Advanced Therapy Medicinal Products (ATMPs)—including gene therapies, somatic cell therapies, tissue‑engineered products, and their combinations—represent a paradigm shift in modern medicine, offering curative potential for previously untreatable diseases. However, their biological complexity, prolonged activity, and potential for irreversible genetic modification introduce unique safety challenges that are not encountered with conventional drugs. Recognizing this, the Saudi Food and Drug Authority (SFDA) has issued a dedicated Good Pharmacovigilance Practices (GVP) guidance specifically for ATMPs: Product‑ or Population‑Specific Considerations III: Advanced Therapy Medicinal Products (Version 1.0, 12 April 2026).
This article provides a detailed medical and regulatory analysis of the guidance, covering risk management plans (RMPs), identification of safety and efficacy concerns, adverse reaction reporting, periodic safety update reports (PSURs), post‑authorisation safety and efficacy studies, signal management, safety communication, and risk minimisation measures. The guidance is set to take effect on 12 April 2027, providing a one‑year transition period for stakeholders. Understanding and implementing these requirements is essential for marketing authorisation holders (MAHs), healthcare professionals, and regulators to ensure the safe and effective use of these transformative therapies.
1. Introduction: The Rise of ATMPs and the Need for Specialised Pharmacovigilance
Advanced Therapy Medicinal Products (ATMPs) are a new class of biological medicines based on living materials—cells, tissues, or genes—and are divided into four categories: gene therapy medicinal products, somatic cell therapy medicinal products, tissue‑engineered products, and combined ATMPs (which incorporate a medical device). Unlike traditional small‑molecule drugs or even monoclonal antibodies, ATMPs are dynamic, often patient‑specific, and designed to achieve durable or even curative effects through permanent genetic modification, cellular engraftment, or tissue regeneration.
While this transformative potential offers unprecedented hope for patients with rare genetic disorders, haematological malignancies, and degenerative conditions, it also introduces unique and complex safety risks. These include:
- Insertional oncogenesis – integration of viral vectors into the host genome may activate oncogenes or disrupt tumour suppressor genes.
- Off‑target gene editing – unintended genetic modifications may cause malignancy or other adverse outcomes.
- Immunogenicity – unwanted immune responses can lead to graft rejection, cytokine release syndrome, or neutralising antibodies that abrogate efficacy.
- Tumourigenicity – especially with pluripotent stem cells or extensively expanded cells.
- Vector shedding and transmission – potential for spread of replication‑competent vectors to close contacts or the environment.
- Delayed adverse events – some risks may only become apparent years after treatment (e.g., secondary malignancies, autoimmunity).
In light of these challenges, the Saudi Food and Drug Authority (SFDA) has developed a dedicated Good Pharmacovigilance Practices (GVP) guidance for ATMPs. Issued on 12 April 2026, with implementation on 12 April 2027, the guidance supplements the general SFDA GVP Modules I–XVI and provides product‑ and population‑specific considerations for the entire ATMP lifecycle—from pre‑authorisation clinical development through post‑marketing surveillance.
2. Scope and Regulatory Framework
2.1 What ATMPs Are Covered
The guidance applies to all ATMPs as defined in the SFDA Guideline on Classification of Advanced Therapy Medicinal Products. This includes:
- Gene therapy medicinal products – containing recombinant nucleic acids intended to regulate, repair, replace, add, or delete a genetic sequence.
- Somatic cell therapy medicinal products – containing cells or tissues that have been manipulated to alter their biological characteristics for therapeutic purposes.
- Tissue‑engineered products – containing cells or tissues that have been modified to regenerate, repair, or replace human tissue.
- Combined ATMPs – products that incorporate a medical device as an integral part of the therapy.
