IVD Assessment Approach

Risk classification

The risk posed by the use of an IVD can be categorized or classified according to a set of classification rules. These rules were created by the Global Harmonization Task Force (GHTF), a voluntary group of representatives from regulatory authorities (United States, Canada, European Union, Japan, and Australia), as well as representatives from the medical device industry. In 2012 GHTF was replaced by a regulators-only group, the International Medical Device Regulators Forum (IMDRF), which has adopted the GHTF classification rules and other GHTF regulatory guidelines. IMDRF continues to maintain GHTF guidelines and develop more guidance that will encourage international regulatory convergence and support innovation and timely access to safe and effective medical devices globally.

GHTF and IMDRF documents have been created and approved by working parties icluding both regulatory authorities and major industry groups, ensuring that the recommendations are acceptable and implementable at a global level. Internationally, the outputs of IMDRF and GHTF are being adopted by several countries introducing regulation of IVDs and other medical devices. Additionally, established regulatory agencies are also converging practices in line with the recommendations of GHTF and IMDRF, in recognition of the fact that these represent regulatory best practice for a global market. GHTF created the risk classification rules to determine the level of pre-market regulatory assessment that is required for an IVD, with the purpose that these controls are considered to be sufficient for each risk class to safeguard the health and safety of patients, users and other persons. The outcome of the rules is to group IVDs into one of four classes representing increasing individual and public health risk (Classes A to D), shown in Table 1.

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

This risk classification system is based on two regulatory principles. First, the level of scrutiny afforded a device is dependent upon the risk the device presents. Second, the safety and performance of medical devices can be best assessed through a balance of pre-market scrutiny, adequate manufacturer quality management systems (QMSs), and the implementation of effective postmarket surveillance mechanisms.

It is the responsibility of the manufacturer to apply the risk classification rules and determine the risk class, based on the intended use of the IVD. The manufacturer should document the justification for placing the IVD into a particular risk class. However it is the responsibility of the regulatory authority or conformity assessment body to confirm that the risk class determined by the manufacturer is consistent with applicable classification rules and appropriate for the intended setting.

When applying the rules, risk considerations will vary depending upon the setting in which a product is intended to be used. For example, several critical aspects are particular to risk considerations for IVDs used in resource-limited settings compared to high-income countries. These include differences in endemicity and prevalence of various diseases, the way the test result is used for clinical-decision making, the level of treatment and care available for a patient with the disease, the availability of follow-up or reference testing, and significant variations in the level of training of professional and non-professional staff utilizing the IVD. This means that the risk classification of an IVD in a low- or middle-income country can be considerably different (usually posing higher risk) to that when evaluated for use of the IVD in a high-income country.

It is important to note that the risk classification does not determine the level of effort to be undertaken by the manufacturer to create sufficient evidence of safety and performance of the IVD. All IVDs, no matter the risk class, should be designed and manufactured under conditions that will result in a quality product with an expected level of performance. Rather, risk classification is intended to provide the appropriate amount of oversight by a regulatory authority or conformity assessment body. For instance, the classification does not determine the size and complexity of the clinical performance studies to be undertaken. These are determined by other factors, guided by an appropriate risk analysis conducted by the manufacturer that addresses factors such as the design of the IVD, as well as all performance claims related to intended use such as the intended users and testing population. However, the risk classification may influence the type of information required for assessment. For example, only summary data are usually required for lower risk products, whereas complete data sets are assessed for higher risk products, and information supporting the design and development of a IVD are needed to assess higher risk or novel IVDs.

By using an internationally recognized risk classification scheme for IVDs to determine routine regulatory oversight, regulatory authorities and conformity assessment bodies ensure that the level of assessment is proportionate to the degree of risk, taking into account the benefits offered by the IVD. Such an approach to IVD assessment takes into account the number and diversity of IVDs available, as well as the limited resources available to undertake assessment. Another proven advantage is that the classification scheme is rules-based and not prescriptive. This means it can accommodate new and innovative IVDs. WHO recommends the adoption of this approach for WHO Member States regulating IVDs and those considering doing so.

