Newletter March 2012
IVDD Revisions To Include vCJD Assay
The specter of BSE (bovine spongiform encephalopathy) and its human counterpart, Variant Creutzfeldt-Jakob disease (vCJD) still looms large in Europe as health authorities still don’t know the extent of the harm reached from outbreaks in the 1980s and 1990s. To properly monitor and potentially stop the spread of the disease from other healthy populations, the European Commission recently amended the IVD Directive to include vCJD assays in Annex II List A. This will allow the assays to have an appropriate pre-market control system in place, so authorities can better monitor and research the fatal disease that is poised to plague Europe for decades to come.
Variant Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob disease is a degenerative neurological disorder that can be transmitting through one of three ways: spontaneously, genetically, or via contaminated blood or tissue. It is a prion disease, or a disease caused by a protein as opposed to bacteria or a virus. According to the Merck Manual, a prion disease is one that is usually characterized by a “progressive deterioration of mental function, leading to dementia…and staggering when walking.” Prion diseases, like CJD, are difficult to track and prevent because until recently there were no tests to confirm a diagnosis before an autopsy. CJD usually manifests spontaneously or genetically in people who are middle-aged or the elderly, and can have an incubation period of months to decades.
CJD that is transmitted via contamination, or vCJD, can affect people of all ages but also has the same incubation period. vCJD is easier to prevent because the contamination sources, for the most part, are known: beef infected with BSE processed into cattle feed and packaged meats. However, because of vCJD’s long incubation period, the steps that Europe took in the 1980s and 1990s to prevent new cases of vCJD won’t prevent currently infected people from potentially living with the effect of the disease for a long time. For example, the UK government’s actions to protect its public’s health, such as banning the use of bovine offals and making vCJD a notifiable disease helped to stop new cases of vCJD from forming. However, a report in 2004 stating that vCJD could be transmitted via blood transfusions from someone already infected with vCJD means that there could be many more cases in the next few decades.
Before the use of blood assays for vCJD, doctors relied on various tests combined to help rule out or diagnose vCJD. Even with the blood assays, a definitive diagnosis isn’t always available without a brain autopsy.1 To detect CJD and vCJD, physicians used:
The new blood tests also test for a particular protein but are more accurate at detecting the proteins earlier and even before symptoms manifest themselves. The tests’ inclusion in the IVD Directive will prove to be very important at monitoring the spread of the disease and potentially stopping new and preventable cases.
Annex II List A – Directive 98/79/EC - Why vCJD is here
In Vitro Diagnostic devices, or IVDs, are medical devices that are used to test for diseases and monitor a patient’s vital statistics. While the Directive includes ways for all IVDs to receive CE Marking to be sold in Europe, it specifies two groups of IVDs for special treatment. These groups are included in Annex II of the IVD Directive, broken up into two lists. The lists correspond to the risk of the disease for which the IVD tests to humans. For example, List A devices include tests to determine blood type, detect HIV 1 and 2, HTLV I and II, and Hepatitis B, C, and D. List B devices include tests to detect congenital and human infections like rubella and chlamydia, measuring blood sugar, and other important markers. The vCJD assays are added to List A of Annex II,3 highlighting the risk of the disease and the importance of the test for future generations. The Common Technical Specifications take into account the state of the art and the current scientific knowledge on vCJD, and are listed in the Commission Decision.4
Additionally, the European Commission issued a MEDDEV that gives guidance on how the assays can meet the minimum performance requirements of the Directive.5 The guidance document is specific to blood assays for abnormal PrP in human blood plasma. Little is known about vCJD and as a result, there are very few samples that manufacturers can use to test their assay’s performance. As a result, the guidance document states that it is almost impossible for a manufacturer to meet the IVDD’s minimum performance requirement. This is also because the blood infectivity level is unknown, so the guidance document states that a requirement of the highest sensitivity is unreasonable. Instead, the document sets a minimum acceptable requirement for assays to meet. The guidance document also gives direction as to the sample size that manufacturers should use and the actual samples, especially when not enough human samples are available.
Because the vCJD assays are included in Annex II List A, the IVD Directive states that a manufacturer must receive approval via an Annex IV Full Quality Assurance system or a combination of an Annex V EC Type-Examination and an Annex VII Production Quality Assurance. LNE/G-MED’s IVD experts guide IVD manufacturers to their device’s CE marking every day, helping manufacturers to ensure the public’s health through diagnosing and monitoring the various diseases. As a Notified Body able to provide guidance and certification to all European Directives, including the IVD Directive, LNE/G-MED can help bring your IVD device to market ensuring it is poised to join in the fight against diseases. For more information on how LNE/G-MED can help, contact us.
Guidance on IVD Definition Issues Released
One question that many manufacturers ask when they ask for LNE/G-MED’s services is whether or not their device is actually a “Medical Device” under the definition of the MDD.6 Defining whether or not a device is a Medical Device is important because the definition also defines the regulatory scheme the manufacturer must follow to sell their product in Europe. Likewise, many manufacturers have questions about whether or not their IVD is actually an IVD as defined by the IVD Directive.7 After determining if their IVD is an IVD, manufacturers must then determine their IVD’s class. In response to these two conundrums, the European Commission issued a Guidance Document8 to help explain the borderline cases of when an IVD is actually an IVD, and clarify the IVD classification system.
What is an IVD?
According to the IVDD9, an IVD is:
…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:
The essential characteristics of an IVD are that:
In short, the manufacturer must both intend the device to be an IVD and the IVD must be a medical device.
While the definition may seem comprehensive, borderline cases where the question of whether or not the device meets the IVDD definition still exist. The Guidance Document delineates some of those borderline cases and spells out which are IVDs and which are not.
IVDs Do Not Include…
Determining which regulatory scheme a device should follow is a key decision that a medical device manufacturer must make. Products that could fit either definitions in the IVDD or the MDD are borderline cases in which manufacturers had to make a hard choice without much guidance. However, with the MEDDEV Guidance Document, manufacturers should have an easier job in determining which regulatory scheme to which their device must conform. LNE/G-MED has IVD-dedicated project managers that can point manufacturers down the right path when determining their product’s regulations. For more information on how LNE/G-MED can help, contact us.
3COMMISSION DIRECTIVE 2011/100/EU of 20 December 2011 amending Directive 98/79/EC of the European Parliament and of the Council on in-vitro diagnostic medical devices.
4COMMISSION DECISION of 20 December 2011 amending Decision 2002/364/EC on common technical specifications for in vitro diagnostic medical devices.
5MEDDEV 2.14/4 January 2012
8Guidelines on Medical Devices: IVD Medical Device Borderline and Classification Issues: A Guide for Manufacturers and Notified Bodies, MEDDEV 2.14/1 revision 2, January 2012.
10Id. at Art. 1(2)(b).
11MEDDEV 2.14/1 revision 2, p. 5.
12MEDDEV 2.14/1 revision 2.
13MEDDEV 2.14/1 revision 2.
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