>> Heather Fitter: Hi, I'm Heather Fitter.
I'm a Clinical Team Leader
from the Division of Neurology at the FDA.
And I'm going to talk to you today
about the approval pathway for migraine and headache products.
The views expressed in this presentation are my views,
and not necessarily an official statement
of the Food and Drug Administration.
I'm going to focus, today, on the approval pathways
for migraine and cluster headache.
Because these are two indications
that are handled by the Division of Neurology.
I'll start with migraine, which is a syndrome
that is associated with pain,
but it's not just a pain syndrome.
There are also other associated symptoms,
nausea, photophobia, and phonophobia.
And for a drug to be approved for migraine,
it has to have an effect on all of these.
It has to have an effect on pain,
as well as the associated symptoms.
The International Headache Society put together
a classification system for headache disorders.
And according to that classification system,
for a patient to get a diagnosis of migraine
they have to have at least five attacks
that fulfills the following three categories.
The headache should last four to 72 hours if untreated.
The headache should have at least two
of the four features, unilateral location,
pulsating quality, moderate or severe pain intensity,
and aggravation by a physical activity.
And the headache should have at least one of the following too.
Nausea and/or vomiting, photophobia and phonophobia.
Some patients get an aura,
which is a reversible neurologic symptom
that normally will occur within 30 minutes of the onset of pain.
So, products that are marketed for migraine
should demonstrate an effect on the coprimary, pain freedom
and, in the past, we used to have four coprimaries,
so it had to demonstrate an effect on absence of nausea,
absence of photophobia, and absence of phonophobia.
More recently, with -- after negotiations with industry,
we've come to a new endpoint
which is absence of most bothersome symptom.
So, now the treatment trials for migraine
can have a coprimary made up of the absence of pain,
which is measured on a four point scale.
And the expectation is that patients
will treat their migraine if --
in the trial if it has moderate to severe pain,
and then at two hours we want to see that they have no pain.
In terms of the most bothersome symptom,
we ask patients to select whether this is nausea,
photophobia, or phonophobia.
And then, there's two ways to design a study to test this.
Either patients will identify this
at the time of randomization, and then they'll treat --
they'll only treat a migraine with the investigational product
if it is associated with their most bothersome symptom
that was identified at that point.
Alternatively, patients can --
they can identify their MBS at the time of their migraine.
And we just have to be very careful
and make sure that it's documented
that this is selected prior to taking study drug.
In migraine treatment trials, we also like to measure
sustained pain free at 24 or 48 hours.
And this is defined as pain free at two hours
and every interim assessment until 24 or 48 hours
with no relapse of pain and no rescue medication.
The other endpoints that I have listed here
are endpoints that we also like to see in some of the trials.
We're working closely with sponsors
on development of clinical outcome assessment tools
to assess changes in quality of life or function with treatment.
Although we talk about acute treatment of migraine,
we consider the treatment of migraine
to be chronic/intermittent.
And the reason why is because many patients
don t just take a pill for their migraine
once a month or every other month.
We know that many patients are taking medications
almost daily or every other day.
So, we require a safety database of 300 patients for six months,
or -- and, sorry, and 100 patients for one year.
And normally, this is obtained from a long-term
extension study.
These could offer until after the adult drug
application is submitted.
So, in the past two years we've approved three new drugs
for acute treatment of migraine. Two are in the calcitonin
and gene related peptide antagonist group
and they're oral agents. And one is a serotonin agonist,
but it's different than the triptans in that it works
on different receptor sub-types.
And the receptor sub-type that we believe is involved
in causing coronary vasospasm
is not one of those subtypes that this new drug works on.
So, we think that it may be safer in patients
that have cardiovascular risk factors.
So, much of what I have just said is summarized in guidance
for industry that we updated in February 2018.
So, some patients are taking medication frequently
and they may be candidates for preventive treatment.
And this can depend on the number of days
that they're having migraines, the severity of
the migraine, or the amount
that those migraines affect their daily life.
We ask sponsors to study these two populations
separately, episodic migraine, which is defined as less than
or equal to 14 headache days a month.
And chronic migraine, which is
defined as greater than or equal to 15 headache days a
month where eight of these are migraine.
And this has been going on for greater than three months.
We believe that there is different
characteristics of these headaches,
and that there may be different treatment effects.
