FDA and U.S. Regulatory References
33 references
| Reference | Source / Status | GxP Area / Standard / Lifecycle | QA Description and Validation Relevance |
|---|---|---|---|
| Computer Software Assurance for Production and Quality Management System Software | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Guidance 2026-02-03 |
GMP manufacturing / quality systems 21 CFR Part 820 (QSR) Development, Deployment, Maintenance |
FDA final guidance offering a risk-based framework for computer software assurance (CSA) in production and quality management systems. It describes steps to identify intended use, determine appropriate assurance activities based on risk, and generate objective evidence to meet regulatory requirements GxP validation relevance: Provides non-binding recommendations for validating automation software used in manufacturing and quality systems; emphasises focusing assurance activities on high-risk functions and reducing unnecessary testing. Key controls: Risk-based assurance, objective evidence, documentation of intended use, scaled testing based on impact and risk. |
| Artificial Intelligence and Machine Learning in Drug Development | U.S. Food and Drug Administration United States Regulator program / policy resource Policy resource 2025-03-25 |
Drug development / regulatory submissions Not specified (guidance refers to draft regulatory approach). Development, Regulatory submission |
FDA CDER page notes increasing use of AI/ML across the drug lifecycle. It references a January 2025 draft guidance on using AI to support regulatory decision-making and outlines FDA initiatives to provide transparent frameworks for safe and effective use of AI in drug development GxP validation relevance: Highlights FDA’s recognition of AI’s role in drug development and points sponsors to draft guidances and programs addressing AI model credibility, risk assessment, and regulatory submission expectations. Key controls: Risk-based credibility assessment for AI models, transparency and explainability, adherence to draft guidance for AI in regulatory decision-making. |
| Using Artificial Intelligence and Machine Learning to Support Regulatory Decision-Making for Drug and Biological Products | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Draft guidance 2025-01-16 |
Drug development / regulatory submissions Not specified (draft guidance). Development, Submission |
Draft guidance provides recommendations on using AI-generated data or models to support regulatory decision‑making for drugs and biological products. It outlines a risk‑based credibility assessment framework with steps such as defining the question of interest, context of use, assessing model risk, and evaluating credibility evidence GxP validation relevance: Establishes expectations for sponsors who use AI to generate evidence supporting submissions, ensuring AI models are credible, transparent, and appropriate for regulatory decisions. Key controls: Risk-based credibility assessment, documentation of model development and validation, defined context of use, transparency of data sources, performance metrics. |
| Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence/Machine Learning-Enabled Device Software Functions | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Guidance 2025-08-30 |
Medical devices (SaMD / AIaMD) PCCP concept under 21 CFR 820 and device premarket pathways Development, Deployment, Post-market |
Final guidance details how manufacturers should develop a Predetermined Change Control Plan (PCCP) for AI-enabled device software. It supports iterative improvement by describing planned modifications, methodologies for development and validation, and impact assessments within marketing submissions to ensure safety and effectiveness GxP validation relevance: Informs manufacturers how to seek regulatory pre-approval for future AI model updates without resubmitting a new application, aligning AI software changes with risk management and lifecycle control. Key controls: Define scope of changes, risk-based impact assessment, validation of modifications, performance monitoring. |
| Artificial Intelligence/Machine Learning Software as a Medical Device Action Plan | U.S. Food and Drug Administration United States Regulator program / policy resource Action plan 2021-01-12 |
Medical devices Not specified (policy plan) All lifecycle phases |
The AI/ML SaMD Action Plan outlines a five-part strategy: update the regulatory framework via draft PCCP guidance, harmonise Good Machine Learning Practice principles, support transparency for AI-enabled devices, advance regulatory science methodologies including bias mitigation, and pilot real-world performance evaluation GxP validation relevance: Provides context for FDA’s evolving regulatory approach to AI-enabled medical devices and frames future guidance and policies. Key controls: Development of PCCP, harmonisation of GMLP, transparency initiatives, regulatory science research, real-world performance pilots. |
| Transparency for Machine Learning-Enabled Medical Devices: Guiding Principles | U.S. Food and Drug Administration International International harmonization Guiding principles 2023-06-00 |
Medical devices, Clinical decision support Not applicable (guiding principles) All lifecycle phases |
The guiding principles define transparency as communicating information about intended use, development, performance and logic (explainability) of ML-enabled devices to stakeholders. They outline who needs information, why, what to communicate, where and when to provide it, and how to present it effectively. Transparency supports patient-centred care, identification of biases and performance degradation, and fosters trust GxP validation relevance: Provides high-level guidance for developers and regulators on communicating AI model information to users, supporting safe and effective human-AI interaction. Key controls: Human-centred design, disclosure of intended use, training and test data characteristics, performance metrics, risks and limitations, appropriate communication media. |
