Risk Management Principles for Devices and Pharmaceuticals
85
Introduction
Background
This chapter discusses how early preclinical
assessment of potential toxicology liabilities, com-
bined with exploratory toxicology evaluations, can
benefit the final toxicology assessment for a can-
didate biotherapeutic molecule. This early effort at
hazard identification can facilitate the following
steps of risk assessment and risk management.
Rather than choosing a minimal set of standard
toxicology studies that may meet the regula-
tory review requirements, sponsors and patients
alike are better served by a drug development
plan incorporating information obtained from
exploratory toxicology investigations. Exploratory,
or early discovery toxicology as it also may be
called, generally involves mechanistic or hypoth-
esis-driven studies during the lead optimization
or drug-selection phase. In other cases, it simply
means characterizing drug effects on receptors,
pathways, and potential target organs at expo-
sures that tend to be higher than those typically
used in animal models seeking to demonstrate
efficacy. But by taking either approach, the design
of standard toxicology studies can be customized
based on the findings and interpretations derived
from actual pilot data, including drug-related
pharmacology and pharmacokinetics, with the
candidate molecule itself.
The topic of exploratory toxicology and
where it fits into drug development schemes is
the subject of several reviews.1–5 This chapter
highlights how the melding of early toxicity
studies with the pharmacology-profiling phase
of drug development provides a strong scientific
base for dose selection and specific study design
considerations during preclinical development.
An overall driver for implementing this approach
is to facilitate the preclinical to clinical transition
by identifying potential toxicology liabilities as
early as possible, then mitigating these through
the inclusion of toxicology studies that have been
optimally designed to address these concerns.
Using Discovery Pharmacology and
Exploratory Toxicology for Risk
Minimization
Discovery in pharmaceutical development
involves the selection of the best candidate drug
molecule. This endeavor relies on the evaluation
of preclinical pharmacokinetics and dose-re-
sponse pharmacology endpoints in animals
to choose the molecule with the best efficacy,
The Impact of Preclinical Planning
and Study Outcome on the Risk
Management of Biologicals
Michael Engwall, DVM, PhD, DSP
6
85
Introduction
Background
This chapter discusses how early preclinical
assessment of potential toxicology liabilities, com-
bined with exploratory toxicology evaluations, can
benefit the final toxicology assessment for a can-
didate biotherapeutic molecule. This early effort at
hazard identification can facilitate the following
steps of risk assessment and risk management.
Rather than choosing a minimal set of standard
toxicology studies that may meet the regula-
tory review requirements, sponsors and patients
alike are better served by a drug development
plan incorporating information obtained from
exploratory toxicology investigations. Exploratory,
or early discovery toxicology as it also may be
called, generally involves mechanistic or hypoth-
esis-driven studies during the lead optimization
or drug-selection phase. In other cases, it simply
means characterizing drug effects on receptors,
pathways, and potential target organs at expo-
sures that tend to be higher than those typically
used in animal models seeking to demonstrate
efficacy. But by taking either approach, the design
of standard toxicology studies can be customized
based on the findings and interpretations derived
from actual pilot data, including drug-related
pharmacology and pharmacokinetics, with the
candidate molecule itself.
The topic of exploratory toxicology and
where it fits into drug development schemes is
the subject of several reviews.1–5 This chapter
highlights how the melding of early toxicity
studies with the pharmacology-profiling phase
of drug development provides a strong scientific
base for dose selection and specific study design
considerations during preclinical development.
An overall driver for implementing this approach
is to facilitate the preclinical to clinical transition
by identifying potential toxicology liabilities as
early as possible, then mitigating these through
the inclusion of toxicology studies that have been
optimally designed to address these concerns.
Using Discovery Pharmacology and
Exploratory Toxicology for Risk
Minimization
Discovery in pharmaceutical development
involves the selection of the best candidate drug
molecule. This endeavor relies on the evaluation
of preclinical pharmacokinetics and dose-re-
sponse pharmacology endpoints in animals
to choose the molecule with the best efficacy,
The Impact of Preclinical Planning
and Study Outcome on the Risk
Management of Biologicals
Michael Engwall, DVM, PhD, DSP
6