Okay, let's talk about something a little bit different.
Let's talk about phases of drug development. So this mythical
pharmaceutical company called Gargantua Pharmaceuticals has
developed an eye drop that can give humans X-ray vision.
So far rats have been able to see cheese through solid walls.
And dogs can see chew toys through sheets of plywood.
Okay sounds like a fun drug. The chief executive officer comes
to you and wants to know what is the next phase of drug
development. Is it phase 1, 2, 3 or 4. In order to answer
this question let's go through what the different phases are.
So when we are testing a drug we talk about the pre-clinical
phase. This is where we do in vitro testing in little test tubes
and little beakers. And then we go on to animal testing and
then animal safety testing. That's the preclinical phase.
Then we move on to the clinical phase which is in human,
phase 1, 2, 3, and 4. When we talk about in vitro testing
we're really talking about various chemical parameters. We
measure pKa, we measure tissue stability, tissue binding.
Whether or not a drug in sensitive to light or not. Whether
or not it will actually leech into the plastic of a pill container.
All kinds of things are tested at this stage of development.
We do environmental testing because we want to know if this
drug is dropped into the sewer, is it going to cause damage
to fish and to wildlife. And we do stability testing.
Whether it's hot temperatures, if you leave the drug on the
dash of your car, or if you accidentally let it freeze
in a cold climate. Animal testing is always tested on at least
two species. We test acute toxicity and subacute toxicity.
And then we do animal safety testing which is a pharmacologic
profile and reproductive toxicity. Let's move on to some
pregnancy risk categories because that's going to be relevant
in our next part of our lecture. Category A risk drugs
have controlled studies. They are done in women and they fail
to show any kind of harm in the first trimester which is
embryogenesis. So these are very very safe drugs. Category B
drugs have animal reproduction studies. They have shown no
fetal risk in the animals and no evidence in human women that
there is going to be any fetal risk. If there are adverse events
in animals they are not confirmed in women. That makes it a
category B drug. A category C drug shows animal reproduction
studies showing teratogenic or embryocidal effect on foetus
and no controlled studies on women. There is no studies on
women available, that's what defines category C but we've
seen harm in animals. Category D drugs show both animal and
human studies where there is definitive human risk and life
threatening. The drug is only used in life threatening situations.
And category X are drugs where sometimes the risk outweighs
the benefits. Sometimes the benefits outweigh the risk
but category X drugs are generally drugs that we don't want
to use and nowadays we generally have other drugs that we can
choose from. So let's move on to the clinical phase. The
clinical phase can be phase 1, 2, 3 or 4. In phase 1
studies we do dose response relationship in healthy male
volunteers. In the United States we can do anywhere from
20-200 volunteers. In the United Kingdom and in Canada it's
generally between 80 and 200 volunteers. You may use volunteers
in smaller numbers in cancer patients as well. In terms of
evaluation of patients with disease, now in phase 2 studies
they are much larger, 100-250 patients. Sometimes they are
even larger than that. There is usually with a placebo
controlled arm and pharmacokinetic and pharmacodynamic
data is collected at this point. Once this information is
definitely analysed and definitely verified, independantly
we move on to phase 3 trials. So phase 3 trials are the big
ones that we always talk about. There is generally a placebo
arm. Generally it's compared against oral therapy, pardon me
older therapy. We monitor for rare forms of toxicity and
adverse events. And if that phase 3 study is successful,
the drug company will submit a new drug application or NDA to
the FDA. In Canada, that NDA goes to the health protection branch.
And in the European Union there are multiple agencies like the
EMEA or CHMP, or sometimes national organizations or subnational
organizations that will be able to evaluate this for them.
Phase 4 refers to post marketing surveillance. Manufacturers
are always required globally to inform the FDA at regular
levels and inform the regulatory agency within whatever country
that they are operating in. It depends upon you. So you as a
physician need to notify the drug company if you see an adverse
event. I personally have filled out probably 2000-3000 phase 4
forms over the course of my career. So it's an important part
of development of drugs and you play a very important part. So
let's go back to our question. We were asking whether or not
the next phase of development is phase 1, 2, 3 or 4. Well,
clearly Gargantua Pharmaceuticals finished or completed much
of their animal trials. They are ready for human trials. So
the answer is going to be phase 1. And in case you are
wondering, yes that's my dog Tucker in the picture and he
always lies like that each morning and watches me get dressed.
I hope you enjoyed this lecture and if you have any questions
you can certainly email us. There are more lectures to follow
and we're gonna as lots of questions and we're gonna
make you much better at writing your exam.