| Part 11, Electronic Records; Electronic Signatures — Scope and Application | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Guidance 2003-08-00 |
GMP manufacturing, Clinical trials, Pharmacovigilance 21 CFR Part 11 All lifecycle phases |
This guidance clarifies the scope and application of 21 CFR Part 11. FDA explains that it will interpret Part 11 narrowly and exercise enforcement discretion while re-examining the regulation. Part 11 applies to electronic records used to satisfy predicate rule requirements, but FDA will not enforce validation, audit trail, and record retention requirements of Part 11 for some records during this re-examination Underlying predicate rules still apply GxP validation relevance: Establishes expectations for electronic records and signatures in GxP environments, impacting validation of AI systems that generate or manage regulated records. Key controls: Ensure compliance with predicate rules, narrow interpretation of Part 11, risk-based enforcement discretion, continued adherence to underlying GMP/GCP regulations. |
| MFDS Korea: Revised Regulations on Classification and Designation of Digital Medical Products | Ministry of Food and Drug Safety (MFDS) South Korea Trade / legal / consulting article Trade article 2026-05-12 |
Medical devices and digital health products Korea Digital Medical Products Act (DMPA) All lifecycle phases |
This article summarises the 2026 revision of Korea’s Regulations on Classification and Designation of Digital Medical Products (Notice 2026‑4). It notes that the Digital Medical Products Act (DMPA) entered its second phase on January 24 2026. Key changes include new labelling requirements, expanded definitions, formal recognition of digital health support products, clearer exclusion criteria for wellness technologies, improved treatment of hybrid products, and reinforcement that clinical purpose and risk profile determine regulatory status The revision allows pre‑approved change management plans for AI models, similar to PCCPs, and introduces digital quality management systems and cybersecurity obligations GxP validation relevance: Provides industry perspective on Korea’s evolving digital medical product regulations, highlighting classification, AI change management plans, digital QMS, and cybersecurity obligations. Key controls: Classification based on intended use and risk, digital quality management system requirements, pre-approved AI change management plans, cybersecurity obligations and software bill of materials. |
| Good Machine Learning Practice for Medical Device Development: Guiding Principles | U.S. Food and Drug Administration International International harmonization Guiding principles summary 2025-01-17 |
Medical devices IMDRF GMLP All lifecycle phases |
FDA’s Good Machine Learning Practice (GMLP) page summarises the IMDRF final document identifying 10 guiding principles to support development of safe, effective and high‑quality AI/ML medical devices. It emphasises a risk‑based total product lifecycle approach and international harmonisation across regulators GxP validation relevance: Provides a succinct overview of global consensus principles for AI medical devices, highlighting the importance of harmonised practices in design, development, validation and post-market monitoring. Key controls: Ten GMLP principles including data quality, transparency, human oversight, risk management, performance monitoring, and lifecycle management. |
| Draft Guidance on Artificial Intelligence and Machine Learning-enabled Device Software Functions | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Draft guidance summary 2025-01-06 |
Medical devices FDA Device Regulations Development, Submission |
This draft guidance proposes lifecycle and marketing submission recommendations for AI-enabled device software functions. It outlines risk management considerations across the total product lifecycle and design and development issues that manufacturers should consider when preparing marketing submissions GxP validation relevance: Provides early insights into FDA’s regulatory expectations for AI-enabled devices before the final guidance was issued. Key controls: Risk-based lifecycle considerations, design documentation, submission requirements, performance monitoring. |
| HSA and Korea MFDS Guiding Principles for Clinical Trials of Machine Learning-enabled Medical Devices | Health Sciences Authority (HSA) & Ministry of Food and Drug Safety (MFDS) Singapore and South Korea Regulatory guidance / non-binding agency guidance Guidance announcement 2023-11-00 |
Clinical trials / GCP HSA–MFDS Guiding Principles Clinical evaluation |
The HSA digital health page notes that HSA collaborates with Korea’s MFDS to release guiding principles for clinical trials of machine learning‑enabled medical devices, emphasising alignment of regulatory requirements and support for evidence generation GxP validation relevance: Shows international collaboration to standardise regulatory expectations for clinical trials of AI medical devices, improving global harmonisation. Key controls: Guiding principles for design and conduct of clinical trials for ML-enabled devices, cross-agency collaboration, evidence generation requirements. |
| Medical Devices; Quality System Regulation Amendments (QMSR Final Rule) | U.S. Food and Drug Administration United States Regulatory law / final rule Final rule 2024-02-02 |
