My name is Gayatri Rao
and I'm the Director for
the Office of Orphan
Products Development at
FDA.
My office's mission is to
promote the development of
products like drugs,
biologics, devices, and
medical foods for patients
with rare diseases.
One very common stumbling
block in rare disease drug
development is that we
don't know enough about
the natural history of
the rare disease being
studied.
Without having a solid
understanding of how a
disease progresses and
what the disease's natural
clinical course is, it
becomes very difficult to
develop a drug and
evaluate whether it is
safe and effective.
Patients and patient
advocacy groups can play a
critical role in
developing this vital
information, because
they're motivated well
organized and have strong
network within the patient
community.
Typically, the only
thing that prevents
organizations like patient
advocacy groups from
conducting a natural
history study is funding.
To help fill this gap, I'm
very excited to announce
that my office will be
launching a new grant
program to fund targeted
rare disease natural
history studies that will
meaningfully inform and
guide product development
for rare diseases, whether
it be the development of
drugs, biologics, devices
or medical foods.
The program is generally
open to all applicants,
including patient advocacy
groups, academicians and
industry.
We plan to fund studies
with the best scientific
merit, which can include
prospective studies,
retrospective studies
and survey type studies.
More information about
this new grant program,
along with contact
information, can be found
on our website at
www.fda.gov/orphan

> .
In conjunction with the
launch of our new natural
history grant program,
we have developed the
following webinar to
provide some basic
information about natural
history studies, what they
are, why they're important
and how you, as a patient
or a patient advocate, can
make a real difference.
Hi, my name is
Richard Klein.
I'm the Director of the
Patient Liaison Program at
the Food and Drug
Administration's Office of
Health and
Constituent Affairs.
Our office is the primary
point of contact for
patients and patient
advocacy organizations.
And it's my pleasure to
be the moderator for this
important discussion on
natural history studies
for rare diseases.
I'm joined in the studio
by Tim Frost, a patient
with Alpha-1 Antitrypsin
Deficiency; Gayle Greene
is a caregiver for
family members with Von
Hippel-Lindau Syndrome;
Dr. Theresa Strong is
Director of the Research
Programs at the Foundation
for Prader-Willi Research,
and from the Food and Drug
Administration Center
for Drug Evaluation and
Research, Dr. Andrew
Mulberg, Deputy Director
of the Division of
Gastroenterology and
Inborn Errors Products,
and Dr. Jonathan
Goldsmith, Associate
Director for the Rare
Diseases Program.
Welcome everyone.
I think probably the best
place to start is the
definition and the
expansion of what is a
natural history study.
Jonathan, probably you're
the best person to answer
that question.
Thanks.
Well, natural history
study is a well-designed,
well-thought out, and
well-planned attempt to
learn about what happens
to people who are affected
by a particular
specific rare disease.
So you try to collect data
that really is obtained
early in the course of the
disease, later on in the
course of the disease
when people may become
symptomatic, when they may
actually progress to have
symptoms and without
intervention they might
get better spontaneously,
they might not get better
or they might die
from a disease.
So a natural history study
is trying to capture
people at all those
different parts of time in
a way that uses uniform
medical terms so that the
information can be used
later on by scientists and
investigators, as well as
by people at the Food and
Drug Administration when
they begin to look at drug
applications, they
can understand this
information.
So is that different
than a patient registry?
Yes, I think it is.
A registry could
be very simple and
straightforward, like for
instance, a list of names
and emails, so that a
stakeholder organization,
a patient advocacy group
that was trying to build
up its organization might
create a registry like
that.
It tells you a lot about
people potentially who are
interested in learning
more about the disease or
being part of a
large organization.
But it doesn't, it doesn't
give you much information
about the disease process.
A lot of registries are
collected from health
records.
And health records are now
broadly available, lots of
electronic mechanics for
us to get data from.
And they're not
necessarily aimed at your
specific rare disease and
the information that we
need to get about your
specific disease.
So registries kind of fall
down in some of these
areas.
Even though they're well
intentioned as a source of
information, they may
not have the kind of
information that really
supports critical
scientific judgments that
have to be made about what
goes on with your disease.
Registries can also be
collected as a part of
clinical care again.
And so a lot of
the information is
fragmentary.
And again, it's not really
a robust scientific
database, which I
think is what clinical
investigators, patient
advocacy groups and
regulators all want out of
having a natural history
study.
So just to try to put it
in some kind of context,
Andrew at FDA, FDA's very
concerned with the outcome
of clinical trials and I
know that natural history
studies would feed into
clinical trial studies.
Can you talk about how
they contribute and how
they set up endpoint
selection, for example?
Sure.
I do want to also
supplement Jonathon's
comments about registries
first, in that there are
some good examples of
registries that have been
developed through clinical
care that have been
standardized that
have been useful to
Dr. Goldsmith's point
about it being useful for
scientific investigations.
And the example, of
course, that comes to mind
is the cystic fibrosis
registry which has been a
prime example, a model
for many, which has used
declaration of clinical
care attributes in a very
standardized way, as Dr.
