Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition 2
Risk Management Definition
FDA defines “risk management” as a process of measures above and beyond basic safety
measures routinely applied “throughout a product’s lifecycle” to control risk. These
risk management measures must be based on careful risk evaluation.4 Under the Risk
Minimization Action Plan (RiskMAP) program, a REMS predecessor, FDA spelled out
risk management as an “iterative process” consisting of: 1) assessing the drug’s bene-
fit-risk ratio 2) developing and applying risk minimization tools 3) evaluating the tools’
effectiveness, including their impact on the benefit-risk ratio and 4) making adjust-
ments to the tools as needed (see Figure 1-1). The FDA RiskMAP guidance document
introduced the concept of evaluating the effectiveness of the risk minimization measures
on an ongoing basis, although evaluation was voluntary. It also created the new term,
“benefit-risk balance,” to replace “risk-benefit ratio,”5 perhaps to place the emphasis
on the positive “benefit” rather than the negative “risk,” and to emphasize the positive
connotations of “balance.”
Drug Product Risks Are Measured in Adverse Events
Drug product risks, like other consumer product risks, are among the potentially dan-
gerous circumstances to which everyone is exposed throughout life. Drug product risks
represent only one aspect of the risks patients are exposed to during an illness, particu-
larly in the hospital setting.
Drug product risks are quantified by measuring adverse events. “Adverse event” was
re-defined by FDA in September 2010 as “any untoward medical occurrence associated
with the use of a drug in humans, whether or not considered drug related,” i.e., without
regard to causality. At the same time, FDA defined “suspected adverse drug reaction” as
any untoward occurrence when causality is “a reasonable possibility.”6 Nevertheless, in
a risk mitigation discussion, it seems reasonable to insist on including some degree of
suspected causality when using the term “adverse event.”
Adverse events due to medical care are common. In a study of 1,000,000 Medicare
patients,7 almost one patient in seven (13.5%) had an adverse event while in the hospi-
tal. A deeper analysis of a smaller sample found that 41% of these adverse events were
related to a medication.8
Adverse Events and Never Events
In 2010, the HHS Office of the Inspector General9 defined two categories of untoward
occurrences associated with drug products:
The term “adverse event” describes harm to a patient as a result of medical care,
such as infection associated with use of a catheter. The term “never events” refers
to a specific list of serious events, such as surgery on the wrong patient, that the
National Quality Forum (NQF) deemed “should never occur in a health care
setting.”
In 1999, the Institute of Medicine (IOM) (since 2015, the National Academy of
Medicine) issued a landmark report on the problem of preventing death and disability in
the healthcare system by preventing medical errors.10 It set forth a goal of reducing pre-
ventable medical errors by 50% in five years. An evaluation in 2005 concluded that the
Risk Management Definition
FDA defines “risk management” as a process of measures above and beyond basic safety
measures routinely applied “throughout a product’s lifecycle” to control risk. These
risk management measures must be based on careful risk evaluation.4 Under the Risk
Minimization Action Plan (RiskMAP) program, a REMS predecessor, FDA spelled out
risk management as an “iterative process” consisting of: 1) assessing the drug’s bene-
fit-risk ratio 2) developing and applying risk minimization tools 3) evaluating the tools’
effectiveness, including their impact on the benefit-risk ratio and 4) making adjust-
ments to the tools as needed (see Figure 1-1). The FDA RiskMAP guidance document
introduced the concept of evaluating the effectiveness of the risk minimization measures
on an ongoing basis, although evaluation was voluntary. It also created the new term,
“benefit-risk balance,” to replace “risk-benefit ratio,”5 perhaps to place the emphasis
on the positive “benefit” rather than the negative “risk,” and to emphasize the positive
connotations of “balance.”
Drug Product Risks Are Measured in Adverse Events
Drug product risks, like other consumer product risks, are among the potentially dan-
gerous circumstances to which everyone is exposed throughout life. Drug product risks
represent only one aspect of the risks patients are exposed to during an illness, particu-
larly in the hospital setting.
Drug product risks are quantified by measuring adverse events. “Adverse event” was
re-defined by FDA in September 2010 as “any untoward medical occurrence associated
with the use of a drug in humans, whether or not considered drug related,” i.e., without
regard to causality. At the same time, FDA defined “suspected adverse drug reaction” as
any untoward occurrence when causality is “a reasonable possibility.”6 Nevertheless, in
a risk mitigation discussion, it seems reasonable to insist on including some degree of
suspected causality when using the term “adverse event.”
Adverse events due to medical care are common. In a study of 1,000,000 Medicare
patients,7 almost one patient in seven (13.5%) had an adverse event while in the hospi-
tal. A deeper analysis of a smaller sample found that 41% of these adverse events were
related to a medication.8
Adverse Events and Never Events
In 2010, the HHS Office of the Inspector General9 defined two categories of untoward
occurrences associated with drug products:
The term “adverse event” describes harm to a patient as a result of medical care,
such as infection associated with use of a catheter. The term “never events” refers
to a specific list of serious events, such as surgery on the wrong patient, that the
National Quality Forum (NQF) deemed “should never occur in a health care
setting.”
In 1999, the Institute of Medicine (IOM) (since 2015, the National Academy of
Medicine) issued a landmark report on the problem of preventing death and disability in
the healthcare system by preventing medical errors.10 It set forth a goal of reducing pre-
ventable medical errors by 50% in five years. An evaluation in 2005 concluded that the