Section II: Benefit-Risk Management Principles and Practices
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
92
incident with an FIH biotherapeutic. Generally,
the default safety factor for a starting dose is
determined by dividing the human equivalent
dose derived from the animal NOAEL by a
factor of 10.17 But the guidance warns this may
not be acceptable, and a larger factor is warranted
where higher risk is perceived, such as with those
variables listed in Table 6-2. The starting dose
for a biotherapeutic candidate, in many cases,
is based on the pharmacologically active dose
rather than on toxicity (NOAEL). This dose
may be significantly lower than the calculated
maximum recommended safe dose (MRSD),
especially when a safety factor is then applied to
the pharmacologically active dose. A pertinent
example is the administration of drugs that target
T lymphocytes, which could potentially trigger
a cytokine storm in a host at pharmacological
doses. Applying a safety factor to the pharma-
cologically active dose calculation is similar to
the minimum-anticipated-biological-effect-level
(MABEL) approach detailed in the EMA
guideline.17 Hence, it is important to perform
a comprehensive preclinical pharmacology
characterization to optimally position the dose
justification for the sponsor’s IND application
and subsequent FIH trial.
End Result: Addressing Safety Issues
in All Components of the Preclinical
Safety Package
The goal of preclinical testing strategies is to
minimize any potential risks to humans to whom
a new pharmaceutical substance will be adminis-
tered. Preclinical testing refers to the entire safety
risk assessment process. As stated by Olejniczak
and Gunzel:
“Thus, preclinical studies constitute a program
whose results are to offer as much safety as
possible during every phase of use in humans.
...Moreover, this program is not a sequence of
certain tests which could be regarded or carried
out in isolation but is rather intertwined into the
development process of medicinal products.”26
It is also important for biotherapeutics to include
the different manufacturing components as
part of the preclinical package, such as charac-
terization of the production cell substrate, raw
materials, impurities, and final active pharma-
ceutical ingredients.27 The emphasis in an initial
Phase 1 chemistry, manufacturing, and controls
(CMC) submission generally should be placed on
providing information that will allow evaluation
of subject safety in the proposed study. A project
can be placed on clinical hold if the formulation
has unknown or impure components or subopti-
mal characterization of the impurity profile and
potential health hazards that can be avoided by
well-executed preclinical toxicology studies.
Briefly, the primary categories (also reviewed
in Reference 21) that need to be addressed in
preclinical studies for a successful regulatory
submission are:
Scientific Review and Early Risk
Assessment
• Comprehensive review of scientific literature
and databases
• Initial determination of toxicology and
safety liabilities
• Development of preclinical strategy and a
risk mitigation plan
Table 6-2. Factors Affecting the Safety Margin Calculations for FIH
Steep dose-response curve Unexplained mortality
Severe toxicities Large variability
Non-monitorable toxicity Nonlinear pharmacokinetics
Toxicities without premonitory signs Inadequate dose-response data
Variable bioavailability Novel therapeutic targets
Irreversible toxicity Animal models with limited utility
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
92
incident with an FIH biotherapeutic. Generally,
the default safety factor for a starting dose is
determined by dividing the human equivalent
dose derived from the animal NOAEL by a
factor of 10.17 But the guidance warns this may
not be acceptable, and a larger factor is warranted
where higher risk is perceived, such as with those
variables listed in Table 6-2. The starting dose
for a biotherapeutic candidate, in many cases,
is based on the pharmacologically active dose
rather than on toxicity (NOAEL). This dose
may be significantly lower than the calculated
maximum recommended safe dose (MRSD),
especially when a safety factor is then applied to
the pharmacologically active dose. A pertinent
example is the administration of drugs that target
T lymphocytes, which could potentially trigger
a cytokine storm in a host at pharmacological
doses. Applying a safety factor to the pharma-
cologically active dose calculation is similar to
the minimum-anticipated-biological-effect-level
(MABEL) approach detailed in the EMA
guideline.17 Hence, it is important to perform
a comprehensive preclinical pharmacology
characterization to optimally position the dose
justification for the sponsor’s IND application
and subsequent FIH trial.
End Result: Addressing Safety Issues
in All Components of the Preclinical
Safety Package
The goal of preclinical testing strategies is to
minimize any potential risks to humans to whom
a new pharmaceutical substance will be adminis-
tered. Preclinical testing refers to the entire safety
risk assessment process. As stated by Olejniczak
and Gunzel:
“Thus, preclinical studies constitute a program
whose results are to offer as much safety as
possible during every phase of use in humans.
...Moreover, this program is not a sequence of
certain tests which could be regarded or carried
out in isolation but is rather intertwined into the
development process of medicinal products.”26
It is also important for biotherapeutics to include
the different manufacturing components as
part of the preclinical package, such as charac-
terization of the production cell substrate, raw
materials, impurities, and final active pharma-
ceutical ingredients.27 The emphasis in an initial
Phase 1 chemistry, manufacturing, and controls
(CMC) submission generally should be placed on
providing information that will allow evaluation
of subject safety in the proposed study. A project
can be placed on clinical hold if the formulation
has unknown or impure components or subopti-
mal characterization of the impurity profile and
potential health hazards that can be avoided by
well-executed preclinical toxicology studies.
Briefly, the primary categories (also reviewed
in Reference 21) that need to be addressed in
preclinical studies for a successful regulatory
submission are:
Scientific Review and Early Risk
Assessment
• Comprehensive review of scientific literature
and databases
• Initial determination of toxicology and
safety liabilities
• Development of preclinical strategy and a
risk mitigation plan
Table 6-2. Factors Affecting the Safety Margin Calculations for FIH
Steep dose-response curve Unexplained mortality
Severe toxicities Large variability
Non-monitorable toxicity Nonlinear pharmacokinetics
Toxicities without premonitory signs Inadequate dose-response data
Variable bioavailability Novel therapeutic targets
Irreversible toxicity Animal models with limited utility