Evangeline Loh and Sage Farrar09.13.10
Another Fishing Expedition, Charting New IVD Waters
In 2008, the July/August edition of this column reported that the European Commission was fishing for stakeholder feedback on the recast of the Medical Devices Directive.
Two years later, the Commission has “gone fishin’” yet again with a recent questionnaire for public comment on in vitro diagnostic devices.Thus, in order to strike while the iron is hot, we’ll discuss a topic never before covered in Euro News: in vitro diagnostics (IVDs). We’ll provide a brief overview of their governing legislation and upcoming changes, including this second fishing expedition.
IVDs Defined
IVDs are medical devices that are characterized by the In Vitro Diagnostic Devices Directive IVDD 98/79/EC, Article 2(b) as:
“… any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:
• Concerning a physiological or pathological state, or
• Concerning a congenital abnormality, or
• To determine the safety and compatibility with potential recipients, or
• To monitor therapeutic measures…”
Note that an in vitro device, appropriately, no longer is considered an IVD as soon as the device contacts humans (e.g., a needle is a medical device and not an IVD simply because it contacts humans). One issue inherent with some IVDs is that they also are on the border of general lab products. On this, the IVDD stipulates that such products are not IVDs unless, “in view of their characteristics, [they] are specifically intended by their manufacturer to be used for in vitro diagnostic examination.”
MDD is to Medical Devices as IVDD is to IVDs
As commented above, IVD regulations are delineated in IVDD 98/79/EC.
Medical devices must be compliant to the relevant parts of the essential requirements provided in Annex I of the MDD. Similarly, IVDs also must meet the essential requirements of the IVDD.
Annex I’s essential requirements are broken down into two categories: general and design and manufacturing. The second heading, design and manufacturing requirements is further subdivided into: chemical and physical properties, infection and microbial contamination, manufacturing and environmental properties, devices that are instruments or apparatus with a measuring function, protection against radiation, requirements for medical devices connected to or equipped with an energy source, requirements for devices for self-testing, and information supplied by the manufacturer.
Certain standards also can be voluntarily applied to IVDs, including: ISO 13485, ISO 14971, and EN 980, and manufacturers that are compliant to European Norm harmonized standards published in the Official Journal of European Communities are presumed to be compliant with the relevant essential requirements. There also are guidance documents (MEDDEVs) designed to assist IVD manufacturers. As one example, MEDDEV 2.14-3 revision 1 allows manufacturers of IVDs that are not intended for self testing or point-of-care to place their instructions for use online instead of including a paper version with the product itself, a phenomenon known as “e-labeling.”
Classification & Conformity Assessment Procedures
The classification scheme for IVDs is particularly interesting. Devices are categorized into four groups: general IVDs (hereafter self-certified IVDs), self-test IVDs, Annex II List A IVDs and Annex II List B IVDs. As would be expected, the selected conformity assessment route depends on the classification, the details upon which are elaborated in Article 9. As a side note, based upon this classification scheme, it is possible that certain IVDs would be Class III in the United States and self-certified in the European Union.
With the exception of the self-certified IVDs, all IVDs must be reviewed by a notified body. Typically, a manufacturer considers if its devices are delineated in Annex II List A or Annex II List B first.
List A and List B of Annex II
Specific devices are assigned to either one of two lists in Annex II: List A or List B.These products, as discussed in Article 9.2 and 9.3 are subject to further scrutiny. In fact, the conformity assessment procedures for IVDs of List A are listed in Section 9.2 (a) and (b), respectively.Generally, manufacturers apply as their route to Conformity Assessment Annex IV, Full Quality Assurance.
Self-Test IVDs
Self-test devices are those devices used by patients in their home (excluding any self-tests IVDs specified in either List A or List B of Annex II—for example, glucose measuring devices for diabetics, though operated by a lay user in his or her home environment, are found in List B of Annex II and therefore are subject to the conformity assessment route for those products and not that of self-test IVDs). An example of a self-test is a standard
pregnancy test.
Self-test IVDs are subject to the regulatory requirements delineated in Annex III, European Commission Declaration of Conformity, Section 6. In addition to similar requirements outlined above for self-certified IVDs, self-test IVDs also must be reviewed by a notified body. In fact, an application must be made for the examination of the design. Upon review by the notified body, if the self-test is deemed compliant to the relevant provisions of the IVDD, the notified body CE marking certificate will be issued. According to the IVDD, this certificate shall contain “the conclusions of the examination, the conditions of validity, the data needed for identification of the approved design and, where appropriate, a description of the intended purpose of the product.” (Annex III, Section 6.2)
Self-Certified or “General” IVDs
Appropriately named, self-certified IVDs are those for which a manufacturer may self-certify its product, as stipulated in Annex III. In this way, notified body involvement is obviated, and the manufacturer, in self-certifying its product, is attesting that their product conforms to the IVDD. Examples of self-certified IVDs include bacteriological culture media or specimen containers.
