The University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences Drug Development course brings you lectures from both faculty and industry experts. With this course, recorded on campus at UCSD, we seek to share our access to top people in the field who bring an unprecedented range of expertise on drug development. In this course you will learn the different stages of clinical development as well as the regulatory including but not limited to, an Investigational New Drug Application (IND), New Drug Application (NDA), and product labeling. Additionally you will learn how to Incorporate study design methods for consideration in the design of clinical protocols to assess safety, tolerability, and efficacy in multiple therapeutic areas. In this course you will learn the different phases of clinical development: * Phase 1 or early stage clinical trial are conducted primarily to determine how the new drug works in humans, its safety profile and to predict its dosage range. It typically involves between 30 and 100 healthy volunteers. * Phase 2 or Proof of Concept POC studies test for efficacy as well as safety and side effects in a group of between 30 to 200 hundred patients with the disease for which the new drug is being developed. * Phase 3 or late stage clinical development involve much larger group of patients, between a few hundred to thousands, depending on the indication, which will help determine if the new drug can be considered both safe and effective. It will involve control groups using placebo and/or current treatment as a comparison. * Product registration and approval process after a drug is considered safe and effective from Phase 3 trials, it must be authorized in each individual country before it can be marketed. All data generated about the small molecule or biologic is collected and submitted to the regulatory authorities in the US at the FDA, Food and Drug Administration FDA, in Europe the EMA or European Medicines Agency, Japan Ministry of Health and other countries which may require their own national approvals. This course is intended as part 2 of a series: Drug Discovery (https://www.coursera.org/learn/drug-discovery), Drug Development and Drug Commercialization (https://www.coursera.org/learn/drug-commercialization). We would highly recommend that you take the courses in order since it will give you a better understanding on how a drug is discovered in the lab before being tested in clinical trials and then launched in the market place.
Clinical Trials: Phase 1 Part III
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Do curso por University of California San Diego
Drug Development
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Clinical Trials: Phase 1, Yazdi Pithavala, Ph.D.
This module we will hear from Dr. Yazdi Pithavala, Senior Director, Clinical Pharmacology at Pfizer.
Conheça os instrutores
Williams S. Ettouati, Pharm.D.Director, Industrial Relations & Development; Health Sciences Associate Clinical Professor, N.S.
Skaggs School of Pharmacy and Pharmaceutical Sciences
Joseph D. MaAssociate Professor of Clinical Pharmacy
Skaggs School of Pharmacy and Pharmaceutical Sciences
So, like I mentioned, safety is the primary imperative of Phase 1 studies.
And when you do a Phase 1 study, there are certain standard safety measurements
that you will always do, okay. So, you will always.
To a physical examination you will do laboratory tests.
So, you, you want to look if there isn't any changes in blood electrolytes, any
changes in blood counts, any changes in patient's liver function or kidney
function. So, there is standard hematology, serum
chemistry, and urinalysis test that you will do.
You will look for vital signs, okay, you will look at blood pressure, you will
look at heart rate and pulse rate, and so forth.
And then you will look at ECG assessments for cardiac function.
And then you will also do adverse event monitoring.
And what, I'll come to you in a minute. Adverse event monitoring is quite simply
literally asking a subject, you know, how are you feeling?
You know, because people in such a setting might not feel very emboldened to
say you know, I kind of have a you know, pain in the back of my neck.
Or, you know, I, I feel really hot, or you know, whatever.
So, you have to very proactively ask people if they're having any adverse
events. I'm sorry go ahead.
>> what do you do in terms of screening people who already enrolled in previous
Phase One or clinical trials in the past. >> Yeah.
So, we'll come to that. We typically when you write a protocol
for a Phase One study we have criteria. Entry criteria.
And one of the entry criteria always says that you should not have participated in
another trial or donated blood or a whole bunch of things, you know, up to x days
before. The, you know, day one of this particular
study. >> Do people generally like.
>> Yes. There are, there are, professional
participants to Phase 1 studies, yes. >> It's a. [LAUGH].
>> IE college students. >> IE college students, yes.
So, yes, very often, they. Because, because you're looking for
reasonably healthy subjects who have. You know, pretty well defined body
weights or who have a pretty well defined age range.
And, you know, students tend to, tend to be a good, good they fall in that
category. Yes.
>> I know you're focused mainly on talking about Phase 1 studies.
But obviously, safety carries out. >> Mm-hm.
