FDA & Drug Development (CFSAC Fall 2012)

Uploaded by USGOVHHS on 10.10.2012

Next topic, the FDA drug development we're pleased an
honored to have rear admiral Sandra Kweder.
And I have to read these because people are not able to watch us
so they are listening. So let me read a little bit
about you so they'll know who you are.
Cover your ears so you don't turn red.
Dr. Kweder graduateed from the university of Connecticut in
and attended the University of North Carolina school of
public health in chapel hill. She was commissiond in the U.S.
public health service in , upon entering the uniform
services university of health sciences.
She was awardd M.D. in , a great year, I graduated the same
year. Along with the Surgeon General's
award for outstanding PHS graduates, she completed
internship and residency in internal medicine at Walter Reed
where she was also chief
resident I share your pain with that as well.
She is certified by the American board of internal medicine,
fellow of the American college of physicians.
In -- sorry, , rear ad Merrill Kweder joind the U.S.
food and drug administration in the division of antiviral drugs
to address HIV drug development. She's since held number of
positions including leadership of the division of post
marketing surveillance an epidemiology in the office of
anti-microbial products and spent two years on sabbatical at
brown university as clinical fellow in obstetric an
consultative medicine. Deputy director office of new
drugs in FDA center for drug evaluation and research since
. I could read on forever.
Most important thing is she would be an acknowledged expert.
We appreciate so much taking the time to come to talk to us today
about FDA drug development. Can you hear me?
Okay. I want to apologize to the
people behind me. I feel funny how people are
looking at my back. Hopefully maybe the slides will
be interesting. We were asked in all of this to
address a couple of questions which I intend to do.
But I want to tell you I have encounterd this condition in
many ways. Over the course of my career.
I encounter several patients who had just what I would consider
for classic cases of chronic fatigue syndrome aqueue onset
when I was in training and in practice.
And since I have been at the FDA, I have periodically worked
with our staff who are trying to look at data for products that
might be used to treat this condition unfortunately they
have been few an far between but I feel like I have seen every
phase of this, this difficult area.
I'm excited to see this group becoming more active, really
taking the bull by the horns and getting progress in this field
an done it in other fields we can do it here today.
It's not something any one agency, research center or group
can do alone. This is complicated stuff.
So with that I'm going to launch into just a very quick -- not
this one? Which is mine okay.
So I one over there and hide it, right?
Okay. Good.
Don't give me too many little gadgets.
I want to give a perspective of FDA.
Terry Michelle represents us beautifully but we are the
largeest regulatory agency in the government, one of the large
agencies in the government. of every dollar is on a
product regulated by FDA. that was before we started to
regulate tobacco. So I don't know how that stacks
up now. Hopefully not too much more.
Probably some more. We are six centers, mostly
Washington area. The people here today, myself
and Dr. My shell in the center for drug evaluation approximate
research, we're not the only ones and I think over time there
are other centers have some interest and expertise to bring
to the conversation about addressing chronic fatigue
syndrome and me, including biologics, at our medical
devices center where we might hope some day to have some
diagnostics that could facilitate work in this area.
We're huge. We have a lot of field offices
as well as our headquarters staff that does policy and
scientific drug review. While we do laboratory work,
unlike what many people in the public think, FDA does not do
the research that needs to be done to address conditions like
CFS me. Many were anxious but that's not
what we do. So I will try to give you
framework of what we do and how it applies to CFS and me.
Really try to address the questions that are left to
conclude with, why there are not drugs for this and what should
the committee recommend. So I will try to do that at warp
speed. I want to go quickly through
history, I'll be quick with this but our history goes become to
. You can see fat obesity cream
rattlesnake oil, all kinds of things like this that were used
by consumers widely, with no oversight.
They didn't have to contain anything at all.
There they were on the shelf. This remind me a great deal of
walking down the aisle in the GNC store.
There's a lot of similarities there.
Not complete overlap but a lot of similarities.
The food and drug act came in that was intended to
address misbranding of those products.
So that to try to ensure that whatever the company making this
stuff said was in the jar was in the jar and met some standard,
not really a federal standard but a standard of strength and
purity. What really stimulated that was
as much foods as drugs, in fact, the Sinclairs the jungle which I
suspect many of you have read, I read it in high school and about
three times because I couldn't believe it.
And there was a companion drug book about the patent medicine
industry called the great American fraud.
That really got Congress's attention and Teddy Roosevelt's
attention in passing the the food and drug act.
The great story about Teddy Roosevelt, his rough riders also
got serious food poisoning. And he was just determined the
food was not going to be poisson any more.
And that's driving force that -- behind his interest in this act.
Was it enough? No.