Manufacturers of self-certified IVDs, similar to the above classes of IVDs, must prepare technical documentation including details on the product, quality system documentation, design information, drawings and diagrams, results of design calculations and inspections, test reports, performance evaluation data, labels, instruction for use, and results of stability studies, where applicable. However, this documentation is not reviewed by a notified body. Similar to the other classification of IVDs, a manufacturer issues an European Commission Declaration of Conformity, which includes the legal statement that the products are complaint to the IVDD. In addition, the manufacturer must “take necessary measures to ensure that the manufacturing process follows the principles of quality assurance as appropriate for the products manufactured” and maintain an active and current systematic procedure for post-market surveillance. These regulations are described in detail in Annex III.
Obtaining Public Consult
The European Commission recently issued a questionnaire for public comment. The responses garnered from the questionnaire will be taken into consideration when the much anticipated revision to the IVDD is drafted.The questionnaire solicited feedback regarding the following: possible implementation of the Global Harmonization Task Force four-tier, risk-based classification system for IVDs (recently adopted as regulation in Australia); whether the current conformity assessment procedures for IVDs should be modified; the use of common technical specifications for high-risk IVDs; if the specific exemption for “in-house tests” should be lifted, preserved,or modified; whether all genetic tests (and not only those only with a medical purpose) ought to be covered by the revised IVDD; if additional requirements for genetic, point-of-care and near-patient tests should be made; the need, if any, for further clarification or additional requirements regarding clinical evidence, clinical validity, and/or the “notion” of clinical utility (i.e., should demonstration of clinical utility be required?); the possible need for clarification of companion diagnostics; and finally, input on the notion of “conditional CE marking.”
In addition to comments on the specific questions above, the European Commission sought information on the likely socio-economic impact of the possible changes; the impact on the health and safety of patients, healthcare professionals, and other users; the functioning of the internal market; and the competitiveness and innovativeness of the industry, in particular small and medium-sized enterprises.
The European Commission will post comments to the medical device section of its website (barring any requests for confidential comments). And so, the industry waits for the “catch” from the commission’s latest fishing trip.
Evangeline Loh, Ph.D., R.A.C., is vice president of regulatory affairs for Emergo Group, an international consulting firm providing regulatory, quality assurance and distribution consulting services. Emergo has offices in the United States, Europe, Japan, China, Canada, Mexico and Australia. Evangeline can be reached at evangeline@emergogroup.com. Sage Farrar is a regulatory research associate at the Emergo Group.
In 2008, the July/August edition of this column reported that the European Commission was fishing for stakeholder feedback on the recast of the Medical Devices Directive.
Two years later, the Commission has “gone fishin’” yet again with a recent questionnaire for public comment on in vitro diagnostic devices.Thus, in order to strike while the iron is hot, we’ll discuss a topic never before covered in Euro News: in vitro diagnostics (IVDs). We’ll provide a brief overview of their governing legislation and upcoming changes, including this second fishing expedition.
IVDs Defined
IVDs are medical devices that are characterized by the In Vitro Diagnostic Devices Directive IVDD 98/79/EC, Article 2(b) as:
“… any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:
• Concerning a physiological or pathological state, or
• Concerning a congenital abnormality, or
• To determine the safety and compatibility with potential recipients, or
• To monitor therapeutic measures…”
Note that an in vitro device, appropriately, no longer is considered an IVD as soon as the device contacts humans (e.g., a needle is a medical device and not an IVD simply because it contacts humans). One issue inherent with some IVDs is that they also are on the border of general lab products. On this, the IVDD stipulates that such products are not IVDs unless, “in view of their characteristics, [they] are specifically intended by their manufacturer to be used for in vitro diagnostic examination.”
MDD is to Medical Devices as IVDD is to IVDs
As commented above, IVD regulations are delineated in IVDD 98/79/EC.
Medical devices must be compliant to the relevant parts of the essential requirements provided in Annex I of the MDD. Similarly, IVDs also must meet the essential requirements of the IVDD.
Annex I’s essential requirements are broken down into two categories: general and design and manufacturing. The second heading, design and manufacturing requirements is further subdivided into: chemical and physical properties, infection and microbial contamination, manufacturing and environmental properties, devices that are instruments or apparatus with a measuring function, protection against radiation, requirements for medical devices connected to or equipped with an energy source, requirements for devices for self-testing, and information supplied by the manufacturer.
Certain standards also can be voluntarily applied to IVDs, including: ISO 13485, ISO 14971, and EN 980, and manufacturers that are compliant to European Norm harmonized standards published in the Official Journal of European Communities are presumed to be compliant with the relevant essential requirements. There also are guidance documents (MEDDEVs) designed to assist IVD manufacturers. As one example, MEDDEV 2.14-3 revision 1 allows manufacturers of IVDs that are not intended for self testing or point-of-care to place their instructions for use online instead of including a paper version with the product itself, a phenomenon known as “e-labeling.”
