|Regulations & Standards|
Everybody welcomes the adoption of risk-based classification rules based on GHTF guidelines, but too few people realize that this will represent a fundamental change in the way that IVD products are regulated.
The ride started on September 26, 2012, with the publication by the European Commission of the proposed new EU IVD regulation.
So far, nothing much has happened at the official level, but industry has had enough time to attentively read the 143-page document. This led to nascent concerns and an uneasy feeling that some elements of the proposal, if wrongly interpreted and applied, could seriously jeopardize the EU regulatory framework for IVDs that has been in place for a dozen or so years and been quite successful.
This article attempts to highlight industry concerns with a view to raise public awareness and, thus, avoid some of the looming pitfalls.
Everybody welcomes the adoption of risk-based classification rules based on Global Harmonization Task Force (GHTF) guidelines, but still too few people realize that this will represent a fundamental change in the way that IVD products are regulated.1 Under the current IVD directive (98/79/EC), approximately 80% of IVD products are grouped in the self-certification class, while 20% require a premarket third-party intervention of some type, depending on the related conformity assessment procedure.
The new classification rules in the draft IVD regulation will completely reverse these percentages: according to current estimates, only 20% of IVD products will remain in the self-certification category, while a form of third-party premarket intervention will be required for the remaining 80% of products.
This is a fundamental change for the IVD industry that will dramatically raise compliance costs and workloads. For this reason, industry, led by Europe’s diagnostics manufacturers association EDMA, has lobbied aggressively for a five-year transition period.2 The European Commission fully understood this need, coupled with the necessity for manufacturers to have full access to Notified Bodies, which is why a five-year transition period is mentioned in the proposed text. However, it is still not known how the EU Parliament and Council of Ministers will react. Pressed by public concern over health risks, triggered by recent scandals that have nothing to do with IVDs, they may ask for a much shorter transition period and quicker implementation of the more-stringent regulatory framework.
A mad MAID has been unleashed in the text of the proposal. MAID is an acronym for manufacturer, authorized representative, importer, and distributor. It’s mad because the roles and responsibilities of these economic operators are not clearly defined.
The Commission’s attempt to broaden the scope of the proposed IVD regulation to include all economic operators involved in the trade of IVDs is a good initiative. It responds to the limitations of the current 98/79/EC directive that essentially regulates only manufacturers and authorized representatives. While industry welcomes the extension of regulations to importers and distributors, there is considerable confusion on who is who and who is supposed to do what.
Let me offer two examples:
• Rules are rather unclear on how access should be granted to technical documentation for economic operators other than the manufacturer. Anyone can legally buy CE-marked IVDs in a non-EU country and import them into the EU without having any contractual agreement with the manufacturer. This makes the buying entity the “importer,” as defined in the proposed regulation. This importer, thus, is authorized to request and obtain the technical documentation related to the imported products.
• While the situation for an EU-based manufacturer of IVDs is fairly clear, confusion arises when an IVD made outside the European Union is imported. Here, the role of the importer seems to grossly overlap the role of the EU Authorized Representative and the distributor, making it unclear who is really responsible for holding information, making verifications, and so forth. Everyone seems to be responsible for ensuring that the device fully complies with regulatory requirements, that a Declaration Of Conformity is in place, that the device is properly classified, and so forth.
To compound the complexity, more than one importer can be involved. In addition, the proposal seems to be written in such a way as to blur ultimate responsibility for the IVD device between the manufacturer and importer.
The requirement to show clinical evidence for IVDs is not new-it’s in the current IVD directive-but there is a general feeling, particularly among the various EU Competent Authorities, that manufacturers have only focused on proving and documenting the analytical performance of their tests. For this reason, the proposed regulation has a strong focus on the need to prove and demonstrate clinical evidence of the various IVD assays.
Clinical evidence is explained in Chapter VI, Article 47, of the proposal: “The clinical evidence shall include all the information supporting the scientific validity of the analyte, the analytical performance and, where applicable, the clinical performance of the device, as described in Section 1 of Part A of Annex XII.” Manufacturers are required to summarize this data in a “clinical evidence report” referenced in Section 3, Part A, of Annex XII of the proposal.
For clarity on clinical evidence and how it should be documented, industry refers to the work done by SG1 of GHTF.3 These documents have migrated to the International Medical Device Regulators Forum (IMDRF) and can be found on the IMDRF website.
In the opinion of industry, the GHTF documents on clinical evidence represent a good approach to this important subject and should be used as a foundation in the new IVD regulation.