In , many of you probably remember hearing about elixir
SULFANILIMIDE. Testifies used widely to treat coughs and
respiratory illness about children, there were deaths
around the country from that. It contained diethylene glycol
though diethylene glycol was not printd on the label.
The bonus question why is DEG in children eased medicine, the
answer is because it's very sweet.
It's anti-freeze and it was sweet and it was to make it more
appealing. Fortunately we're pretty much
past that stage. But what it did, it changed
Congress's mind of the adequacy of the the food and drug act and
and got to propose drugs must be safe before marketing.
Pure. Now they have to be shown to be
safe. Many are alive in .
It was actually the first -- it was really brought about the
concept of prescription medicine.
Physicians wrote prescriptions but there were no limitations
whether to buy a medicine with a prescription.
It was the food drug cosmetic act that launched the concept.
What about effectiveness? my parents were years
old. So medicines that their -- that
were given to them by the doctor and form cyst or parents did not
have to be shown to do anything in particular.
So this is an ad from the ,s, it's a photo, ozone
treatment is still with us today, it's not aproved for
anything in particular but it's around.
And this gentleman is demonstrating the use of this
device called an ozoneATOR. You wear this hat and this Shaw
that contains lead, very heavy and you take the cone and
breathe into the cone where ozone is generate bid some
device that cranks out, not sure what it was.
It was intendd to cure schizophrenia.
Widely marketd. The makers of this made a
fortune. I don't know if there were ever
reports of curing schizophrenia. But we laugh but this was common
place, absolutely common place stuff.
So yesterday we celebrated the anniversary of the Harris
amendments. For the first time drug
manufacturers were required to demonstrate that drugs had
efficacy, that they worked. To be marketing.
The first time informed consent was required to test
investigational drugs. .
I show you these slides because I want to help us not be so
frustrated by our shortcomings and being able to know answers
how to test drugs and how to show that they work.
, years was not all that long ago.
The concept the things we accept today about standards in how you
show a medical product is safe and effective, how you conduct
clinical trials, didn't exist in .
No one knew how to design or statistically analyze well a
controlled clinical trial in .
People had to figure it out. If you look at drugs approved
back in 's and the dossier that underpins their approval,
oh, my gosh, they -- that would never be acceptd today.
Because we have learned so much. With so much more sophisticated
in our thinking about what it takes.
So my point is, it was not that long ago we should not beat
ourselves up that we're not smart enough, we have to plot on
realizing that we're growing all the time in these fields.
We have learned how to study what folks do and concept of
drug discovery and manufacturing sophistication.
Has just grown exponentially. Society developed expectations
for medicines as a main stay of health maintaining ability to
function, not just treating disease.
was about treating disease. We had to build new tools to do
that. Today, given legislative
underpinnings our mission in FDA is to promote and protect the
public health by assuring safe effective drugs are available to
Americans. To meet criteria to make those
determinations requires careful judgment by people like Terry
apply to scientific assessments of risk and benefit balance.
In the context of the patient population of concern, that
always matters, why you see us spending more time today
communicating with patients an healthcare providers who take
care of them. What we mean by safe is on the
slide that risks are managed, that quality is assured if you
look at the package, it contains -milligrams of drug X, it
truly contains -milligrams of drug X, not , .
You can be assuredd every time you take one of those pills
regardless of who makes it. That advertising is appropriate
and isn't like fat off cream and Indian rattlesnake oil an
information is available about drugs to consumers an
prescribeers. In terms of effective drugs are
studied with proper end points and standards, the drugs of
today and how they are studied are not those of a century ago,
not even years ago and probably not even years ago.
And that quality is maintaind. Because if the drug season
manufactured to quality standard, it's not going to work
the way one is expecting it to work.
The traditional model shiftd. I would say with society's
dependence on pharmaceuticals, if you think that's not the
case, all you have to do is think about your grandparents
and what they died of. And whether or not if they
developed diagnoses today, would they have died when they did.
From my own grandparents the answer is absolutely no.
They would be alive today. The conditions they died of are
chronic conditions, they would be using pharmaceuticals and
other medical interventions to maintain wellness despite their
dig knowsis of coronary artery disease or difference kinds of
cancer or atrial fibrillation. With that, we had to have a
vocal communiquetive with the FDA communicating the public.
When I started working with FDA no one knew what we did.
I would go to conferences trying to keep one the field in
medicine and people would see me and fully expect that I had
packd heat and had a badge. You would never let me pack
heat. Never.
And I have never had a badge. There are FDA people who have
badges an guns out in the field but that's not us at
headquarters. We're the doctors.
