IVD Controls

IVD Controls: The accuracy and precision of in vitro diagnostic (IVD) tests are essential for effective disease detection and patient care. A vital but often understated component in achieving this accuracy is the use of quality control (QC) materials, also referred to simply as controls. From the U.S. Food and Drug Administration (FDA) perspective, controls are integral to IVD design, validation, and routine clinical use.

Controls are substances or reference materials with known properties that are used to monitor the reliability and performance of diagnostic assays. Based on their purpose, controls are categorized as follows:

• Positive controls: contain the target analyte and must yield a reactive result.
• Negative controls: lack the analyte and are expected to return a non-reactive result.
• Internal controls: integrated into test kits to verify sample handling and reagent integrity.
• External controls: processed separately from test samples but evaluated in parallel.
• Blank controls: analyte-free materials used to detect contamination or set baseline signals.
• Calibration Controls: These are used to calibrate the IVD instruments and ensure that the test is accurately measuring the analyte.
• Instrument-Specific Controls: These are designed to work with specific IVD instruments and help verify that the instrument is functioning properly.
• Third-Party Controls: These are produced by independent manufacturers and offer advantages like versatility, longer shelf life, and the ability to monitor multiple analytes with a single control.

Controls may appear as liquid reagents, lyophilized materials, control strips, or dedicated control wells depending on the assay format.

The FDA emphasizes the importance of quality control materials in the safety and effectiveness of IVDs. They are required to provide validation data, demonstrate appropriate control ranges, and include controls in analytical sensitivity/specificity, precision, and reproducibility studies. The FDA mandates clear labeling and instructions for use (IFU) for IVD products, specifying the type and frequency of controls, instructing users on interpreting results, and stating actions to take if controls fall outside the acceptable range. Quality System Regulation (QSR) compliance requires manufacturers to implement design and process controls, verify lot-to-lot consistency of test kits, conduct stability and shelf-life studies, and support corrective and preventive actions (CAPA) in case of field issues.

Controls are crucial for clinical and regulatory purposes as they verify test integrity, detect errors, support compliance and traceability, and mitigate patient safety by reducing the risk of false results leading to misdiagnosis or incorrect treatment. They ensure proper functioning of reagents, instruments, and procedures, and help identify issues like reagent degradation, instrument malfunction, or operator error.

Selecting the right controls ensures regulatory compliance, improves study robustness, and enhances the clinical relevance of results. Whether for IVD validation, drug bioanalysis, or personalized therapies, controls must be biologically and technically aligned with the study objective. Proper characterization, traceability, and documentation of these materials are essential—especially under FDA scrutiny.

In-Vitro Diagnostic (IVD) applications use controls to validate devices, calibrate instruments, and ensure accuracy. Bioanalytical analysis applications use controls to quantify anticoagulants in various species, including human, rat, mouse, canine, and NHP samples. Preclinical traceability involves using serum/plasma in custom matrices with specified anticoagulants to validate consistency across studies.

Biomarker studies use controls to confirm assay performance and signal generation, with positive controls confirming assay stability and expression level, negative controls confirming absence of signal and false positives, and blank controls detecting contamination or background noise.

In cell and gene therapy applications, controls are used in cohorts, including viral vector testing, transduction/expansion, and therapy development. These controls ensure vector efficiency, formulation, and patient-specific responses in various applications. They also help in assessing the effectiveness of treatments in different populations.

Despite their importance, several challenges persist in the implementation of IVD controls:

• Matrix compatibility must closely mimic clinical samples.
• Control materials must remain stable under varied storage and operating conditions.
• User training and interpretation variability may affect how control data is used.

The FDA emphasizes risk mitigation in all these aspects and expects thorough documentation and validation of control materials and procedures.

Controls are not just supplementary components in IVDs—they are core pillars of test reliability and regulatory compliance. The FDA’s perspective underscores their importance in ensuring public health through accurate diagnostic outcomes. Manufacturers must integrate well-validated controls into their test systems, provide clear guidance in their labelling, and maintain robust quality systems throughout the product lifecycle.

Controls are foundational to ensuring IVD test integrity, clinical utility, and regulatory acceptance. With the FDA’s increasing focus on quality, reproducibility, and patient safety, integrating well-characterized controls is not only good practice but a regulatory imperative. As diagnostics evolve with advanced molecular tools and AI-enhanced platforms, the role of robust, well-defined controls will continue to be central to achieving reliable and trustworthy diagnostic outcomes.

Content owner: Ms. Amrutha Rai, Team Lead, 510k Compliance