Section II: Benefit-Risk Management Principles and Practices
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
86
specificity, and pharmaceutical properties.
Traditionally, relatively low doses are used at this
phase, with the singular focus being on profiling
the molecule’s primary pharmacological effects.
Exploratory toxicology, on the other hand, refers
to the practice of using an expanded dose range
of a candidate molecule in studies to look for
potential target organ toxicities during the lead
optimization and discovery phases of develop-
ment. Typically limited to acute or single-dose
exposure, the studies are intended to identify
any overt on- or off-target toxicities in relevant
animal species. The information then is used
to justify species selection, and to aid in dose
setting, inclusion of appropriate endpoints, and
analyses for subsequent preclinical toxicity stud-
ies. Many sponsors today combine both aspects
of pharmacological profiling and exploratory tox-
icology during the drug-discovery phase due to
the cost, both in time and money, of unexpected
or unmanageable toxicity. What advantages are
realized by executing an exploratory toxicology
strategy? Foremost is the identification of liabil-
ities for the biotherapeutic before making large
resource and time commitments. Much infor-
mation can be obtained in the exploratory phase
of development with experiments using minimal
animal numbers and are specifically designed to
identify toxicity liabilities. Once determined, a
judgment can be made whether the toxicity can
be monitored and/or managed. A decision also
can be made to attempt preclinical experiments
at this phase that may clarify hypothetical liabili-
ties or perhaps explore using toxicity biomarkers.
The information then is evaluated considering
what is known about the mechanism of drug
action, what preclinical and clinical pharma-
cology or safety data are already available, and
whether there are pharmaceutical precedents
(class effects) known for similar therapeutic
molecules. For a new biotherapeutic molecule,
the conclusions reached about the preceding can
be documented in a summary fashion in an early
toxicology liability assessment (ETLA) with the
information organized by headings as suggested
in Table 6-1.
The ETLA document itself becomes a
component of the formalized drug project plan
and a record for the development team on the
early decision and planning process for the drug
candidate. In addition to identifying toxicology
liabilities, other relevant information can be
captured, including:
• Reasons for dose and species selection for
GLP toxicology studies that will support
first-in-human (FIH) dosing,
• Explanation of the drug candidate’s mech-
anism of action that also may lead to the
identification of clinically useful biomarkers,
and
• Supporting data and criteria for selection of
the drug candidate based perhaps on early
screening of multiple molecules.
As aptly stated by JL Stevens6 regarding the
implementation of exploratory toxicology:
Table 6-1. Summary Elements of an ETLA
Target Drug name, therapeutic indication, description of the target, and mechanism
On Target Risks Listing and brief explanation of potential target related toxicities
Off Target Risks Listing and brief explanation of potential off target toxicities related to secondary
pharmacology
Previous Target Experience Drug class information, clinical trial experience, and competitive intelligence
Summary Overview of the intended mechanism of action of the drug molecule and the potential
liabilities or adverse effects gleaned from the toxicology assessment
Recommendations Toxicologist’s recommendations on specific studies or concerns to be addressed during
preclinical development and on a possible risk mitigation strategy
Timeline Stage in development at which major liabilities should be addressed
Impact Risk to program development if potential toxicology issues are not mitigated
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
86
specificity, and pharmaceutical properties.
Traditionally, relatively low doses are used at this
phase, with the singular focus being on profiling
the molecule’s primary pharmacological effects.
Exploratory toxicology, on the other hand, refers
to the practice of using an expanded dose range
of a candidate molecule in studies to look for
potential target organ toxicities during the lead
optimization and discovery phases of develop-
ment. Typically limited to acute or single-dose
exposure, the studies are intended to identify
any overt on- or off-target toxicities in relevant
animal species. The information then is used
to justify species selection, and to aid in dose
setting, inclusion of appropriate endpoints, and
analyses for subsequent preclinical toxicity stud-
ies. Many sponsors today combine both aspects
of pharmacological profiling and exploratory tox-
icology during the drug-discovery phase due to
the cost, both in time and money, of unexpected
or unmanageable toxicity. What advantages are
realized by executing an exploratory toxicology
strategy? Foremost is the identification of liabil-
ities for the biotherapeutic before making large
resource and time commitments. Much infor-
mation can be obtained in the exploratory phase
of development with experiments using minimal
animal numbers and are specifically designed to
identify toxicity liabilities. Once determined, a
judgment can be made whether the toxicity can
be monitored and/or managed. A decision also
can be made to attempt preclinical experiments
at this phase that may clarify hypothetical liabili-
ties or perhaps explore using toxicity biomarkers.
The information then is evaluated considering
what is known about the mechanism of drug
action, what preclinical and clinical pharma-
cology or safety data are already available, and
whether there are pharmaceutical precedents
(class effects) known for similar therapeutic
molecules. For a new biotherapeutic molecule,
the conclusions reached about the preceding can
be documented in a summary fashion in an early
toxicology liability assessment (ETLA) with the
information organized by headings as suggested
in Table 6-1.
The ETLA document itself becomes a
component of the formalized drug project plan
and a record for the development team on the
early decision and planning process for the drug
candidate. In addition to identifying toxicology
liabilities, other relevant information can be
captured, including:
• Reasons for dose and species selection for
GLP toxicology studies that will support
first-in-human (FIH) dosing,
• Explanation of the drug candidate’s mech-
anism of action that also may lead to the
identification of clinically useful biomarkers,
and
• Supporting data and criteria for selection of
the drug candidate based perhaps on early
screening of multiple molecules.
As aptly stated by JL Stevens6 regarding the
implementation of exploratory toxicology:
Table 6-1. Summary Elements of an ETLA
Target Drug name, therapeutic indication, description of the target, and mechanism
On Target Risks Listing and brief explanation of potential target related toxicities
Off Target Risks Listing and brief explanation of potential off target toxicities related to secondary
pharmacology
Previous Target Experience Drug class information, clinical trial experience, and competitive intelligence
Summary Overview of the intended mechanism of action of the drug molecule and the potential
liabilities or adverse effects gleaned from the toxicology assessment
Recommendations Toxicologist’s recommendations on specific studies or concerns to be addressed during
preclinical development and on a possible risk mitigation strategy
Timeline Stage in development at which major liabilities should be addressed
Impact Risk to program development if potential toxicology issues are not mitigated