Risk Management Principles for Devices and Pharmaceuticals
87
“Proactive safety assessment at this stage is
largely an in cerebro and/or in silico exercise.
Safety issues inherent in modulating a target can
be anticipated from existing drug precedent for
example, agonists for peroxisome proliferator-ac-
tivator receptors (PPAR) might be anticipated
to be tumorigenic, increase heart weight, and
produce plasma-volume expansion in preclinical
studies. For novel targets, safety concerns must
be inferred from literature on genetic studies
in humans and lower organisms, or by mining
pathways involved in a disease process.”
An example of an ETLA summary for a hypothet-
ical GLP-1 analog is provided as Appendix 6-1.
Safety Pharmacology and
Exploratory Toxicology
An ETLA also complements the required reg-
ulatory safety pharmacology assessments. These
latter studies are conducted per the International
Conference on Harmonisation (ICH) S7A
guideline7 and consist of a base set of studies
designed to characterize drug effects on the
cardiovascular, respiratory, and central nervous
system. The overall purpose is to investigate
a new drug candidate’s potential undesirable
pharmacological effects on critical organ system
functions.8–10 However, the guideline indicates
flexibility in the design of such studies and
suggests supplemental studies on different organ
systems may be required (such as renal, GI,
immune, and autonomic nervous system). A
recently published Q&A from the E14 and S7A
guidelines provides more detailed discussion on
the use of nonclinical data to address risk for
QTc prolongation.11 This may be particularly
important for biotherapeutics, since most of
these entities have been exempted from routine
safety pharmacology testing. On the other hand,
most biotherapeutics have pharmacology that is
highly specific for a particular system, such as the
immune system. Several novel bio-immunothera-
peutics have been developed for the treatment of
autoimmune disorders, such as asthma, rheuma-
toid arthritis, psoriasis, and others. Many of these
agents produce no toxicity and often no pharma-
cological effects in normal or diseased animals in
preclinical studies. In the latter case, conducting
directed preclinical experiments in normal ani-
mals or in animal disease models specific for the
drug’s indication, for the purpose of identifying
potential pharmacology biomarkers, would
seem appropriate. Identifying such markers
offers significant advantages in the drug’s clinical
development if such markers can be monitored
clinically. These studies can be conducted either
separately in early discovery, or they can be
conducted in the context of a safety pharmacol-
ogy paradigm where both pharmacological and
toxicological exposures are characterized.
Combining a safety pharmacology approach
with the pharmacology-profiling phase offers a
chance to clarify hypothetical liabilities identified
during the ETLA. If done with forethought,
these investigations can contribute to defining,
in relation to pharmacology and toxicology, a
dose-response effect, time-course of action, dose
for maximum effect, metabolism, and pharma-
cokinetics, biomarkers of pharmacology and/
or toxicology, and identification of safety issues.
At the least, such information adds to a more
complete mechanistic understanding of a drug’s
overall action that is important, especially in early
development, before experience is gained with
the drug in the actual clinical setting. Further,
high-dose pharmacological profiling may dis-
close unintended effects that are a direct result
of drug-receptor interactions, or via nonselective
or off-target effects. Understanding whether
unintended toxicity is related to the mechanism
of action is essential in clinical safety interpreta-
tion.12 Ideally, these studies would be done prior to
planning the standard toxicology screening studies
to aid in defining the maximum tolerated dose.
Designing Risk-Mitigating GLP
Toxicology Studies
The overarching reasons for conducting pre-
clinical toxicology studies are because they are
required by regulation and because of the need
to define the initial FIH dose selection. But
rather than using a template approach, there is
an opportunity to design these screening studies
in a manner providing support for clinical trials
in the way of biomarker characterization and
87
“Proactive safety assessment at this stage is
largely an in cerebro and/or in silico exercise.
Safety issues inherent in modulating a target can
be anticipated from existing drug precedent for
example, agonists for peroxisome proliferator-ac-
tivator receptors (PPAR) might be anticipated
to be tumorigenic, increase heart weight, and
produce plasma-volume expansion in preclinical
studies. For novel targets, safety concerns must
be inferred from literature on genetic studies
in humans and lower organisms, or by mining
pathways involved in a disease process.”
An example of an ETLA summary for a hypothet-
ical GLP-1 analog is provided as Appendix 6-1.
Safety Pharmacology and
Exploratory Toxicology
An ETLA also complements the required reg-
ulatory safety pharmacology assessments. These
latter studies are conducted per the International
Conference on Harmonisation (ICH) S7A
guideline7 and consist of a base set of studies
designed to characterize drug effects on the
cardiovascular, respiratory, and central nervous
system. The overall purpose is to investigate
a new drug candidate’s potential undesirable
pharmacological effects on critical organ system
functions.8–10 However, the guideline indicates
flexibility in the design of such studies and
suggests supplemental studies on different organ
systems may be required (such as renal, GI,
immune, and autonomic nervous system). A
recently published Q&A from the E14 and S7A
guidelines provides more detailed discussion on
the use of nonclinical data to address risk for
QTc prolongation.11 This may be particularly
important for biotherapeutics, since most of
these entities have been exempted from routine
safety pharmacology testing. On the other hand,
most biotherapeutics have pharmacology that is
highly specific for a particular system, such as the
immune system. Several novel bio-immunothera-
peutics have been developed for the treatment of
autoimmune disorders, such as asthma, rheuma-
toid arthritis, psoriasis, and others. Many of these
agents produce no toxicity and often no pharma-
cological effects in normal or diseased animals in
preclinical studies. In the latter case, conducting
directed preclinical experiments in normal ani-
mals or in animal disease models specific for the
drug’s indication, for the purpose of identifying
potential pharmacology biomarkers, would
seem appropriate. Identifying such markers
offers significant advantages in the drug’s clinical
development if such markers can be monitored
clinically. These studies can be conducted either
separately in early discovery, or they can be
conducted in the context of a safety pharmacol-
ogy paradigm where both pharmacological and
toxicological exposures are characterized.
Combining a safety pharmacology approach
with the pharmacology-profiling phase offers a
chance to clarify hypothetical liabilities identified
during the ETLA. If done with forethought,
these investigations can contribute to defining,
in relation to pharmacology and toxicology, a
dose-response effect, time-course of action, dose
for maximum effect, metabolism, and pharma-
cokinetics, biomarkers of pharmacology and/
or toxicology, and identification of safety issues.
At the least, such information adds to a more
complete mechanistic understanding of a drug’s
overall action that is important, especially in early
development, before experience is gained with
the drug in the actual clinical setting. Further,
high-dose pharmacological profiling may dis-
close unintended effects that are a direct result
of drug-receptor interactions, or via nonselective
or off-target effects. Understanding whether
unintended toxicity is related to the mechanism
of action is essential in clinical safety interpreta-
tion.12 Ideally, these studies would be done prior to
planning the standard toxicology screening studies
to aid in defining the maximum tolerated dose.
Designing Risk-Mitigating GLP
Toxicology Studies
The overarching reasons for conducting pre-
clinical toxicology studies are because they are
required by regulation and because of the need
to define the initial FIH dose selection. But
rather than using a template approach, there is
an opportunity to design these screening studies
in a manner providing support for clinical trials
in the way of biomarker characterization and