For patients that are taking a lot of acute migraine medication
may develop medication overuse headache.
And this is defined as a headache occurring on greater
than or equal to 15 days a month in a patient
with a pre-existing primary headache.
And a patient that regularly overuses acute
headache medication for more than three months.
So, what we end up seeing is as a patient is taking more
and more of these medications,
they're getting more days with headache rather than less.
And we see this with over the counter analgesics,
prescription migraine medication,
as well as prescription analgesics.
And this is something we certainly want to avoid.
So, in the preventive treatment of migraine trials
we like to see a primary endpoint of change from baseline
in monthly migraine days
over a 12-week period or change from baseline
in monthly headache days over a 12-week period.
We also like to see
the measurement of the use of rescue medication
so we can see if there's a reduction of this
and the 50 percent responder rate
compared between treatment groups.
In the past three years, we have actually approved
four new medications
for the preventive treatment of migraine.
They're all biologics, they're injectable,
and they're in the calcitonin gene related peptide category --
sorry, in that class of drugs.
So, they're all monoclonal antibodies.
And the treatment effect that we've seen
is about a reduction of one to two migraine days a month,
which may seem relatively modest.
But that's why I want to show you the next slide
which is a figure that we have in the label of Aimovig,
which is the first of its class that was approved.
And you can see that there are --
there is a sub-group of patients
that have a higher treatment effect.
But we just -- we don't --
we are not able to prospectively identify these patients.
So, trial and error the way you can see which patients
going to have a greater response.
I also want to point out in the slide
that in migraine trials,
we often have a high placebo response.
And you can see that here.
And this is one of the reasons it's so important
to have an appropriate comparative in these trials.
I'm going to switch gears to acute treatment
of cluster headache. Cluster is defined as a severe,
or very severe, unilateral, orbital, super orbital,
and/or temporal pain lasting 15 to 180 minutes
that's associated with either or both.
The first bullet are signs
that we see with sympathetic neuro system dysfunction.
So, you may see any one of these, conjunctival injection,
facial sweating, miosis or ptosis, to name a few,
and a sense of restlessness.
The frequency varies.
You might see one every other day,
or some patients may have eight per day.
But there is a circadian rhythm associated with this
and they often occur at the same time.
The primary outcome has to consider the fact
that there is so much variable. There's so much --
there's so much variability between individuals.
So, we don t want to measure the natural history of a cluster
and just, you know, measure -- follow a patient until it --
their cluster would naturally resolve.
So, we pick an early time point for the primary endpoint.
What we like to see is pain relief at 15 minutes
sustained one to two hours.
You can see with cluster, we ask --
we want to see that patients are getting pain relief
because this is such a severe pain
that they have with this type of headache.
So, we've polled patients that have cluster headache
and what we've heard is that pain relief
at 15 minutes is satisfactory.
With migraine, as you saw, we ask that products
be able to achieve pain free at two hours.
And this was based -- this was based on also getting community
input and asking migraine patients about what it is
that they think they should get out of a drug for migraine.
And they said that the expectation was that
they would be pain free.
So, although in the past we had had primary
endpoints related to pain relief.
Now, we ask sponsors to demonstrate
that their product can make people pain free at two hours.
So, there -- when sponsors are studying treatment
of cluster headache, and they're trying to evaluate
how to have a cluster period stop, or have --
or reduce the number of clusters that patient --
or the number of attacks the patients are having.
They will study these two sub-groups, episodic is defined
as patients that have at least a three month pain free period,
whereas chronic cluster headache patients
don't have that three month period.
We don't have as standardized end approach
to studying cluster headache as we do for migraine.
So, there are several primary endpoints
that we find acceptable for studying episodic cluster.
A reduction in weekly cluster headache attacks
over two, three, or four weeks. And the goal here,
and the reason there is variability here,
is it's hard to predict how long a patient's cluster will last.
And so, the goal is to capture that before the cluster resolves
so we can see a treatment effect.
The primary endpoint for chronic cluster studies
is reduction in weekly cluster headache attack
from baseline over a 12-week period.
In conclusion, we have standardized approaches
to study acute migraine
and the preventive treatment of migraine.
We're working with sponsors to develop study designs
for other headache types where there's less standardization,
such as cluster headaches.
We've had a very productive three years,
but we still have more work to do to provide more therapies
to patients with migraine and headache disorders.
Thank you for your attention.