Goldsmith has pointed
out to be critical and has
been useful for us to be
able to be part of the
drug development process.
With regards to natural
history studies, as you
point out, natural history
studies are an important
component, almost a
prerequisite before a drug
development program should
be initiated for a rare
disease.
A natural history study
is critical to be able to
serve in a
non-interventional way,
provide an understanding
of how that disease
manifests in children,
adults, in the patient
population of interest.
And is critical for
the investigation to
understand how we can
assess the potential
impact of future
therapeutic agents, as you
point out, outcome
assessments are important
to understand how they can
be developed through the
process of what patients
are suffering from.
And that can be gleaned
from a longitudinal
natural history study.
: So we know where rare
diseases, by definition,
really don't have a lot of
patients to work with in
clinical trials.
Can natural history
studies serve as a control
group?
: With the proper
considerations and
understanding of what's
required, a natural
history study can
potentially serve as a
historical control.
But it requires strict
attention to the issues
that Dr. Goldsmith and I
and you have just talked
about, which is the
attention to matching
populations and to
strictly ensuring that the
data collected will be of
value in a statistical and
regulatory sensitive
manner to be served as a
historical control.
: One of the problems with
historical controls is
that the way that the data
was collected and the era
when it was collected may
be quite different from
what contemporary
medicine is all about.
For instance, diagnostics
may have been different 10
or 15 years ago.
Supportive care may be
quite different at that
time - the actual
potential treatment
availabilities - so that a
historical control is not
always the best control
for what's going on.
I would think that the
best way to do a natural
history study is to have
a prospectively planned
trial and to collect
data so that it's
contemporaneous, it's all
collected from the same
people at the same time
when hopefully the
standard of care is pretty
uniform and that it moves
forward in time to see
what the impacts are of
your intervention
potentially or to learn
just what the background
pace of the disease is.
: Theresa, I know that
you've been involved in
these types of studies and
can you talk a little bit
about what the patient
advocacy or patient role
is in recruiting and
retaining people, and how
these studies are
affecting patients who
participate?
: Yeah, I think it's
important for patients to
be involved in all aspects
of the study and that
helps with recruitment
and retention, because if
patients feel ownership
and they understand how
the study is important to
them, important to people
in the community, I think
in rare diseases we have
some very strong
community.
And so once patients
understand how the data is
going to be used, why it's
so important, why it's
important as you're
planning drug
interventions, even if
there's not a drug on the
horizon, how getting that
information will help
develop good clinical
trials and allow those
trials to go more
efficiently, then I think
people are very motivated.
I think we have to keep in
mind though, that even in
a very motivated
population, a population
that's committed to seeing
research moving forward in
many rare diseases,
families are overwhelmed
with the consequences
of the rare diseases.
So they have doctor
visits, they have therapy
visits, they have things
that have to go on at the
school.
So it's important for the
patient advocacy groups to
give them a lot of
opportunities to be
involved, to come back if
they're overwhelmed with
medical things now, maybe
six months from now they
won't be overwhelmed, to
share data with them as we
move along to keep them
engaged and motivated to
see the study through.
: And Tim, I know you've
been a participant in a
natural history study and
so you're very aware of
the role of institutional
review boards in the
conduct and making sure
that people know what
they're getting into.
But there are, I think, in
addition to the importance
of informed consent, there
are things that people
should expect that
are unexpected.
Maybe you can talk a
little bit about your
experience.
Absolutely.
I will first sort of echo
what Theresa said, the
importance of the patient
advocacy groups are
Alpha-1 Antitrypsin
Organization, the Alpha-1
Foundation is very active
in reaching out to
patients to get them
motivated to help them
understand what studies
may be out there to
include natural
history studies.
Among the benefits that we
all see, particularly in
my disease, is the role of
the basic science that had
been done for Alpha-1
Antitrypsin lung disease
and many people to include
working with NIH and FDA
in the 80s, resulted in
therapies and successful
therapies to stabilize
our lung disease.
Now we're all being called
upon to look at the
Alpha-1 Antitrypsin
liver disease to help
researchers understand, as
Dr. Mulberg said, what are
the mechanisms in this
disease, how do we
understand disease
progression?
So I'm involved in a five
year natural history study
to look at the progression
of disease over five
years.
And when you, Richard,
when you talk about
unexpected, that's very
important for patients
going into a natural
history study.
It starts with simple
things like how much
paperwork, how many forms,
how many questionnaires,
how much research do you
have to do to understand
your family history?
Is the center close
to home or not?
Do I have to travel?
Is that travel going
to be reimbursed?
Will I have to stay
longer than expected?
You have to socialize all
of these kinds of things
with the natural history
study coordinator and with
the principle
investigator.
In my case, I actually had
a complication, in the
part of the first year of
the study was to have a
liver biopsy.
Now I have hyper inflated
lungs, and unfortunately
during the course of the
livery biopsy, my right
lung got punctured, which
then caused me to suffer a
deflated lung.
