MDCG 2020-16 is a key document outlining the classification rules for in vitro diagnostic medical devices (IVDs) under the EU IVDR. Revision 3 of this guidance document introduces specific changes aimed at improving clarity and compliance within the IVD sector, thereby ensuring the safety and performance of devices placed on the market. By detailing the classification rules set out in Annex VIII of the IVDD, the document helps to resolve potential ambiguities, thereby facilitating a more effective application of the regulations.
This article is structured into two main sections: the first part outlines the specific updates and clarifications introduced in Rev.3 of the guidance; the second part provides an analysis of significant IVD categories including Companion Diagnostics (CDx), Next-Generation Sequencing (NGS), self-testing, and Near-Patient Testing (NPT) in the MDCG 2020-16.
Key Updates in MDCG 2020-16 Rev.3
Definition of ‘Kit’
A significant addition in Rev.3 is the formal definition of a ‘kit’, which states: “‘Kit’ means a set of components that are packaged together and intended to be used to perform a specific in vitro diagnostic examination, or a part thereof.”
Rule 3(a)
Now includes Monkeypox Virus in the list of examples.
Rule 4(a)
The MDCG 2020-16 rev.3 includes clarifications for self-testing IVDs.
Clarification in the classification for self-testing.
- Devices for detecting pregnancy, fertility, and cholesterol levels in any specimen, along with those for glucose, erythrocytes, leukocytes, and bacteria in urine, are classified as Class B.
- If a device detects both a Class C marker and a marker listed as an exception (Class B), the device will be classified as Class C according to implementing rules 1.8 and 1.9.
- Devices meeting certain criteria under implementing rules 1.8 and 1.9 are classified as Class D, including self-testing kits for HIV detection from a fingerprick blood sample.
Information Society Services:
- The updates clarify the role of information society services in self-testing, stating that devices intended for such services are considered self-testing devices when lay persons perform part of the testing procedure, like adding reagents or placing the specimen on a test cassette. Importantly, actions solely required for collecting the specimen or ensuring its integrity and stability do not qualify the device as for self-testing.
Standalone Specimen Receptacles:
- The revisions specify that standalone specimen receptacles and kits intended solely for specimen collection by laypersons, even those offered through information society services, are not considered devices for self-testing.
Clarification in the examples
- Meters and strips with integrated testing reagents for self-testing of capillary blood glucose are classified in Class C.
- Devices intended to measure levels of calprotectin, where the lay person collects the stool specimen, performs the testing procedure using the test cassette, and sends an image of the result for interpretation by a healthcare professional, are also in Class C.
- Self-testing kits for the detection of HIV antibodies from a fingerprick blood sample are classified in Class D.
Rule 5(c)
The guidance includes the rationale and additional examples.
Classification and Definition:
- Specimen receptacles are defined as containers or tubes (evacuated or non-evacuated), which may be empty or prefilled with a fixative solution or other general reagent. These are intended for primary containment, preservation, transport, and storage of biological specimens such as cells, tissues, urine, and feces for the purpose of in vitro diagnostic examinations.
- These receptacles are classified as Class A under IVDR, highlighting their fundamental role in sample collection without any integrated testing functions, ensuring the integrity and stability of the specimens.
Integration in Kits:
- Specimen receptacles can be marketed as standalone devices or as components of kits intended for specimen collection or testing.
- Kits intended for specimen collection must include at least one IVD component (the specimen receptacle) and may contain other non-IVD components. Such kits are typically classified as Class A, in alignment with the classification of the included specimen receptacle.
Actions by Users:
- The use of these devices or kits may require actions by the user, such as mouthwash, gargling, pipetting, or buffer addition to ensure specimen integrity. These actions are defined in the instructions for use (IFU) and are not considered part of the testing procedure.
Market Placement and Combination Use:
- Specimen receptacles and kits intended for specimen collection can be marketed separately but are intended to be used in combination with another IVD. In such cases, implementing rule 1.2 applies, and both the receptacle and the other IVD should be classified independently.
- If a specimen collection kit is used by lay persons and includes steps that are part of the testing procedure, then the entire kit is considered a device for self-testing as per Rule 4. However, the specimen receptacle itself, within such a kit, is not considered a device for self-testing.
Examples Clarifying Usage and Classification:
- Standalone Devices: Examples like a urine collection cup, stool container, saliva collection tube, or a blood spot collection card are all classified as Class A.
