>> Elektra Papadopoulos: Hello.
My name is Elektra Papadopoulos, and I work in the Division
of Clinical Outcome Assessments in the
FDA's Office of New Drugs.
And our mission is to promote the development
and implementation of patient-focused
endpoints and medical product development.
And today, I'd like to discuss some of the key considerations
in clinical outcome assessments.
Of course, I'll be expressing my own views,
and not necessarily an official FDA position.
Over the next 15 minutes or so,
I'll discuss some of the regulatory considerations
for clinical outcome assessments for use
in medical product development to
assess the benefit of therapeutics.
And following that, I'll describe some of the ways
that stakeholders can engage with FDA
in development or selection of COAs.
And now, I'll talk a little bit about the role of COAs
in assessing clinical benefit.
Before we go into the details
of measured development and selection,
let's step back and think about the broader context
of what we're trying to do in clinical trials.
Ultimately, we're trying to evaluate clinical benefits.
Meaning to evaluate whether that medical product
has some positive impact on something
that is really important to patients,
such as how long they live
or how they feel or function in daily life.
And so, I'm sharing here the definition of clinical benefit,
which is from the BEST Glossary, and this is a
-- living resource that was developed jointly by the FDA
and the NIH to harmonize on concepts
related to biomarkers, COAs, and other tools.
So, how do we assess clinical benefit?
What are some of the tools that we have in our tool kit?
Well, Dr. Leptak in his presentations
discussed validated surrogate endpoints.
But for the purpose of my presentation
I'll focus on COAs.
COAs are measures that can be reported
by patients themselves, clinicians, or observers.
They can also include other measures,
such as performance outcome measures.
How do we now determine which type of COA
is best for our clinical trial or contact [unintelligible]?
Well, patient-focused drug development
doesn't necessarily mean we must always use CRO assessments.
Rather, it means that we need to think about
what is important to measure in a particular population.
What is really clinically meaningful to clinicians,
to patients, and other stakeholders?
Or what can be potentially modified by a therapeutic
or any type of intervention during a clinical trial.
And then, we can determine how best to measure it
in a particular clinical trial.
It may be that we are interested
in assessing symptoms in that population.
And the population can report for themselves.
But in this case, we reviewed a PRO assessment.
And clinical judgement is required
to interpret an observation
then we turn to a clinician reported outcome.
It is observed -- if the outcome is observable,
and it is in daily life,
then we may select an observer reported outcome.
And this is, in fact, what is very commonly used
when our patients are young children
or in patient populations you can't provide self-report.
And in some cases, a natural demonstration of the defined
task may be appropriate.
And then, we reduce performance outcome measures.
Last but not least, we're also seeing increasing interest
in using digital health technologies
that can possibly collect continuous data from patients
on important functions, such as activity or sleep,
as they go about their daily lives.
So, for reference, this slide shows
the definitions of the different types of COAs
from the current version of the BEST Glossary.
And this resource also includes a discussion of each type,
as well as some examples.
Now, I'd like to talk a little bit more
about clinical benefits.
You can think about clinical benefit
in terms of direct evidence, as well as indirect evidence.
Direct evidence of clinical benefit is derived and studied
with endpoints that measure survival
or how patients feel and function
in their lived experiences.
While indirect evidence of clinical benefit
is derived from studies
with endpoints that measure things other than
that are related to how patients survive, feel, or function.
And so, let's explore this concept a little bit more.
And it might be helpful to think of --
in terms of a continuum of direct
and indirect evidence of clinical benefits.
Depending on how indirect something is,
the more evidence we may need.
So, for example, let's take performance outcome measures,
such as timed walking tests or word recall tests.
These measures are thought to be somewhat indirect
because they are not measuring exactly how a patient
feels or functions in their daily life.
But, instead, they are intended
to closely approximate patient's lived experience.
And with these types of performance measures,
it is critical to really understand
what the performance test is actually measuring,
what that score represents, and what all that means
in terms of meaningful benefit to patients.
Biomarker endpoints that -- which we see on the right side,
are generally considered surrogates for clinical benefit
and are at the far indirect spectrum --
side of the spectrum.
Now, that we have discussed the important role of COAs,
let's talk about the FDA review of COAs.
Why is it important for FDA
to evaluate our outcome assessments?
And this really stems from our direct regulations,
which highlight the need for well-defined
and reliable assessment methods.
In essence, our endpoints and assessment methods
form the basis of labeling claims
which cannot be false or misleading.
