Progress Report: April 2011
Public Consultation on the IVD Directive:
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Broad Support for a Risk-based Classification
by LNE/G-MED North America Team
Should the European regulations governing IVDs be revised to include the adoption of a risk-based classification for In Vitro Diagnostic medical devices?
That’s the message, according to public comments solicited by the European Commission from a varied category of stakeholders, which include: IVD manufacturers, health care providers, regulatory bodies and other industry groups.
Results of the Commission’s "public consultation" on the In Vitro Diagnostic Directive (IVDD), in place since 2003, were released earlier this year. Along with support for a risk-based classification, other measures such as clarifying the requirements for clinical evidence and maintaining exemptions for "in-house" tests received broad support. However, issues such as extending requirements for clinical validity were less popular with manufacturers.
This newsletter summarizes the opinions of those who responded on issues such as conformity assessment routes, batch release verification, conditional CE Marking, companion devices and other study areas, to give manufacturers insight into the likely direction of eventual changes.
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Public Consultation Launched
In June 2010, the European Commission launched a "public consultation" which targeted issues related to in vitro diagnostic medical devices. The EC received 183 responses, from clinical labs, genetic labs, manufacturers, industry associations, competent authorities and notified bodies. LNE/G-MED submitted a joint response in conjunction with other notified bodies. The below summary of results is based on the full 25-page document, which can found in its entirety on the European Commission website.
Adoption of a Risk-based Classification
Stakeholders were nearly unanimous that a risk-based classification would be an improvement of the current system, with 93% agreeing that such a system, if based on the Global Harmonization Task Force (GHTF) model, would allow for better protection of public health, ensure timely access to the market for new tests and allow for more robust technological progress.
Nonetheless, stakeholders expected such a move to increase the costs for regulatory requirements, with more frequent involvement of notified bodies for the conformity assessment procedures, particularly for Class B and C tests. However, those costs were expected to bring about an improvement of safety for public health and could be mitigated by allowing manufacturers a sufficient transitional period, perhaps five years.
Another issue raised by some stakeholders was the fact that the risk-based classification has to be detailed enough to avoid any controversial or inconsistent implementation, which could lead to discrepancies and fragmentation within the internal market.
Conformity Assessment Procedure
In the context of changing to a risk-based classification according to the GHTF model, 75% of respondents agreed that an amendment of the current conformity assessment procedure would be necessary. Some suggested changes include:
- Deleting Annex VI (or limiting it to specific products like IVD instruments), as this conformity assessment procedure is rarely used and does not include an assessment of the vigilance system
- Aligning conformity assessment with the GHTF model. In particular, self-tests could see major changes, including alignment of their assessment procedures to match those applied to Annex II, List B tests (i.e., tests for detection for and quantification in human samples of rubella, toxoplasmosis, etc.)
- Clarifying requirements set up in Annex V (Type Examination)
Pre-market Control of Quality Management System
Near 90% of respondents suggested that a Quality Management System (QMS) should be put in place for IVD medical devices (Class B, C and D) according to the GHTF model and that this QMS should be controlled by a third party (as laid down in GHTF/SG1/N046:2008). In addition, some respondents underlined that the requirements on the QMS should be extended to Class A devices. However, some stakeholders expressed concern that this alone would not be sufficient to ensure the safety of products.
Batch Release Verification
More than 4 out of 5 of respondents expressed the need for batch release testing for high-risks IVDs to ensure consistency between batches and a uniform level of quality for high-risk tests. Other rationales included:
- To ensure compliance of each batch of a high-risk IVD medical device with the Common Technical Specifications set up for tests listed in Annex II, List A of Directive 98/79/EC
- To provide independent evidence that the sensitivity, specificity and quality of each batch of an IVD medical device are acceptable when compared to the original approved assay for the purpose of the granting CE marking
- To prevent low quality batches of high-risks tests to be placed on the market (in this instance, referring to pre-market batch release testing)
While a majority of respondents agree on the general purpose and the benefits of the batch release testing, there are some divergent opinions on how and by whom this batch release verification should be performed.
Many respondents suggested that this verification be performed by the manufacturer, within the quality control and quality management system of the manufacturer, under the control of its notified body, based on a systematic verification or periodic inspections. Manufacturers overwhelmingly pointed to this approach, indicating that internal batch release testing is already performed by manufacturers as an integral part of their QMS, under the supervision of notified bodies for high-risk products, with reference materials and the panels used for this batch release testing approved and controlled by the notified body.
However, a smaller number of respondents suggested the need for a batch release testing to be performed by an independent laboratory or by the notified body. However, manufacturers stressed that this would duplicate their own testing, be too costly and not bring added value in terms of safety and quality.
