Risk Management Principles for Devices and Pharmaceuticals
93
Chemistry, Manufacturing, and Controls
• Description of manufacturing process
• List of reagents, solvents, and catalysts
• For biotech drugs, relevant information on
animal/human sources of reagents
• Specification or proposed acceptance criteria
and certificate of analysis
• Stability, including stability study summary
and analytical procedures
Pharmacology
• Identification of relevant animal models,
preferably two species
• Mechanism of action
• Receptor binding characterization and
occupancy level
• In vivo target dose-response relationships in
• Normal and disease model
• Absorption, distribution, metabolism excre-
tion, and duration of pharmacologic activity
Safety Pharmacology
• “Exaggerated pharmacology” effects on the
drug target
• Unintended or off-target effects
• Identification of most sensitive animal
species
• Characterization of drug effects on major
organ system functions
Toxicology
• One, three-, or six-month repeat dose toxi-
cology studies
• Genetic toxicology studies
• Reproductive toxicology studies
• Toxicokinetic evaluations
• Two species (unless justification for only one
or alternatives)
• GLP tissue cross-reactivity characterization
(antibody therapeutics)
Interpretation and Final Risk Assessment
• Analysis and integration of all relevant phar-
macology, pharmacokinetics and toxicology
data
• Risk determination
º Seriousness of potential adverse effects
º Calculation of safety factor
º Calculation of first human dose
-Based on no adverse effect level
NOAEL (or highest NOEL)
-Based on minimum anticipated
biological effect level (MABEL)
-Based on pharmacologically active
dose (PAD)
Table 6-3. Hypothetical Risk Management Strategy for GLP-1 Agonist Biotherapeutics
Target Organs Potential Risks Preclinical Risk Management Plan
GI Dose-dependent nausea and vomiting are com-
mon at the initiation of GLP-1 agonist therapy
Decrease the dose of the GLP-1 agonist and
titrate slowly as tolerated
Hematopoietic Decreases in erythrocyte counts, hemoglobin,
platelets increased reticulocytes
Monitor standard hematological parameters
Liver Increases in AST, ALT Monitor liver function
Heart
GLP-1 receptor agonists have the potential to
influence traditional cardiovascular risk factors
and cardiac physiology
monitor cardiac function
Kidney Changes in urine osmolality and increased blood
creatinine and urea nitrogen
Monitor standard blood chemistry and urinalysis
Pancreas Pancreatitis
Monitor for symptoms of pancreatitis and eval-
uate if necessary serum amylase or lipase levels
should be evaluated and abdominal imaging if
required
Thyroid C-cell hyperplasia, adenoma Monitor calcitonin serum levels
Immunogenicity Anti-drug antibodies that cross-react with
endogenous GLP-1
Monitor anti-drug antibodies and, if present,
characterize for neutralizing of GLP activity
93
Chemistry, Manufacturing, and Controls
• Description of manufacturing process
• List of reagents, solvents, and catalysts
• For biotech drugs, relevant information on
animal/human sources of reagents
• Specification or proposed acceptance criteria
and certificate of analysis
• Stability, including stability study summary
and analytical procedures
Pharmacology
• Identification of relevant animal models,
preferably two species
• Mechanism of action
• Receptor binding characterization and
occupancy level
• In vivo target dose-response relationships in
• Normal and disease model
• Absorption, distribution, metabolism excre-
tion, and duration of pharmacologic activity
Safety Pharmacology
• “Exaggerated pharmacology” effects on the
drug target
• Unintended or off-target effects
• Identification of most sensitive animal
species
• Characterization of drug effects on major
organ system functions
Toxicology
• One, three-, or six-month repeat dose toxi-
cology studies
• Genetic toxicology studies
• Reproductive toxicology studies
• Toxicokinetic evaluations
• Two species (unless justification for only one
or alternatives)
• GLP tissue cross-reactivity characterization
(antibody therapeutics)
Interpretation and Final Risk Assessment
• Analysis and integration of all relevant phar-
macology, pharmacokinetics and toxicology
data
• Risk determination
º Seriousness of potential adverse effects
º Calculation of safety factor
º Calculation of first human dose
-Based on no adverse effect level
NOAEL (or highest NOEL)
-Based on minimum anticipated
biological effect level (MABEL)
-Based on pharmacologically active
dose (PAD)
Table 6-3. Hypothetical Risk Management Strategy for GLP-1 Agonist Biotherapeutics
Target Organs Potential Risks Preclinical Risk Management Plan
GI Dose-dependent nausea and vomiting are com-
mon at the initiation of GLP-1 agonist therapy
Decrease the dose of the GLP-1 agonist and
titrate slowly as tolerated
Hematopoietic Decreases in erythrocyte counts, hemoglobin,
platelets increased reticulocytes
Monitor standard hematological parameters
Liver Increases in AST, ALT Monitor liver function
Heart
GLP-1 receptor agonists have the potential to
influence traditional cardiovascular risk factors
and cardiac physiology
monitor cardiac function
Kidney Changes in urine osmolality and increased blood
creatinine and urea nitrogen
Monitor standard blood chemistry and urinalysis
Pancreas Pancreatitis
Monitor for symptoms of pancreatitis and eval-
uate if necessary serum amylase or lipase levels
should be evaluated and abdominal imaging if
required
Thyroid C-cell hyperplasia, adenoma Monitor calcitonin serum levels
Immunogenicity Anti-drug antibodies that cross-react with
endogenous GLP-1
Monitor anti-drug antibodies and, if present,
characterize for neutralizing of GLP activity