But we have to engage with patient and medical community to
understand better what the needs are, where the therapeutic gaps
are, not that we can create drugs to fill those needs, but
do whatever we can to facilitate of those that exist and
encourage companies to the best we can to take up development of
those medical products. We can't maybe anybody study
anything or make anything. But we can use our influence to
encourage and we do that whenever we can.
The other thing that's happened as a result of this societal
interest in transparency and understanding is we have gotten
much better at FDA of factoring in to everything we do how a
particular medicine might immediate an individual patient
population's needs. Those needs vary a lot depending
on disease. For example, patients with
serious diseases or life threatening diseases are willing
to tolerate different degree of risk than people with mild or
annoying symptomatic condition. If you think -- if you're
facinging something that you think is going to take your life
in the next six months and you have run out of therapies, you
probably are willing to take risks with a new therapy than
people who expect to be alive for another years.
We try to understand that and factor that into our judgment
about the science an risk and benefit.
Who does this? What happens, and I apologize if
it's I don't havely simplistic to many of you but it's
companies who attend to market drugs who study through
researchers who have expertise in studying those diseases.
It's a huge forest, a huge enterprise of clinical trials
centers, discovery -- drug discovery centers an
entrepreneurs, large drug companies, small drug companies,
clinical research organizations, academic, commercial, in the
community. We oversee that forest.
Our first job is to assure and that appropriate regulations are
followd to protect the patients who are in those clinical
trials. That's job one for us.
When a new drug starts to be developed.
Once that begins, any time somebody -- and I'll get to this
again, but any time that begin, once we are engageed with
sponsor who studies an individual product, it's with us
for life. We, there are points in time
they come back to us for new things to tell us about new
studies they want to do. We advise them on what we think
about the safety of that and even what we think about their
planned strategy. One advantage we have is we see
everybody's work. So we see everybody's mistakes.
And so we know if company X had difficulty in phase trial for
a particular disease and company Y is coming in and they want to
do the same clinical trial. We know what the pitfalls were
in that trial. We can't tell them, you're a
competitor over there really blew it on such and such.
But we can take that knowledge and use it to guide the next
company along thinking about doing things differently.
When the company feels like clinical trial are done, make a
long story short, we -- they come to us with an application
for marketing and NDA. And we have six or ten months to
make a decision whether that product is approved for
marketing. I will go into that a little
bit. Who does this?
Terry doesn't do it alone. I done do it alone.
There are -- FDA is like a mini university.
We have Ph.D. and M.D. experts in all of the fields you see on
this slide. Chemists, animal toxicologists,
statisticians, physicians, clinical pharmacologist,
manufacturing experts, planned inspectors and we engage public
advisory committees impaneled with other experts and patients
and consumers to help review the data that companies bring to us
about marketing applications. We are foolish when we try to do
it in a small team. We are so much richer and the
public is benefits so much when there is widespread expertise
brought to the table discuss those new products.
It's not easy. So the investigational phase to
give you an idea of what this is like, any time an experimental
drug is given to humans, not something on the market to be
repurposed but those FDA as well some circumstances but a new
product, the researcher, the sponsor needs to come to FDA
with an investigational new drug application.
And we oversee that and again, the fundamental requirement for
that is is it safe. Is it safe for this clinical
trial to proceed. , INDs are processd in CDR
annually. ,.
are for products that of those products, brand new
products being developed commercially to treat any
medical disease you can think of.
The rest are by researchers who do a small study.
Sometimes they commit or contribute to commercial
development but not all the time.
Once you have gotten an IND it stays active many years, we have
, new ones, we have , currently active at any given
time. We have to review elements of
all those, about , actions to go back to a company on the
IND every year. What about new marketing
applications. Fewer because a lot of drugs
don't make it all the way through the IND phase, the
clinical trials just don't pan out, they get withdrawn.
We have about several hundred new drug applications from
marketing, submitted every year. All those are not for brand new
products. A lot are for second uses of
already marketd products. Additional uses.
A drug is approved to treat purple polka dot syndrome and
now the company also wants TV it approved to treat green stripe
syndrome so that counts, that's one thing we might be counting.
For brand new product? We save to a year but the
past few years we're and plus on new.
You can see we also do generic drug approvals separate from new
ones. What do we look for?
We want to know what the chemical is, animal studies for
a new product precede human studies because again, we need
to be assured that those patients and that clinical
trial, the first time anybody takes this medicine, will be
safe. What do we understand how the
drug is metabolized and potential effects.
And what we look for what is the clinical protocol designd to
ensure the patients are protected.
What's the range of doses that's going to be studied?
And how does investigator or sponsor know what doses to
choose? What's the preliminary work they
have done so they have been the best shot of sharing that
something does what they hope it will do.
