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 I
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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, as Williams mentioned, I'm Yazdi Pithavala and like he said, that's a
mouthful. should you find yourself falling asleep
during the next hour repeat my name in your head a couple times it will keep you
alert. but I'm, I'm, I'm a clinical
pharmacologist down the road at Phizer.. I got that PhD in clinical
pharmacokinetics from the University of Minnesota and following that I, I did a
post structural fellowship at UNC and at GlaxoSmithKline at that time.
And after that I started working in the pharmaceutical industry.
I started at little Agouron Pharmaceuticals which used to be down the
road here. And through a series of merges and
acquisitions, now I'm part of Pfizer. I've been there for about 15 years and
have been mostly working in the clinical development of oncology drugs, drugs for
cancer. And I'm absolutely delighted to be here
to talk about Phase 1 studies. It's something that we do a lot and we
spend a lot of our time doing. So really glad to be here.
just a few things I want to mention, one is since this is my first time here I
really want this to be very interactive. So if you guys have any questions please
feel free to throw them to me. if I'm the only one who's spoken to the
end of the hour then I'll have done horribly.
So, I really want this to be a discussion.
second thing is I tend to speak fast and I have an accent so again, if something
doesn't make sense please stop me once, twice, as, as often as you want.
you'll find it's very difficult to offend me.
You'll have to try really hard, so all, all questions.
[audience laughs]. All questions, all questions are good,
just, just throw them my way. and let's go ahead and get started.
So, Phase 1 clinical studies that's what we're here to talk about.
phase 1 means different things for different people and that's one of the
things I wanted to mention during, during the next hour.
See here's, here's a brief overview of what we're going to cover and depending
on how much time we have we can delve into, into more detail on any of these
topics. And incidentally if any of you have
questions afterwards feel free to reach out to me as well.
So, I wanted to go over the terminology. speak about what the typical objectives
might be for a Phase 1 study. and then spend the meat of the time
during the hour talking about study designs.
How would you do a good Phase 1 study? on the face of it seems like a pretty
obvious thing. It seems like a fairly straightforward
thing to do but, you know, the devils in the details.
And, and you can go through study design issues and then at the end of the hour if
we have time we can delve into dose selection.
How do you pick a dose for a Phase 1 study?
And that by itself you know, you could do a thesis on it that you know, you could,
you could spend several hours talking about dose selection but, we'll, we'll,
we'll see how far we can get. So, here's the crux of Phase 1 studies.
a Phase 1 study literally is, you know, in the most general sense, the very first
time you're going to dose a human. 'Kay, and, and the reason why Phase 1
studies are challenging I think is because this set, this set of the crux of
two objectives which are kind of competing with each other.
The very first objective is, this is the first time you're doing a study in a, in
a human being, you want to get as much information out of it as possible, right?
You want to find out what this drug does to humans.
And so greedily, as a scientist, you want to get as much information out of it as
possible. But the bigger imperative, and this is
where the conflict comes, is you should never do it at the cost of the safety of
the subjects that are enrolling in that Phase 1 study.
So, the number one primary imperative of the Phase 1 study is to find out how safe
that drug is. And you should never ever want to
compromise the safety of those individuals.
So, the challenge arise in finding that sweet spot where you get as much as you
can out of that study while still ensuring, you know, very solemnly, the
safety of the people who are going to participate in the study.
this is something which should be very, very familiar to you.
This is like a general clinical drug development paradigm.
And you, you guys should all know that, when you start with preclinical testing
typically you would do a fairly wide battery of, of studies.
You would in vitro studies, you would do studies in animals, you would do
toxicology studies. in, in the old days before you could do
electronic submissions you would truly have like two big trucks full of paper
which would get submitted to the FDA for an IND.
So, all the studies that you've done, even before you've dosed humans for the
very first time, you would put all that information together, send it to the FDA.
And essentially at the IND stage, the investigational new drug application
stage, you're asking the FDA if it's okay to dose a human being.
If you've collected enough information that it's, it's feasible to go, to move
into humans. Yeah?
just, just from a regulatory perspective, what the idea actually grants you is the
license to ship a drug for investigational use.
But, but we all know that it's actually for use within humans.
