diagnostic tests intended to detect current infection.
FDA notes that serology, antibody and other adaptive immune-response tests are generally outside the scope because they are typically not used to diagnose an acute current infection.
The framework may nevertheless apply across a range of diagnostic settings, including:
CLIA-certified laboratories;
point-of-care settings;
home testing.
Generic EUA Template Available
FDA has also made available a General IVD Emergency Use Authorization Request/Pre-EUA Template.
The template reflects the Agency’s current thinking regarding the data and information manufacturers should provide in emergency submissions.
FDA may also issue pathogen-specific templates during particular outbreaks.
Validation Must Demonstrate the Device May Be Effective
FDA explains that the EUA framework uses a “may be effective” standard rather than the full “effectiveness” standard generally applied to product approvals.
Validation should therefore demonstrate that:
the device may be effective for its intended use;
known and potential benefits outweigh known and potential risks.
FDA also recognises that emergency conditions may prevent manufacturers from generating every recommended data element immediately.
Validation Should Preferably Use the Final Device Design
Where possible, validation should be performed using:
the final device design;
the proposed Instructions for Use;
the final instruments;
reagents;
software;
other relevant components.
For innovative technologies, additional technology-specific studies may be requested.
However, FDA notes that where lawfully marketed instruments or components are already well characterised, additional component-specific validation may not always be necessary.
Clinical Performance Evaluation
Clinical performance studies should assess how accurately the test detects the target analyte under conditions representative of actual clinical use.
Study design will depend on:
pathogen;
test technology;
specimen availability;
comparator methods;
outbreak stage;
testing needs.
FDA Provides a Benchmark of 30 Positive and 30 Negative Specimens
For certain viral nucleic acid tests using established high-sensitivity technology, FDA states that at least 30 positive and 30 negative clinical specimens may typically be sufficient when samples and an appropriate comparator are available.
FDA cautions that evaluating fewer specimens may not adequately characterise true test performance.
The guidance cites previous experience where an EUA request initially supported by only 12 positive samples showed perfect apparent performance, but performance dropped substantially when additional samples were tested.
Alternative Specimen Types During the Early Outbreak Phase
Natural clinical specimens remain FDA’s preferred validation material.
However, early in an outbreak, suitable clinical samples may not yet be available.
In such circumstances, FDA may accept:
archived clinical specimens;
contrived specimens;
synthetic materials where pathogen stocks are unavailable.
Synthetic material should closely mimic the natural pathogen target.
Post-Authorization Clinical Evaluation May Be Required
Where a test is initially validated using contrived or synthetic specimens, FDA may impose a Condition of Authorization requiring additional clinical performance evaluation using natural patient specimens once they become available.
This reflects the need to balance rapid emergency access with continued evidence generation.
Prospective Studies Remain the Preferred Approach
FDA states that, ideally, clinical performance should be demonstrated through a:
prospective;
all-comers;
intended-use environment study;
using intended users;
and natural clinical specimens.
For tests involving different specimen types, manufacturers may need to validate each relevant matrix separately.
Intended Population Must Be Represented
The study population should reflect the intended users of the test.
For example, where a test is intended for asymptomatic individuals, manufacturers should document how participants were screened to confirm the absence of symptoms before enrolment and specimen collection.
FDA Recommends PPA and NPA Analysis
Clinical data analysis should generally include:
Positive Percent Agreement (PPA);
Negative Percent Agreement (NPA);
95% confidence intervals.
Performance targets may vary depending on the test type, intended population and benefit-risk context of the outbreak.
Human Subject Protection
Clinical investigations involving human specimens remain subject to applicable requirements for:
Institutional Review Board review;
informed consent;
Investigational Device Exemption requirements where applicable.
FDA also notes that some minimal-risk studies may qualify for waiver or alteration of informed consent under applicable regulations.
Analytical Validation Remains Essential
Clinical performance data must be complemented by appropriate analytical validation.
The guidance provides recommendations covering:
Limit of Detection;
inclusivity;
specimen stability;
basic safety;
software validation;
cybersecurity;
EMC;
usability;
user comprehension;
flex studies.
Limit of Detection
FDA defines Limit of Detection (LoD) as the lowest analyte concentration consistently detected in at least 95% of replicates.
The guidance recommends establishing a preliminary LoD using serial dilutions and then confirming it using at least 20 replicates.
The final LoD is the lowest concentration where at least 19 of 20 replicates are detected.
Inclusivity and Emerging Variants
For molecular tests, FDA generally recommends evaluating whether primers and probes remain compatible with known pathogen sequences.
In silico analysis should be supplemented with wet testing of circulating variants where appropriate.
For antigen tests, circulating variants should also be evaluated through wet testing.
Monthly Inclusivity Monitoring Recommended
A particularly important recommendation is that manufacturers evaluate inclusivity monthly to account for newly emerging clinically significant mutations.
Where a mutation causes more than a three-fold reduction in analytical sensitivity, manufacturers should conduct a risk assessment and consider additional mitigations.