2.2 Key Regulatory Principles
| Principle | Implication for ATMPs |
|---|---|
| Proportionality | The content and extent of the Risk Management Plan (RMP) must be proportionate to the identified and potential risks of the specific ATMP. |
| Lifecycle approach | Safety and efficacy follow‑up must begin in early‑phase clinical trials (Phase I) and continue through the post‑authorisation period. |
| Holistic data generation | Developers are encouraged to plan data collection holistically, integrating pre‑ and post‑authorisation studies to address long‑term safety and efficacy questions. |
| Traceability | Adverse reaction reports must contain batch numbers; patient alert cards should include batch recording. |
| Long‑term follow‑up | For integrating gene therapies, follow‑up of at least 15 years is typically required. |
3. Risk Management Plans (RMPs) for ATMPs
The Risk Management Plan is a cornerstone document that identifies, characterises, and minimises the important risks associated with a medicinal product. For ATMPs, the RMP must be submitted as part of the initial marketing authorisation dossier and should reflect the product’s unique characteristics.
3.1 Identification of Safety and Efficacy Concerns
The guidance lists specific risks in chronological order of the product lifecycle—from manufacturing to clinical follow‑up. Key categories include:
| Risk Category | Examples |
|---|---|
| Product quality, storage, and distribution | Cold‑chain breaches, stability issues, loss of biological activity leading to treatment failure. |
| Transmission of infectious diseases | Viral, bacterial, or parasitic infections transmitted from donor cells/tissues (allogeneic products) or arising during ex vivo culture. |
| Tumourigenicity | Particularly with extensively cultured cells (e.g., mesenchymal stem cells, iPSCs) or products with potential for insertional mutagenesis. |
| Unwanted immunogenicity | Anaphylaxis, graft‑versus‑host disease, graft rejection, neutralising antibodies, cytokine release syndrome. |
| Risks related to conditioning | Adverse events associated with pre‑treatment regimens (e.g., chemotherapy, immunosuppression). |
| Risks from genetic modification | Apoptosis, altered cell growth/differentiation, malignancy, off‑target mutations. |
| Vector‑related risks | Persistence, latency/reactivation, integration into host genome, prolonged transgene expression, altered host gene expression. |
| Administration and re‑administration | Dosing errors, maladministration, complications from surgical or interventional procedures (e.g., burr holes, catheter placement). |
| Persistence of the product | Need for rescue procedures; late complications (malignancies, autoimmunity); potential for germline integration and foetal transmission. |
| Risks to close contacts and the environment | Shedding of replication‑competent vectors; transmission to healthcare workers, caregivers, or offspring. |
3.2 Safety Specifications
Based on the identified risks, applicants must prepare a safety specification summarising important identified risks, important potential risks, and important missing information. Examples include:
- Transmission of infectious agents to the patient and close contacts.
- Treatment failure (e.g., graft dysfunction/rejection).
- Induction of autoimmunity or immunogenic reactions.
- Induction of malignancies/tumour formation.
- Impossibility of discontinuing or removing the product in case of emerging risks.
- Potential for vector latency, reactivation, integration, and germline transmission.
- Unwanted tissue formation, including abnormal cell proliferation.
4. Management and Reporting of Adverse Reactions
4.1 General Requirements
Reference is made to SFDA GVP Module VI (Collection, management and submission of reports of suspected adverse reactions). For ATMPs, the following points are emphasised:
- Traceability: Adverse reaction reports lacking batch numbers should be actively followed up to obtain this information, enabling proper linkage of events to the product lot.
- Signal detection optimisation: Systems must be tailored to detect new risks or changes in existing risks, including risks related to conditioning, administration procedures, and follow‑up treatments.
- Occupational exposure monitoring: Transmission and exposure of healthcare professionals, caregivers, and others should be monitored (see GVP Module IX on signal management).
4.2 Parent‑Child and Special Population Reporting
Specific attention is given to parent‑child risks, including foetal transmission of vectors, biologically active substances, cells, or infectious agents, as well as transmammary exposure through breast milk. These require dedicated reporting pathways.