Okay? Once you move into your Phase 1 study,
your primary imperative of a Phase 1 study is to find out the safety of the
compound. it's, it's, it's that imperative, that
first do no harm. So, very often, for the majority of
drugs, even before you will ever find out if the drug has its intended effect, you
will first need to find out that it's safe.
So before you ever test, say if I'm developing a drug for asthma, you know,
long before I'll ever give it to a patient who has asthma to find out if the
drug actually has any effect, I would have had to find out if the drug is safe
first. So you need to find out safety.
And that's really the purpose of your Phase 1 study.
and a typically small study. About 2200 subjects at most.
And typically there are two studies done in Phase 1.
And, and we'll go through that in a bit of detail.
so typically, your goal of your Phase 1 study is to find out safety, and to find
out what dose you might want to take for subsequent clinical development.
Now, you know, they're exemptions to everything.
nine out of ten times your Phase 1 studies will be done on healthy
volunteers and, and why is that? You don't want any confounding factors
absolutely, absolutely. So, if you do it in patients, patients
might be taking a lot of other drugs, you are concerned with drug interactions.
It, it's perceivable that you, that a, a patient who has a disease already has
their health compromised. And if, if you have an untested new drug,
you don't know what the safety of that is.
The perception of that is a healthy person might be able to tolerate that a
little bit better than a person who's diseased.
So typically for those reasons, you would go to a healthy volunteer population.
there are exceptions. Oncology drugs, very often you go
straight into cancer patients for obvious reasons.
and, and, and if you have time we'll, we'll go through that.
Then you move into your Phase 2 study. And Dr Parivar who sits right next to me
incidentally, at Pfizer, he will be going over Phase 2 studies next, next week with
you. the goal of the Phase 2 studies.
This is now the first time you're actually going to test your drug in the
intended population, okay? And you want to try to get early signs
whether your drug is doing what it is meant to do at the dosage you have
picked, okay? If it's a drug for diabetes, is it really
reducing blood sugar? If it's a drug for asthma is it, is it
causing a reduction in your fev, so, so that's.
You do your small study and you confirm whether your drug actually has the
intended effect. And once you know that your drug has the
intended effect, add doses where you can manage it fairly safely.
Then, you go to a Phase 3 setting which is meant to replicate the larger
real-world setting. And you would a do a confirmatory larger,
you know, set of studies. in thousands of patients at that point to
confirm your findings from Phase 2. And once you have all of that, you know
God speed, you go ahead and submit to the FT again.
Even more data and then your drug will hopefully get, get approved at that
point. So, let's jump into Phase 1.
Phase 1 means different things to different people.
the first definition which is based on chronology is the most commonly used
definition. That's the definition that we will be
using for the purpose of this class. Phase 1 literally means the very first
phase, the very first set of clinical studies you do.
So that's, that's typically what people, people mean when they say Phase 1.
Very often, even in the literature right now, you will find people using the term
Phase 1 to actually define something based not on when the study's done but
the population in which the study's done. So, suppose I'm already into Phase 2 or
Phase 3 trials for a compound for asthma, right?
And while I'm doing that, I need to do a study to evaluate the effect of food on,
on my compound. Should I take the drug with food or
without food? Well, I go to a healthy volunteer
population and I do a study at that point.
So even though I'm doing the clinical development continuum, I might be in
Phase 2 or Phase 3 because I'm going back to the healthy volu-, volunteer
population. Some people might call that study a Phase
1 study. Does that make sense?
So, by virtue of the population, anything done in healthy volunteers is sometimes
called a Phase 1. And then the third the third context in
which Phase 1 is often used is in terms of the intent of the study.
So, a great example, suppose I've developed a drug for cancer.
Phase 1, Phase 2, Phase 3 went to the FDA, got approval.
It's out on the market, everybody's using it.
Now I decide, I want to try it for another tumor type, okay?
Another indication. But this time I want to use it in
combination with chemotherapy, okay? So now I'm going with a new combination,
an untested combination for the first time.
And that, because you're assessing the safety of this combination for the very
first time, people use the Phase 1 terminology for that study as well.
Okay? Make sense?
But again for the purpose of this study, you're going to stick with the very early
studies which are conducted.
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