GMP manufacturing / quality systems 21 CFR Part 820 (QMSR); ISO 13485:2016 Development; Manufacturing; Post-market |
This final rule amends the device CGMP requirements in 21 CFR part 820 by incorporating ISO 13485:2016 and aligning it with FDA-specific provisions. It adds definitions and clarifications to avoid inconsistencies, harmonizes U.S. quality management system requirements with international standards, and reduces duplicative regulatory burdens. The rule emphasises global harmonization, risk-based QMS, and improved patient access. It becomes effective February 2 2026 GxP validation relevance: Provides legally binding requirements for medical device manufacturers’ quality management systems, forming the foundation for validating AI-enabled devices and ensuring their manufacture complies with international standards. Key controls: Risk-based quality management system incorporating ISO 13485, control of records and complaint files, design and development documentation, harmonization with international standards. |
| Medical Devices; Quality Management System Regulation Technical Amendments | U.S. Food and Drug Administration United States Regulatory law / final rule Technical amendment 2025-12-04 |
GMP manufacturing / quality systems 21 CFR Part 820 (QMSR) and related parts Regulatory compliance update |
Technical amendments update 179 sections across 18 parts of the CFR to replace references to the Quality System Regulation with references to the Quality Management System Regulation, effective February 2 2026. They modify exemption provisions, design control references, and authority citations to ensure consistency, clarify terminology, and correct typographical errors. The amendments are non‑substantive and do not impose new regulatory requirements GxP validation relevance: Ensures that all FDA regulations consistently reference the new QMSR, which is essential for medical device manufacturers implementing AI-enabled systems to maintain compliant quality records and design controls. Key controls: Updates references to §820.35 (Control of Records), design control provisions, and authority citations; clarifies that amendments are editorial and non-substantive. |
| General Wellness: Policy for Low Risk Devices | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Guidance 2026-01-06 |
Digital health / non‑GxP (wellness) Section 3060 of 21st Century Cures Act; 21 CFR Part 820 (QMSR) not applied Development; regulatory determination |
This guidance clarifies the FDA’s compliance policy for low‑risk general wellness products that promote a healthy lifestyle. It notes that Section 3060 of the 21st Century Cures Act excludes software intended solely for maintaining or encouraging a healthy lifestyle from the device definition and states that CDRH does not intend to examine or enforce device regulations for such low‑risk products. General wellness products must be intended only for general wellness use and present a low risk to users; examples include exercise equipment, audio/video programs, and wellness apps. The guidance lists types of acceptable claims (weight management, fitness, relaxation, mental acuity, self‑esteem, sleep management, sexual function) GxP validation relevance: Helps developers of AI‑enabled wellness applications determine whether their products qualify for enforcement discretion, reducing unnecessary validation burdens and focusing GxP efforts on higher‑risk medical devices. Key controls: Defines criteria for exclusion from device regulation; clarifies enforcement discretion for general wellness products; emphasises that such products do not need premarket authorization or QMSR compliance if they meet the criteria. |
| Clinical Decision Support Software – Guidance for Industry and FDA Staff | U.S. Food and Drug Administration United States Regulatory guidance / non-binding agency guidance Guidance 2026-01-29 |
Clinical decision support / digital health Section 520(o)(1)(E) of the FD&C Act; 21 CFR Part 820 (QMSR) if classified as device Development; classification; premarket |
This guidance clarifies the types of clinical decision support (CDS) software functions that are not regulated as medical devices. To be considered non‑device CDS, a software function must meet four criteria: it cannot acquire, process, or analyze medical images or signals; it is intended to display, analyze, or print medical information; it supports or provides recommendations to a health care professional about prevention, diagnosis or treatment; and it provides sufficient information for the professional to independently review the basis for recommendations. If any criterion is not met, the software is considered a device. The guidance provides examples of non‑device CDS and device CDS functions GxP validation relevance: Informs developers of AI/ML‑enabled clinical decision support tools about regulatory scope and classification, helping them determine whether their software falls under device regulation and requires formal validation. Key controls: Ensure that CDS software avoids processing medical images or IVD signals, provides transparent rationale to clinicians, and allows independent review; if regulated as a device, follow QMSR and premarket requirements. |
| Technology-Enabled Meaningful Patient Outcomes (TEMPO) for Digital Health Devices Pilot | U.S. Food and Drug Administration United States Notice / pilot program Notice 2025-12-08 |
Digital health / post‑market & clinical use 21 CFR part 812; 21 CFR parts 50 & 56; FD&C Act Real‑world evidence; pilot; premarket; post‑market |
