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.
| GHTF RISK CLASSES AND RISK LEVEL | |||
|---|---|---|---|
| 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.
Quality management system (QMS)
Manufacturer's responsibility: An appropriate QMS should be in place for all classes of IVDs. A QMS ,when implemented effectively, will ensure the manufacturer has in place mechanisms that not only ensure quality production (and an uninterrupted supply), but also that the IVD will be safe and effective. Such mechanisms include the use of risk management procedures (with risks identified, monitored and addressed) throughout the product life cycle. The scope and complexity of the QMS that a manufacturer needs to establish is influenced by varying needs, objectives, the products provided, processes employed, the size and structure of the organization, and specific regulatory requirements. Examples of quality management standards for IVDs that are acceptable to regulatory authorities include ISO 13485:2016 Medical devices – Quality management systems – Requirements for regulatory purposes) and the United States Food and Drug Administration Quality System Regulations (Code of Federal Regulations Title 21, Part 820).
Regulatory authority (RA)/conformity assessment body (CAB) responsibility: Assessment of the effectiveness of a manufacturer's QMS is influenced primarily by the class of the IVD. For Class C and Class D IVDs, the assessment process will verify that not only is the control of manufacturing and other processes effective, but also that the design and development of the IVD and that form the basis for its manufacture, are controlled. As shown in the table below, assessment for classes B to D can range from review of relevant certification to comprehensive on-site inspection and auditing of the manufacturer's QMS. Factors other than risk class that can influence the form and depth of the assessment include the RA's or CAB's knowledge of the manufacturer (assessed during previous inspections for other products), external reports of quality issues associated with the product or the manufacturer, and the findings of other inspection reports generated as part of a comprehensive regulatory review process.
| ASSESSMENT OF QMS SYSTEMS ACCORDING TO RISK CLASSIFICATION | ||
|---|---|---|
| Class | Manufacturer's responsibility | RA/CAB responsibility |
| A | Establish and maintain a full QMS or a QMS without design and development controls. | Pre-market regulatory audit not required. |
| B | Establish and maintain a full QMS or a QMS without design and development controls. | Be satisfied that a current and appropriate QMS is in place or otherwise conduct a QMS audit prior to marketing authorization. |
| C | Establish and maintain a full QMS. | Be satisfied that a current and appropriate QMS is in place or otherwise conduct a QMS audit prior to marketing authorization |
| D | Establish and maintain a full QMS. | Be satisfied that a current and appropriate QMS is in place or otherwise conduct a QMS audit prior to marketing authorization. |
Technical documentation
Manufacturer's responsibility: Sufficient technical documentation should exist to prove that the GHTF Essential Principles of Safety and Performance of Medical Devices (identified as simply the Essential Principles [EP]) have been met. Manufacturers of all classes of IVDs are expected to demonstrate conformity of the IVD to the EP through the preparation and holding of technical documentation that shows how each IVD was developed, designed and manufactured, together with the descriptions and explanations necessary to understand the manufacturer's determination with respect to such conformity. This technical documentation is updated as necessary to reflect the current status, specification, configuration and post-market experience of the IVD.
RA/CAB responsibility: An assessment body assessing conformity to the EP (e.g. an RA) will review the STED at greater depth as the risk class increases.
The GHTF document notes that the documentation for a Class C IVD medical device will contain less elaborate information than the STED for a Class D device. The main difference for a Class D STED would be in the level of details in the clinical/performance data and details of the manufacturer’s QC release programme. Although a regulatory authority/conformance assessment body should not normally require more elaborate information for a Class C device, this does not preclude the RA/CAB from requesting such information in specific cases.