I didn't know that until I
arrived at home that the
center was in middle
America, I flew home to
Washington, D.C., my home,
and when I got back to the
ground, I realized that
I was having a hard time
breathing.
But the benefits of these
studies are very great.
In fact, even for me as
a patient, one of the
conditions of this study
is the patient gets all
the results back.
So I am taking those
results to my medical
community so they have
that data to help them as
they work with me.
And then in my case, I
reported back to the study
my situation, shared with
them the data that I got
from the hospital, so they
now have included that as
an adverse result of their
work and have put in
protocols that will
be attentive to the
possibility of a
pneumothorax being
created.
So they've taken that back
into the feedback for the
study.
: It was interesting for
me to hear about the
natural history study
that you're in, because I
mostly fill out forms and
surveys for my husband and
daughter.
I do a lot of it online,
most of it online.
And, you know, biopsies,
doctor visits, as part of
the study are not
something that we're
accustomed to,
just lots of forms.
And I'd say that for us,
the most complicated part
so far has been trying
to get films or CDs over
images, you know, to
be part of the study.
That's been the
hardest part.
Maybe in the future,
there might be, you know,
tissues or something like
that that become part of
the study.
But right now, we haven't
had to make special trips.
And we've been talking
about natural history
studies as if they're a
single animal, but I guess
there are different types
of natural history studies
that are appropriate for
different purposes and
different places.
Can we talk a little bit
about the differences in
the types of studies
and when they're most
appropriate?
: When you think about
different kinds of natural
history studies, I don't
know if we emphasized this
enough, but there's
basically, there are kind
of three ways to do it.
You can do a prospective
study, you can do a
retrospective study, or
you can do what I think of
as a snapshot study.
So a prospective study
is one that's formally
organized and begins
to collect data from a
certain point in time.
It goes forward for
whatever the period of
time of collection that
you want to learn about
the natural history,
probably measured in
years.
The retrospective we
talked about in terms of
trying to gather
information that's already
collected, perhaps in
medical charts or other
kinds of documents that
may exist, and to try and
see if that can be used
against the current
standards,
what's going on.
And then the snapshot is
trying to, this is not
what really happens, but
I was thinking you got
everybody with a
particular rare disease in
the room on a given day,
they would be at all
different stages of the
disease, and you would
basically get information
about each of them and
their perception of their
disease and how they feel
and function and survive
with the disease.
And you would get that
information across a whole
group of people and that
would give you some
insights in terms of what
happens over the passage
of time as people are
affected by these rare
diseases, they become
more symptomatic.
But it's not as good as
following an individual
longitudinally, where you
actually know specifically
what happened to that
person at all these
different data points.
: So who actually
conducts these studies?
Who's responsible for
funding them, for
conducting them and
assessing them?
: I know with VHL, our
advocacy group administers
and possesses that data
and funding is an issue
that we talk about
in the group.
We have a real rare
disease, so it's a small
group and fundraising is
something that's difficult
and the administration
does require funds.
But we do it
all ourselves.
So Gayle, you basically
initiated the study and
funded it and
designed it as well?
Right, the VHL Alliance
did that and they continue
to validate the
data as it comes in.
They do that.
Personally I just fill out
the surveys, but the group
does that.
And that's what we've
done with Prader-Willie
Syndrome as well as.
But it does take involving
the experts in the field
and you know, especially
for many rare diseases,
there's many systems that
are affected, so you know
going to the experts
and engaging them and
developing the right
questions to ask is
critical, and looking at
the data as it's coming in
and continuing to refine
is also important.
But funding is an issue
and we, too, have funded
through grassroots
fundraising efforts and
it's just been a priority
for our community to do
that.
But it is always a
challenge to have the
adequate funding.
So as the people who look
at these studies afterward
and use them in assessing
drug applications, do you
find that there's
different styles or
different designs of
studies that work or
don't, or there's missing
information or things that
advocacy organizations
and others who do these
studies should be aware of
prospectively before they
actually begin
designing a study?
First of all, the FDA has
a critical role working
with the companies to help
engage the patient groups
and the academic
physicians involved in the
care of these
children and adults.
Without the engagement of
the academics who are the
experts, I think the
patient groups are not
going to be able to
accomplish the task.
We are very eager to
work with patient groups
through our
patient engagement
responsibilities; also,
with the companies who
have a very important role
to engage the patient
groups.
But ultimately, the burden
of collection of these
data, in my mind and my
opinion, needs to involve
the academics early and
really needs to be a
global effort.
As I think we've talked
about already, these are
diseases that are not just
centered in the United
States, and I would be
curious to understand how
my colleagues in the
patient engagement area
have addressed that
concern about a global
disease that just doesn't
affect, you know, US
children and adults.
But to answer directly
your question, there are
often deficiencies in what
comes to us, not by the
fault of anyone, but it
really becomes an issue at
the stage of when
it's initiated.
Often natural history
studies are not started
early enough in the
process of drug
development, which then
causes companies and
others to expedite often
collection of data that is
necessarily insufficient.
