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My name is John Kapeghian.
I'd like to welcome you to
my presentation entitled
Regulatory Guidance on Toxicity
Testing of Pharmaceuticals: ICH.
Just to help clarify early on,
ICH is the abbreviation for
International Conference on Harmonization
of Technical Requirements for
Registration of
Pharmaceuticals for Human Use.
Now you can understand why people
just refer to this as ICH.
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The talk is divided into
five main sections.
First, a brief history of
regulatory guidance and
regulations in drug safety.
Second, the five Ws of ICH.
Third, some discussion of
the key regulatory documents
that, hopefully,
you'll find useful in
planning or conducting
non-clinical or
also referred to as
pre-clinical safety studies.
We'll use the terms
non-clinical and
pre-clinical interchangeably
in this talk.
Fourth, real-life
examples of using
the guidance documents and
how to make sure they really
work for you as
they were intended.
Fifth, let's take a look
at our crystal ball for
pre-clinical drug
safety assessment
in the next several years.
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Let's take a look at how
guidance documents
and regulations
regarding pre-clinical
testing and
drug safety first
came into being.
Prior to the 1930s in
the United States and
the rest of the world
for that matter,
there was no government
regulation of
the manufacture or
distribution of medicines.
And where regulations
were in place,
they were unfortunately found
to be highly inadequate.
This was highlighted
in a tragic way in
1937 when a cold
medication containing
the antibacterial agent
sulfanilamide was
formulated in a new liquid form
to make it easier for
patients to take.
The reputable
pharmaceutical firm
SE Massengill out of
Tennessee had distributed
hundreds of bottles of the
new drug formulation called
Elixir of Sulfanilamide all
over the United States.
Anecdotal evidence of
deaths associated with
elixir of sulfanilamide
prescriptions began surfacing
and FDA inspectors began
immediately trying
to track down all of
the drug prescriptions.
Meanwhile, government
chemists discovered that
the vehicle used in
the new formulation was
a chemical called
diethylene glycol.
Many of you probably
know this as
the typical active
ingredient in antifreeze.
Even at that time,
diethylene glycol
was known to be
extremely nephrotoxic,
essentially destroying
all kidney function.
But no one at the drug firm
had done any
literature review of
the chemical and there were
no safety tests required.
Over 100 people died from taking
the elixir of sulfanilamide.
Many of them being children.
Legislation was enacted
in 1938 that created
the Food, Drug, and Cosmetic
Act in the United States.
For the first time,
there was a provision
for the government to
review new drug registrations
for both safety and efficacy.
You might say that
this Act created
the first regulatory requirement
and guidance for
toxicity testing of
new pharmaceuticals
in the United States.
Another tragedy,
this time averted in the US but
happening in Europe and
in other regions
around the world,
occurred in the late
1950s and early '60s
with the use of a
sedative sold as
a morning-after pill for
nausea due to pregnancy.
That drug was
called thalidomide.
While under review at the FDA,
the new drug application or NDA,
as it is called,
was stalled because of
lack of safety data according
to an FDA reviewer.
However, the drug was being
sold and distributed
to pregnant women in
many countries
around the world and
quickly became associated with
a very rare type of
birth defect in newborns
called phocomelia or
incomplete development
of the limbs.
In 1962, the Food, Drug,
and Cosmetic Act of 1938
was amended by
the now famous
Kefauver-Harris Amendments
that outlined more specific
pre-clinical toxicity studies,
especially in reproductive
and developmental toxicology
that were needed prior to use in
sensitive human populations.
Interestingly enough,
around the rest of the world,
similar types of
government regulations
were being enacted due to
the thalidomide tragedy
as well as other sequela
of serious drug toxicities
in unsuspecting
populations of patients.
Between the late
1960s and mid '80s,
