Risk Management Principles for Devices and Pharmaceuticals
91
the better the discussion of this information’s
relevance in relation to overall human risk-as-
sessment predictions.
The strength of the rationale regarding
mechanism of action and target interactions
rests primarily on the principle that relevant
animal species and models were used to obtain
this information. Simply put, a relevant model is
one that is pharmacologically responsive to the
investigational drug.
However, no single animal model fully
simulates or reproduces the human condition. It
also should be obvious the quality or sagacity of
preclinical data interpretation is an important
component of judging the adequacy or relevance
of the animal studies performed with the drug.
As seen in the retrospective analysis of Tegenero,
it was not that the cynomolgus monkey was an
inappropriate test species so much as there was
a lack of prior knowledge about the differences
in CD28 immunobiology between humans
and nonhuman primates combined with mis-
interpretation of the significance of the safety
signals from those studies.18 It is very important
sponsors document and justify in detail the steps
taken or the rationale used to justify the species
selection prior to conducting the preclinical
studies and provide a discussion of how the pre-
clinical data (e.g., pharmacology, target toxicity)
did or did not support the decision.
Important for supporting that rationale are
data obtained from pharmacology studies in the
relevant animal model together with pharmaco-
kinetic and toxicokinetic evaluations. Without
a dose-response curve or knowledge of the
relationship of plasma levels with pharmacolog-
ical and toxicological endpoints, it is essentially
impossible to have a defensible dose justification
for FIH.
FDA Guidance for Industry—Estimating
the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult
Healthy Volunteers
This separate guidance also aids in transitioning
from the preclinical phase to the clinical, but
with an emphasis on applying preclinical study
data to the selection of a safe starting dose for
FIH dosing. There are many reviews covering
multiple aspects of dose selection for FIH
trials.19–23 Fundamental to all dose selection strat-
egies is the reliance on preclinical toxicity data in
the context of adequate ADME characterization.
Again, the obvious theme in each review is the
more comprehensive the preclinical data, the
more confidence there can be in dose projections.
“The NOAEL is a generally accepted benchmark
for safety when derived from appropriate animal
studies and can serve as the starting point for
determining a reasonably safe starting dose of
a new therapeutic in healthy (or asymptomatic)
human volunteers.”
“As a general rule, an adverse effect observed in
nonclinical toxicology studies used to define a
NOAEL for the purpose of dose-setting should
be based on an effect that would be unacceptable
if produced by the initial dose of a therapeutic in
a Phase 1 clinical trial conducted in adult healthy
volunteers.”24
Traditionally, the starting dose for an FIH study
is derived from calculations, or dose extrapo-
lations, based on the NOAEL determined in
the most sensitive animal species in toxicology
studies. In general, this has worked well for small
molecule, chemical drug entities, provided the
appropriate allowances for species differences in
ADME characteristics (e.g., metabolism, drug
distribution) are factored into the equations prior
to administering the agent to humans. However,
for biologicals, the biotherapeutic often has no
pharmacologic activity or toxicity in the nor-
mal animal models used in preclinical testing,
even when relatively large amounts of drug are
repeatedly administered in these studies. Other
preclinical data available then must be consid-
ered, such as the mechanism of action, binding
affinity, and projected similarities in pharma-
cokinetics between the models and humans. In
other words, it is necessary to rely on preclinical
pharmacokinetic data, which may be available
only from discovery studies that used a disease
animal model. A large portion of the 2005 FDA
guidance for estimating the maximum safe
starting dose17 addresses this situation, which
obviously aims to avoid another Tegenero-type
91
the better the discussion of this information’s
relevance in relation to overall human risk-as-
sessment predictions.
The strength of the rationale regarding
mechanism of action and target interactions
rests primarily on the principle that relevant
animal species and models were used to obtain
this information. Simply put, a relevant model is
one that is pharmacologically responsive to the
investigational drug.
However, no single animal model fully
simulates or reproduces the human condition. It
also should be obvious the quality or sagacity of
preclinical data interpretation is an important
component of judging the adequacy or relevance
of the animal studies performed with the drug.
As seen in the retrospective analysis of Tegenero,
it was not that the cynomolgus monkey was an
inappropriate test species so much as there was
a lack of prior knowledge about the differences
in CD28 immunobiology between humans
and nonhuman primates combined with mis-
interpretation of the significance of the safety
signals from those studies.18 It is very important
sponsors document and justify in detail the steps
taken or the rationale used to justify the species
selection prior to conducting the preclinical
studies and provide a discussion of how the pre-
clinical data (e.g., pharmacology, target toxicity)
did or did not support the decision.
Important for supporting that rationale are
data obtained from pharmacology studies in the
relevant animal model together with pharmaco-
kinetic and toxicokinetic evaluations. Without
a dose-response curve or knowledge of the
relationship of plasma levels with pharmacolog-
ical and toxicological endpoints, it is essentially
impossible to have a defensible dose justification
for FIH.
FDA Guidance for Industry—Estimating
the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult
Healthy Volunteers
This separate guidance also aids in transitioning
from the preclinical phase to the clinical, but
with an emphasis on applying preclinical study
data to the selection of a safe starting dose for
FIH dosing. There are many reviews covering
multiple aspects of dose selection for FIH
trials.19–23 Fundamental to all dose selection strat-
egies is the reliance on preclinical toxicity data in
the context of adequate ADME characterization.
Again, the obvious theme in each review is the
more comprehensive the preclinical data, the
more confidence there can be in dose projections.
“The NOAEL is a generally accepted benchmark
for safety when derived from appropriate animal
studies and can serve as the starting point for
determining a reasonably safe starting dose of
a new therapeutic in healthy (or asymptomatic)
human volunteers.”
“As a general rule, an adverse effect observed in
nonclinical toxicology studies used to define a
NOAEL for the purpose of dose-setting should
be based on an effect that would be unacceptable
if produced by the initial dose of a therapeutic in
a Phase 1 clinical trial conducted in adult healthy
volunteers.”24
Traditionally, the starting dose for an FIH study
is derived from calculations, or dose extrapo-
lations, based on the NOAEL determined in
the most sensitive animal species in toxicology
studies. In general, this has worked well for small
molecule, chemical drug entities, provided the
appropriate allowances for species differences in
ADME characteristics (e.g., metabolism, drug
distribution) are factored into the equations prior
to administering the agent to humans. However,
for biologicals, the biotherapeutic often has no
pharmacologic activity or toxicity in the nor-
mal animal models used in preclinical testing,
even when relatively large amounts of drug are
repeatedly administered in these studies. Other
preclinical data available then must be consid-
ered, such as the mechanism of action, binding
affinity, and projected similarities in pharma-
cokinetics between the models and humans. In
other words, it is necessary to rely on preclinical
pharmacokinetic data, which may be available
only from discovery studies that used a disease
animal model. A large portion of the 2005 FDA
guidance for estimating the maximum safe
starting dose17 addresses this situation, which
obviously aims to avoid another Tegenero-type