5 Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition
age groups that are at higher risk for the adverse event than the general population, but
in which too few patients were included from those subpopulations to draw meaningful
conclusions.
Quantifying Risk
Risk can be quantified in various ways and then compared for different events. The
incidence of a particular adverse event or of all adverse events can be measured. The type
of adverse event and how soon it follows exposure to the drug product can be quantified.
As discussed earlier in this chapter, ICH defines risk as “the combination of the
probability of occurrence of harm and the severity of that harm,”22 which is known as
“the Probability x Severity concept.”23 Thus, the risk is quantifiable because the degree
of severity is a significant quantifiable measurement. How often is the adverse event
life-threatening? How often does it cause hospitalization or an extension of hospital-
ization? How many days of work loss does it cause? To what extent does it reduce the
quality of life, which can be measured as Quality-Adjusted Life Years (QALYs) or with
other metrics? The financial impact of the adverse event, including the societal cost or
the total cost from both the resulting medical care and the loss of the patient’s role in the
workforce, also can be measured.
Anxieties About Risk
It could be said that anxieties about risks are relative. For instance, in one discussion24
about the risk of developing progressive multifocal leukoencephalopathy (PML), a neu-
rologic disease, as a complication of treatment with Tysabri (natalizumab) for multiple
sclerosis (MS), the risk was 1:1,000. Patients were asked if they were willing to assume
this amount of risk in exchange for controlling their MS, and many were unwilling to
do so. However, compared to a 1:100 lifetime risk of dying in a car accident, a 1:625
lifetime risk of being killed by a car while walking across the street and a 1:1,000
lifetime risk of drowning, the risk of PML from this drug did not seem so high. In fact,
the 1:1,000 lifetime risk of dying by drowning sounds almost unbelievably high for an
event we consider rare, which makes the risk of PML as an adverse event associated with
Tysabri seem even smaller.
Responses to a comparison of measured risks are a reflection of how well individuals
are able to handle anxiety about risks in general. Any individual patient’s response to a
quantifiable risk may be high or low due to innate personality characteristics, the disease
severity or the presence of other anxieties unrelated to the disease.
FDA’s Risk Management Process
Risk management is a process that involves multiple activities aimed at the single goal
of minimizing risk. This process consists of “identifying, assessing, analyzing, treating,
monitoring, and communicating” risks,25 whether they are linked to using drug products
or to air travel. One FDA official has suggested drug product risks are risks to “pharma-
ceutical quality,” a risk of impairing “a consistent delivery of label performance, lack of
contamination, and product availability.”26 In addition, risk management includes the
selection, implementation and evaluation of measures to reduce risk.
age groups that are at higher risk for the adverse event than the general population, but
in which too few patients were included from those subpopulations to draw meaningful
conclusions.
Quantifying Risk
Risk can be quantified in various ways and then compared for different events. The
incidence of a particular adverse event or of all adverse events can be measured. The type
of adverse event and how soon it follows exposure to the drug product can be quantified.
As discussed earlier in this chapter, ICH defines risk as “the combination of the
probability of occurrence of harm and the severity of that harm,”22 which is known as
“the Probability x Severity concept.”23 Thus, the risk is quantifiable because the degree
of severity is a significant quantifiable measurement. How often is the adverse event
life-threatening? How often does it cause hospitalization or an extension of hospital-
ization? How many days of work loss does it cause? To what extent does it reduce the
quality of life, which can be measured as Quality-Adjusted Life Years (QALYs) or with
other metrics? The financial impact of the adverse event, including the societal cost or
the total cost from both the resulting medical care and the loss of the patient’s role in the
workforce, also can be measured.
Anxieties About Risk
It could be said that anxieties about risks are relative. For instance, in one discussion24
about the risk of developing progressive multifocal leukoencephalopathy (PML), a neu-
rologic disease, as a complication of treatment with Tysabri (natalizumab) for multiple
sclerosis (MS), the risk was 1:1,000. Patients were asked if they were willing to assume
this amount of risk in exchange for controlling their MS, and many were unwilling to
do so. However, compared to a 1:100 lifetime risk of dying in a car accident, a 1:625
lifetime risk of being killed by a car while walking across the street and a 1:1,000
lifetime risk of drowning, the risk of PML from this drug did not seem so high. In fact,
the 1:1,000 lifetime risk of dying by drowning sounds almost unbelievably high for an
event we consider rare, which makes the risk of PML as an adverse event associated with
Tysabri seem even smaller.
Responses to a comparison of measured risks are a reflection of how well individuals
are able to handle anxiety about risks in general. Any individual patient’s response to a
quantifiable risk may be high or low due to innate personality characteristics, the disease
severity or the presence of other anxieties unrelated to the disease.
FDA’s Risk Management Process
Risk management is a process that involves multiple activities aimed at the single goal
of minimizing risk. This process consists of “identifying, assessing, analyzing, treating,
monitoring, and communicating” risks,25 whether they are linked to using drug products
or to air travel. One FDA official has suggested drug product risks are risks to “pharma-
ceutical quality,” a risk of impairing “a consistent delivery of label performance, lack of
contamination, and product availability.”26 In addition, risk management includes the
selection, implementation and evaluation of measures to reduce risk.