Another important consideration is that the measurement
should minimize variability or noise.
And so, that this can be sensitive to true change
in a patient's condition.
So, now that we've discussed the why,
how does the FDA review COAs further adequacy
to support regulatory decision making?
Importantly, FDA evaluates an instrument
in the context of its intended use.
In other words, in its context of use.
And this includes things like the clinical trial
in patient populations where the COAs will be used.
How they will be used,
including whether they will be used to support labeling claims,
and what claims are actually being targeted.
In other words, there is no such thing as an instrument
that has been validated for all purposes.
The FDA PRO Guidance of 2009 describes good measurement
principles that are applicable to all COA types more broadly.
So, let's talk a little bit
about the measurement properties that we review.
We start with content validity, which is defined as the extent
to which the content of an instrument
represents important aspects of what it claims to measure.
That is to say, the concept in that intended use
in patient populations.
This is, of course, key as we want to ensure
that the labeling is accurate
with respect to the concept of measurement
and is not misleading in any way.
Content validity is supported by both qualitative
and quantitative evidence.
Importantly, if content validity evidence is inadequate,
then it's really little reason to test
or consider other measurement properties.
Other measurement properties that we review are shown here.
And these are primarily quantitative in nature.
They include reliability or reproducibility as a measure,
such as test/re-test reliability or inter-rater [phonetic]
reliability, construct validity,
which assesses whether the quantitative associations
with other variables are as expected.
And finally, ability to detect change.
So, what are some of the common COA review issues
that we encounter?
Well, one question that we ask is,
"Was the instrument developed with an -- was the instrument
developed with input from the relevant stakeholders?"
If not, the risk is that it may omit
what is most important and relevant.
It may include irrelevant content.
Or its instructions, questions, and response options
may not be well understood.
And this can lead to noise in measurement,
as well as lack of clarity on what we were actually measuring,
and whether that is in alignment with what is intended.
Some other -- some common COA review issues are shown here.
Is the instrument appropriate
for the study design/patient population or research question?
If not, the risk is that it may be poorly matched
to severity of the patient,
so that the patient may be either
at the low end of the scale or the high end of the scale.
It may not be reliable, valid, or responsive to change.
For example, use of a dexterity test
developed for the general population
wouldn't be appropriate for use in patients
with visual impairment, for example.
It may capture something important to patients,
but not what the drug is targeting.
The other thing is --
are the instrument's concept clear and well-defined?
Is the content reflective of the concept
that we're trying to measure?
And, if not, it may be very difficult or impossible
to accurately describe what is measured in product labeling.
So now I'd like to say a few words
about seeking advice from the FDA.
To meet the challenges of patient-focused
outcome measurements,
and to ensure outcome assessments are fit
for purpose for drug development,
we recommend early complication in close collaboration
with the FDA throughout drug development.
And we have three pathways I'd like to just highlight here
[unintelligible] engagement and the center for drugs.
First, of course, CDER routinely provides advice
within individual drug development programs.
And we encourage drug companies to begin discussions
about their COAs as early as possible in drug development,
including in the pre-IND stage
to ensure there's enough time to [unintelligible]
the COA development and selection
before the phase three clinical studies.
The other two pathways I'm highlighting here
are outside of particular drug development programs.
One is the drug development tool qualification programs
where we can work with stakeholders to create
and qualify COAs, biomarkers,
and other tools that meet on that public health need
and can be used publicly across multiple drug development
programs within the appropriate context of use.
Another pathway is through various meetings,
such as critical path innovation meetings
where stakeholders can have informal discussion
and receive general non-binding feedback
from the FDA on specific methodologies or tools,
including COAs or biomarkers.
And now I'd like to say just a few words
about the drug development tool qualification pathway
for seeking advice.
A drug development tool, or DDT,
is defined in statute of the biomarker,
a COA, or any other method, material, or measure determined
to aid drug development and regulatory review.
The DDT qualification process,
which was initiated approximately 10 years ago now,
is codified as part of 21st century
Cures legislation and the process formalized.
Qualification is simply a regulatory review process
for drug development tools and is completely voluntary.
If a tool has been qualified,
it means that within the stated context of use,
the tool can be relied upon
to have a specific interpretation and application
in drug development and regulatory review.
The program allows us to qualify tools
that will be publicly available for use
in any drug development programs
in the qualified patient population,
and context of use
without necessitating re-review by the agency.
And there are three qualification programs
currently as shown here.
With that, I thank you for your attention.
And I'd like to leave you with some helpful resources.