But we thankfully have
wonderful examples in our
legion of drugs that we've
approved that have done it
very well and serve as
very good models for
others to follow.
So natural history
studies, at least the way
I think about it, is
that you should begin to
initiate these very early
in the drug development
process.
You know, a lot of firms
wait until they're ready
to do their definitive -
what's called Phase Three
trial - and then they want
to go out and start to do
this.
Well, it takes a few years
to get together some
natural history data and
they've kind of moved past
the point where they have
the time available to do
these studies.
And that creates
a problem.
If they'll move it back
in the drug development
process once you have
a candidate drug, for
instance, something that
has gone through some
testing by basic
scientists and information
is known about potential
mechanisms of action, the
kind of infrastructure of
science that we look for
for drug development.
At that point in time, I
think that the firm that's
doing the development
or the patient advocacy
group, if they're doing
drug development, because
we're beginning to hear
about that as well, it's
time for them to really
build some bridges from
the developer to the
scientific community.
So they can understand
more about what happens
with this disorder
clinically to different
people.
And if it's not, if it's
not a patient advocacy
group that's actually
doing the work, then
that's the time for the
firm to reach out, to make
connections to the people
who are actually the key
stakeholders in this whole
process, because they'll
be able to help you
understand what's
meaningful to them, what's
clinically meaningful to
patients and families
who are affected by this
disease.
And they'll also be able
to help the firm as they
move into early testing
where they want to recruit
subjects, and they'll be
able to identify people
who are willing to
participate as research
subjects in studies.
And they'll be able to
help in terms of other
ways, in terms of maybe
retention in studies.
Sometimes the resources
from stakeholder groups
can pay for things like
taxi cabs, which sometimes
make a difference, get a
person from Point A across
town to Point B where
the clinical center is.
It's a big deal.
It's hard to do
for some people.
So they can play really
important roles that way.
They can also help think
about trying to keep the
studies as open
as possible.
And just to explain
that a little bit.
When you design a study
you usually have what are
called inclusion and
exclusion criteria -
Inclusion criteria kind
of the people who want to
bring into a trial.
And the exclusion people
you want to keep out,
because maybe they have
other complicated diseases
and it will be hard to
understand what's going on
with the disease that
you're really interested
in.
But a lot of these rare
diseases are very complex.
And to not include really
a broad spectrum of people
who are affected early in
the game, I think, is a
place where the
firms fall down.
They don't really get the
full, the full dimension
of the natural history.
And if they'll pay
attention to that earlier
in the drug development
process, I think that
they'll have a much easier
time of it as they move
through sequential phases
of drug development.
There's a lot in what
Jonathan has offered here
and I do want to comment
on a couple of issues.
One which, to underscore
the criticality of the
initiation of this and the
involvement of the patient
engagement groups that
currently 7,500 or so of
these diseases has been
characterized to some
degree many of them, if
not the greatest majority,
don't have therapeutic
agents targeted to
development of
these diseases.
This is the time that
those physicians involved
in the care of these
children, adults, affected
people, needs
to be initiated.
And not when the time of
a drug is currently in a
vial ready for
human testing.
In, I think our
experience, that's when I
think, as Dr. Goldsmith
has stated, it's often too
late and often results
in trying to expedite
programs without full
understanding of the
breadth of the
heterogeneity of where
these diseases present
themselves differently in
children versus adults.
The issues that are,
you're talking about
drawbacks.
The drawbacks are not
getting started early
enough and of course, I'm
oversimplifying my role
because I'm not paying for
these studies and I'm not
coordinating them, so I'm
not underestimating the
critical importance
of all of that.
But it doesn't lessen to
me the criticality of
doing it now, of getting
things started, and then
when the science comes
to bear and a brilliant
scientist comes and says I
have a drug that I want to
test, we can accomplish
expediting the pathway
eventually, hopefully,
to a drug approval.
And you've asked
for examples.
Well, you know two
examples, and there are
numerous that have used
natural history studies I
think successfully in
historical controls, one
is a life threatening
disorder called Lysosomal
Acid Lipase Deficiency
that can present very
severely to fatal outcomes
in newborns presenting
with swelling of their
body and low proteins and
liver failure.
Babies often will die less
than the first year of
life.
And this is a disease
which is extremely rare,
with a disease prevalence
of less than one in a
million, one in
five million.
Yet, a therapy has
been developed for the
treatment of this disease,
predominantly in the
infant and older child
form, which is much less
severe, called sebelipase
or Kanuma, but for the
historical control
developed for the infant
approval of the indication
relied upon survival
analysis.
And in this case, this was
a fatal disease that there
was ability to identify
a very large number of a
very severely affected
number of infants, of
course we're talking about
a small population, but
was extremely useful for
the approvability of the
indication in infants.
They used historical
control data based on
survival and
growth failure.
So that is to me, one of
the best recent examples
that we've had.
