Haja El Mubarak: Hello, everybody, and thank you for the opportunity
to share some insight about the analytical validation of IDEs. I’ll just jump into
the topic. I’m glad to be here. I -- I actually -- I’m a reviewer at the Division of Microbiology
Devices, so I’ll give a perspective on IDEs which are submitted for infectious diseases.
Typically, when we get IDEs, which is very rare -- I would like to say that most -- the
majority of studies you won’t really need an IDE, but when we get them in the infectious
disease area, this will be for markers, for example, viral or microbial markers which
could help in -- as a prognostic marker, for example, for cancers or for -- or diagnostic
markers. So it’s mostly for those studies that utilize or detect the virus DNA as a
marker for whether it’s saying that this individual has an increased risk of asserting
cancer, for example. So, in my talk today, I’ll just -- these are not genetic testing
that I’m talking about. It’s molecular tests. I’ll quickly walk you through the
analytical studies. I’ll just touch on the principles of an IDE submission and I’ll
talk about the analytical study requirements and wrap up.
As you probably heard in also the previous talks, for a successful IDE submission you
would like to cover these bases; clear and precise intended use, a complete device description,
scientific evidence supporting the intended use, analytical performance, and labeling.
Essentially, what you need to do is show us -- give us enough evidence to help us understand
what your device is and how it does what it’s intended to do. This slide -- I won’t go
into the details of it, but the intended use should cover all these aspects. It should
help us be able to understand the indications; for example, if it’s risk stratification
or aid in diagnosis, clinical context and also to understand what the patient population
is, the different sample type that is used for the essay, and the technology. So, sufficient
information about all these four aspects. This will help us in understanding what kind
of analytical performance is needed.
Device description. Typically, what we would like to see is a principle -- a description
of the principle of the test from the beginning, from the sample all the way to the result,
and also a complete description of the reagents as partial components of the essay itself,
and how the target was selected. Again, this was focused on molecular tests, how you picked
that specific region or that specific gene from the virus that you are testing for. Any
instrumentation involved and the quality control and procedural limitations of your essay.
We would also like to see how the results of the essay are interpreted, like a list
of the possible result categories and the recommended interpretation. For example, for
quantitative tests, if you could define the different levels of the quantitation and their
clinical significance; for qualitative tests, to describe how a positive versus negative
result will be used for patient management, and also equivocal results, if you have that
as part of your essay, and to define any other clinical information required for the test
interpretation and patient management; for example, if your test is not a stand-alone,
like in addition to this test result you need to use this other marker, this additional
test. All this is building a good understanding, and these are the concepts that could be applied
or -- you could apply them to any technology if it increases complexity, changes in technology,
just -- the core is to help us understand what the test is, what does it do, how does
the result -- how is the test result used for patient management.
After that, the analytical studies -- the analytical performance studies are quite,
like, typical. It’s what you do in the lab, so let’s -- if you take how we validate
our essays in the lab to see that a positive result is positive and it’s repeatedly positive.
Essentially, this is the start point, and you could think about, depending on what the
essay is, what the analyte is that you’re looking for, how frequent is it available
in that body compartment or sample type that you’re looking at. You could think about
a level -- a very -- or diverse level of requirements that you could think about; precision, reproducibility,
analytical sensitivity, limit of blank, limit of detection as applicable, linearity, traceability.
And we would work with the information -- also, sample stability, matrix effects, reagent
stability, cross-reactivity, and interference. And what I would like to -- I think I would
like you to take home from here is think about what you do in the lab to evaluate. Think
about all these topics or all these points that I mentioned here as the typical performance
studies that you would do in the lab for you to be comfortable that these performance -- targeted
performances are met. We take what you bring to us and we can tell you if this was enough,
so we’re not going -- in an IDE submission we don’t say you have to test exactly this
number of samples to show us that a nasal swab was stable when it was stored from So-and-so
and you could still detect this. We won’t tell you that for a cross-reactivity you have
to test all these analytes, but we want you to think about all the common agents.
For example, if you’re testing for EBV virus, think about all other herpes viruses that
could be available. If you’re thinking about BK virus and JC virus, if these are two different
viruses that typically would cross-react, then a good study to demonstrate that there’s
no cross-reactivity or if there is cross-reactivity; interference with common medications that
could be found in that sample type; if it’s swab sample, if it’s a respiratory sample,
versus if it’s a skin sample like mucocutaneous or cutaneous sample. And the same applies
for the precision; the analytical sensitivity, the linearity. These need to be addressed
and we could accept or look at different levels of study that are performed on a case by case
basis.
We struggle like you do with determining what is the minimum requirement. However, we all
utilize or go back to the same standards, for example, traceability and commutability
for quantitative methods when there are no reference standards. I put here, and I’m
not going to go into details, but these are all standards that we recognize. Pharmacological
traceability; ISO standards; for linearity, we look at CLSI-EP6; commutability. This is
the definition here for commutability, but due to the time constraint I won’t go into
details; basically, we want to see that you address all these elements of the device performance,
and if there is an available international standard for the analyte that you’re looking
at, we strongly recommend that you do that. We also accept data that’s collected from
different studies. For example, in some cases the labs have performed a harmonization study
where the results of the analyte have been shown to be equivalent and be transferable
to our reference material. You can get sometimes or pull out data to support different studies
from a study that was culled differently in your hands in your lab, so there’s a big
nomenclature gap. But if you send us what you did, we could break it down as well and
discuss [unintelligible] in pre-submission that “I have performance studies that did
this and this, and this and this, and I compared all these aspects, and I was able to find
this material.” It could also be sufficient for us to fill gaps in precision, in reproducibility.
And for standard materials also -- likewise may be different nomenclature, but we struggle
with calibration, hierarchies, sample types, and [unintelligible]. EBV, for example; for
an IDE -- there is no standard material that is available for nasal swab samples, but there’s
a WHO standard which is available, a quantitative standard, for blood samples. So, sample type
is different, and adjusting this standard material to a different sample type is also
a challenge.
The common goal -- our goal is the same. If there is a device that you believe could help
the public or help a specific target patient population to achieve something, then we would
like to do the same thing. We want to get with you to the same spot. A pre-submission
will be a good place to start because we understand that there’s a big, huge gap between labs,
for example, or essays which are developed simply, and what is required for a pre-market
approval of clearance. However, given that common goal, we work together to understand
how the essays perform and share protocols of essays and data that has already been collected,
submissions and so on, papers -- all this could happen in the pre-submission phase for
the IDE, and we strongly encourage that.
I think we have touched on covered the principles of an IDE submission for viral in vitro diagnostic
tests, for example, and talked about the essence of analytical study requirements. I’ve provided
some additional slides which will guide some thinking and might be useful for the participants
to understand more detailed aspects of what’s a device and IDE submissions in general. Thank
you very much.
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