- Kits for Lay Use: Standalone kits for layperson use, such as those for collecting saliva for SARS-CoV-2 detection or stool for fecal occult blood testing in colorectal cancer screening, are also in Class A. These kits may include additional components like a plastic stick for sample collection and a pre-filled tube for conservation and transport, yet still retain a Class A classification.
Rule 6
Includes a change in the example of the device intended for the detection of Influenza A/B virus, from non-pandemic to highly virulent.
Classification of Key Diagnostic Tools in the MDCG 2020-16 Rev.3
Next Generation Sequencing (NGS)
NGS technology plays a central role across various diagnostic applications within the MDCG 2020-16 Rev.3 document:
- Companion Diagnostics (CDx) (Rule 3(f), Page 24): NGS is essential for identifying genetic variants that influence the efficacy of specific medical treatments, thereby supporting personalized medicine by enabling tailored therapeutic strategies.
- Cancer Diagnostics and Staging (Rule 3(h), Page 27): NGS is utilized for comprehensive cancer screening, diagnosis, and staging. This involves detailed analysis of cancer-related genes, which is crucial for developing precise treatment plans and managing patient care effectively.
- General Laboratory Use (Rule 5(a) and 5(b), Pages 40-41):
- Rule 5(a): NGS is specifically mentioned in the context of “Library Prep reagents for the preparation of DNA for downstream analysis by NGS sequencing.” This example highlights the role of NGS in preparing genetic material for detailed analysis, reflecting its importance in the preliminary steps of genetic testing.
- Rule 5(b): Instruments that enhance the utility of NGS, such as “PCR thermocyclers, sequencers for NGS applications, and clinical chemistry analyzers,” are listed. These devices are integral to executing NGS procedures, demonstrating the technology’s critical role in performing complex genetic analyses within laboratory settings.
Companion Diagnostics (CDx) in the MDCG 2020-16 Rev.3
Rule 3(f), Page 22: Companion diagnostics are defined as essential devices for the safe and effective use of corresponding medicinal products. These devices are crucial for:
- Identifying patients who are most likely to benefit from a specific therapeutic product, thereby optimizing treatment efficacy.
- Detecting risks of adverse reactions, crucial for minimizing potential negative effects from treatments.
CDx must be explicitly linked to a medicinal product identified by an International Non-proprietary Name (INN), emphasizing their integral role in targeted therapy regimes.
Rule 3(f), Page 22: This rule outlines the regulatory framework for CDx, highlighting their use before or during treatment. This flexibility allows for adjustments in therapy based on patient responses and biomarker changes over the course of treatment, ensuring ongoing efficacy and safety.
CDx have transformative implications across various medical fields:
- Oncology: Tests like those for ALK protein or PD-L1 expression determine eligibility for targeted cancer therapies, significantly improving outcomes in conditions like NSCLC.
- Chronic and Genetic Diseases: Genetic tests for mutations in genes such as DPYD help predict metabolism of drugs like fluorouracil, preventing severe side effects in metabolically compromised patients.
Page 24, Rule 3(f): MDCG 2020-16 Rev.3 provides several examples:
- Genetic Variants: Devices that detect KRAS/NRAS variants are crucial for colorectal cancer treatment decisions.
- Biomarker Detection: Immunohistochemical devices for PD-L1 help determine eligibility for immunotherapy in cancer treatment.
- Next-Generation Sequencing (NGS): NGS-based CDx assess multiple genetic variants, aiding in comprehensive treatment decisions for multifactorial diseases.
Annex II: Decision Flowchart Rule 3(f): Includes a flowchart to assist in determining whether an IVD qualifies as a CDx. This tool is vital for navigating the regulatory landscape, ensuring correct classification and utilization in line with therapeutic contexts.
Self-testing references in the MDCG 2020-16
Rule 4(a) on Page 37: Self-testing devices are intended for use by laypersons and require designs that ensure ease of use, reliability, and accuracy. This rule ensures that these devices, used outside traditional clinical settings, meet rigorous safety standards to prevent misuse and potential harm.
Near-Patient Testing references in the MDCG 2020-16
Rule 4(b) on Page 39: Near-patient testing devices are classified distinctly to ensure they provide rapid and reliable results essential for immediate clinical decision-making. These devices are crucial in settings like emergency rooms or clinics where quick diagnostic information is vital.
Conclusion
MDCG 2020-16 Rev.3 introduces clarifications that enhance the regulatory framework for IVD devices within the EU.
By refining the definitions and classifications of key diagnostic tools, including Companion Diagnostics, Next-Generation Sequencing, self-testing, and Near-Patient Testing devices, this guidance ensures guidance for manufacturers and stakeholders.