Another recent example
is one for a very rare
disease that causes very
brittle bones in infants
and children and adults
that comes in various
forms.
But understanding how
this disease that affects
brittle bones, called
hypophosphatasia, impacted
the way a child will walk,
was able to be assessed
retrospectively in a large
way to be able to help the
approvability of this
drug, Strensiq, for this
indication.
So these are just two
examples of a slew that we
have been gracefully been
able to approve, not in
our division only, but
in the FDA to develop
treatments for
rare problems.
And it seems that without
that kind of information
that's generated by these
studies, particularly if
they're started early,
it would be very hard to
tease out what the effect
of a proposed drug really
is, because you don't
know what the arc of the
underlying disease
progression would look
like, depending on age,
state of disease, all
kinds of environmental
factors that might impact
them.
So they're very, very
important studies to get
done and to get done
early, so that you have a
basis for assessing the
effect of a proposed drug.
And Gayle, you were
talking about funding and
fund raising and I don't
know if you can talk a
little about what does it
take to get one of these
studies off the ground and
how do you get the funds
to pull it off?
Right, so in our
organization, it was
something that we
talked about for years.
For a long time we talked
about developing a
registry and a natural
history study.
And I think for a while,
we were just too small to
fund it and to have the
manpower to even meet with
other experts to help.
And I think that we got to
a point where we were just
large enough to support
the enterprise and to do
more fund raising.
And it is very grassroots.
It's a grassroots effort
to do the fundraising.
And then we got to a point
where NORD also consulted
with us.
And I wasn't really a part
of that whole process.
But I just knew that I
think it took a point in
our organization where
we were large enough to
support it.
And you mentioned NORD.
I know that NORD and
organizations like NORD,
Genetic Alliance, for
example, do make available
platforms that
organizations can use to
collect and analyze this
information and get you
off the ground I guess.
That helped us start.
But I know there was a
lot of work within the
organization
beyond that, too.
And there continues to be.
There's a lot of
different platforms, and I
think it's really
important for patient
groups to do their
homework about the
different platforms and
the, you know, there's
many very good platforms,
but they are different.
And so depending on the
kind of data that you want
to get, the flexibility
that you need, the level
of support you need,
whether who's going to own
the data, all of these
issues are different
across the different
platforms.
So it is lot of work, but
I think it's, especially
when these things are
initiated by the patient
groups, it's worth going
out there and finding this
information about the
available platforms.
And a lot of times that's
networking with people at
various meetings
through these umbrella
organizations, like NORD
or Genetic Alliances, as
you've mentioned.
But really looking at that
very carefully before you
kind of jump in, it's
really worth that effort.
Right.
And Theresa raised what
I think is a really
interesting point of who
does own that data, how do
you parlay that data with
companies, with FDA?
And the other thing
that came to my mind is
confidentiality.
How do people get assured
of confidentiality,
because they're probably
providing a lot of very
personal and identifiable
information?
And that's where, again,
it's really important to
understand the platforms
because there's different
levels of that and
different levels of
sophistication of that.
And not only to understand
the platforms, but then to
be able to communicate
that back to your patient
community so that
everybody in the community
understands, you know,
what are, how is the data
secured, what level of
protection, those kinds of
issues.
So it's very diverse out
there and people need to
look at that very
carefully, I think and
communicate that well.
In the case of the
Alpha-1 Foundation, we
have a fairly mature
organization and process,
so we do have a medical
committee and a research
committee, so that we're
constantly looking at and
partnering with the
medical community to look
at where are the areas
that we need to put our
research emphasis.
And many of the sort of
Alpha-1 experts across the
country, as Dr. Mulberg
said, the international
aspect of bringing in
Alpha-1 communities from
overseas also into I'll
call the brain trust and
where do we need
to put our money?
And we generally try to
fund, continue to fund
foundational science on
all aspects of Alpha-1
Antitrypsin Deficiency.
What more can we learn
about this disease that
may translate later in
translational therapy.
And then we also look at
where can we put funding
for clinical research to
help develop therapies?
We also have what we call
a philanthropic venture
capital company that also
puts funding, and this is
a for-profit company,
that puts funding into
companies that are
developing potential
therapies that will
benefit the Alpha-1
Antitrypsin community.
So we try to develop,
I'll call it a pallet of
research, and then we use
our national conferences,
we have regional
conferences, our patient
support groups around
the country to encourage
Alpha-1 patients to be
involved in whether it's a
natural history study,
whether it's a clinical
study.
And we have, as both
Gayle and Theresa have
discussed, we have
very motivated patient
communities that want to
participate and want to
participate in the hope
that it may help them, but
on the promise that it
will help also those who
follow; the future
children that are born
with our rare diseases.
How can we help them?
So you mentioned, you
know, collecting this
information and learning
as you go along.
Have you changed the
natural history study as
you've gone to accommodate
things that you're
learning, and are there
places in FDA that patient
advocacy organizations can
go or anybody can go to
get advice on when and how
and whether they should be
doing that?