Ones that they hope a drug will do and how are they going to
measure that? So every time there's a new
drug, every time there's a clinical protocol, our staff
look at these questions and work with the developers of that
protocol to really understand what the concepts are behind the
study and work with them to assure that it's designed and
going to be implementd in the way that's likely to get the
most best information possible for the patient resources that
are going into that clinical trial.
Ultimately in clinical studies, the gold standard, we want most
of the time what companies are looking for, they want a drug
approved for marketing. The ultimate access.
Marketing approval. The standard of the law says in
order to be approved for marketing, a drug must have at
least show substantial evidence of effectiveness through
adequate and well-controlled studies.
That should be a plural. Adequate and well controlled
studies. Those studies have been designed
well enough to be able to distinguish the effect of a drug
from other influences. Such as natural history of
disease, placebo effect or biased observation.
It seems really straight forward, never straight forward.
Never, never easy. No two drugs and clinical
conditions or clinical trial protocols are alike, it's why
I'm still at FDA all these years later.
That's always a nuance, there's always a challenge when you
start thinking about different patient populations and
different end points. It permits valid comparison with
control. You have to compare it to
something and you have to compare the patients getting the
drug to the same time patients maybe getting something else,
maybe it's a placebo. Maybe it's no treatment and just
standard of care. Maybe it's a different dose of
the same drug, maybe it's a historical control.
But most important -- most important thing is you have to
have, to make this work, you have to have a really well
defined patient population. If your patient population is
largely heterogeneous, object scientific standpoint you raise
your ability to show difference between treatment and control.
It's just gone. You can't show a difference.
End measures must be taken to minimize bias in assessment. Of
of those patients. Methods of assessment have been
well defined. And that the tools to measure
are reliable tools. So for example, one of the big
challenges that we have is in depression trials.
Many people know that if you look across all clinical trials
of drugs to treat depression, % show nothing.
% of trials drugs to treat depression show nothing.
No effect. Partly because the measurement
tools in depression are not that good.
Unless you have a really tight good tool, it's really harder to
show anything with an experimental agent.
The trials are better with more defined reliable measurement
tools for depression, that's one example.
The analysis of results needs to be adequate to assess effects of
the drug itself. I won't go into a lot of detail
about that, but the statistical analysis needs to be -- be able
to stand up to pure rigorous examination and not have been
Jerry rigged to get the results you wanted after the fifth
attempt. That's a problem we see in a lot
of clinical development programs.
We see less of it today, as the feel has grown and people have
gotten smarter about this. All these things are pretty
straight forward when you have a disease that is well defined,
and has objective well establishd measures of disease
progression or improvement. That's -- our challenge here
with CFS and me is getting there.
So the clinical trials are really -- they're the -- they're
where we need to go with this. When we talk about measures, I
want to emphasize, measures matter.
We need things that are easy to quantify.
And in the symptomatic world, when you think signs an
symptoms, signs are easier. Biomarkers easier.
Blood pressure, kidney function, viral counts in blood.
Incidents of myocardial infarction.
Death. Those are easy.
You can measure them, everybody agrees on what the -- for the
most part you can find agreement on definition.
Where it's difficult is when you don't have an objective measure
and when you have symptoms of disease.
Pain, fatigue, weakness, headache, depression.
Very difficult because they involve how the patient feels or
functions and measurement tools to measure vary in how to do
that. There is a field of measurement science that is
exploding that can be brought to bear on this but in these
conditions, the tools to measure acute and chronic pain are
different and they're different in patients with cancer compared
to patients with arthritis. Compared to patient whose are
just had surgery. The tools are different.
The best tools and symptomatic conditions measure symptoms or
patient reported outcomes within -- they have been shown to work
really well in patients with a particular clinical condition.
Again, the wrong tool leads to poor ability to measure he can
I've -- effectiveness of drug in a disease.
Many have failed because the wrong tool was used to measure
the patient reported outcome. So tools need to be targetd an
specific. And specific to the symptom of
concern. For example, a lot of times in a
lot of areas of clinical assessment particularly
symptomatic conditions, you see patient global assessment scale
or physician global assessment scale.
They're not good tools. They are medicine three decades
ago because they mix symptoms. So the patient says I'm well,
I'm better, well, what's better? Is it your pain that's better?
Is it your ability to go about your activities of daily living
that's better? Is your headache better?
Is your vision better? They mix all of those things.
So targetd to the specific issue of concern.
This is a picture we use about but you can see how what I'm
talking about is focusing on the core symptomatic conditions.
That core of symptoms are decrements and specific
functions related to a specific condition and one that links to
how we define that disease. That has to be our number one
focus, trying to grow a field of therapeutics.