Common Technical Specifications (CTS)
More than 90% underscored the need to maintain the CTS, at least for tests used in the context of blood transfusion and/or for Class D tests, according the GHTF classification. Although the majority of the respondents were in favor of not extending the CTS to other IVD tests, a few responses stated that it might be beneficial to extend the CTS to tests within Class C.
Maintain the Exemption for "In-house Tests"
Over 85% of respondents want to maintain the exemptions for "in-house tests" – those devices manufactured and used only within the same health institutions as provided for in Article 1(5) of Directive 98/79/EC. Some respondents defended this approach to ensure the availability of specific tests and enable rapid response to changing needs. However, to avoid unfair competition between CE marked IVD devices and in-house tests, various survey participants pointed out the need to better define the exemption and restrict it to situations where no similar commercial IVD devices are available or applicable. Others suggested different approaches: applying the exemptions only to low risk, low volume tests; using similar rules as for custom made medical devices; or restricting these exemptions to specific situations that are kept within strict limits.
In a follow-up question listing potential limitations, a higher number of respondents supported clarifying the definitions related to what constitutes in-house testing, while much less popular were suggestions to require all tests, or even just high-risk ones, to fulfill the essential requirements of Directive 98/79/EC.
The proposal to exempt IVDs intended for diagnosis and monitoring of rare diseases or conditions as defined above was not supported by 69% of the respondents, who pointed to difficulties in this approach such as in cases where there is no commercially available test for infrequent but not rare conditions, cases where there is no commercially available test for a specific condition (e.g. newly identified condition and cases where conditions may be different in the Member States).
The requirements regarding the demonstration of performance for IVDs need to be clarified, according to 90% or stakeholders, who suggest the current requirements on the demonstration of performance are misleading and may be interpreted as being only analytical requirements.
In addition, respondents agreed that the requirements regarding clinical evidence should be more detailed in the Directive and that the Directive should include some requirements on how to demonstrate clinical evidence. A suggestion made by the stakeholders was to better align the requirements on clinical evidence for IVDs to those required for medical devices, by introducing a specific Annex on the requirements on clinical evidence, aligned with Annex X of the Directive 93/42/EEC, with the level of requirements adapted to the different classes of the IVD medical devices. The GHTF is currently working on a guidance document on clinical evidence for IVDs.
Other Topics Addressed
The public consultation covered a wide range of topics related to IVDs. Other findings revealed include:
- Genetic Tests: Extending the IVDD’s scope to genetic tests, including those with direct and indirect medical purposes, proved unpopular with a majority of respondents who cited potential ambiguity. However, 86% supported additional requirements/restrictions for direct to-consumer genetic tests.
- Amending the Definition of "Putting Into Service": More than 4 of 5 respondent want to make it clear that the Directive also covers the in vitro diagnostic medical devices that are not placed on the market but used for the delivery of results within the European Community, such as at an economic operator’s facility.
- "Point of Care" or "Near Patient" IVDs: About 65% saw the need for a specific requirement to ensure that testing conditions provide the same level of clinical sensitivity or specificity as those performed in a lab.
- Tests Used for Diagnostic Services. More than 80% of the respondents were in favor of introducing specific requirements for tests used for diagnostic services, especially when the results of the tests are provided directly to consumers.
- Clinical Validity: Extending the requirements to cover this area is generally supported by 81%, with nearly all feeling that clinical validity should be extended at least to the demonstration of Negative Predictive Value and Positive Predictive Value, which are not clearly mentioned in Directive 98/79/EC. However, few manufacturers supported this position, arguing that validity should be proportional to the risk linked to the use of the IVD medical device and then adapted to the risk-based classification.
- Clinical Utility: Most respondents (67%) expressed a negative view of requiring the demonstration of potential usefulness and added value to the patient management decision-making, mainly raising concerns over how such an evolving concept can be addressed in a regulatory framework, particularly in a pre-market assessment process.
- Conditional CE Marking: About three quarters of respondents consider "conditional CE marking" useful in certain situations, such as pandemics or unmet medical needs. However, some raised concerns that such a policy could allow the marketing of low quality tests, and that article 9(12) of Directive 98/79/EC already addresses emergency situations on a national level.
- Companion IVDs (e.g. Pharmacogenomic Assays, Biomarker Assays): Nearly all respondents said that Companion IVDs, those that are developed and/or used in direct combination with specific medical products or which are co-developed with new medicinal products, must be subject to the IVD Directive, which will ensure an appropriate level of quality and safety. Currently, most companion diagnostics are self-certified by the IVD manufacturer.
At this point, no one can predict the exact changes to the IVD Directive. With the number and scope of significant ideas in the works, IVD manufacturers would be wise to monitor these developments to anticipate how such changes would affect their regulatory routes and quality management system requirements, particularly for new products in development.