Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition 4
everyday activities. As a result, the concept of risk has been widely studied and discussed.
Specific discussions about drug product risks have occurred within the medical care
system, as well as in Congress, the executive branch of government, the press and among
the public.
“The One Percent Doctrine,” a risk anticipation concept, developed in the midst of
the “zero risk culture,” as US government agencies sought to achieve an acceptable level
of security against terrorist threats after the 11 September 2001 attacks on the World
Trade Center and Pentagon. The One Percent Doctrine seeks to maintain a risk level in
which there is less than a 1% chance a serious event will occur. A corollary to this phi-
losophy, as described by Sunstein,17 is that when the risk’s results would be devastating,
such as an attack that could cause many deaths, it becomes reasonable to consider a 1%
risk the same as certainty of risk. Thus, “if there’s a one percent chance [of an attack] …
we have to treat it as a certainty in terms of our response.”18 This means trying to keep
the risk far lower than 1%.
To FDA, the risk of a devastating adverse event, such as loss of life, loss of sight,
etc., justifies application of something similar to the One Percent Doctrine. For instance,
the drug Sabril (vigabatrin), approved in August 2009, is a GABA transaminase inhib-
itor indicated for treating infantile spasms and refractory complex partial seizures in
adults. Safety concerns in children were based on visual field loss in 30% of adults
taking the drug, although the risk for pediatric patients had never been clearly defined.
Abnormal changes in MRI scans were seen in some infants’ brains, although the neuro-
logical significance was unknown. Following a philosophy resembling the One Percent
Doctrine, FDA required a REMS for Sabril,19 in part to address a potential risk for
children that had not been seen yet, based in a 30% risk in adults and the devastating
character of the untoward event in question (i.e., visual field loss).
The “Potential Risk” Concept
The medical community’s focus on zero risk eventually led to a backlash, a reactive con-
cept based on the realization that, in many situations, risk may be so difficult to quantify
that all of the worries and preventive measures are focused on “potential risk” rather than
risk. “Potential risk” in drug products has been defined as “an untoward occurrence for
which there is some basis for suspicion of an association with the medicinal product of
interest but where this association has not been confirmed.”20 These occurrences include:
• safety concerns based on nonclinical studies that have not been observed or
have been resolved in clinical studies
• adverse events observed in clinical trials or epidemiological studies for which
the difference from the comparator group (in which patients were given either
placebo, another active substance or no treatment) is large enough to raise a
suspicion, but only a suspicion, of a causal relationship
• a signal arising from a spontaneous adverse event reporting system
• an event known to be associated with other products of the same class or that
could be expected to occur based on the product’s properties21
In some cases, “potential risks” have been identified, but not verified or clarified, such
as risks based only on clinical trials that were small or were not designed to detect them.
“Potential risks” also can appear in clinical trials that included specific racial groups or
everyday activities. As a result, the concept of risk has been widely studied and discussed.
Specific discussions about drug product risks have occurred within the medical care
system, as well as in Congress, the executive branch of government, the press and among
the public.
“The One Percent Doctrine,” a risk anticipation concept, developed in the midst of
the “zero risk culture,” as US government agencies sought to achieve an acceptable level
of security against terrorist threats after the 11 September 2001 attacks on the World
Trade Center and Pentagon. The One Percent Doctrine seeks to maintain a risk level in
which there is less than a 1% chance a serious event will occur. A corollary to this phi-
losophy, as described by Sunstein,17 is that when the risk’s results would be devastating,
such as an attack that could cause many deaths, it becomes reasonable to consider a 1%
risk the same as certainty of risk. Thus, “if there’s a one percent chance [of an attack] …
we have to treat it as a certainty in terms of our response.”18 This means trying to keep
the risk far lower than 1%.
To FDA, the risk of a devastating adverse event, such as loss of life, loss of sight,
etc., justifies application of something similar to the One Percent Doctrine. For instance,
the drug Sabril (vigabatrin), approved in August 2009, is a GABA transaminase inhib-
itor indicated for treating infantile spasms and refractory complex partial seizures in
adults. Safety concerns in children were based on visual field loss in 30% of adults
taking the drug, although the risk for pediatric patients had never been clearly defined.
Abnormal changes in MRI scans were seen in some infants’ brains, although the neuro-
logical significance was unknown. Following a philosophy resembling the One Percent
Doctrine, FDA required a REMS for Sabril,19 in part to address a potential risk for
children that had not been seen yet, based in a 30% risk in adults and the devastating
character of the untoward event in question (i.e., visual field loss).
The “Potential Risk” Concept
The medical community’s focus on zero risk eventually led to a backlash, a reactive con-
cept based on the realization that, in many situations, risk may be so difficult to quantify
that all of the worries and preventive measures are focused on “potential risk” rather than
risk. “Potential risk” in drug products has been defined as “an untoward occurrence for
which there is some basis for suspicion of an association with the medicinal product of
interest but where this association has not been confirmed.”20 These occurrences include:
• safety concerns based on nonclinical studies that have not been observed or
have been resolved in clinical studies
• adverse events observed in clinical trials or epidemiological studies for which
the difference from the comparator group (in which patients were given either
placebo, another active substance or no treatment) is large enough to raise a
suspicion, but only a suspicion, of a causal relationship
• a signal arising from a spontaneous adverse event reporting system
• an event known to be associated with other products of the same class or that
could be expected to occur based on the product’s properties21
In some cases, “potential risks” have been identified, but not verified or clarified, such
as risks based only on clinical trials that were small or were not designed to detect them.
“Potential risks” also can appear in clinical trials that included specific racial groups or