However, there are already signs that some EU Competent Authorities want to include additional requirements. This should be avoided because it will, again, contribute to the deharmonization of the regulatory framework for medical devices on a worldwide basis.
The core of the discussion is the degree to which demonstration of clinical evidence will be pursued by the authorities (either directly or acting on behalf of Notified Bodies) for those countless IVD products that have been on the market for several years for which no formally structured clinical evidence data is readily available.
Another area of concern for industry in the proposed regulation is a stipulation that each device be accompanied with a Declaration of Conformity (DOC), essentially applying the same requirements to the DOC as the instructions for use (IFUs).
IFUs can be provided electronically, so it is hoped that this will apply to DOCs as well, at least for professional-use products. For home-use (self-tests) and point-of-care devices, manufacturers may need to include DOCs translated into multiple languages with each product. This is perceived by industry as a waste of paper that will not increase patient safety but will drive up costs.
It is indisputable that IVDs are fundamentally different from medical devices. The EU Commission recognized this when it diplomatically rejected initial proposals to merge all three EU directives dealing with medical devices into a single regulation.
Nevertheless, some text in the proposed IVD regulation appears to have been carried over from the medical device regulation. Here are some examples.
• The proposed IVD regulation reads: “… when Class A devices are intended for near-patient testing, have a measuring function or are sold sterile, a Notified Body shall verify respectively the aspects related to design.” Although the text seems to refer only to IVDs that provide quantitative assays where metrological traceability of calibration is of primary importance, care should be taken to avoid interpreting this requirement too broadly to encompass practically all IVDs (instruments and reagents).
• IVDs sold as sterile (see above) are rare, if they even exist. Even culture media plates do not carry a sterile claim. This requirement could be applicable to some specimen containers specifically intended for subsequent IVD testing.
• Similarly, a requirement that the single-use status of an IVD device be made explicit on the product label is more relevant to medical devices, where it’s essential to specify whether a device can or cannot be reused. The applicability of this requirement to IVDs should be clarified.
The so-called scrutiny procedure described in Article 42 requires Notified Bodies to notify, via the EU Commission, an Expert Committee (formed by competent members appointed by the various EU health authorities) of manufacturer applications for Class D devices.
This Expert Committee, also defined in the proposed regulation as the Medical Device Committee Group (MDCG), upon the request of a single member, can essentially decide to subject the device to what amounts to a full premarket approval process that will be delegated to EU reference laboratories as described in Article 78.
The official text even defines a maximum length of three to four months for this review process.
This procedure, indeed, could represent a valid measure to strengthen the future EU regulatory framework and, thus, ensure a high level of quality of the approved devices and improved protection for patients. But this is dependent on sparing use of the procedure based on sound science and health-related concerns and with a sprinkling of good-old common sense. If it is applied systematically to the majority of Class D applications, then it would quickly become the slippery slope to a burdensome FDA-like premarket approval process for all high-risk (Class D) IVDs. It could also spiral and affect some Class C devices.
There are no doubts as to the good intentions of the Commission, but this formidable tool could be misused, with dire consequences.
Several other areas require further clarification. These include a clear definition of “interventional studies” and their applicability to typical IVD evaluation studies; the presence of redundant requirements for companion diagnostics; the introduction of a new class of “near-patient tests” with related conformity assessment procedures; and the almost unlimited powers the Commission has bestowed on itself via numerous “implementing or delegated acts.”
We’ve only just begun this ride. The pace of discussions will pick up in January 2013, when Ireland takes its turn presiding over the EU Parliament.
So stay tuned and, perhaps, read the book written by Ray Bradbury, which inspired the title of this article. You may be pleased to find out that, in spite of everything, it has a happy ending.
1. The GHTF classification rules for IVDs are laid down in guidance document GHTF/SG1/N045:2008, titled,“Principles of In Vitro Diagnostic (IVD) Medical Devices Classification,” adopted on Feb. 19, 2008.
2. European (in-vitro) Diagnostic Manufacturer Association. See: www.edma-ivd.eu.
3. Three documents have been developed by the GHTF SG1 IVD subgroup and approved at the GHTF SC meeting on Oct. 30, 2012: SG5/N6:2012, Clinical Evidence for IVD medical devices – Key Definitions and Concepts”; SG5/N7:2012, “Clinical Evidence for IVD medical devices – Scientific Validity Determination and Performance Evaluation”; SG5/N8:2012, “Clinical Evidence for IVD medical devices – Clinical Performance Studies for In Vitro Diagnostic Medical Devices.”
Maurizio Suppo, PhD, is principal consultant at Qarad, Caselle T.s.e., Italy. He can be reached via e-mail at email@example.com.