FDA’s Center for Devices and Radiological Health, in partnership with CMS’s CMMI ACCESS model, announced the TEMPO pilot to promote access to digital health devices while safeguarding patient safety. Beginning January 2 2026, manufacturers can submit statements of interest to participate. The pilot tests a payment option tied to patient outcomes and allows selected device manufacturers to request enforcement discretion from certain premarket and investigational requirements. Participants must collect real‑world data and work towards marketing authorization. The pilot targets devices intended to improve outcomes in four clinical use areas and limits participation to about ten manufacturers per area GxP validation relevance: Offers AI‑enabled digital health device manufacturers a pathway to deploy products in clinical practice while collecting real‑world evidence under regulatory oversight; provides insight into post‑market monitoring and enforcement discretion. Key controls: Collect and share real‑world data, meet patient safety criteria, request regulatory enforcement discretion, focus on specific clinical use areas, maintain records similar to IDE documentation. |
| Quality Management System Regulation – Frequently Asked Questions | U.S. Food and Drug Administration United States Regulatory guidance / FAQ FAQ 2026-02-02 |
GMP manufacturing / quality systems 21 CFR Part 820 (QMSR); ISO 13485:2016 Manufacturing; inspection; compliance |
This FAQ page explains that the FDA’s final rule issued January 31 2024 incorporates ISO 13485:2016 into 21 CFR part 820 and renames the regulation to the Quality Management System Regulation (QMSR). It clarifies that the QMSR aligns U.S. device QMS requirements with international standards, promotes consistency, and provides safe, effective, high‑quality devices. The QMSR became effective February 2 2026, replacing the Quality System Regulation. The FAQ notes that FDA is updating inspection processes, training staff, and engaging stakeholders. It highlights that under the QMSR, FDA may review management review, quality audits, and supplier audit reports that were previously exempt, and that a new inspection program replaces the Quality System Inspection Technique GxP validation relevance: Provides additional guidance to device manufacturers on implementing the QMSR, preparing for inspections, and understanding new requirements, which is crucial for validating AI‑enabled devices under the updated quality management framework. Key controls: Highlights adoption of ISO 13485, clarifies QMSR implementation and inspection processes, emphasises management review and audit record availability, encourages comparative analysis of existing records to meet QMSR requirements. |
| Cybersecurity in Medical Devices: Quality Management System Considerations and Content of Premarket Submissions | U.S. Food and Drug Administration United States Regulatory guidance / non-binding Guidance 2026-02-03 |
GMP manufacturing / quality systems; design & development; post‑market 21 CFR Part 820 (QMSR); FD&C Act Section 524B; FDA cybersecurity guidance Design; development; verification; validation; post‑market |
This final guidance recognises that increasing network connectivity, portable media and information exchange heighten cybersecurity risks for medical devices. Past cyber incidents (e.g., WannaCry, URGENT/11 and SweynTooth vulnerabilities) have disrupted hospital operations and highlighted the potential for patient harm; therefore, robust cybersecurity controls are essential to ensure device safety and effectiveness The guidance applies to all devices containing software or firmware, including those without network capabilities, and covers all premarket submission types (510(k), De Novo, PMA, IDE, HDE, PDP, BLA and IND) as well as devices that do not require premarket review It emphasises a total product lifecycle approach, shared responsibility among manufacturers, healthcare facilities and users, adoption of a secure product development framework, and continuous risk management to mitigate vulnerabilities GxP validation relevance: Provides essential cybersecurity requirements for AI‑enabled medical devices, ensuring secure design, risk management and documentation across the quality management system and premarket submissions. Key controls: Requires threat modelling, vulnerability assessments, security architecture design, software bill of materials (SBOM), patch and vulnerability management plans, incident response procedures, and postmarket monitoring to be documented in premarket submissions and integrated into the QMS. |
| Digital Medical Products Act and Subordinate Regulations for AI and Software-Based Devices (South Korea) | Ministry of Food and Drug Safety (MFDS) – Presentation at IMDRF South Korea Regulatory presentation / guidance Presentation 2025-09-00 |
R&D; clinical trials; manufacturing; post‑market Digital Medical Products Act; ISO 13485; IEC 62304; IMDRF guidelines Development; clinical investigation; manufacturing; post‑market |