| ASSESSMENT OF TECHNICAL DOCUMENTATION ACCORDING TO RISK CLASSIFICATION | ||
| Class | Manufacturer's responsibility | RA/CAB responsibility |
| A | Upon request prepare STED. | Premarket submission of STED not required. May be requested to investigate specific safety or regulatory concerns. |
| B | Upon request prepare STED. | Pre-market submission normally not required but if requested, receive and conduct a review of the STED to determine conformity to Essential Principles. |
| C | Prepare and submit STED for review. | Receive and conduct a pre-market review of the STED to determine conformity to Essential Principles. |
| D | Prepare and submit STED for review. A STED for this class should contain more extended information such as full performance evaluation reports. | Receive and conduct a pre-market review of the STED to determine conformity to Essential Principles. |
Post-market surveillance
Manufacturer's responsibility: A system for post-market surveillance of the product should be in place to monitor manufactured product quality, safety and performance. Before putting the product on the market, the manufacturer will put in place, as part of its QMS a process to assess the continued safety and performance of the throughout the IVD's life cycle. This process will include having procedures for, at a minimum, complaint handling, vigilance reporting, procedures for recalls, and corrective and preventive action.
RA/CAB responsibility: An assessment body can review the effectiveness of post-market surveillance mechanisms through inspection on site and/or through the availability of relevant documentation (including existence of appropriate standard operating procedures). The level of review should again be strongly influenced by the risk class of the IVD, as well as the additional factors identified above for assessment of the QMS.
All regulatory authorities should have in place an adverse event reporting procedure.
| ASSESSMENT OF POST-MARKET SURVEILLANCE ACCORDING TO RISK CLASSIFICATION | ||
| Class | Manufacturer's responsibility | RA/CAB responsibility |
| A | Establish and maintain an adverse event reporting procedure according to GHTF SG2 guidance. | May audit post-market to investigate specific safety or regulatory concerns. |
| B | Establish and maintain an adverse event reporting procedure according to GHTF SG2 guidance. | Be satisfied that a current and appropriate adverse event reporting procedure is in place as part of the QMS. |
| C | Establish and maintain an adverse event reporting procedure according to GHTF SG2 guidance. | Receive and conduct a premarket review of the STED to determine conformity to Essential Principles. |
| D | Establish and maintain an adverse event reporting procedure according to GHTF SG2 guidance. | Be satisfied that a current and appropriate adverse event reporting procedure is in place as part of the QMS. |
Declaration of conformity
Manufacturer's responsibility: A declaration of conformity to the Essential Principles is likewise a requirement, providing assurance that the manufacturer is meeting appropriate standards for quality in the design and manufacture of its IVD.
RA/CAB responsibility: Review for compliance with the Essential Principles is a necessity for three of the four risk classes.
| ASSESSMENT OF POST-MARKET SURVEILLANCE ACCORDING TO RISK CLASSIFICATION | ||
| Class | Manufacturer's responsibility | RA/CAB responsibility |
| A | Prepare, sign and maintain. | On file with the manufacturer; available upon request. |
| B | Prepare, sign and maintain. | Review and verify compliance with requirements. |
| C | Prepare, sign and maintain. | Review and verify compliance with requirements. |
| D | Prepare, sign and maintain. | Review and verify compliance with requirements. |
Registration of manufacturers and their devices
Registration of manufacturers and their devices is viewed as a basic regulatory requirement for any IVD and therefore it is necessary that the manufacturer registers as appropriate for the regulatory system and that the regulatory authority/conformity assessment body maintains the registry and verifies registration as appropriate.
| ASSESSMENT OF POST-MARKET SURVEILLANCE ACCORDING TO RISK CLASSIFICATION | ||
| Class | Manufacturer's responsibility | RA/CAB responsibility |
| A | Perform according to regulatory requirements. | Maintain and verify as appropriate.. |
| B | Perform according to regulatory requirements. | Maintain and verify as appropriate.. |
| C | Perform according to regulatory requirements. | Maintain and verify as appropriate.. |
| D | Perform according to regulatory requirements. | Maintain and verify as appropriate.. |
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.
Rule 1: IVD medical devices intended for the following purposes are classified as Class D:
- Devices intended to be used to detect the presence of, or exposure to, a transmissible agent in blood, blood components, blood derivatives, cells, tissues or organs in order to assess their suitability for transfusion or transplantation.
