Newletter March 2012

IVD Updates

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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:  

• Spinal fluid tests and tonsil biopsies to detect particular proteins present with CJD and vCJD;2 
• Genetic testing to determine if family members harbor the gene that causes CJD to run in families;
• MRIs to help determine if there are any physical changes to the brain; and
• Electroencephalograms to help monitor brain electrical activity.

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:

• 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.10

The essential characteristics of an IVD are that:

• They provide information for a medical purpose;
• It may be used alone or in combination with other devices;
• It is used in vitro to examine a specimen that came from a human; and
• The specimen is not reintroduced to the human body.11

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 Include…

• Accessories, if intended to be used with an IVD to perform the intended IVD purpose;
• Specimen receptacles, if intended to be the primary container for the specimens from humans for the purpose of in vitro diagnostic examination;
• Laboratory equipment, as long as it is specifically intended for a particular IVD test;
• IVD kits;
• Microbiological culture media and stains, if specifically intended to give information about a physiological or pathological state about specimens from humans;
• Devices that have intended direct contact with the human body for the purpose of providing information according to the IVDD.12

IVDs Do Not Include…

• Products that are simply labeled “for in vitro diagnostic use;”
• Receptacles into which a specimen is placed during the analytic process (this is general lab equipment);
• Products used to obtain specimens without intended direct contact with the human body;
• Products used to obtain specimens with continuous intended direct contact with the human body (these are Medical Devices under the MDD);
• General laboratory equipment, if it is not intended to be used for a specific IVD test;
• Devices without a medical purpose, such as those involved in biological or chemical warfare or law enforcement.13

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.

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