The following criteria are used to apply the GHTF rules for classification of IVDs:

  • the intended use and indications for use as specified by the manufacturer (including aspects such as the specific disorder, condition or risk factor for which the test is intended, the intended setting/environment for use)
  • the technical/scientific/medical expertise of the intended user (lay person or professional)
  • the importance of the test result to the diagnosis (sole determinant or one of several), taking into consideration the natural history of the disease or disorder including presenting signs and symptoms which may guide a physician
  • the impact of the result (true or false) to the individual and/or to public health.

The risk classification rules for IVDs as described by GHTF are given below 1. In some cases, more than one classification rule may be applicable to an IVD; in this case the higher risk classification is applied.

Assessing IVDs – critical elements

GHTF identified elements that should be considered in the regulatory assessment of an IVD:

  • QMS
  • post-market surveillance
  • technical documentation
  • declaration of conformity to the Essential Principles of Safety and Performance
  • registration of manufacturers and their devices.

The following sections outline what GHTF identifies as the manufacturer's responsibility for each of these elements and what level of assessment of each element by either the regulatory authority or the conformity assessment body (CAB) is most appropriate for each risk class of IVD. IVDs that present the greatest risk (Classes C and D) typically require objective evidence of the safety, quality, performance, benefits and risks of the IVD. Such evidence is usually documented in a technical file available at the site of manufacture. An inspection of the manufacturer's QMS would typically include the review of particular records from the technical file. In addition, a product dossier that includes selected records from the technical documentation is assessed as part of the pre-market assessment. The GHTF document, Summary technical documentation for demonstrating conformity to the Essential Principles of Safety and Performance of In Vitro Diagnostic Medical Devices (this documentation is referred to as the STED), provides recommendations for dossier content for Class C and D IVDs. In some jurisdictions, an independent performance evaluation to verify the claims (performance and operational characteristics) made by the manufacturer in the product dossier and associated quality documentation may be performed.

Performance evaluation and lot release testing

GHTF also acknowledges that performance testing is another element to be considered as part of conformity assessment.

Manufacturer's responsibility: IVDs should have performance characteristics (such as sensitivity, specificity, linearity, etc.) appropriate for the intended setting when used by intended users. Special considerations for the variable conditions encountered in diverse settings should be considered in the design and development of the IVD to ensure that these performance characteristics can be achieved. Such considerations may include use of the IVD in areas with extremes of temperature and humidity, and with operators of various skill levels. The manufacturer should have considered these aspects in a thorough risk assessment and hold evidence through performance testing and other means that the benefits of using the IVD in the intended use setting by intended users will outweigh any residual risk.

Additionally, the manufacturer should have in place effective lot release procedures to ensure performance characteristics are maintained for each lot of product manufactured. Lot release testing should thus ensure that where appropriate, the sensitivity and specificity, or other critical performance characteristics remain unchanged for each lot by the testing of sufficient numbers of relevant specimens. Maintenance of lot release panels is therefore a critical procedure within the QMS to ensure ongoing consistency.

Regulatory authority (RA)/conformity assessment body (CAB): In many cases, regulatory/evaluating bodies rely solely on information from studies conducted by, or on behalf of, the manufacturer to evaluate the IVD's performance. Others conduct their own independent evaluation through performance studies to supplement or verify those performed by the manufacturer. The need to undertake independent evaluation should follow the risk based principles identified in GHTF guidance Principles of conformity assessment for in vitro diagnostic (IVD) medical devices, taking into account considerations such as the risk class of the IVD, the novelty of the technology, the manufacturer’s experience level with the type of IVD and if the type of IVD raises specific public health concerns. The evaluation can take the form of a performance study verifying the manufacturer’s performance claims, and/or through lot testing to ensure each lot meets set criteria. Performance studies for regulatory are different in their purpose than those for health technology assessment (HTA) purposes. The goal for regulation usually encompasses verification of clinical validity, whereas for HTA, clinical utility is being reviewed. HTA studies investigate implementation aspects such as cost–benefit ratios, taking into account aspects such as training, educational and facility requirements.

Lot testing can be performed by the RA or the CAB to ensure the quality of the assays before distribution in view of the potential effect of transportation on product performance when it is shipped into country. Depending on the risk class of the product and its use in a particular jurisdiction, an alternative to lot testing by the regulatory authority is review of the manufacturer's lot release data for each of the lots accepted into that jurisdiction.