I don't have an answer to
the question, whether what
we've found has changed
the course of the study
yet, but I think we've
had the first round of
patients.
And that's a really good
question that I would want
to ask the principle
investigator.
After the first round, are
they going to change how
they do things, have they
found results in the first
year interim that
have surprised them?
And does FDA offer advice?
I'm sure Jonathan
can answer this more
completely, but I will
offer that I was curious
as to whether you all have
approached the FDA through
the stages of developing
your registries/natural
history studies to get
counsel and to ensure that
data collection was being
done in the most rigorous
way to kind of preclude
some of the problems that
often face that data are
often collected and then,
unfortunately, without
proper consultation with
us, which I think we, as
a division and I'm sure
throughout the FDA through
the Center for Drug
Evaluation Research for
the divisions that do
manage rare diseases.
I believe I would speak on
their behalf, saying we'd
rather hear from the
patient engagement groups
who are doing this
innovative work early in
the process and offer the
assistance that I know
Dr. Goldsmith can expand
upon, because we want to
prevent problems on data
collection that isn't as
useful as it could be.
Yeah.
I think there are multiple
potential layers for
consultation within
the Food and Drug
Administration.
And so the Rare Diseases
Program that I'm the
Associate Director of
within the Office of New
Drugs, we meet with people
who do drug development,
whether they be from
the corporate side or
sometimes from the
stakeholder side, to try
and help them address some
of these issues early in
the game, to try and
make sure that their
understanding of what's
probably needed down the
road is a good
understanding.
So informal consultations
are always possible.
We also have meetings.
We usually also try and
bring people to these
meetings from the
review divisions.
So if your disease
happens to affect say, a
neurological problem, we
have the people from that
particular product review
division come and they can
speak in that
kind of a format.
FDA has a cooperative
agreement with the
National Organization for
Rare Disorders to use for
NORD, which is what it's
known as, for them to use
their registry platform to
try and create some new
natural history studies
for as many as another 10
or maybe 11 different
disease affected groups.
And they have an
application process
actually that's ongoing
now, but there's this
cooperative agreement was
the result of interactions
between NORD and the
Center for Drug Evaluation
and Research.
Jonathan, can you tell
us a little bit about the
critical path innovation
meetings that FDA has been
holding?
I think this is a very
important kind of
interaction between
the Food and Drug
Administration and
regulated industry that's
been going on for
several years now.
I think it's reached a
fairly mature stage.
These are discussions not
about the development of a
particular drug, but
they're about technology
and science.
But those techniques of
technology and science are
things that actually often
result in new drugs.
They're part of the
infrastructure.
They range from things
like measurement of a
particular substance
in a human, to actually
different classes of
drugs, and they interact
with the human genome
in a certain way.
And it's a chance for
FDA investigators, our
scientists, to speak with
scientists from regulated
industry in a very open
and interactive way,
because sometimes there
are important questions of
a regulatory nature we
need to have answered.
And they actually have the
wherewithal to do that.
And vice versa.
We may have the scientific
basis to answer issues
that they're interested in
that really pertain to the
broad area of drug
development, not to a
particular product at all.
And how do people find
out or initiate those
meetings?
Would they go to the FDA
website, for example?
Office of Translational
Sciences, OTS, within the
Food and Drug
Administration, organizes
those meetings.
And there's a formal
process, there's an
application process
and then there's an
arrangement process.
It's held as a face to
face meeting at the FDA
facilities in Silver
Spring, Maryland.
So Jonathan, can patient
advocacy organizations
access those critical path
innovation meetings to
talk to FDA about
natural history studies?
Yeah, I think that's a
very appropriate use of
the mechanism.
I didn't emphasize
that enough.
But it's certainly an
avenue that people could
explore.
I would encourage the
stakeholder organizations
to seek that out.
We've talked about how
7,500 rare diseases have
been isolated.
Not all of them have
patient advocacy
organizations.
How does a group that
wants to coalesce learn
how to navigate
the FDA labyrinth?
How do we plug into it?
This is probably the fifth
engagement I've had with
FDA.
I have no idea what your
wiring diagram looks like,
how I would find out that
there are these meetings
that I can go to or I can
find someone who can help
review my natural
history study design.
How do I navigate?
What a great question,
because our office, the
Office of Health and
Constituent Affairs, has a
website, which is the
For Patients website at
www.fda.gov
 .
And on that website, we
list all the upcoming
meetings that people
can participate in.
We list the opportunities
for comment.
So not very many people
read the federal register
every day, but actually
we go through the federal
register, pick out things
that are important to
patients, and list them,
so you know when meetings
are coming up and when
public comment is being
sought.
But the office itself is a
point of entry for you to
come in, we're happy to
meet with people, talk
about how FDA is put
together, how it's
arranged and how we can
set meetings up for
patients and advocates to
talk to people at FDA and
learn what's the best
approach for moving
forward.
And we've been using the
FDA as a patient group
several times and
it's always been very
responsive and you know,
we've invited FDA to some
of our meetings and many
have come and it's been
very good.
