Natural History Studies for Rare Diseases - Lake Harding Association

Natural History Studies for Rare Diseases

By Micah Moen 0 Comment March 26, 2020

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
>. 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
. 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.

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