To the right there's things like related functioning.
Other kinds of signs and symptoms.
Psychological well being and productivity and social
functioning. Hard to measure social
functioning. But if you can get at the core
signs, symptom or decrements in specific functioning, those are
the things that will give us the answers on therapies and what
works and what doesn't. So it's kind of like taking a
history when you have a patient in clinical medicine, and you're
totally confused. The patient had every test under
the sun an can't figure out what's wrong with her.
We see this all the time. Clinics see it all the time.
They can't think of what to do. What do you do?
You go back and to the history and you talk to the patient.
You get back to the disease defineing the signs an symptoms
and what it is that that patient is experiencing.
And usually you'll find your answer.
That action of clinical medicine that the answer in history
physical is the developing the measurement tools.
We know a lot of work in this area at FDA.
There is this document that you can find on our website, it's a
guidance for industry on patient reported outcome measures.
Use in medical product development to support labelling
claims. And I'm not an expert but we
have people in the agency are. This guidance defines how the
agency interprets well defined reliable measurement tools.
It's talks about good measurement principles, whether
you have a patient reported outcome, a provider observed
outcome or any other kind of outcome under the sun.
So I would urge people interested in research to look
at this guidance. We also have guidance that are
disease specific. We done have one for CFS and me
and honestly it will be a great day when we do.
When we can actually put -- because we do have guidance
documents for other conditions, for example, depression.
How to study a drug for depression.
What are some of the pitfall? What are the measurement tool?
How to choose a tool for your patient population.
It links to this guidance as well.
But these are the kind of things we're doing at FDA to try and
further feels like this. How does this apply to chronic
fatigue syndrome? Everybody at this table knows we
have got some real challenges here.
We have heterogeneity of symptoms, and if you don't think
that's the case all you have to do is look at history of the
difficulties coming up with disease criteria.
And the controversy about what the disease criteria are.
Usually there's controversy, it's a signal there's a great
deal of let owe geneity. Objective measures are limited
because the pathophysiology of the conditions are not well
understood. There are Noelle establishd
biomarkers. If there were we probably
wouldn't -- I wouldn't be sitting here talking today.
So clinical trials in drug development are why in this
field have been constrained. Number by these factors.
Not because nobody cares about this condition, because there's
so much encertainty. I wept backwards.
This is illustrative of the uncertainty.
We get , new INDs a year. We have , active INDs in
FDA at any given time. We have nine INDs that we
could find in our system for this condition, for CMS or me in
. Three have had nothing going on
in ten years. Two are still opt books, they're
listed as terminated. Not sure why they're not
withdrawn but there's another example so it's five with no
activity. Four have had active clinical
trials ongoing within the past two years one is commercial,
everybody knows that one, it's been in existence since and
I believe the last control clinical trial ran from to
. There were three research INDs
with very, very small clinical trials, not commercial sponsors,
researcher. We have a single NDA T only one
we have had. As you know AMPLIGEN and I can't
pronounce it, (indiscernible). As you also are aware, it's a
small database of control data as well as open label safety
data. Most published, as the company
announced it was not approved in it was resubmitd in
and goal date for decision in early we have six months
to review it. So why so few applications?
Because the core is still in question.
No acceptd definition for disease no acceptd method for
measuring how patients with CFS are any feel or function.
No acceptd biomarker to provide a simple quantitative measure so
if your a company would you invest in developing a drug to
treat a condition surroundd by that kind of uncertainty?
If you ask companies they'll tell you, here is the answer.
What companies want if they need predictability?
So they need to understand what it is they're studying.
How to measure the effect. That is key.
That, I am convinced, is why there are so few clinical trials
and drugs in development for this condition.
The clinical trial community is scattered an fractionated.
There's not a large collective effort to change this
institution. I if you rememberly believe
things will change. I can give you where that has
happened. That conditions that have had
absolutely the same challenges, irritable bowel syndrome,
functional dislexia, depression, prostate cancer and fibromyalgia
which is not on the list. Those conditions have the same
problems. All of them have new methods of
study and growing therapeutic armamentariums.
Because a generally agreed upon definition with signs an
symptoms an measurement tools that could be employd for that
condition, were agreed upon, developed and then there was
able to be movement forward. I have to tell you I didn't
think I would live to see the day when people agree on
irritable bowel syndrome. But they have and they're
approved therapies for it. There are three approved marketd
drugs for fibromyalgia. That's amazing.
That is absolutely amazing. Progress can be made
particularly the purpose for clinical trials, for irritable
bowel syndrome, there's a lot of people around the edges that may
not qualify for a clinical trial but can be expected to be able
to benefit from this therapies once available.
You don't have to create something completely brand new.
