The Saudi Food and Drug Authority (SFDA), the country’s regulatory agency in the sphere of healthcare products, has published a guidance document dedicated to companion diagnostic IVDs. The document provides a general overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by the parties involved in order to ensure compliance. At the same time, the authority reserves the right to make changes to the guidance and recommendations provided therein, should such changes be reasonably necessary to reflect corresponding amendments to the underlying legislation.
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In particular, the document provides detailed clarification concerning Companion Diagnostic (CDx) in vitro diagnostic (IVD) devices. It is designed to support manufacturers and stakeholders by outlining the specific requirements associated with the development, performance evaluation, and authorization of CDx devices under the Medical Devices Marketing Authorization (MDMA) framework.
The guidance applies to local CDx IVD manufacturers operating within the Kingdom of Saudi Arabia (KSA) or to the authorized representatives of foreign manufacturers who intend to conduct clinical performance studies or obtain marketing authorization. Additionally, it is relevant to healthcare institutions that are involved in the development of in-house CDx assays.
The document is based on the provisions of the relevant legal framework, including Articles 7 and 8 of the “Medical Devices Law” issued under Royal Decree No. (M/54). It is also based on several other related SFDA documents and guidance, such as MDS – REQ1 for MDMA, MDS – REQ2 for clinical trials, MDS – REQ11 for post-market surveillance, and guidance specific to innovative devices and in-house diagnostics.
Understanding Companion Diagnostic IVDs
According to the guidance, Companion Diagnostic IVDs are defined as medical devices that are essential for the safe and effective use of a corresponding medicinal product. These diagnostics are used to identify, either before or during treatment, patients who are most likely to benefit from the use of a specific drug, or those who may be at an increased risk of severe adverse reactions due to such treatment.
The device must be explicitly mentioned in the product information of the medicinal product and intended for use in analyzing specimens obtained from individuals. It is important to note that devices intended solely for compatibility testing – such as assessing the compatibility of blood or tissue from donors – are not classified as CDx.
The guidance clearly distinguishes CDx from other categories of diagnostics such as complementary diagnostics, which, although useful for the safe and effective use of a medicine, are not mandatory. Likewise, diagnostic tests used broadly for disease detection or drug monitoring are not considered CDx unless specifically required in the medicinal product’s labeling.
It is also important to mention that all CDx IVDs, as per the classification rules in MDS – REQ1, are categorized as Class C devices, due to their direct impact on therapeutic decisions.
Development Strategies for CDx IVDs
The guidance recognizes different models for developing CDx devices, with co-development being the preferred approach. Co-development implies the simultaneous development of the CDx IVD and the associated medicinal product. This joint development process ensures that clinical performance studies of the CDx are aligned with the clinical trials of the medicinal product, thus enabling concurrent marketing authorizations.
However, the authority mentions that co-development is not always practical. In many instances, a CDx may already exist for a different use, or its specifications may change during the drug’s development. In such scenarios, it may not be feasible to synchronize the timelines of the CDx and the medicinal product. The document outlines alternative pathways for such cases, including the development of a new CDx for an already approved drug, or development involving a significant change in the biomarker or technology.
An important subset is the “follow-on CDx”, which targets the same biomarker and therapeutic product as a previously approved CDx. In these cases, manufacturers may rely on existing data for scientific validity, and new studies focus on demonstrating analytical and clinical performance compared to the approved device.
Regulatory Pathways and MDMA Considerations
Companion Diagnostic IVDs, being a specific category of IVDs, must fulfill the broader requirements for MDMA as defined in MDS – REQ1. This includes demonstrating compliance with essential safety and performance principles, submitting technical documentation, and undergoing performance evaluation.
As explained in the document, the SFDA employs a collaborative approach during the MDMA review process. The Medical Devices sector is responsible for reviewing CDx IVDs, while the Drug sector reviews the associated medicinal products. For new medicinal products that require a CDx, the Drug sector leads the MDMA process but must coordinate closely with the Medical Devices sector to ensure harmonization.
Manufacturers pursuing simultaneous authorization of both the CDx and the medicinal product are encouraged to initiate early consultations with both SFDA sectors. Novel CDx devices that introduce new technologies or address unmet medical needs may benefit from the streamlined pathways defined for innovative medical devices.
