Section II: Benefit-Risk Management Principles and Practices
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
90
provides for the design of shorter recoveries (less
than 5.5 halflives) where evidence of physiologic
recovery is sufficient rather than demonstration
of complete recovery. However, even with a
shorter recovery period, there still may be cases
where there is evidence of “delayed” toxicity since
pharmacological levels of the monoclonal anti-
body have not receded sufficiently to allow for
a rest period from drug activity. Parenthetically,
some confusion may be avoided by referring to a
“washout period” rather than a “recovery period”
when dealing with monoclonal antibodies in
preclinical studies.
For preclinical evaluations, the value of
immunogenicity data is primarily as an inter-
pretive aid for judging the toxicology study’s
validity. That is, did neutralizing anti-drug
antibodies develop in any of the treatment
groups that resulted in altering the pharmacoki-
netics or pharmacodynamics of the test article?
If the answer is “No,” and there is no immune
system-related toxicity, then it is not necessary
to conduct a preclinical immunogenicity assay.
Strategically, because the decision occurs after
all the data are available poststudy, it is highly
advisable to have a validated immunogenicity
assay in place prior to beginning toxicity studies.
In addition, it is also a best practice to also bank
frozen serum from individual animals before and
after treatment in the event immunogenicity
testing is necessary.13
Integrating the Preclinical Data
Analysis with Risk Management
Tools (Guidelines)
One of the main goals of drug candidate
preclinical testing is to provide a basis for
determining a safe starting dose for FIH
studies. Two guidelines most relevant to this
are the European Medicines Agency’s (EMA)
Guideline on strategies to identify and miti-
gate risks for first-in-human and early clinical
trials with investigational medicinal products16
and the US Food and Drug Administration’s
(FDA) Guidance for Industry—Estimating
the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult Healthy
Volunteers.17 Both documents provide advice on
how to take preclinical safety information that
may have identified potential safety concerns
and apply it to the design and conduct of human
clinical trials, beginning with the estimation of
the initial dose. Some of the factors to be consid-
ered for biotherapeutics are reviewed below.
EMA Guideline on Requirements for First-
in-Man Clinical Trials with Investigational
Drugs
This regulatory document is intended to assist
sponsors in the transition from preclinical safety
development to early clinical development,
in part by determining certain risk factors for
categorizing the candidate drug’s relative risk,
such as being potentially high or low risk prior to
administration to humans. There are three main
risk factor categories:
1. Mode of action
2. Nature of the target
3. Relevance of animal species and models
The mode of action category addresses the con-
cern about investigational drugs that may have
a novel mechanism of action with the potential
to produce severe adverse reactions. Such was
the case with the Tegenero clinical trial,18 where
a cytokine storm was triggered after subjects
received an initial dose of a CD28 agonist. An
example of a drug with potentially low risk might
be a monoclonal antibody that is highly specific
for a single cellular target (such as a tumor anti-
gen). On the other hand, if the in vivo
activity of that same monoclonal antibody
induces massive cytokine release due to tumor
cell lysis, this may increase the risk category.
The above example also applies to the second
risk factor category, the nature of the target, or
the downstream physiological effects occurring as
a result of drug/target interactions. This is where
the quality of the preclinical study information
proves its value. Do the data provide information
on the target specificity, drug distribution, bio-
markers, and pharmacology? How do disease and
individual human variability affect these factors?
Is there any human experience with similar drugs
or disease targets? It stands to reason the more
comprehensive the preclinical safety studies,
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
90
provides for the design of shorter recoveries (less
than 5.5 halflives) where evidence of physiologic
recovery is sufficient rather than demonstration
of complete recovery. However, even with a
shorter recovery period, there still may be cases
where there is evidence of “delayed” toxicity since
pharmacological levels of the monoclonal anti-
body have not receded sufficiently to allow for
a rest period from drug activity. Parenthetically,
some confusion may be avoided by referring to a
“washout period” rather than a “recovery period”
when dealing with monoclonal antibodies in
preclinical studies.
For preclinical evaluations, the value of
immunogenicity data is primarily as an inter-
pretive aid for judging the toxicology study’s
validity. That is, did neutralizing anti-drug
antibodies develop in any of the treatment
groups that resulted in altering the pharmacoki-
netics or pharmacodynamics of the test article?
If the answer is “No,” and there is no immune
system-related toxicity, then it is not necessary
to conduct a preclinical immunogenicity assay.
Strategically, because the decision occurs after
all the data are available poststudy, it is highly
advisable to have a validated immunogenicity
assay in place prior to beginning toxicity studies.
In addition, it is also a best practice to also bank
frozen serum from individual animals before and
after treatment in the event immunogenicity
testing is necessary.13
Integrating the Preclinical Data
Analysis with Risk Management
Tools (Guidelines)
One of the main goals of drug candidate
preclinical testing is to provide a basis for
determining a safe starting dose for FIH
studies. Two guidelines most relevant to this
are the European Medicines Agency’s (EMA)
Guideline on strategies to identify and miti-
gate risks for first-in-human and early clinical
trials with investigational medicinal products16
and the US Food and Drug Administration’s
(FDA) Guidance for Industry—Estimating
the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult Healthy
Volunteers.17 Both documents provide advice on
how to take preclinical safety information that
may have identified potential safety concerns
and apply it to the design and conduct of human
clinical trials, beginning with the estimation of
the initial dose. Some of the factors to be consid-
ered for biotherapeutics are reviewed below.
EMA Guideline on Requirements for First-
in-Man Clinical Trials with Investigational
Drugs
This regulatory document is intended to assist
sponsors in the transition from preclinical safety
development to early clinical development,
in part by determining certain risk factors for
categorizing the candidate drug’s relative risk,
such as being potentially high or low risk prior to
administration to humans. There are three main
risk factor categories:
1. Mode of action
2. Nature of the target
3. Relevance of animal species and models
The mode of action category addresses the con-
cern about investigational drugs that may have
a novel mechanism of action with the potential
to produce severe adverse reactions. Such was
the case with the Tegenero clinical trial,18 where
a cytokine storm was triggered after subjects
received an initial dose of a CD28 agonist. An
example of a drug with potentially low risk might
be a monoclonal antibody that is highly specific
for a single cellular target (such as a tumor anti-
gen). On the other hand, if the in vivo
activity of that same monoclonal antibody
induces massive cytokine release due to tumor
cell lysis, this may increase the risk category.
The above example also applies to the second
risk factor category, the nature of the target, or
the downstream physiological effects occurring as
a result of drug/target interactions. This is where
the quality of the preclinical study information
proves its value. Do the data provide information
on the target specificity, drug distribution, bio-
markers, and pharmacology? How do disease and
individual human variability affect these factors?
Is there any human experience with similar drugs
or disease targets? It stands to reason the more
comprehensive the preclinical safety studies,