A presentation by South Korea’s MFDS summarises the Digital Medical Products Act (DMPA) and its subordinate regulations for AI‑ and software‑based devices. Six subordinate regulations are highlighted: (1) classification and designation of digital medical products; (2) approval, certification and notification processes that introduce software usability evaluation, Predetermined Change Control Plans (PCCP), exemptions for certain clinical decision support systems and enhanced AI‑specific labelling and evaluation frameworks for digital health technologies combined with pharmaceuticals; (3) Good Manufacturing Practice requirements based on ISO 13485 and IEC 62304 that incorporate AI‑specific controls; (4) regulations for protocol approval and conduct of clinical trials, enabling simplified data‑driven and decentralised trials; (5) a cybersecurity regulation covering the AI/software lifecycle aligned with IMDRF guidelines; and (6) special provisions establishing certification criteria for excellent governance systems and a conditional ‘use first, evaluate later’ regulatory sandbox The presentation notes that overlapping requirements between the DMPA and the Korean AI Act are deemed fulfilled when compliance with the DMPA is demonstrated GxP validation relevance: Informs AI‑enabled medical device developers about South Korea’s comprehensive regulatory framework, covering classification, approval, PCCPs, QMS, clinical trials, cybersecurity and sandbox provisions, which are critical for AI validation and post‑market controls. Key controls: Requires risk‑based classification and designation of digital medical products; mandates software usability evaluations and PCCPs; introduces AI‑specific labelling and transparency; requires QMS compliant with ISO 13485/IEC 62304; simplifies clinical trial protocols and allows use of real‑world evidence; mandates cybersecurity controls across the lifecycle; offers conditional approval pathways via a regulatory sandbox. |
| Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products | U.S. Food and Drug Administration United States Regulatory guidance / non-binding Guidance 2024-01-00 |
GMP manufacturing; CMC; clinical trials (GCP) 21 CFR 312.23 Design & development; manufacturing; clinical investigation |
This final FDA guidance clarifies that chimeric antigen receptor (CAR) T cell products are human gene therapy products where T cell specificity is genetically modified to recognize a desired antigen. It provides CAR T‑specific recommendations on chemistry, manufacturing and control (CMC), pharmacology/toxicology and clinical study design. The guidance also covers analytical comparability studies and notes that many recommendations apply to other genetically modified lymphocyte products such as CAR NK cells and T cell receptor‑modified T cells Sponsors are encouraged to communicate with CBER’s Office of Tissues and Advanced Therapies (OTAT) to discuss product‑specific considerations before submitting an IND GxP validation relevance: Although not specific to AI, this guidance outlines regulatory expectations for development of genetically modified cell therapies like CAR T products. It highlights critical quality and clinical considerations that may interact with computational tools and data analysis in product design, manufacturing, and trial management, ensuring such tools align with GxP and regulatory standards. Key controls: Provides detailed CMC and manufacturing control recommendations, pharmacology/toxicology requirements, clinical study design considerations, analytical comparability studies, and encourages early engagement with regulators to address product‑specific issues |
| Human Gene Therapy Products Incorporating Human Genome Editing; Guidance for Industry | U.S. Food and Drug Administration United States Regulatory guidance / non-binding Guidance 2024-01-00 |
GMP manufacturing; clinical trials (GCP); research & development 21 CFR 312.23 Design & development; manufacturing; clinical investigation |
This final FDA guidance provides recommendations to sponsors developing human gene therapy products incorporating genome editing. It advises on the information that should be included in an Investigational New Drug (IND) application to assess the safety and quality of investigational genome editing products, including product design, manufacturing and testing, nonclinical safety assessment and clinical trial design The guidance aims to help sponsors address potential off‑target effects and ensure that genome editing therapies meet regulatory standards. GxP validation relevance: Relevant because CRISPR and other genome‑editing therapies rely on complex design, manufacturing and data‑analysis processes. Understanding regulatory expectations ensures that digital tools and AI‑driven workflows used in genome editing research, manufacturing and clinical development comply with GxP quality and traceability requirements. Key controls: Recommends comprehensive documentation of genome editing product design and manufacturing processes, testing protocols, nonclinical safety studies and clinical trial design; emphasises risk management for off‑target effects and encourages early communication with FDA |
| Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application; Guidance for Industry | U.S. Food and Drug Administration United States Regulatory guidance / non-binding Guidance 2026-05-05 |
GMP manufacturing; CMC; quality systems 21 CFR Part 601 Manufacturing; BLA submission |
This FDA guidance describes how the agency applies flexibility to chemistry, manufacturing and controls (CMC) requirements for human cellular and gene therapy products being developed for Biologics License Applications (BLAs). It explains that FDA uses a flexible approach to ensuring CMC requirements are met while expediting development and patient access to safe and effective CGT products for serious or life‑threatening conditions The guidance clarifies when CMC flexibilities may be appropriate, directs sponsors to consider this guidance alongside other CMC recommendations, and notes that it does not comprehensively address all CMC information required for licensure GxP validation relevance: Important for developers of gene and cell therapies implementing advanced manufacturing technologies or computational tools. It highlights regulatory flexibility while maintaining compliance, ensuring that digital or AI‑supported manufacturing controls align with GxP and quality requirements. Key controls: Encourages risk‑based, flexible CMC strategies for gene therapy products; emphasises documentation of manufacturing processes, quality controls, comparability studies and alignment with other CMC guidance |