- Devices intended to be used to detect the presence of, or exposure to, a transmissible agent that causes a life-threatening, often incurable, disease with a high risk of propagation.
Rationale: The application of this rule as defined above should be in accordance with the rationale that follows: Devices in this class are intended to be used to ensure the safety of blood and blood components for transfusion and/or cells, tissues and organs for transplantation. In most cases, the result of the test is the major determinant as to whether the donation/product will be used. Serious diseases are those that result in death or long-term disability, that are often incurable or require major therapeutic interventions and where an accurate diagnosis is vital to mitigate the public health impact of the condition. Examples: Tests to detect infection by HIV, hepatitis C (HCV), hepatitis B (HBV), human T-lymphotropic virus. This rule applies to first-line assays, confirmatory assays and supplemental assays.
Rule 2: IVD medical devices intended to be used for blood grouping, or tissue typing to ensure the immunological compatibility of blood, blood components, cells, tissue or organs that are intended for transfusion or transplantation, are classified as Class C, except for ABO system [A (ABO1), B (ABO2), AB (ABO3)], rhesus system [RH1 (D), RH2 (C), RH3 (E), RH4 (c), RH5 (e)], Kell system [Kel1 (K)], Kidd system [JK1 (Jka), JK2 (Jkb)] and Duffy system [FY1 (Fya), FY2 (Fyb)] determinations which are classified as Class D.
Rationale: The application of this rule as defined above should be in accordance with the rationale for this rule which is as follows: A high individual risk, where an erroneous result would put the patient in an imminent life-threatening situation places the device into Class D. The rule divides blood grouping devices into two subsets, Class C or D, depending on the nature of the blood group antigen the IVD medical device is designed to detect, and its importance in a transfusion setting. Examples: human leukocyte antigen, Duffy system (other Duffy systems except those listed in the rule as Class D are in Class C).
Rule 3: IVD medical devices are classified as Class C if they are intended for use.
- In detecting the presence of, or exposure to, a sexually transmitted agent. Examples: Sexually transmitted diseases, such as Chlamydia trachomatis, Neisseria gonorrhoeae.
- In detecting the presence in cerebrospinal fluid or blood of an infectious agent with a risk of limited propagation. Examples: Neisseria meningitidis or Cryptococcus neoformans.
- In detecting the presence of an infectious agent where there is a significant risk that an erroneous result would cause death or severe disability to the individual or fetus being tested. Examples: diagnostic assay for cytomegalovirus (CMV), Chlamydia pneumoniae, methycillin-resistant Staphylococcus aureus.
- In pre-natal screening of women in order to determine their immune status towards transmissible agents. Examples: Immune status tests for rubella or toxoplasmosis.
- In determining infective disease status or immune status, and where there is a risk that an erroneous result will lead to a patient management decision resulting in an imminent life-threatening situation for the patient. Examples: enteroviruses, CMV and herpes simple virus in transplant patients.
- In screening for selection of patients for selective therapy and management, or for or for disease staging, or in the diagnosis of cancer. Example: personalized medicine. Note: Those IVD medical devices where the therapy decision would usually be made only after further investigation and those used for monitoring would fall into class B under rule 6.
- In human genetic testing. Examples: Huntington’s Disease, cystic fibrosis.
- To monitor levels of medicines, substances or biological components, when there is a risk that an erroneous result will lead to a patient management decision resulting in an immediate life-threatening situation for the patient. Examples: cardiac markers, cyclosporin, prothrombin time-testing.
- In the management of patients suffering from a life-threatening infectious disease. Examples: HCV viral load, HIV viral load and HIV and HCV geno- and subtyping.
- In screening for congenital disorders in the foetus. Examples: spina bifida or Down's syndrome.