Classification & Conformity Assessment Procedures
The classification scheme for IVDs is particularly interesting. Devices are categorized into four groups: general IVDs (hereafter self-certified IVDs), self-test IVDs, Annex II List A IVDs and Annex II List B IVDs. As would be expected, the selected conformity assessment route depends on the classification, the details upon which are elaborated in Article 9. As a side note, based upon this classification scheme, it is possible that certain IVDs would be Class III in the United States and self-certified in the European Union.
With the exception of the self-certified IVDs, all IVDs must be reviewed by a notified body. Typically, a manufacturer considers if its devices are delineated in Annex II List A or Annex II List B first.
List A and List B of Annex II
Specific devices are assigned to either one of two lists in Annex II: List A or List B.These products, as discussed in Article 9.2 and 9.3 are subject to further scrutiny. In fact, the conformity assessment procedures for IVDs of List A are listed in Section 9.2 (a) and (b), respectively.Generally, manufacturers apply as their route to Conformity Assessment Annex IV, Full Quality Assurance.
Self-Test IVDs
Self-test devices are those devices used by patients in their home (excluding any self-tests IVDs specified in either List A or List B of Annex II—for example, glucose measuring devices for diabetics, though operated by a lay user in his or her home environment, are found in List B of Annex II and therefore are subject to the conformity assessment route for those products and not that of self-test IVDs). An example of a self-test is a standard
pregnancy test.
Self-test IVDs are subject to the regulatory requirements delineated in Annex III, European Commission Declaration of Conformity, Section 6. In addition to similar requirements outlined above for self-certified IVDs, self-test IVDs also must be reviewed by a notified body. In fact, an application must be made for the examination of the design. Upon review by the notified body, if the self-test is deemed compliant to the relevant provisions of the IVDD, the notified body CE marking certificate will be issued. According to the IVDD, this certificate shall contain “the conclusions of the examination, the conditions of validity, the data needed for identification of the approved design and, where appropriate, a description of the intended purpose of the product.” (Annex III, Section 6.2)
Self-Certified or “General” IVDs
Appropriately named, self-certified IVDs are those for which a manufacturer may self-certify its product, as stipulated in Annex III. In this way, notified body involvement is obviated, and the manufacturer, in self-certifying its product, is attesting that their product conforms to the IVDD. Examples of self-certified IVDs include bacteriological culture media or specimen containers.
Manufacturers of self-certified IVDs, similar to the above classes of IVDs, must prepare technical documentation including details on the product, quality system documentation, design information, drawings and diagrams, results of design calculations and inspections, test reports, performance evaluation data, labels, instruction for use, and results of stability studies, where applicable. However, this documentation is not reviewed by a notified body. Similar to the other classification of IVDs, a manufacturer issues an European Commission Declaration of Conformity, which includes the legal statement that the products are complaint to the IVDD. In addition, the manufacturer must “take necessary measures to ensure that the manufacturing process follows the principles of quality assurance as appropriate for the products manufactured” and maintain an active and current systematic procedure for post-market surveillance. These regulations are described in detail in Annex III.
Obtaining Public Consult
The European Commission recently issued a questionnaire for public comment. The responses garnered from the questionnaire will be taken into consideration when the much anticipated revision to the IVDD is drafted.The questionnaire solicited feedback regarding the following: possible implementation of the Global Harmonization Task Force four-tier, risk-based classification system for IVDs (recently adopted as regulation in Australia); whether the current conformity assessment procedures for IVDs should be modified; the use of common technical specifications for high-risk IVDs; if the specific exemption for “in-house tests” should be lifted, preserved,or modified; whether all genetic tests (and not only those only with a medical purpose) ought to be covered by the revised IVDD; if additional requirements for genetic, point-of-care and near-patient tests should be made; the need, if any, for further clarification or additional requirements regarding clinical evidence, clinical validity, and/or the “notion” of clinical utility (i.e., should demonstration of clinical utility be required?); the possible need for clarification of companion diagnostics; and finally, input on the notion of “conditional CE marking.”
In addition to comments on the specific questions above, the European Commission sought information on the likely socio-economic impact of the possible changes; the impact on the health and safety of patients, healthcare professionals, and other users; the functioning of the internal market; and the competitiveness and innovativeness of the industry, in particular small and medium-sized enterprises.
The European Commission will post comments to the medical device section of its website (barring any requests for confidential comments). And so, the industry waits for the “catch” from the commission’s latest fishing trip.
Evangeline Loh, Ph.D., R.A.C., is vice president of regulatory affairs for Emergo Group, an international consulting firm providing regulatory, quality assurance and distribution consulting services. Emergo has offices in the United States, Europe, Japan, China, Canada, Mexico and Australia. Evangeline can be reached at evangeline@emergogroup.com. Sage Farrar is a regulatory research associate at the Emergo Group.