| Safety Assessment of Genome Editing in Human Gene Therapy Products Using Next-Generation Sequencing; Draft Guidance for Industry | U.S. Food and Drug Administration United States Regulatory guidance / non-binding (draft) Draft guidance 2026-04-14 |
Preclinical studies; safety evaluation (GLP) Not specified Nonclinical development; preclinical safety evaluation |
This draft FDA guidance provides recommendations on using next‑generation sequencing (NGS) methods in nonclinical studies to support initiation of clinical trials for investigational human genome editing products. The recommendations supplement the January 2024 guidance on genome editing gene therapy products and emphasise that development programs should address both gene therapy product risks and additional risks associated with genome editing, such as off‑target editing and unintended genomic changes The guidance aims to guide design of nonclinical studies using NGS and bioinformatics to evaluate potential safety risks for Investigational New Drug (IND) and Biologics License Applications GxP validation relevance: Relevant for CRISPR and other genome editing therapies because it outlines regulatory expectations for evaluating off‑target editing and genomic integrity using NGS and computational analyses. Compliance with these recommendations supports safe and effective development of genome editing therapies and ensures data integrity in GxP preclinical studies. Key controls: Recommends designing nonclinical studies that use NGS and bioinformatics to evaluate off‑target editing, chromosomal integrity and genome integrity; emphasises addressing genome editing‑specific risks alongside standard gene therapy product risks and integrating these assessments into IND and BLA submissions |
| Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause; Draft Guidance | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2026-02-25 |
Clinical development; regulatory submission Not specified Development and submission |
Draft FDA guidance introducing a ‘plausible mechanism’ framework for individualized therapies targeting specific genetic conditions. The document explains that sponsors may justify effectiveness and safety by showing a scientifically plausible mechanism linking a genetic abnormality to disease and demonstrating that the therapy addresses that mechanism. It emphasises generating substantial evidence of effectiveness through well‑characterized natural history data, one well‑controlled clinical investigation, confirmatory evidence, and robust chemistry, manufacturing and controls (CMC) data. The guidance clarifies that nonclinical, clinical and CMC data must collectively demonstrate that the individualized therapy is safe, effective and can be manufactured to regulatory standards GxP validation relevance: Although not specific to AI/ML, the guidance is relevant to gene therapy and biologics developers because it provides a regulatory pathway for bespoke treatments (which may include CRISPR‑edited or CAR T‑based products). Understanding how to generate evidence using a plausible mechanism framework can inform validation strategies and data requirements for highly personalised gene or cell therapies. Key controls: Recommend documenting the biological plausibility linking genotype to disease, using well‑characterized natural history datasets, designing at least one well‑controlled study with confirmatory evidence, and ensuring CMC processes can reliably produce high‑quality individualized therapies |
| Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Draft Guidance for Industry | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2025-09-25 |
Clinical development; regulatory submission Section 506(g) of the FD&C Act Development and submission |
This draft guidance describes FDA programs that expedite development and review of regenerative medicine therapies for serious or life‑threatening conditions. It explains that under section 506(g) of the FD&C Act, products that meet certain criteria can receive a Regenerative Medicine Advanced Therapy (RMAT) designation. The guidance outlines how RMAT designation enables sponsors to access accelerated approval pathways, discusses eligibility criteria, and describes the range of expedited programs (fast track, breakthrough therapy and priority review) available for regenerative medicine products. It also provides considerations for clinical development and opportunities for sponsors to interact with CBER review staff GxP validation relevance: Relevant to developers of gene and cell therapies because it clarifies how products such as CAR T cells, gene therapies or tissue‑engineered products can obtain expedited review and accelerated approval. Knowing the RMAT criteria and available programs helps sponsors plan regulatory strategies and align evidence generation with accelerated pathways. Key controls: Identify whether a product qualifies for RMAT designation, engage early with CBER, design clinical programs that meet accelerated approval requirements, and document safety and efficacy to support conditional or accelerated approval |
| Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products; Draft Guidance for Industry | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2025-11-04 |
Post‑market surveillance Not specified Post‑market (pharmacovigilance) |