But it is, we do usually
go through your office.
So from the patient
advocacy perspective, one
of the things I'm
wondering is, you guys
have all had experience
with natural history
studies and are there
pitfalls, challenges,
things that you think
you've encountered along
the way that would be
helpful for people who are
following down that same
path, things that would
smooth the path out a
little bit by not having
to make the same mistakes
that might have been
encountered in never
having done it and trying
to create a natural
history study?
Well, I can comment
from the perspective of
somebody who's provided
data as a caregiver more
than on the
development side.
But it is a time consuming
process to go through as a
patient or caregiver and I
think that if an advocacy
group makes that clear,
but also makes it clear to
patients and caregivers
that they can provide a
little bit of data at a
time, I always like to
say, don't let the great
be the enemy of the good.
You can do a little
bit at a time.
If there's a question
that's difficult to
answer, you can skip
it and come back.
I think that
would be helpful.
I know with our study,
there are follow ups where
you fill out the same
questionnaires at
intervals.
And those questionnaires
are the same
questionnaires you filled
out in the past but they
don't have the information
that you've put in.
And I think they were
designed that way so that
people would not be
tempted not to think about
the questions and
not to update them.
But it's extra time
consuming and frustrating
at times.
So those are the pitfalls
from my perspective, but
I'm not developing
the survey.
We hear that and we've
heard that a lot.
I mean one thing we've
really learned was that
patients are really
committed, our families
are.
But it is really hard and
we want to make it as easy
as easy as it can be for
them, so we want to give
them multiple avenues
to complete these long
surveys, which they're
going to complete.
And not everybody is so
well versed in what a
consent is and
what an assent is.
So our individuals with
PWS oftentimes have
intellectual disabilities
so there's an assent
process in addition
to the consent.
And you know people don't
know that much about that.
And it can be complicated.
So we learned pretty
quickly that we needed
multiple ways to
communicate that to the
families.
So we made a video that
will walk you through the
process of the consent and
assent and registration.
And we have a
downloadable document.
And we set up a Facebook
page, a closed Facebook
page, so people could, if
they wanted to, join it
and then ask questions if
they had questions that
popped up.
And we have webinars
where you can call in.
So we have tried to make
multiple ways for people
to be drawn in, and
encourage them along the
way because sometimes
people, we can, which is
nice, do some of the
surveys, but not all of
them, but then bringing
them back to complete the
surveys is the challenge,
so keeping people
motivated.
So if you put a lot of
thought into that at the
front end, making it as
easy as possible for
people to complete these
natural history studies,
whether they be surveys on
the web or whether they be
going to a clinical place
and doing a trial and get
the patient input on how
to make that as easy.
I think it's a huge plus
for getting things done.
I think that
communication is very
important.
I think having the patient
advocacy organization with
patients work with a
principle investigator in
the design phase is really
important to make sure
that everyone understands
what's needed, how it's
needed, what the impact is
on a patient, rather than
having any particular
party going off into their
own little cubby, but have
everybody looking at that.
Can that questionnaire
be done in a phased way?
Can the clinical work be
done close to home or do
you have to travel
are important issues.
And as I always say,
provide feedback to that
patient, keep them
motivated and even
rewards.
Even if you say, god that
was a really, you really
did a really great job on
that questionnaire, that
was very, very
helpful to us.
So there's a
feedback loop.
So that all of it is
to engage your patient
community to help them
help the principle
investigator have a
successful study, do all
those things that we've
talked about, build that
foundational science and
then be able to take the
next steps into
development of drugs and
therapy.
If we can, as patients,
see that continuum, we
will be highly motivated
and keep that feedback
loop going.
It's very, very important.
One point that has been
brought up to some degree,
but I think is worth
discussing a little bit
more is the
diversity issue.
I think we want a good
representation of our
disorder and we're
thinking of diversity in
all sorts of ways.
So obviously, ethnic
and racial diversity,
socio-economic diversity,
but also age diversity,
because like many rare
diseases disorders in
children is very different
and sometimes opposite of
what it is in adults, so
we want to make sure we're
reaching both parents of
young children who are
often more engaged, and
then parents of older
children who may be a
little bit harder to reach
and then the
entire spectrum.
So kids who are doing
really well may not be as
engaged in the patient
advocacy community because
their kids are
doing really well.
And kids who are doing
really poorly may have so
many medical issues that
they're not as engaged as
well.
So I think from the
patient advocacy group,
it's very important to
keep that in mind as
you're developing these
strategies to reach out
into the population.
Social media's great, but
it really is a skewed
population compared to
your entire patient
population.
So thinking of different
ways to be reaching the
very diverse patient
population, educating
people why it's important
to see the most difficult
cases, as well as the best
case scenario, so that we
can really understand
the full spectrum of the
natural history.
I think Theresa's point is
critical in that we have
to understand the way this
disease presents, both
from the youngest of child
to the eldest of adult.