5. Periodic Safety Update Reports (PSURs)
In addition to the standard PSUR requirements outlined in GVP Module VII, ATMP PSURs must include:
- Exposure data: Age‑ and sex‑specific exposure data from post‑marketing experience, including cumulative exposed patients and the method of exposure calculation.
- Long‑term follow‑up results: Efficacy and safety information from long‑term follow‑up of clinical trial participants.
- Newly finished post‑authorisation studies: Results of safety and efficacy studies, including comparative designs or justifications for lack thereof.
- Trend analysis: Monitoring for changes in the standard of care that may affect the ongoing risk‑benefit assessment.
6. Post‑Authorisation Safety and Efficacy Studies (PASS/PAES)
6.1 General Principles
Given the limited pre‑authorisation experience with ATMPs, post‑authorisation studies are often essential. The guidance encourages a holistic development plan that integrates pre‑ and post‑authorisation data collection.
Key recommendations include:
- Start early: Enrol patients in clinical trials (starting at Phase I) with appropriate consent for long‑term follow‑up.
- Use registries: Disease registries or other data sources should be considered early in development to facilitate long‑term data collection.
- Data sharing agreements: Establish agreements between hospitals, registry owners, patients, and developers to allow legitimate use of patient data for regulatory purposes.
- Combined studies: Where possible, safety and efficacy follow‑up should be combined into a single study.
6.2 Methodological Considerations
| Element | Guidance |
|---|---|
| Number of patients | Follow‑up may be required for all recipients or a defined subset; scientific justification must be provided if only a subset is followed. |
| Duration of follow‑up | Established on a case‑by‑case basis. For gene therapy using integrating vectors or with latency/reactivation potential, follow‑up of up to 15 years is typically expected. |
| Design | Randomised controlled trials are preferred, but observational studies (cohort, case‑control) may be acceptable for rare events or when randomisation is not feasible. Pragmatic trials may allow longer follow‑up. |
| Comparators | Surgery, standard‑of‑care, historical controls – the choice must be justified. Changes in the standard of care over time may be addressed through disease registries. |
| Endpoints | Should be appropriate for the product type. For tissue‑engineered products, structural endpoints (tissue functionality, structural aspects, persistence) are relevant. |
6.3 Objectives for Long‑Term Follow‑Up
6.3.1 Efficacy Objectives
- For cell‑based products: assess duration of effect, cell persistence, and need for re‑administration.
- For gene therapies: monitor sustainability of efficacy over time.
- For combined ATMPs: evaluate the medical device’s suitability and persistence.
6.3.2 Safety Objectives
For cell‑based products:
- Monitor long‑term immunity/rejection (xenogeneic/allogeneic cells).
- Monitor malignant transformation/mutagenesis (especially for heavily manipulated cells, iPSCs, embryonic stem cells).
For gene therapy:
- Evaluate risk of insertional oncogenesis.
- Monitor immunisation against the expressed therapeutic protein and vector.
For combined ATMPs:
- Assess the medical device’s capacity to retain therapeutic function and structural integrity (e.g., containment of allogeneic/xenogeneic cells).
7. Signal Management
7.1 Definition and Processes
A signal is defined as information suggesting a new potentially causal association (or a new aspect of a known association) between an intervention and an event, judged to be of sufficient likelihood to justify verificatory action (GVP Module IX). ATMPs are subject to the same signal management processes as other registered medicinal products in Saudi Arabia:
- Signal detection
- Signal validation
- Signal analysis and prioritisation
- Signal assessment
- Signal recommendations
7.2 Sources of Information
Sources for identifying ATMP signals include spontaneous reporting, product quality data, non‑clinical studies, clinical trials, pharmacovigilance data, and pharmaco‑epidemiological data.
7.3 MAH Responsibilities
Marketing authorisation holders must:
- Monitor the safety of their ATMP products continuously.
- Perform routine scanning for ATMP signals at least once monthly.
- Submit signal assessments and cover letters for each ATMP signal.
- Adhere to the timelines specified in GVP Module IX.C.1.