Market Access and In-House Use
CDx devices may be introduced to the market either as distributed test kits or as Laboratory Developed Tests (LDTs), also known as in-house tests. LDTs are commonly used for targeted therapies and are developed and validated within a single laboratory or healthcare institution.
In the Kingdom, manufacturers of in-house CDx tests must obtain an establishment license and adhere to the conditions outlined in MDS – REQ9. The Point of Care (POC) Manufacturing scheme also applies and is regulated under MDS – G9 and MDS – G22.
For LDTs developed and performed outside KSA, whether by private laboratories or institutions, the POC provisions do not apply. Such tests are subject to the standard MDMA regulatory pathway.
Clinical Performance Studies in the Context of Medicinal Product Trials
Under the applicable regulatory requirements, the clinical performance of CDx IVDs must be demonstrated through studies conducted in accordance with Annex (7) of MDS – REQ1. When these studies are carried out within Saudi Arabia, they must also comply with MDS – REQ2 and receive formal approval from the Medical Devices sector of the SFDA.
These studies must be aligned with ethical principles such as those in the Declaration of Helsinki and conform to international standards like ISO 20916. If the CDx study is embedded within a clinical trial for a new drug, additional coordination with the SFDA Drug sector is required. In some cases, even if the patient sample testing is performed abroad, study protocols must still be submitted for SFDA review.
Annex (2) of the guidance elaborates on different clinical trial designs and scenarios involving CDx use, highlighting the associated risks and regulatory approval requirements based on whether the CDx is used for patient selection, management, or stratification.
Analytical and Clinical Performance Requirements
The guidance outlines that robust evidence must support the scientific validity, analytical performance, and clinical performance of a CDx. This includes confirming that the diagnostic correctly detects the biomarker, performs consistently under various conditions, and supports the intended clinical decision-making.
The performance evidence must consider not only the standalone diagnostic test but also its integration with associated instruments, software, and other reagents. For multiplex assays involving multiple biomarkers, analytical performance must be demonstrated for each component.
For novel biomarkers without established literature, scientific validity must be demonstrated through feasibility studies or new clinical trials. For follow-on CDx devices, clinical studies may compare the new device against the previously approved one using the same clinical specimens when available. If that is not feasible, specimens collected under similar criteria may be used to validate the device.
Labelling Requirements
The authority additionally emphasizes that clear and specific labelling of both the CDx IVD and the associated medicinal product is vitally important. The CDx must state its role as a companion diagnostic, include the International Non-Proprietary Name (INN) of the drug, and define the intended target population.
Manufacturers may also include the brand name of the therapeutic product in the Instructions for Use (IFU).
Conversely, the medicinal product labelling must indicate that the use of an approved CDx is essential. It is generally preferred to refer to the diagnostic generically rather than by brand.
Post-Market Surveillance and Vigilance
CDx IVDs are subject to comprehensive post-market requirements under MDS – REQ11. Manufacturers must have procedures in place to investigate complaints, report adverse events to the National Center for Medical Devices Reporting (NCMDR), and ensure ongoing safety.
Given the direct relationship between the diagnostic and the medicinal product, both manufacturers must coordinate closely in the event of adverse events. Any serious adverse incidents must be reported to both SFDA sectors, and thorough assessments must determine whether the issue originates from the diagnostic or the drug.
The evaluation must be well-documented, using methods such as those outlined in ISO 20916:2024 to categorize adverse events and assess their sources.
Managing Post-Authorization Changes
In accordance with the applicable regulatory requirements, significant modifications to a CDx after MDMA require prior notification to the SFDA, as specified in MDS – G12. The guidance provides examples of such changes:
One common scenario is the transition from centralized laboratory testing to a distributed reagent kit. This change necessitates analytical performance validation and bridging clinical studies comparing the kit against the original centralized test.
Another example is the addition of new specimen types, such as introducing liquid biopsies to a CDx initially validated for tissue samples. In such cases, comparative studies must confirm concordance and predictive value using retrospectively collected specimens.
When a CDx is expanded to cover a new medicinal product, new clinical performance evidence must be provided. However, the addition of a generic drug with the same active ingredient does not constitute a significant change, provided that bioequivalence has already been demonstrated.
Conclusion
In summary, the guidance provides a detailed overview of the relevant regulatory requirements the parties involved should comply with in the course of their activities related to CDx. The document also emphasizes the key aspects to be taken into consideration in order to ensure the safety of patients.
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