FDA draft guidance discussing methods to capture postapproval safety and efficacy data for cell and gene therapy (CGT) products. Because CGT products often have durable effects and are studied in small clinical trials, long‑term follow‑up and real‑world evidence are critical. The guidance recommends approaches to monitor safety and effectiveness after approval, including patient registries, observational studies, and active surveillance systems. It clarifies that the guidance does not address data collection for expanding clinical indications GxP validation relevance: Important for validation professionals because it highlights regulatory expectations for post‑market monitoring of CGT products. Sponsors developing gene editing therapies or CAR T products must plan long‑term safety and efficacy surveillance, integrate real‑world data collection, and maintain data quality in compliance with GxP. Key controls: Implement robust post‑approval monitoring plans using registries and observational studies; ensure data collection methods capture long‑term safety and effectiveness; use risk‑based approaches to determine duration and intensity of follow‑up |
| Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations; Draft Guidance for Industry | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2025-09-25 |
Clinical development; trial design Not specified Clinical trials (GCP) |
This draft guidance provides recommendations for designing clinical trials of cell and gene therapy products intended to treat rare diseases or conditions affecting small populations. It advises sponsors on selecting appropriate trial designs (e.g., adaptive or Bayesian designs), choosing meaningful endpoints, and using innovative statistical methods to generate evidence of safety and effectiveness when traditional randomized trials are not feasible. The guidance emphasises early engagement with FDA and encourages sponsors to consider patient‑centric approaches to trial design GxP validation relevance: Relevant for gene therapy and CAR T developers working on rare diseases, as it outlines regulatory expectations for innovative trial designs that maximise data from limited patient populations. These designs may incorporate real‑world evidence and adaptive elements, which influence data quality and validation strategies. Key controls: Use adaptive trial designs, select clinically meaningful endpoints, engage early with FDA to discuss statistical methods, and ensure data integrity when using innovative designs |
| Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products; Draft Guidance | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2024-11-21 |
Product development; regulatory strategy Not specified Development and submission |
This draft guidance compiles answers to frequently asked questions (FAQs) about developing potential cellular and gene therapy (CGT) products. It addresses common regulatory, CMC, pharmacology/toxicology, clinical and clinical pharmacology issues faced by sponsors. The guidance is intended to facilitate development of safe, effective and high‑quality CGT products by clarifying the FDA’s expectations across multiple disciplines and pointing sponsors to relevant regulations and guidances GxP validation relevance: Although not AI‑specific, the FAQ consolidates regulatory advice for CGT development, helping sponsors navigate complex requirements and improve GxP compliance. It is relevant for gene therapy and CAR T programmes using novel technologies such as CRISPR or viral vectors. Key controls: Consult the FAQ to understand FDA expectations across CMC, nonclinical and clinical disciplines; ensure cross‑functional teams align processes with regulatory recommendations and maintain thorough documentation |
| Safety Testing of Human Allogeneic Cells Expanded for Use in Cell‑Based Medical Products; Draft Guidance | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2024-05-15 |
Preclinical development; manufacturing Gene Therapy CMC guidance (Jan 2020) Development and submission |
Draft guidance offering recommendations for safety testing of human allogeneic cells expanded in culture for use in cell‑based medical products. The FDA advises sponsors to perform a risk analysis when designing safety testing, considering the expansion potential of the cells, reagents used in culture and the number of patients the product may treat. Appropriate cell safety testing supports Investigational New Drug (IND) and Biologics License Application (BLA) submissions. The guidance complements existing CMC guidances for gene therapy and somatic cell therapy products GxP validation relevance: Important for manufacturers of allogeneic cell therapies and gene therapy products because it outlines risk‑based testing strategies to ensure cell safety, identity and purity, which are critical for GxP compliance and product quality. Key controls: Develop risk‑based cell safety testing strategies considering expansion potential and culture reagents; implement assays to detect contaminants; document testing procedures in IND/BLA submissions |
| Considerations for the Use of Human‑ and Animal‑Derived Materials in the Manufacture of Cell and Gene Therapy and Tissue‑Engineered Medical Products; Draft Guidance | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2024-05-15 |
Manufacturing; CMC CMC guidance for gene therapy and cell therapy products (Jan 2020) Development and submission |