Rationale: The application of this rule as defined above should be in accordance with the rationale for this rule which is as follows: Devices in this class present a moderate public health risk, or a high individual risk, where an erroneous result would put the patient in an imminent life-threatening situation, or would have a major negative impact on outcome. The devices provide the critical, or sole, determinant for the correct diagnosis. They may also present a high individual risk because of the stress and anxiety resulting from the information and the nature of the possible follow-up measures.
Rule 4: IVD medical devices intended for self-testing are classified as Class C, except those devices from which the result is not determining a medically critical status, or is preliminary and requires follow-up with the appropriate laboratory test in which case they are Class B. IVD medical devices intended for blood gases and blood glucose determinations for near-patient testing would be Class C. Other IVD medical devices that are intended for near-patient should be classified in their own right using the classification rules.
Rationale: The application of this rule as defined above should be in accordance with the rationale for this rule which is as follows: In general, these devices are used by individuals with no technical expertise and thus the labelling and instructions for use are critical to the proper outcome of the test. Example for self-testing class C: blood glucose monitoring, Example for self-testing class B: pregnancy self-test, fertility testing, urine test-strips.
Rule 5: The following IVD medical devices are classified as Class A:
- Reagents or other articles which possess specific characteristics, intended by the manufacturer to make them suitable for IVD procedures related to a specific examination.
- Instruments intended by the manufacturer specifically to be used for in vitro diagnostic procedures.
- Specimen receptacles.
Note: Any product for general laboratory use not manufactured, sold or represented for use in specified IVD applications are not deemed to be IVD medical devices, as defined in this document. However, in certain jurisdictions products for general laboratory use are considered to be IVD medical devices.
Rationale: The application of this rule as defined above should be in accordance with the rationale for this rule which is as follows: These devices present a low individual risk and no or minimal public health risk. Examples: selective/differential microbiological media (excluding the dehydrated powders which are considered not to be a finished IVD medical device), identification kits for cultured microorganisms, wash solutions, instruments and plain urine cup.
Note 1: In certain jurisdictions there may be differences as to whether a device classified in this rule is considered an IVD medical device.
Note 2: The performance of software or an instrument that is specifically required to perform a particular test will be assessed at the same time as the test kit.
Note 3: The interdependence of the instrument and the test methodology prevents the instrument from being assessed separately, even though the instrument itself is still classified as Class A.
Rule 6: IVD medical devices not covered in Rules 1 through 5 are classified as Class B.
Rationale: The application of this rule as defined above should be in accordance with the rationale for this rule which is as follows: These devices present a moderate individual risk as they are not likely to lead to an erroneous result that would cause death or severe disability, have a major negative impact on patient outcome or put the individual in immediate danger. The devices give results that are usually one of several determinants. If the test result is the sole determinant, however, other information is available, such as presenting signs and symptoms or other clinical information which may guide a physician, such that classification into Class B may be justified. Other appropriate controls may also be in place to validate the results. This class also includes those devices that present a low public health risk because they detect infectious agents that are not easily propagated in a population. Examples: blood gases, Helicobacter pylori and physiological markers such as hormones, vitamins, enzymes, metabolic markers, specific immunoglobulin E assays and celiac disease markers.
Rule 7: IVD medical devices that are controls without a quantitative or qualitative assigned value will be classified as Class B.
Rationale: For such controls, the qualitative or quantitative value is assigned by the user and not the manufacturer.
WHO guidance
A risk-based approach for the assessment of in vitro diagnostics (IVDs) (PQDx_152 v1, 13 May 2014)
Global Harmonization Task Force (GHTF)* guidance
GHTF/SG1/N070:2011 Labels and instructions for use of medical devices
GHTF/SG1/N046:2008 Principles of conformity assessment for in vitro diagnostic (IVD) medical devices
GHTF/SG1/N045:2008 Principles of in vitro diagnostic (IVD) medical devices classification
GHTF/SG1/N68:2012 Essential Principles of Safety and Performance of Medical Devices
* 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.
International Organization for Standardization guidance
ISO/IEC Guide 51:2014 Safety aspects – Guidelines for their inclusion in standards