>> In all the phases. So I know there's always concern with
under reporting and over reporting. >> [CROSSTALK] Mm-hm.
>> And there's a lot of patient-driven systems for to help the research subjects
to report their, you know. >> [CROSSTALK] Mm-hm.
>> [INAUDIBLE] data. So, how is that being dealt with, what,
what. >> So, there's tremendous regulatory
scrutiny right now, to make sure that when you're doing a study.
There's absolutely no under-reporting. So, very often we err on over reporting
instead of under reporting. our protocols get reviewed by ethics
committees, by institutional review boards, before they get approved.
they get reviewed by, you know we submit them to the FDA.
and, and you need to demonstrate that you have the right.
Tools in order to capture adverse events that you know, if, for example, if you
give a drug and let the patient go away, you know, go home two hours after you
dosed him and you don't bring him back or ask him any questions until seven days
later. That's going to be suspect because you
know somebody might have had a bit of a rash but it went away after three hours,
they never reported it. So you need to demonstrate that when you
were doing your study, you had the right mechanism, you timed your, your, your
collections, you timed your, your monitoring and your questioning for
adverse events frequent enough that you, you, you did pick that up.
So obviously, when you're writing this, this, this Phase 1 study protocol you
need to be very careful how to time all of these assessments.
So a great example might be. you know I, we, we, I worked for about
ten years on a compound we just got in the market, it's an anti-androgenic drug
for, for renal cancer. all of this, this class of drugs, they
all cause an increase in blood pressure. That, that, that's a side effect, they
cause an increase in blood pressure. It typically might happen about two to
four hours after you give your, give your first dose.
Well, if I'm doing vital signs. Right before dosing, half an hour after
dosing, one hour after dosing, six hours after dosing, eight and 12 hours after
dosing. I'll have completely missed picking up
the blood pressure increase and the patient won't be symptomatic for, you
know for, for most likely, you know, the blood pressure will go up, but you'll
never pick it up. So you need to be very careful when you,
when you design your protocol based on what you know about the compound, based
on what you know about other drugs in the same class.
That you have, that you time these measurements very carefully and for
example, when we got these protocols, the exact timing of the ECGs, the vital
signs, the blood, the blood pressure reporting that goes through tremendous
scrutiny and people make sure that you haven't missed any opportunity for
missing a drug related effect. in addition to those standard safety
parameters, you make, you, you often will include additional safety measures.
And, and what drives these additional safety measure measures?
Usually what you know about that compound.
Right? So if I know, for example, that the, I,
I, you know, I have a, a brand new target.
This is the first drug that has been developed against this particular target.
But you gave the drug to animals and you noticed some kind of ocular toxicity,
okay? In a typical Phase 1 study, nobody's
going to measure visual function, okay? Nobody's going to do any kind of ocular
examination. But if you've seen this in your animal
studies, then in your Phase 1 study, it is your imperative to make sure that you
have the appropriate. Ocular testing, whatever is necessary,
included in your study to, to characterize that for the compound.
Okay. Fairly.
Makes sense. Fairly, fairly obvious.
if you know that your drug, for example causes changes in you know, the left
ventricular ejection fraction volume. Okay, then you might want to include MUGA
scans in your Phase 1 study. So, depending on what you have seen in
your animal studies, depending on what you know about the class of agents, you
would build in additional safety measurements in your Phase 1 study.
and then, this is the, this is the clinch, right?
This is the thing that is very hard to handle, anytime okay, you have reason to
believe that there might either severe. Irreversible, acute, or potentially
clinically silent effect. Okay, so that's the kind of safety you
cannot manage. More safety events, if they happen
gradually, they happen, if they are symptomatic that, that you can put them
up. If they are reversible, that even if you
get a headache, you, you, you know hopefully the headache will go away.
those are the kinds of safety events you can manage.
But if it's a safety event which is irreversible.
That's, that's horrible because that event is never going to go away.
or if it's potentially clinically silent. So, something really bad is happening but
there are no symptoms that you're going to see.
Those are the kind of safety events that you need to be very vigilant about.
A great example might be suppose a drug causes cardiac necrosis.
Okay it's slowly destroying your cardiac muscles.
Okay they're actually dying. Your, the cells in your, in your cardiac
tissue is dying. Well unless you do a very, very
particular test. Okay nobody's going to right after the
first few doses. Nobody's going to symptomatically.