FDA draft guidance advising manufacturers on using human‑ and animal‑derived materials in the manufacture of cell and gene therapy products and tissue‑engineered medical products. It highlights risks such as transmission of adventitious agents, lot‑to‑lot variability and material identity. The guidance provides recommendations to ensure the safety, quality and identity of materials of human or animal origin, including material qualification, supplier controls and testing. It also outlines the CMC information that should be included in IND submissions related to the use of these materials The guidance supplements existing CMC guidances for gene and cell therapy products GxP validation relevance: Relevant to gene therapy and CAR T developers because controlling source materials is crucial for product safety and consistency. The guidance supports GxP compliance by detailing quality system considerations for procuring and qualifying human or animal‑derived materials. Key controls: Establish robust material qualification processes, implement supplier controls, perform testing to detect adventitious agents, and provide detailed CMC documentation in regulatory submissions |
| Potency Assurance for Cellular and Gene Therapy Products; Draft Guidance | U.S. Food and Drug Administration United States Regulatory guidance / non‑binding (draft) Draft guidance 2023-12-28 |
Manufacturing; quality control Not specified Development and manufacturing |
Draft guidance outlining recommendations for developing a science‑ and risk‑based strategy to assure the potency of cellular and gene therapy (CGT) products. The guidance defines a potency assurance strategy as a multifaceted approach incorporating manufacturing process design, process control, material control, in‑process testing and potency lot release assays. It emphasises that the goal of potency assurance is to ensure each released lot has the specific ability to achieve the intended therapeutic effect and highlights the need for assays and controls to mitigate potency risks GxP validation relevance: Potency assurance is critical for gene therapies and CAR T products because it directly affects product efficacy and patient outcomes. The guidance provides a regulatory framework for designing potency assays and controls, which supports GxP manufacturing and validation. Key controls: Develop a potency assurance strategy integrating process design, material controls, in‑process testing and lot release assays; use risk‑based assessments to identify critical quality attributes and ensure each lot meets potency criteria |
| Flexible Requirements for Cell and Gene Therapies to Advance Innovation | U.S. Food and Drug Administration United States Regulatory policy resource / program Policy resource 2026-01-11 |
Development; manufacturing; regulatory submission 21 CFR 210 and 211 Clinical development and submission |
FDA policy statement describing a more flexible approach to chemistry, manufacturing and control (CMC) requirements for cell and gene therapies (CGT). Announced January 11 2026, the policy notes that the agency’s flexibility helps expedite development and will guide evaluations for Biologics License Applications. Key flexibilities include: not requiring compliance with 21 CFR part 211 before investigational products are manufactured for phase 2 or 3 trials; permitting permissive product quality release criteria during early investigational studies; allowing minor manufacturing changes with comparability data; offering flexibility in commercial release specifications for CGT products due to small patient populations; and enabling concurrent process validation and fewer process performance qualification (PPQ) lots The policy encourages sponsors to consult with FDA review divisions and recognises the rapid pace of scientific advancement. GxP validation relevance: While not AI‑specific, this policy resource informs developers of gene therapy and CAR T products that regulatory flexibility is available in CMC requirements. Understanding these flexibilities can accelerate development timelines and influence validation strategies, including how data are generated and reported. Key controls: Plan CMC strategies that leverage FDA’s flexible requirements: defer full compliance with part 211 until later phases; set provisional release criteria for early clinical trials; justify minor manufacturing changes with comparability data; and discuss process validation plans with FDA reviewers |
| FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease (Casgevy & Lyfgenia) | U.S. Food and Drug Administration United States Regulatory announcement / press release Press announcement 2023-12-08 |
Regulatory approval; post‑market surveillance Not specified Approval and post‑market |
FDA press release announcing approval of two gene therapies, Casgevy and Lyfgenia, for the treatment of sickle cell disease in patients aged 12 years and older. Casgevy uses CRISPR/Cas9 genome editing to modify patients’ hematopoietic stem cells, making it the first FDA‑approved therapy that employs CRISPR gene editing technology. The modified cells engraft in bone marrow and increase fetal hemoglobin production, preventing sickling of red blood cells. Lyfgenia uses a lentiviral vector to modify stem cells to produce HbA^{T87Q}, a gene‑therapy derived hemoglobin, reducing sickling and occlusion. Both therapies involve one‑time infusion after myeloablative conditioning and will require long‑term follow‑up studies The press release highlights the significance of these approvals and notes that both products received Priority Review, Orphan Drug and Regenerative Medicine Advanced Therapy designations GxP validation relevance: This milestone regulatory approval is notable for GxP practitioners because it demonstrates successful regulatory evaluation of gene therapies using genome editing and viral vectors. It underscores the need for robust CMC, safety and efficacy data to support approval and sets precedent for future CRISPR‑based therapies. Key controls: Ensure comprehensive CMC and clinical evidence for gene therapy approvals, including detailed description of genome editing mechanisms, manufacturing processes, conditioning regimen, and long‑term follow‑up plans |