Jeffrey Seidman: Thanks for having me here today.
I’m a pathologist; I’ve been at the FDA OIR for three years, and today I’m going
to try to help you understand when you need an IDE, how do you know when you need an IDE.
I think the rules for that are relatively simple.
Sometimes they’re easy to apply, sometimes they’re not, and we’ll get into that.
From our code of federal regulations, a significant-risk device is defined as an investigational device
that -- and we -- for in vitro diagnostic devices, we use really parts three and four
of this definition.
It’s for use of substantial importance in diagnosing, curing, mitigating, or treating
disease, or otherwise preventing impairment of human health, and presents a potential
for serious risk to the health, safety, or welfare of a subject, or otherwise presents
a potential for serious risk to the health, safety, or welfare of the subject.
Now, there are different types of devices, and we want to make a clear distinction between
in vitro diagnostic devices, which is what we deal with and what we’re talking about
today, versus implanted devices.
In an implanted device, it’s very simple; if you have a prosthetic heart valve, the
risk of the trial is the same as the risk of the device.
It’s very easy.
It’s different for in vitro diagnostic devices.
The risk of the trial depends on how the information generated by the device is used.
There’s a distinction that doesn’t really have to be made between the device and the
trial because the determination is really based on both.
The risk determination question for in vitro diagnostic devices is what is the risk of
the use of this device in this specific trial?
The use of the identical device, one device, can be either significant risk or non-significant
risk, depending on how it’s used in the trial.
And you can have two trials using the same device; one would be an SR trial, the other
would be an NSR trial.
I want to bring up something that Dr. Conn raised earlier.
He mentioned a device master file.
I you show us a device and you give us all possible information about it, we can’t
tell you if it’s SR/NSR unless you tell us how it’s being used in a trial, but if
you’re using a single device in multiple trials, you can make it easier on yourself,
and on us, if you submit a device master file.
Then, trial by trial, if you need an IDE for a trial, you can send in that IDE and reference
the analytical validation data in the master file.
That’s just one way of sort of simplifying the process if you’re in that situation.
Now, I’m a pathologist, as I said; I deal with mainly with companion diagnostic devices
for oncology trials.
I’m not a molecular biologist, but the general principles that I’m going to give you in
these oncology and drug examples -- the same general principles apply to genomics devices.
We use the same rules.
There may be some finer points that some of the other people today can get into, but I’m
going to give you the basic rules that we use in the oncology trials, and there are
basically four key questions with respect to risk.
First, will the results from the device be used for enrollment?
Second, will the results from the device cause patients to forego known effective or proved
therapy?
Third, will the results from the device cause patients to be subjected to unacceptable toxicities?
And, fourth, will the results from the device cause patients to undergo a potentially high-risk
biopsy?
There’s one additional question that we usually don’t have to address because there’s
usually not enough data from drug trials, but sometimes there is.
Based on available data, is there a known biomarker effect with respect to either toxicity
or effectiveness?
If there is a known effect, then the use of the device could be a risk by increasing toxicity
or diverting a patient from more effective therapy.
There are certain things that we don’t consider at all in a risk determination.
We don’t consider benefit; we only look at risk.
As David indicated earlier, in the evaluation of an IDE we do look at risk and benefit,
but the question of whether you need an IDE, potential benefit is not a part of that equation;
it’s only risk.
Another thing we don’t consider is the number of patients at risk.
If you have a trial with three patients in it, it’s not NSR just because you have three
patients.
We undergo the same decision-making process regardless of the number of patients in the
trial.
Incorrect exclusion from a trial would not be considered a risk because we would expect
management of that patient to revert to standard of care.
So what do you need for a risk determination for an in vitro diagnostic device?
Well, we like to see a complete clinical trial protocol.
This would, of course, include the inclusion and exclusion criteria, proposed interventions
based on the device, how is the in vitro diagnostic device used to make decisions about treatment
or enrollment.
We like a general understanding of the device and sampling requirements.
Now, I have a black box here, and I use that black box intentionally.
When I downloaded this presentation last night onto my iPhone, this box was green; I’m
glad that it’s black right now.
But you know, it’s a black box because we -- you know, the truth is we don’t really
look much at the details of the device in this risk determination; we look at the device
output and how the information is being used.
Very simply, a device will give you, say, a marker negative or a marker positive result.
If that result is used for enrollment or arm assignment or stratification or other purposes,
that will determine the level of risk and whether the study is significant or nonsignificant
risk.
The most -- the simplest example of an NSR trial is a device where the output is used
purely for exploratory purposes.
The information is not being used to drive anything -- is not being used to put patients
in a particular arm of the trial or drug treatment.
So if it’s purely for exploratory, most likely a trial like that would be an NSR trial.
Now, if the device output is used as a criterion of enrollment, then the device exposes the
patient to all the risks of being in the trial, and these risks could include the foregoing
of known effective therapy, drug toxicities, or new biopsies performed solely for trial
purposes.
