Regulatory Open Forum

Hello RAPS members, 

I have a question relating to IVDR, ISO 20916 and GHTF/SG5/N7 and the use of a non-CE marked IVD device in a clinical performance study. 

We are developing a novel SaMD IVD product, which we had intended to use a currently CE marked device (the current gold standard) as a comparative method. 
The conversations we have been having with our Scientific Advisory Board is that there is a change to the gold standard for testing on the horizon and some individual labs are moving to use lab developed tests (LDTs) instead of the current gold standard. 

This introduces complexity to us for planning our clinical performance study, as we wouldn't be comparing our device to a CE-marked or FDA approved product, and there is not a huge amount of published literature on the LDT method.  

Reading GHTF/SG5/N7, it says 'for novel tests, it may not be possible to demonstrate trueness since recognized reference materials or a suitable comparative method are not likely to be available. If there are no comparative methods then different approaches can be used (e.g. comparison to some other well-documented method, comparison to the composite reference method).
In the absence of such approaches, a clinical performance study comparing test performance to the current clinical standard practice would be needed.'

Does anyone have experience or guidance for such a situation where a novel test is being compared against a novel LDT? 

I should also confirm, the study would be a non-interventional study, done with left over samples. 

Kind Regards, and thanks in advance for any help that can be provided. 
Alice

------------------------------
Alice Geaney
Belfast
United Kingdom
------------------------------

Hello Alice,

The discussion around your topic may be quite involved for the forum as there are not always clear regulatory pathways and even philosophical discussions around using tests still in "research".  The concept of laboratory developed tests results from looking at genetic markers as evolved significantly with multiple combinations of markers being attributed or potentially attributed to a disease condition or potential disease condition.  Your question about using a LDT as now the gold standard is becoming more common as genetic tools are often more specific than say just presence of antibodies.  The only advice could give in this situation is your test has to stand on its on.  While comparative studies can be done to these novel LDT, the clinical performance of your device needs to support many aspects.  This can be difficult because then what is really the gold standard?  The IVD industry has used this term gold standard as the test methodology which has been used for many years and/or been established as the most analytically correct.  It does not mean this novel LDT is now the gold standard, but there may be quite a lot of research needed showing how the gold standard, this novel LDT, and your device all contribute to the intended purpose of the test.

------------------------------
Richard Vincins ASQ-CQA, MTOPRA, RAC
Vice President Global Regulatory Affairs
------------------------------

Original Message:
Sent: 08-Apr-2022 09:51
From: Alice Geaney
Subject: Non-CE marked device in a clinical performance study - IVDR, ISO 20916 and GHTF/SG5/N7

Hello RAPS members,

I have a question relating to IVDR, ISO 20916 and GHTF/SG5/N7 and the use of a non-CE marked IVD device in a clinical performance study.

We are developing a novel SaMD IVD product, which we had intended to use a currently CE marked device (the current gold standard) as a comparative method.
The conversations we have been having with our Scientific Advisory Board is that there is a change to the gold standard for testing on the horizon and some individual labs are moving to use lab developed tests (LDTs) instead of the current gold standard.

This introduces complexity to us for planning our clinical performance study, as we wouldn't be comparing our device to a CE-marked or FDA approved product, and there is not a huge amount of published literature on the LDT method.

Reading GHTF/SG5/N7, it says 'for novel tests, it may not be possible to demonstrate trueness since recognized reference materials or a suitable comparative method are not likely to be available. If there are no comparative methods then different approaches can be used (e.g. comparison to some other well-documented method, comparison to the composite reference method).
In the absence of such approaches, a clinical performance study comparing test performance to the current clinical standard practice would be needed.'

Does anyone have experience or guidance for such a situation where a novel test is being compared against a novel LDT?

I should also confirm, the study would be a non-interventional study, done with left over samples.

Kind Regards, and thanks in advance for any help that can be provided.
Alice

------------------------------
Alice Geaney
Belfast
United Kingdom
------------------------------

Hi Richard,

Thank you very much for your response - I agree my situation above doesn't present a clear regulatory pathway. I was feeling quite confident with using the current gold standard as a comparison device as there is a lot of use data available and it is currently cited by professional bodies as the standard of care. But, the fun bit of regulatory affairs is such challenging situations present themselves to challenge us. 

I appreciate your point about the device having to stand on its own, and all information I have found to date in standards, blogs, regulatory forums point to the use of the 'current clinical standard practice'. Which is why I am struggling to find a way out of this situation to ease the access to market. 

We have discussed running a parallel study to compare the LDT to the current gold standard and then aim to show equivalence of the current gold standard = LDT  = Our device.
I have two concerns about this route, (1) that regulators may not look favorably on this as the study would be limited to one laboratory, when we are hoping to sell this commercially and (2) actually getting commitment from the lab to publish a paper on the LDT = gold standard test. 

Kind Regards, 
Alice

------------------------------
Alice Geaney
Belfast
United Kingdom
------------------------------

Original Message:
Sent: 11-Apr-2022 01:54
From: Richard Vincins
Subject: Non-CE marked device in a clinical performance study - IVDR, ISO 20916 and GHTF/SG5/N7

Hello Alice,

The discussion around your topic may be quite involved for the forum as there are not always clear regulatory pathways and even philosophical discussions around using tests still in "research".  The concept of laboratory developed tests results from looking at genetic markers as evolved significantly with multiple combinations of markers being attributed or potentially attributed to a disease condition or potential disease condition.  Your question about using a LDT as now the gold standard is becoming more common as genetic tools are often more specific than say just presence of antibodies.  The only advice could give in this situation is your test has to stand on its on.  While comparative studies can be done to these novel LDT, the clinical performance of your device needs to support many aspects.  This can be difficult because then what is really the gold standard?  The IVD industry has used this term gold standard as the test methodology which has been used for many years and/or been established as the most analytically correct.  It does not mean this novel LDT is now the gold standard, but there may be quite a lot of research needed showing how the gold standard, this novel LDT, and your device all contribute to the intended purpose of the test.

------------------------------
Richard Vincins ASQ-CQA, MTOPRA, RAC
Vice President Global Regulatory Affairs

Original Message:
Sent: 08-Apr-2022 09:51
From: Alice Geaney
Subject: Non-CE marked device in a clinical performance study - IVDR, ISO 20916 and GHTF/SG5/N7

Hello RAPS members,

I have a question relating to IVDR, ISO 20916 and GHTF/SG5/N7 and the use of a non-CE marked IVD device in a clinical performance study.

We are developing a novel SaMD IVD product, which we had intended to use a currently CE marked device (the current gold standard) as a comparative method.
The conversations we have been having with our Scientific Advisory Board is that there is a change to the gold standard for testing on the horizon and some individual labs are moving to use lab developed tests (LDTs) instead of the current gold standard.

This introduces complexity to us for planning our clinical performance study, as we wouldn't be comparing our device to a CE-marked or FDA approved product, and there is not a huge amount of published literature on the LDT method.

Reading GHTF/SG5/N7, it says 'for novel tests, it may not be possible to demonstrate trueness since recognized reference materials or a suitable comparative method are not likely to be available. If there are no comparative methods then different approaches can be used (e.g. comparison to some other well-documented method, comparison to the composite reference method).
In the absence of such approaches, a clinical performance study comparing test performance to the current clinical standard practice would be needed.'

Does anyone have experience or guidance for such a situation where a novel test is being compared against a novel LDT?

I should also confirm, the study would be a non-interventional study, done with left over samples.

Kind Regards, and thanks in advance for any help that can be provided.
Alice

------------------------------
Alice Geaney
Belfast
United Kingdom
------------------------------