But that's the key. What I think HHS should do going
forward is use every tool possible to facilitate finding
condition for research purposes that can be widely agreed.
In order to do that you have to include all parties with
expertise and interest in this condition.
That must include patient representation in the consensus.
Consensus doesn't mean everyone has to agree on every point.
Consensus means we can move forward.
Again, you need a research definition that's just that.
So that we can move forward and begin to study things.
It maybe subject to change over time.
That's okay but the only way you learn is by starting Um
someplace. Clinical therapeutics are not
going to be developed until the system.
So I think HHS needs to invest in tools to measure functions of
chronic fatigue and me populations, we are very willing
to work with those groups who may get funded or charged with
developing those tools. And I think that through the
department we should partner with organizations and centers
who are equipped to conduct clinical trials using them.
Not every place will be. So I'm going to stop there and
I'm happy to take your questions.
Is what if we get four or five expert whose have a
population of chronic fatigue syndrome patients that we can
agree on, have chronic fatigue syndrome, at least from a
clinical standpoint just like depression, and come up with
scales to determine whether those -- how ill those patients
are. Do you think -- is that enough
of a standard? That's my first question.
Secondly, is it an easyer process to get an old drug
that's being repurposed for another condition approved?
Let me go backwards. The process for getting an old
drug, it doesn't matter whether the drug is old or new, if you
can't measure its effect. Ultimately you need to be able
to measure effect of the drug. Back to your first question, the
real key is coming up with a definition that's agreed that is
-- and tools to measure signs an symptoms that you really expect
will be useful in that particular patient population.
There are things that -- ways to assess those tools and our
guidance can help with that. But -- that's the key.
Your description of getting -- finding a patient -- finding
four or five places in the country where there are these
patients, coming -- getting those investigators orically
anythings to come together and say where are the commonaltys
that we all agree on and what are the tools we have to measure
changes in those signs or sip Toms.
Just one follow up to that. We just finishd a -- the lipKIN
study where we supposedly four or five experts around the
country able to determine these are true severely disabled CFS
patients an therefore feel we have that.
Perhaps something like the treadmill test could be used and
then assessment too many.
I think that so let me just pick up on treadmill testing I
think the main thing, before you just assume the treadmill
testing is a useful tool, you need -- there's a good example
of is it a useful tool in this population?
I don't know the answer to that one way or another.
But you may end up -- you have to be careful who you apply it
to. Are the patients so sick in a population that you're not
going to be able to distinguish anybody differences on a
treadmill within the patient population.
Or are you looking at a patient population less ill where you
could measure an improvement or decrement based on treadmill
function testing. Remember, what treadmill testing
is ultimately, it's a test of energy expendd, cardiac
We're going around on this specific topic.
Remember to identify yourself for the radio.
Steve crabcheck. With respect to the treadmill
testing, what I understand it does is it measures post
exertional fatigue by taking the an aerobic threshold day one
versus day and looking at it against normative populations
which I assume would be a useful outcome measure.
Terry can probably comment on that better than I.
She spent time thinking about treadmill testing in this
condition. But you know, your explanation
what it is you're doing and how has that tool been utilized to
assess this patient population in the past, would have been the
successes of that is really one of the most important questions.
Identifying cognitive problems.
The other question I would have is when LYRICA and other
fibromyalgia drugs were approved, were they focusing on
pain or something like the fibromyalgia impact
questionnaire validated over many years?
John, do you know the answer?
All the products that those are not in our division.
I thought they were. That's right.
Because all of those products were approved on a pain input.
So those products reside in division of anesthesia and anal
geeia products. Fascinating.
So the fatigue is in your belly --
We have clinical therapeutic divisions.
So my office oversees all of those divisions and the
clinicians in those divisions usually come from rheumatology
or neurology, we assign drug based on where we think the
expertise for the measures in the trial and patient population
maybe. So if you ever want to know what
a drug was approved on the basis of if you go to the package
insert there's a section called clinical trials that will tell
you exactly what was studied.
I haven't looked.
I haven't looked at it in a long time either.
You said he were interestd in outcome measures.
Wondering if you can start with the FIQ and see if you can
modify it and use it to measure fatigue related conditions.
It is a tool that is widely used in research at least with
fibromyalgia. Thank you.
Going around.
Eileen holderman. Thank you, Dr. Kweder, that was
fascinating. Like I said before, the patients
are very optimistic. But it's also on the flip side,
for three decades we have been waiting, there's not been a
single drug approved. Something you said popped out at
me. You said FDA can use influence
to encourage institutions an researchers and earlier Mary Ann
Fletcher said that for years now they have found measured
efficiencies in NK cytotoxicity.