A trial might be stratified using known or suspected prognostic indicators; for example,
age, gender, or smoking history.
And if the device output is used purely for stratification within trial arms, then this
would not change the risks to which the patient is exposed, and that would generally be an
NSR trial.
However, sometimes you have, for example, a trial where subjects are accrued without
respect to device results until, let’s say, 50 marker negatives are enrolled and, subsequent
to that point, only marker positives will be enrolled.
The determination with that would be the same as a marker-based enrollment and that would
determine -- the risk of that would be determined by what happens to the patient based on the
test.
So let’s say you have a trial where a patient -- everybody’s enrolled, but Arm A you put
marker positives; in Arm B you have marker negatives.
Well, this would be an NSR trial, but only if there’s equipoise, i.e., if the arms
are both equal or of unknown risk.
And that’s sometimes true, but it’s often not true.
For example, if you have Arm A and Arm B where Arm A is an experimental agent and Arm B’s
patients get standard of care treatment which is known to be effective, anybody who’s
enrolled in Arm A is going to forego known effective therapy, therefore an incorrect
test result will potentially deprive a patient of alternative effective therapy, and this
would generally be classified as a significant risk trial.
Now, the experimental agent might prove to be better than the standard of care, but it
might be worse; we just don’t know.
So it’s clearly a risk.
Now, there’s a situation where sometimes everybody in a trial gets standard of care,
but the experimental agent is an add-on to standard of care, and in many situations we
consider this nonsignificant risk because everybody’s getting standard of care, but
there is an exception to this with regard to drug trials.
There are some situations where -- there’s usually not a lot of information available
about toxicity of experimental drugs, but sometimes we have enough information to know
that an agent is particularly toxic, or more toxic than what the patient would have otherwise
received.
An arm -- a study where everybody gets standard of care but in one arm the experimental agent
has expected severe toxicity, if the arms are divided by marker positive/marker negative
-- in other words, if the test determines which arm the patients go into, this would
be an SR trial because the patients would be going -- undergoing added toxicity beyond
that expected with standard of care agents.
Okay, now, I’ve used that phase, standard of care.
We could probably talk all day long about what is standard of care.
In oncology and drug trials, and companion diagnostic devices for those trials, we find
NCCN guidelines very useful.
They’re not carved in stone; we know that standard of care does change, but they are
useful and we use them frequently.
There are two things I’d like to point out about NCCN guidelines.
They do use the phrase “clinical trial” in various parts of the guidelines.
Now, you’ll note that on the bottom of every page of every guideline in every edition you
will see this statement: “Clinical trials; NCCN believes that the best management of
any cancer patient is in a clinical trial.
Participation in clinical trials is especially encouraged.”
Well, that’s fine.
I’m not sure if everybody agrees with this, but this does not affect our risk determination.
This does not mean the trial -- all trials are safe or there’s no risk.
However, elsewhere in the NCCN guidelines appear, for example, for patients with renal
cell carcinoma, if they have Stage IV surgically unresectable renal cell carcinoma, first-line
therapy -- there are several options, one of which is clinical trial.
Now, we take this to mean that there really is no really good therapy that the patient
is going to forego, so -- yeah, okay.
But, again, that’s sort of one of the ways we use the NCCN guidelines.
Okay, biopsy risk.
This is sometimes considered, and can be, a complicated question, but it’s important
to recognize that if enrolled patients in a trial will undergo a biopsy beyond what
would be considered standard of care for the sole purpose of development of the test of
the device, then the risks of the biopsies are attributed to the device.
So, accordingly, a high-risk biopsy in this setting would generally warrant a significant
risk determination.
Now, every patient is different and biopsy risk varies widely, and it depends on a lot
of factors.
These include the site of the procedure, the type of the procedure, patient’s disease
and underlying health, and institutional experience and support capabilities.
In the context of a clinical trial, the biopsy risk is controlled according to the clinical
judgment of the healthcare providers.
Now, just as examples of potentially high-risk biopsies, there’s lung mediastinum, brain,
pancreas.
These are generally sites that you don’t want to biopsy unless you really have to.
Examples of biopsies that are likely low-risk are, for example, skin, endoscopic gastrointestinal
biopsies, and cervix.
Now, we acknowledge that in studies, in these oncology studies of recurrent and end-stage
cancers, the site that will need to be biopsied may not be known in advance, and it generally
is not known in advance when the protocol is written.
But it’s important to keep in mind that a patient on a clinical trial using an investigational
device should not undergo a high-risk biopsy solely for device development unless there’s
an approved IDE.
In summary, it’s not the device that’s high risk; it’s not the trial that’s high
risk.
It depends on the specific use of the device in the specific trial, and, again, the output
of the device -- how the output of the device is used on a -- in the trial.
Thank you.
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