Specimen Stability
The guidance also provides detailed recommendations for specimen stability studies.
Manufacturers should assess realistic conditions covering:
transport;
storage;
temperature extremes;
expected storage duration.
Stability should be demonstrated for relevant transport methods and specimen types.
Software Validation and Cybersecurity
IVDs incorporating software must ensure that software inputs and outputs function as intended and that software defects are identified and mitigated.
FDA also expects cybersecurity to be evaluated where devices use external wired or wireless communication interfaces.
This includes technologies such as:
USB;
Ethernet;
Wi-Fi;
Bluetooth;
NFC;
cloud connectivity.
Electromagnetic Compatibility
Electrically powered devices should also demonstrate adequate Electromagnetic Compatibility (EMC).
Usability and User Comprehension
For point-of-care, home collection and home-use tests, FDA recommends usability studies involving representative users.
Where healthcare professionals are not involved, manufacturers should also evaluate whether lay users correctly understand:
test instructions;
warnings;
precautions;
positive results;
negative results;
invalid results.
Flex Studies
Flex studies should evaluate test robustness under realistic variations and stresses.
Potential variables may include:
temperature;
handling;
environmental conditions;
operator errors.
A hazard analysis should first identify the most likely sources of use error.
Additional Testing May Be Required
Depending on test technology and risk, FDA may also request additional studies such as:
high-dose hook effect;
cross-reactivity;
microbial interference;
endogenous and exogenous interference;
carry-over;
fresh-versus-frozen specimen comparison;
analytical equivalency.
FDA Introduces “Change Protocols”
The final guidance includes an important clarification regarding future modifications to EUA-authorized tests.
Manufacturers may consider developing change protocols describing anticipated future modifications and how those changes would be validated.
If reviewed by FDA and included in the original EUA, modifications implemented under the protocol may remain covered by the existing authorization.
Change Protocols Are Not PCCPs
The draft guidance previously referred to these arrangements as Predetermined Change Control Plans (PCCPs).
FDA has changed the terminology to “change protocols” to distinguish them from PCCPs used in marketing submissions.
This distinction is particularly relevant for manufacturers working with rapidly evolving diagnostic technologies.
Multi-Analyte Panels
FDA recognises that multi-analyte panels can be valuable during outbreaks because a single specimen can be used to detect multiple pathogens causing similar symptoms.
Each analyte must still be appropriately validated, with particular consideration given to:
cross-reactivity;
microbial interference;
scientific knowledge of each pathogen;
assay format;
specimen availability.
Home Collection and Home Use Tests
Home testing may improve access and reduce potential exposure during infectious disease outbreaks.
FDA recommends that home collection and home-use tests:
use non-invasive collection methods;
require no specialised training;
be suitable for lay users;
address toxicology and hazardous materials;
provide simple instructions.
Quick Reference Instructions
FDA recommends that instructions for lay users be provided as Quick Reference Instructions that are:
limited to one or two pages;
written at no higher than a 7th-grade reading level;
supported by pictures and diagrams.
Home-Use Clinical Studies
Clinical performance studies for home-use tests should include users representative of the intended population and environments that reflect real-world home use.
The full workflow should be evaluated, including:
registration;
specimen collection;
testing;
result interpretation.
Smartphone Applications
Where smartphone software supports test use or result interpretation, the interface should clearly communicate:
positive;
negative;
invalid results;
appropriate follow-up actions.
Software that influences test interpretation should also be included in analytical and clinical performance validation.
Point-of-Care Tests
FDA also provides specific recommendations for point-of-care tests.
Clinical performance studies for tests intended for CLIA-waived environments should generally include:
one or two representative U.S. sites;
four to six operators without laboratory training;
intended-use workflows.
Operators should rely only on the Quick Reference Instructions without additional training.
LoD Performance at Point of Care
For POC tests, FDA recommends additional testing around the LoD using intended users.
Testing should generally include:
10 samples near the LoD;
10 negative specimens per site;
blinded and randomised samples.
Positive and negative agreement should reach at least 95%.
Impact on IVD Manufacturers
For IVD manufacturers preparing for future outbreak scenarios, the guidance provides a detailed roadmap for emergency validation strategies.
Key priorities include:
planning validation before an emergency occurs;
understanding when alternative specimens may be acceptable;
maintaining strong LoD and inclusivity programmes;
monitoring emerging variants;
integrating cybersecurity and software validation;
preparing usability evidence for home and POC tests;
considering change protocols for anticipated modifications.
A More Structured Framework for Future Emergencies
The final guidance reflects lessons learned during previous public health emergencies and seeks to establish a more predictable validation framework before the next emerging pathogen event.
For manufacturers, the message is clear: speed remains important during emergencies, but accelerated access does not eliminate the need for appropriate validation.
FDA’s framework allows flexibility based on outbreak conditions while maintaining expectations around clinical performance, analytical reliability, safety and ongoing evidence generation.