So that seems like a biomarker and we're hearing throughout the
presentation there's no biomarkers, that's no
biomarkers. And CLYMAS and others feel there
are many, especially because this is probably an umbrella
disease with sub sets. How do you reach out to Mary
Annfully tore cultivate what she's studying and then get a
drug that will There's a lot of studies of
biomarkers, I show you the patient report T clinical
outcome measure assessment, we have a whole program in
biomarker qualification. And we are very interested in
seeing biomarkers and understanding their ability to
be utilized in clinical trials as a particular condition.
There is a whole field of understanding how to understand
when biomarkers are predictive or definitive for particular
condition or particular aspect of a condition.
We don't -- there are thousands of researchers looking at
biomarkers for thousands of parts of medicine.
We don't know who they all are. But that -- it's the kind of
research that we'll be trying to make sure it gets highlightd and
discussed at our workshop coming up in the spring.
I want to go back to your point that you said nothing has
been approved. Nothing has been approved
because there aren't people studying the drugs.
You can't approve a drug that hasn't been studied and
submitted to FDA.
So we can't approve what we don't have before us.
That is the fundamental research, the research on
therapeutics has not been done.
(inaudible) from CDC. This was a great presentation.
Your presentation highlights problems and limit we have at
CDC. We often get criticized for not
recommending specific medications and drugs for this
disease. As you rightly showed there's
not a lot of clinical trials done to show any specific drug
to be effective. Inasmuch as you would not be
able the to license drugs before clinical trials are done,
properly shown to be effective, we have the same difficulty
recommending medications for specific treatments for CFS then
those studies shouldn't be done in specific license insure not
completed. So that's an ongoing dilemma and
problem in the way of CDC. And often we get criticized for
that, that's basically the reason.
Unless there's specific clinical trials done, we cannot
specifically recommend drugs and put on our website being useful
for CFS. I wanted to point that out.
Mary Ann Fletcher. Nice to meet you.
Nice to meet you.
I guess -- I have been working on biomarkers for the
last years on chronic fatigue syndrome.
We have found biomarkers and we know they are significantly
associated with chronic fatigue syndrome, most can be found in
other syndromes. Patients with HIV have low
natural killer cells. A lot of patients with cancer
do. This is a function of
lymphocytes, it's real important in holding at bay infections an
cancer. If it goes away, things go out
of control. I think that that does not keep
these things from being useful, monitor a that's diagnoseed with
chronic fatigue syndrome, not HIV disease.
And following markers we know are associated to see whether or
not a given drug helps. The thing about it is, is that
the drug companies are so used to readinging everywhere, that
there are no biomarkers.
What? I'm sorry.
Reading in discussions like today that there are no
biomarkers. There are.
And then there are things that really aren't, for example the
CDC published a big study on C reactive protein as a biomarker.
Finally we decided it was more frequently found in patients who
didn't meet the CFS criteria, they were the ones that were
without the complete symptom pattern, we had a certain --
Probably a long time ago, right?
Yeah. So that one, though it's
recommendd in the new primer for chronic fatigue syndrome, it's
kind of useless. Because it's found all over the
place. There are biomarkers and if we
can get past the insistence of having them be absolutely
specific, like if XMRV turned out to be the cause of chronic
fatigue syndrome, everybody would say yeah, now we have a
biomarker, then we find XMRV was associated with other
disorders. If it really caused it and
really found it and it was gone after you treated, we would
care. So that's kind of my position on
this. I would like to hear what you
think -- You're much more an expert
than I am. The most useful are the
biomarkers you correlate with clinical condition.
So you correlate the degree of -- quantify the biomarker in a
way that correlates, directly correlative with how the patient
feels or functions.
(off mic)
You got it. With the biomarkers present, if
the patient has chronic fatigue syndrome, I'm making this up --
if the patient has purple dots syndrome and they have a
biomarker for purple dot syndrome you hope when the
purple dots went away the biomarker returns to normal.
Whatever the abnormalty was. And demonstrating that change
that there is a clinical correlate of biomarker that give
as useful biomarker. I don't know the specifics in
this condition but that's what you need to have to have it be
useful in a clinical trial setting.
Some are useful, too early for diagnostic purposes.
Some are useful for -- those are really tight and specific
diagnostic things. Other biomarkers are useful for
monitoring the condition of the patient.
Got to decide whichever one you choose, what's its purpose, is
it entry criteria for a trial? Outcome, is the biomarker and
come in and of itself, the quantification of the biomarker.
So those are the things that I think are important to address.
(off mic)
There it is. Let me ask you a question.
My understanding is that you approve drugs all the time that
don't have a specific laboratory biomarker.
