IVD Risk-based Classification
WHO's risk-based assessment approach for in vitro diagnostics (IVDs) uses an internationally accepted classification system that was created by the Global Harmonization Task Force (GHTF) and continues to be maintained by the International Medical Device Regulators Forum. This approach is also used by regulatory authorities to determine the level of pre-market control to apply to IVDs.
GHTF created the risk classification system to determine the level of pre-market regulatory control that is required for an IVD, with the purpose that these controls are sufficient for each class to safeguard the health and safety of patients, users and other persons. The outcome of the system is to group IVDs into one of four risk classes (A to D).
| Classification | Individual health risk | Public health risk | |
|---|---|---|---|
| Class A IVD | Low | and | Low |
| Class B IVD | Moderate | and | Low |
| Class C IVD | High | and/or | Moderate |
| Class D IVD | High | and | High |
WHO has adopted the GHTF classification system to guide the level of stringency and scope of the assessment required for an IVD product undergoing WHO prequalification. WHO applies this classification system by considering the risks posed when the IVD is used in WHO Member States, with particular emphasis on resource-limited settings. Several critical aspects are specific to resource limited settings compared to risk classification when applied in many high-income countries. These include differences in endemicity and prevalence of various diseases, the availability of follow-up or reference testing, and significant differences in the level of training of professional staff utilizing the IVD. This means that the risk classification of an IVD in resource-limited settings can be considerably different (usually posing higher risk) from that when evaluated for use in a high-income setting.
The table below identifies the review procedures that WHO uses to assess each of the GHTF risk classes, to illustrate how the assessment activities would differ if products in these risk classes were to be assessed for prequalification. This is consistent with GHTF recommendations that the depth and timing of the review of the dossier is influenced by the class of the IVD, its complexity, and the extent to which it incorporates new technology.
| Summary of WHO prequalification assessment activities by IVD risk class | ||||||
|---|---|---|---|---|---|---|
| WHO prequalification requirement | Assessment element | Manufacturer responsibility | WHO prequalification assessment | |||
| Class A* | Class B* | Class C | Class D | |||
| Assessment of quality | Quality management system (QMS) | Establish and maintain a full QMS | Inspection normally not required | Have confidence that a current and appropriate QMS is in place or otherwise conduct a QMS inspection | Confirm that a current and appropriate QMS is in place or otherwise conduct a QMS inspection | Confirm that a current and appropriate QMS is in place or otherwise conduct a QMS inspection |
| Post-market surveillance | Establish and maintain a complaint reporting procedure | May inspect to investigate specific safety or performance concerns | Confirm that a current and appropriate complaint reporting procedure is in place as part of the QMS | Confirm that a current and appropriate complaint reporting procedure is in place as part of the QMS | Confirm that a current and appropriate complaint reporting procedure is in place as part of the QMS | |
| Assessment of IVD manufacturer’s claims of safety & performance | Technical documentation | Establish and keep up to date, technical documentation, and prepare and submit a dossier for review | Only subsets of information to be reviewed to determine conformity to Essential Principles | Only subsets of information to be reviewed to determine conformity to Essential Principles | Undertake a review of the product dossier sufficient to determine the product is safe and should perform as intended, including assessment of conformity to Essential Principles. Also ensure that the benefit of using the IVD in a WHO Member State outweighs the risks involved. | Undertake an indepth review of the product dossier to determine the product is safe and should perform as intended, including assessment of conformity to Essential Principles. Also ensure that the benefit of using the IVD in a WHO Member State outweighs the risks involved. |
| Assessment of performance – laboratory evaluation | Laboratory evaluation | Undertake performance studies should support the safe use and performance of the assay | No laboratory evaluation undertaken | Laboratory evaluation undertaken in only exceptional cases identified by Member State needs) | Laboratory evaluation undertaken in the majority of cases to independently evaluate performance and operational characteristics | Laboratory evaluation undertaken to independently evaluate performance and operational characteristics |
*Currently, IVDs undergoing WHO prequalification do not fall into Classes A or B.
The GHTF Principles of conformity assessment for in vitro diagnostic (IVD) medical devices, on which the above table is based, recommends that the documentation submitted in a product dossier for a Class C IVD contain less detailed information than the documentation for a Class D device. For WHO purposes, the main difference for a Class D dossier would be in the level of detail submitted in the clinical/performance data. However, the document also notes that although a regulatory authority/conformity assessment body should not normally require more elaborate information for a Class C IVD, this does not preclude the regulatory authority/conformity assessment body from requesting such information in specific cases. WHO exercises this option for IVDs that present additional risk as a result of their role in clinical decision-making and the areas of use. (See discussion of specific tests below).
GHTF has generated a set of risk classification rules that are used to assign a particular IVD to a particular risk class. When applying these rules to determine the risk class, WHO will also take into consideration not only the rule specific to a given IVD, but also how the IVD is generally used in clinical and laboratory (or non-laboratory testing settings) practice in its Member States. This use, along with other factors particular to Member States such as the variable technical level and/or training of the operator of the IVD, may result in a WHO risk classification higher than that recommended in existing GHTF risk classification rule examples. The drop-down sections describe how IVDs are classified by WHO with reference to the relevant GHTF Classification Rules (see Annex 1), and describes the reasoning for the risk classification ultimately assigned by WHO for each type of IVD. Whereas this document identifies specific examples of existing technologies, as new technologies arise, WHO will consider the risk that they pose, which will in turn dictate the extent of the documentation to be submitted and the scope of WHO review.
Using risk class to determine level of WHO prequalification of diagnostics assessment
Similar to systems implemented by stringent regulatory authorities, WHO IVD prequalification assessment is designed to safeguard the health and safety of patients and users of IVDs. The level of confidence that the WHO Member States will have in a IVD for a priority disease will be based on the safety and performance of these products throughout their life cycle. It is the manufacturer's responsibility to ensure that the IVD meets WHO requirements. However, it is the role of WHO to ensure, by review and assessment, compliance with these requirements. Dossier assessment, manufacturing site inspection, the independent WHO laboratory evaluation, as well as post-market surveillance of IVDs for priority diseases, are complementary review and assessment activities of WHO prequalification. In general, the extent of review for WHO prequalification is proportional to the risk class associated with that IVD. By aligning with the GHTF risk-based classification and assessment recommendations, WHO review and assessment processes are aligned with international best practice.