Clinical Trials: Phase 1 Part V

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Del curso dictado por University of California San Diego

Drug Development

196 calificaciones

University of California San Diego

Drug Development

196 calificaciones

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.

De la lección

Clinical Trials: Phase 1, Yazdi Pithavala, Ph.D.

This module we will hear from Dr. Yazdi Pithavala, Senior Director, Clinical Pharmacology at Pfizer.

Clinical Trials: Phase 1 Part III12:08

Clinical Trials: Phase 1 Part IV9:28

Clinical Trials: Phase 1 Part V5:00

Conoce a los instructores

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. Ma
Associate Professor of Clinical Pharmacy
Skaggs School of Pharmacy and Pharmaceutical Sciences

Stopping Rules for Phase 1 studies. I'm not going to go through this in a lot

of detail but this is something that when you write up your protocol, both for your

single dose study and your multiple dose study, you have to be very clear.

What do I have to see, that'll make me stop dosing?

What adverse events have to transpire that'll make me say, that's it, I've

reached my dose limiting toxicity? Okay, and it, it's usually driven by what

you already know about that class of drugs.

Okay, if I know that my drug is likely to cause hypertension.

You know you might say, once I get malignant hypertension where, you know,

even with giving anti-hypertensive drugs, the blood pressure's not coming down.

That's my dose limiting toxicity. See, you can predefine what your stopping

rule is going to be, okay? And that's something with the IRB, the

Institutional Review Boards usually look at very carefully when they're reviewing

protocols. unfortunately I don't think we have time

to go into dose selection, and so I'm going to skip over that, that, that's a

whole big beast of it's own. all I'm going to say is, is the very

first sentence there. The dose selection for a First-In-Human

study is often a combination of art and science, okay?

You have, you have a lot of science. You have all this information from

animals. You have all this information from, from

assays you have done about how your drug works.

And then, there are four or five or six or seven different methods you can use to

come at it, come at the right dose, and then you have to pick the right one out

of those. And then there's certain considerations

when you're escalating doses. What do I need to see happen in the very

first dose that I'm comfortable with before I move on to the next dose?

Okay, and you need build enough time that after your first period is done with the

first dose that you have enough time to assess safety and PK before you move into

your next dose as well. When you're doing Phase 1 studies, for

example, in the oncology setting, you have to go to patients who have

pre-existing cancer. And, and so there are a lot of challenges

associated with it. Somebody in the back mentioned that these

patients are already compromised in terms of their organ status.

They might be taking con-meds. They might be taking other drugs for

their cancer. So it becomes a lot a more complicated.

You cannot use placebo. You don't want to use a large number of

subjects at the very low doses, because you want to give every cancer patient a

chance of effect from the drug. So, at the lower doses you want to have

as few subjects as possible. And as you start getting to the more

effective doses, that's when you might want more subjects.

So, there are a lot of challenges associated with doing Phase 1 studies in

oncology. I'm going to skip that, and I'm going to

come back to the TeGenero example and we'll be done in a minute.

So, based on everything that we've, you know talked about, was there anything

which could have been done differently with the TeGenero study to, to, to

prevent the outcome that they had? So, you'd mention it yeah.

- Staggering? - I think staggering would have been a

good idea. So, they, they dosed the first six

subjects within ten minutes of each other.

And, you know, within four hours all of them started having the same affects and

it, it was pretty late at that point. - [INAUDIBLE] How would you want to start

them, day or hours? - it's, it's very difficult because I

don't know what my human half life is at that point.

But if I, you can predict the human half life based on the animal studies.

And if I know that, you know, my drug is going to stay in the system, say for 48

hours, then I want to at least wait for three or four days before I bring the

next subject in. Anything else that could have been done

differently? Why did this happen?

- Was it [INAUDIBLE]. - Yeah, because it's, it's, it's, it's,

it's a very, it's a super-agonist of CD28, and CD28, it's, it's a humanized

CD28. And the assumption that was made was that

all these other studies which were done in, in primates, the assumption was that

the effect that you see in primates would be the same effect that you see in

humans. Which for this particular target might

not be the case. So when you have these high risk, so

having been through this now, the, the United Kingdom MHRA their, their, their

equivalent of the FDA has actually changed their regulations.

Saying if your drug is a high risk drug, such as an antibody which affects

T-cells, then you need to be extra cautious when you're doing those studies.

but, but the point of this was that in many ways this, this was probably

unavoidable because every, they did not intentionally go in hoping that this

would happen. They did all of their studies.

They, they, they did the right studies in animals, et cetera.

It's just that the human response was so much more sensitive than what they had

seen in primates. Okay?

The other, the only other thing, I didn't mention this.

The study was done at a paraxial unit. They were actually not very close to an

ICU at all. So patients, it, it took them a while to

get those patients to the ICU. So, I apologize for going over.

I hope this was helpful. If you have any questions, I'm here.

If not, thank you very much.

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