8. Safety Communication
Safety communication for ATMPs follows GVP Modules XV and XVI. Specific objectives include enabling healthcare professionals and patients to make informed decisions, promoting adherence to risk minimisation measures, and supporting informed choices.
The guidance notes that implementing risk minimisation measures for ATMPs requires specific communication skills regarding risks, benefits, and uncertainties—which may be more challenging than for conventional medicines.
Communication must be tailored to different audiences:
- Healthcare professionals: general practitioners, specialists, nurses, pharmacists.
- Patients and their representatives.
- Support personnel, family, and caregivers.
Educational materials should include information on:
- Characterisation of risks (severity, seriousness, frequency).
- Handling, reconstitution, administration, and disposal procedures.
- Monitoring and management of adverse reactions.
- Environmental and transmission risks.
9. Risk Minimisation Measures
Risk minimisation measures are interventions intended to prevent or reduce adverse reactions or to optimise benefits. For ATMPs, both routine and additional measures may be necessary.
9.1 Routine Risk Minimisation Measures
These include the information provided in the Summary of Product Characteristics (SPC), package leaflet, labelling, pack size/design, and the legal (prescription) status of the product.
9.2 Additional Risk Minimisation Measures
The guidance provides detailed examples of additional measures, to be considered on a case‑by‑case basis.
9.2.1 Controlled Access Programmes and Centre Accreditation
- Selection and accreditation of specialised centres.
- Physicians must be adequately trained and experienced.
- The MAH may manage the programme, potentially in collaboration with a relevant medical organisation.
- Regular updates on implementation status (e.g., annual reports) must be provided.
9.2.2 Educational Programmes
Targeted educational materials must be developed for:
| Audience | Key Content |
|---|---|
| Treating physicians | Conditioning, handling/reconstitution/administration/disposal, expected adverse reactions (including cytokine release syndrome), clinical follow‑up, traceability, HCP protection. |
| Pharmacists | Product receipt, storage, reconstitution, handling, disposal. |
| Patients/caregivers | Important safety risks, environmental risks (e.g., shedding), patient alert cards with batch recording, administration process, importance of reporting adverse reactions. |
| Support personnel/family | Early symptoms of important risks, clinical follow‑up procedures, post‑treatment care, accidental transmission risks. |
Notably, English draft versions of educational materials for HCPs, and both English and Arabic drafts for patients, must be submitted for evaluation and approval as part of the marketing authorisation application.
9.2.3 Effectiveness of Risk Minimisation Measures
MAHs must use all relevant post‑marketing data to evaluate the effectiveness of RMMs. Examples include:
- Trend analysis: a large number of adverse events related to administration procedures may indicate inadequate training material.
- Knowledge and skills testing: if an educational plan is in place, testing the target audience can be conducted when there is reason for concern.
10. Implementation Timeline
| Date | Action |
|---|---|
| 14 September 2025 | Draft version prepared by the Pharmacovigilance Executive Directorate. |
| 12 April 2026 | Final Version 1.0 issued (guidance document published). |
| 12 April 2027 | Implementation date – MAHs and applicants must comply with the guidance. |
This one‑year transition period allows stakeholders to adapt their pharmacovigilance systems, update RMPs, and develop educational materials as required.
11. Comparison with International Standards
The SFDA guidance is primarily based on European guidelines on safety and efficacy follow‑up and risk management of ATMPs. This alignment facilitates global harmonisation while accommodating local regulatory requirements.
Key similarities with EMA and FDA frameworks include:
- The 15‑year long‑term follow‑up requirement for integrating gene therapies is consistent with international practice.
- The emphasis on traceability, patient alert cards, and centre accreditation mirrors EMA and FDA approaches.
- The requirement for Arabic‑language patient materials is a Saudi‑specific addition, ensuring patient comprehension in the local context.
The SFDA also acknowledges the rapid evolution of science and technology and the limited worldwide experience with ATMPs, underscoring the importance of a well‑established, flexible pharmacovigilance system.
