1 Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition
Risk Definition
“Risk” has been defined for regulatory purposes by a guideline from the International
Council on Harmonisation (ICH) as “the combination of the probability of occurrence
of harm and the severity of that harm.” This definition has been called “the Probability x
Severity concept.”1 There is no way to ensure a drug product has no serious safety risks,
since every drug has the potential to cause adverse events. This potential for serious
risks exists regardless of how extensively the drug was studied before approval and how
many times it has been dispensed postapproval. It is a truism of drug development
that clinical studies with a few thousand or even tens of thousands of subjects cannot
predict the risks that will occur during use by millions of patients after approval. Even
if a major risk is not identified during the first year after approval, it is not possible to
conclude there is no serious risk the failure to detect risk via surveillance during the first
year of marketing experience only shows the risk is low. Nevertheless, the goal during
drug development is to investigate safety as thoroughly as possible before the product is
widely marketed, and to determine the risks’ magnitude for patients using the drug.
A marketing application submitted to the US Food and Drug Administration
(FDA) for new drug approval must demonstrate the drug is “safe and effective.” In real-
ity, a drug is approved not because it is safe, but because it is “safe for the proposed use,”
i.e., it has a favorable benefit-risk ratio. FDA has defined a “safe product” as one that has
“acceptable risks, given the magnitude of the benefit expected in a specific population
and within the context of alternatives [alternative treatments] available.”2 “Safe” does not
mean “free of risk.” FDA guidance has stated, “a product is considered to be safe if the
clinical significance and probability of its beneficial effects outweigh the likelihood and
medical importance of its harmful or undesirable effects. In other words, a product is
considered safe if it has an appropriate benefit-risk balance for the intended population
and use.”3
1
The Limits of Risk and the
Concept of the REMS
Risk Definition
“Risk” has been defined for regulatory purposes by a guideline from the International
Council on Harmonisation (ICH) as “the combination of the probability of occurrence
of harm and the severity of that harm.” This definition has been called “the Probability x
Severity concept.”1 There is no way to ensure a drug product has no serious safety risks,
since every drug has the potential to cause adverse events. This potential for serious
risks exists regardless of how extensively the drug was studied before approval and how
many times it has been dispensed postapproval. It is a truism of drug development
that clinical studies with a few thousand or even tens of thousands of subjects cannot
predict the risks that will occur during use by millions of patients after approval. Even
if a major risk is not identified during the first year after approval, it is not possible to
conclude there is no serious risk the failure to detect risk via surveillance during the first
year of marketing experience only shows the risk is low. Nevertheless, the goal during
drug development is to investigate safety as thoroughly as possible before the product is
widely marketed, and to determine the risks’ magnitude for patients using the drug.
A marketing application submitted to the US Food and Drug Administration
(FDA) for new drug approval must demonstrate the drug is “safe and effective.” In real-
ity, a drug is approved not because it is safe, but because it is “safe for the proposed use,”
i.e., it has a favorable benefit-risk ratio. FDA has defined a “safe product” as one that has
“acceptable risks, given the magnitude of the benefit expected in a specific population
and within the context of alternatives [alternative treatments] available.”2 “Safe” does not
mean “free of risk.” FDA guidance has stated, “a product is considered to be safe if the
clinical significance and probability of its beneficial effects outweigh the likelihood and
medical importance of its harmful or undesirable effects. In other words, a product is
considered safe if it has an appropriate benefit-risk balance for the intended population
and use.”3
1
The Limits of Risk and the
Concept of the REMS