You know present themselves with anything which would make you tell that this drug
is causing you know cardiac necrosis. So any, anything such as that which
you've seen in your pre-chemical study you need to be hyper vigilant and build
the right kind of assessments when you, when you're designing your Phase 1 study.
Torsade de Pointes, are you guys familiar with that?
That's another thing. it's, a drug can cause a prolongation of
the QT interval in the typical ECG of a drug.
And if you have a prolongation of the QT and tubo that puts you at a much higher
risk for this event, which is Torsade de Pointes, which is essentially a subject
having pretty much without warning a death.
Okay. So, it's, it's the kind of thing which
you obviously want to avoid. And it, it has a lot of scrutiny right
now within, within the pharmaceutical industry when you're developing drugs.
You, you want to watch out for that. You can define certain No Go criteria.
So a good example might be you know, flashback to about 15, 20 years from.
You know from, from right now. Twenty years before from right now.
When people were developing HIV drugs. And the you know, there were, there were
many different classes of HIV drugs which were available.
But a lot of them needed to be taken twice or three or four times a day.
They were very effective, but they just needed to be taken three or four times a
day. If you are, a developer at that point who
wants to develop another drug but the only reason why you bring it to the
market is if your drug needs to be only given once a day.
Okay? You don't want a drug which also has to
be given two or three or four times a day because you'll be just like everything
else on the market. Then in your very first Phase 1 study,
you want to make sure that the pharmacokinetics of the drug is such that
it can be given or once a day. So that's a no go criteria that you might
build and say, if this doesn't happen I'm not going to develop my compound any
further. And if you have such criteria suppose you
have pre clinical signals like, you do animal studies and you find out that your
drug causes time dependent inhibition of its own metabolism.
It's the kind of thing where, while you're giving your drug, your drug levels
change from day to day because it's, it's inhibiting its own metabolism and it's
time dependent. As a physician, that's very difficult to
handle, because on different days you will have different levels of your drug.
And you may decide, I don't want to develop a drug which causes time
dependent inhibition, it causes too much headache down the road.
So, if you see that in your first newman study, you would stop clinical
development right there. >> Okay.
>> Question? >> Yes?
>> Do these things have to actually be defined in terms of, I mean, you don't
want the inhibition. >> Hm-mm.
[INAUDIBLE] inhibition, so if you have to write that into the protocol that, that's
[INAUDIBLE], is it after you evaluate what happens from the Phase 1 and then
stop your Phase 2 and Phase 3 /g. >> You have to very, very clearly
define what you're going to do to assess it.
So, for, for example, if I want to find out if my drug is time dependent
inhibition, I will do an interaction study with Midazolam for example.
So, I need to build that interaction study into, I mean, the details of how
I'm going to assess time dependent inhibition in my phase one study.
But I'm under no regulatory compulsion to actually state that if I see this, I'm
going to stop developing my compound. That's an internal company decision.
>> I, I'm sorry, can you re-explain again why that's bad, the time dependent
inhibition? >> So time dependent inhibition is one
where. you know, I, I take the first dose of my
drug right now. I see a certain drug level.
I keep taking my drug every day. And over a period of time, my drug levels
start increasing. And it's very difficult to predict how
much it's increasing on a day to day basis.
Okay. Until eventually, it'll reach the highest
possible level. But, but as a physician, it's, it's, it's
very difficult. To deal with a drug whose concentrations
are literally changing on a day to day basis.
So you may, you may, you may choose that. sometimes you're developing a drug which
is predominantly metabolized by an enzyme which has tremendous genetic
polymorphism. Are you guys familiar, familiar with
genetic polymorphisms? So, you're genetically predisposed to
having that enzyme being more active than other people or less active than other
people. So what happens is you give the same drug
to a group of people here, in some of them it'll get metabolized a lot more
than others. So now we have these different pop,
sub-populations of people who all have different drug levels who all might have
different affects. Okay, and a pharmaceutical company may
make a decision that I don't want to develop that drug because it, you know,
it, it, it's going to make things much more complicated while you're developing
it. You can still do it, you can test
patients ahead of time for what their metabolizer status is and then dose
accordingly. But you may choose up front, saying that,
that's, that's a burden I don't want to take and you may want to stop your
chemical development right there. And then, like I mentioned, we've already
talked about this. It will be great if you had some marker
of drug activity, okay, in your Phase 1 Study.
It's not always possible, depending on what, what the drug is intended for, but
if you had some measure, that, that will be, that will be great.
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