Absolutely we do.
So it's important to point out that the biomarker doesn't
necessarily, that's with all due respect to my colleagues.
It doesn't necessarily have to be, in the old days there
weren't any.
For example, we're no biomarkers for migraine.
We approve drugs to treat migraines all the time.
So it's not essential, it is great if there is one but it
isn't in and of itself essential.
Correct this statement. If what I'm about to say is
wrong, the essential part is there's a clinical measure based
on drug claim you're going to make that that measure improves
whatever defined way useful drug for this disease and that
indication of this disease. Not to treat this disease.
Thought I rememberd that.
Eileen holderman, on one slide it say there's no acceptd
definition for disease and controversy besides.
There is controversy about the case definition but if you --
but mainstream scientists mainstream me CFS experts agree
on definitions that are really sound and they use them --
there's just a couple of governments that unilaterally
use the Oxford definition or empirical.
So there's a lot of consensus there.
And it -- there was also an inconsistency you said
fibromyalgia has three drug approved -- drugs approved yet
their case definition so that seems inconsistent.
Case definitions do change. There's nothing wrong with when
they -- when you change sometimes you start with one
case definition and you conduct clinical trials around that.
In the course of that you learn the definition needs to be
modified. At least there was consistency
in the clinical trial and you
had a definition you could in that find patient population,
make an assessment of the therapy that could ultimately be
approved. That happens all the time.
Definition of hypertension changed over the past decade.
Is so today in clinical trials of hypertension we may use
different -- we want drugs to lower blood pressure more than
in the past but it doesn't make -- it doesn't mean the old drugs
don't work, just that we have better educated how to define
the condition.
Thank you. Elaine Perry with CMS.
That was a great presentation. I appreciated it and also wanted
to echo some of the compliments I heard earlier on the
stakeholder call that you wanted to compliment you and Terry and
the rest of your team on an excellent policy (inaudible)
Thank you. My question, even if we were
at the point where there was absolute consensus on a case
definition there is still the issue of subgroups which we
think about constantly. And I doubt that we're going to
be in a point any time soon where we fine an agreed upon
subgroup, if you have any agree upon our main population yet.
So my question is, how is that handled in terms of your terms
of assess if we did agree upon a case definition, at that point
we're not going to know for sure all the people define have had
the same disease or pathological processes.
And then with it, we could have subgroups with different symptom
patterns who respond to different types of treatments.
And types of responses are different, someone has a pain, a
primary symptom, their pain might diminish but someone else
may not have that experience. The question is, do you do
studies where you use a fairly broad range of end points and
assessing whether something was effective, do you look at
subgroups and say % responded well to this
Sure. I think I know what you're
asking. When you have a heterogeneous
condition you need large clinical trials.
The reality, need a lot of people because of varyibility
between different courses of treatment.
We see that all the time. So what sometimes happens, if
you think they have subgroups that you can identify before the
trial starts define them, identify them and stratify
randomzation based on subgroups anticipating there might be
differences. That's okay.
The more you define up front the better off you are because you
control for some of that in the beginning.
You may learn there is a particular sub group responds
well to this kind of a treatment and another subgroup response to
a different different chemical or intervention.
When you have a heterogeneous group you need to think about
doing trials bear, largeer.
Time for one last question.
Dr. Fletcher last word.
I'm glad to hear you say that.
There are a couple that would lend themselves very well to
being used in this context. One is acute onset versus
gradual. I believe these two are fairly
different disorders. Treating patients that have
recently become chronic fatigue syndrome.
Those years an years. In particular, involved with
post effect mononucleosis, chronic fatigue syndrome in
adolescents. And their biomarkers are not
similar to adult whose had it for ten years.
They would probably be segregated into a population for
drug studies separate from people who had the disorder
years which are non-common. give you an example of the
stratification of subgroups. With irritable bowel syndrome,
we first start ode somebody have a great general definition of
irritable bowel syndrome. Clinical trials began.
What was learned is patients who -- there's a big difference
between in response to therapies between patients who have
diarrhea predocument innocent versus constipation predominant
irritable bowel syndrome. Drugs are approved for subgroups
in that population and we have one drug only approved for
women. Diarrhea among women, because
the randomzation was stratify bid sex and -- stratified by sex
and the men didn't respond at all so they contributed less
than none to a clinical trial but the women responded
overwhelmingly to the drugs. Very interesting.
You see it. And know one really completely
understands why, there is not a biomarker for that.
There clearly distinct subgroups of that condition.
Admiral Kweder, thank you for your presentation and candor
with us. We appreciate you very much.
Thank you for inviting me, I appreciate it.
Keep up the good work. I'll be along for the ride.
Very good.