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.