12. Practical Implications for Healthcare Professionals
12.1 Prescribing and Monitoring ATMPs
Healthcare professionals involved in the prescription or administration of ATMPs should:
- Understand the specific risks associated with each product (e.g., cytokine release syndrome for CAR‑T cells, insertional oncogenesis for integrating gene therapies).
- Ensure traceability – record batch numbers in patient charts and on alert cards.
- Provide patient education – using approved Arabic and English materials, explain the importance of long‑term follow‑up and reporting adverse events.
- Recognise delayed adverse events – malignancies may develop years after treatment; maintain ongoing surveillance.
- Report all suspected adverse reactions – including those related to conditioning, administration procedures, and occupational exposure.
12.2 Reporting Adverse Reactions
All suspected adverse reactions to ATMPs should be reported to the SFDA’s national pharmacovigilance system. Key information to include:
- Batch number of the ATMP (essential for traceability).
- Timing of adverse event relative to product administration.
- Details of conditioning regimens, concomitant medications, and administration procedures.
- Outcome of the event (including long‑term sequelae).
12.3 Patient and Caregiver Education
Given the novelty and complexity of ATMPs, patient education is paramount. Healthcare professionals should:
- Use the approved educational materials (patient alert cards, brochures).
- Explain the importance of long‑term follow‑up visits (e.g., annual monitoring for secondary cancers).
- Advise patients to inform other healthcare providers of their ATMP history, especially before surgery, immunosuppressive therapy, or pregnancy.
- Counsel patients on the risk of vector shedding and transmission to close contacts (e.g., avoiding unprotected sexual contact or sharing personal items, depending on the product).
13. Future Directions
The SFDA’s GVP for ATMPs is a living document that will evolve as scientific knowledge and clinical experience accumulate. Key areas for future development include:
- Integration of real‑world evidence from disease registries and electronic health records to supplement traditional pharmacovigilance.
- Harmonisation with international standards as global guidance (e.g., ICH E19 on safety data collection) matures.
- Advanced analytics – use of artificial intelligence and machine learning for signal detection in small populations.
- Patient‑reported outcomes – incorporating patient‑reported adverse events into safety monitoring systems.
- Environmental risk assessment – more detailed guidance on managing vector shedding and environmental transmission.
14. Conclusion
The SFDA’s Good Pharmacovigilance Practices (GVP) – Product‑ or Population‑Specific Considerations III: Advanced Therapy Medicinal Products (Version 1.0, April 2026) represents a landmark regulatory document for Saudi Arabia. It recognises that ATMPs—gene therapies, cell therapies, tissue‑engineered products, and combinations—require a fundamentally different approach to safety monitoring than conventional drugs.
Key takeaways for stakeholders:
| Stakeholder | Action Items |
|---|---|
| Marketing Authorisation Holders | Develop robust RMPs incorporating long‑term follow‑up (up to 15 years); establish traceability systems; prepare educational materials in English and Arabic; implement signal detection at least monthly. |
| Healthcare Professionals | Understand ATMP‑specific risks; ensure traceability; educate patients; report all suspected adverse reactions; recognise delayed adverse events. |
| Patients and Caregivers | Participate in long‑term follow‑up; carry patient alert cards; report any new symptoms; follow guidance on vector shedding and transmission. |
| Regulators (SFDA) | Review RMPs and educational materials; monitor signal detection activities; provide ongoing guidance as science evolves. |
By establishing clear expectations for risk management, safety communication, and long‑term follow‑up, the SFDA aims to foster innovation while ensuring patient safety. The one‑year implementation period (until 12 April 2027) provides a window for MAHs to align their systems with these requirements.
As the field of ATMPs continues to advance rapidly—with CRISPR‑based genome editing, allogeneic CAR‑T cells, and regenerative medicine products entering the clinic—the principles outlined in this guidance will serve as a foundation for safe and effective use of these transformative therapies in Saudi Arabia.