Without understanding
that, I don't see, at
least from our experience,
that's when the
interpretability of the
data from a certain
discerning drug effect
on an outcome is very
difficult to make and then
trial design becomes even
more important
and critical.
So I think the point
that Theresa, should be
underscored is that
getting as much
information about the
disease, understanding
what it's doing to every
patient that one can
gather, and again, I would
just like to reiterate and
I'm trying to understand
about how patient groups
try to recruit potential
participants in the study,
because that in itself
could be a bias
population.
So I'm curious to know how
you engage, what is your
scope and breadth of
reaching out to your
population?
You know, we took the
low hanging fruit first,
right, through social
media, which is great and
was very effective.
But now we're doing the
harder work which is going
through clinics, going
through local support
groups, you know, reaching
out in ... we're trying
out a bunch of different
ways through residential
homes that specialize with
people with Prader Willi
Syndrome.
So we're in that sort of
phase of just testing out
ways, but we realized
pretty quickly that we
were getting a very, a
wonderful population, but
not a representative
population.
I think finding those
patients who are
asymptomatic is
so important.
What makes that patient
not present those
symptoms?
That may be a pointer
towards therapies or
drugs.
I mean, we have the same
issue with the Alpha-1
liver disease.
Some have it, some don't.
Why don't some of
them not get it?
What are those
biochemical, those genetic
pointers that protect the
one and not the other?
Why are some Alphas
totally asymptomatic?
Have no lung disease,
no liver disease?
Those are the ones that
you also, I want to bottle
that genie.
I want to understand that
and find those people and
those are the ones that
are hardest to find.
One other question that I
had is, do you find it's
difficult to get
people interested in
participating in these
studies given the
challenges that people
face in data entry,
showing up at study sites
at regular intervals?
Is it difficult to get
people to joint those
studies and then retain
people in those studies?
I think it's challenging.
Yes, again as we've
said, there are so many
pressures on a family
that's dealing with a rare
disorder that it's really
important to try to make
it as easy as possible
for those individuals and
communicate back to them
as much as possible.
But even at that, I mean
day to day life sometimes,
you know, can be
overwhelming.
So I think...with these
rare disorders, we're kind
of a family for a long
term so again, having
multiple opportunities for
them to come back and you
know, participate, maybe
they can't participate now
but maybe later,
and keeping those
possibilities open is
really important to
maintaining that.
Yeah, I think about
joining the study though
and I delayed a little bit
including my daughter and
in that case I thought
well, you know, do I want
to do this for her, how's
she going to feel about it
when she's a teenager?
How is she going to feel
about it when she's an
adult?
Now when she turns 18, she
needs to consent on her
own in order for her
information to remain in
that database.
But ultimately and
especially after hearing
you guys talk, she's a
great source of data
because she's young
and she's relatively
asymptomatic
at this point.
And ultimately knowing
that she'd have to consent
herself at 18 and that she
didn't have to keep data
as part of the study if
she didn't want to, I did
include her.
But that was a barrier
for me at first.
And we do try to make,
you know, as much as you
can make it useful for the
patient, so you mentioned,
Tim, you get the data back
that you can share with
your medical team.
For our families, it's
a place to store all of
their medical information
that they can then print
off, you know all the
different specialists
they've seen, they can
print all that information
off and take it to their
general practitioner so
they have a big
picture view.
So we try to make sure
there's some value back to
the patient that will
hopefully be helpful to
keep them engaged as well.
Right.
Our community is motivated
but at the same time, like
in the case of my
study, it's a five year
commitment that you're
going to be in this study
for five years and that
you will continue to have
the kind of testing
that we have.
It's important and it will
hopefully help research
for therapies, but I've
had other colleagues who
have had also adverse
effects and they're going
like, gee, am I going to
go back the second year?
This was scary for me.
That's where the reward,
that's where the feedback
is so important from the
patient advocacy group,
helping make it easy, the
financial issues are some.
I paid about twice as much
as I was reimbursed for
the study that I was at.
I had to travel half way
across the country, stay
in a hotel for a couple
of days, taxi cabs you
mentioned.
But that's where the
reward comes in where the
PI feeds back, where
patient advocacy groups
say thank you to those
patients that are doing
this work, because it's
going to get us closer to
a cure for all of these
7,500 rare diseases that
we have in this country.
When you add all that up,
that's a lot of people
across this country
who are affected.
I think it's been a
terrific discussion.
I hope it adds value to
people who are watching to
understand what natural
history studies are, what
the challenges are,
what the rewards are.
And I think there's a lot
to be said in all of those
areas.
And as always, people
can contact the FDA.
You can contact us through
our website or call our
office, the Office of
Health and Constituent
Affairs.
Thank you all very, very
much for participating.
We hope you found this
program to be useful and
have learned more about
the nuts and bolts of
natural history studies,
what they are, why they're
so critical for
effectively developing
products for rare
diseases, and the
important role that
patients and patient
advocacy groups can play.
By working together to
build a solid scientific
foundation we can greatly
speed the development of
products for the many
millions of rare disease
patients who need them.
Thank you.
