7 Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition
with increased risks of heart attack and stroke that was withdrawn from the market in
September 2004) and Avandia (rosiglitizone, for the treatment of type 2 diabetes, a drug
whose high risk of heart attacks was recognized in 2007 and which today is subject to
severely restricted distribution) contributed to the environment in which tighter risk
management was sought for high-risk drug products.
The REMS concept reflected a desire to make valuable yet high-risk drugs avail-
able to patients while preventing harm, by calling for cautious observation of their use,
informing and alerting patients about possible adverse events and controlling prescribing
and dispensing to restrict the drugs to those who really need them. In concept and in
practice, the REMS program permitted FDA to approve or leave on the market certain
high-risk drugs that were needed by patients because of proven efficacy. Without the
REMS, the benefit-risk balance of these drugs might have made it impossible for them
to be approved or, in the case of previously approved drugs, impossible to leave them
on the market. For instance (see Chapter 11), the REMS has been used to try to avoid
more-stringent measures suggested by members of Congress seeking greater controls
for long-acting and extended-release opioids. One FDA official even suggested that the
clarity and control the REMS provides for these opioids might help funnel the products
to patients who could benefit from them but whose physicians otherwise might not
prescribe them because of safety concerns.36
REMS Flexibility
One important REMS characteristic is its flexibility: the manufacturer or FDA can
request changes in the REMS as the prescribing situation evolves. Every REMS is
required to undergo a formal assessment of its effectiveness at pre-specified intervals,
usually 18 months, three years and seven years after approval (see Chapter 7). This
assessment is an essential requirement for all REMS and enables FDA to quantify spe-
cific REMS actions’ effects on the benefit-risk balance and require any needed changes
to improve measures that are not functioning adequately. A REMS can be adjusted
incrementally (see Chapter 9) to increase a product’s safety, or some or all REMS con-
trols can be removed when they no longer are needed. It is easier to adjust a REMS than
to withdraw a product from the market, a factor that benefits both the manufacturer
and FDA. It has been stated:
“The adjustability of REMS—including the built-in assessment process that triggers
opportunities to reconsider the balancing act inherent in the regulatory process—is
one of its most powerful features, transforming FDA regulatory decisions from
binary (you are on the market or you are off) into more tiered, nuanced controls.”37
Figure 1-3. FDAAA-Mandated Advisory Commitee Meeting
Requires the agency, at least annually,
• to bring at least one drug with a REMS with elements to assure safe use (ETASU) to
the Drug Safety and Risk Management Advisory Committee (DSaRM)
• solicit views of DSaRM on whether the elements
assure safe use of the drug
are not unduly burdensome on patient access to the drug
to the extent practicable, minimize the burden on the healthcare delivery system
with increased risks of heart attack and stroke that was withdrawn from the market in
September 2004) and Avandia (rosiglitizone, for the treatment of type 2 diabetes, a drug
whose high risk of heart attacks was recognized in 2007 and which today is subject to
severely restricted distribution) contributed to the environment in which tighter risk
management was sought for high-risk drug products.
The REMS concept reflected a desire to make valuable yet high-risk drugs avail-
able to patients while preventing harm, by calling for cautious observation of their use,
informing and alerting patients about possible adverse events and controlling prescribing
and dispensing to restrict the drugs to those who really need them. In concept and in
practice, the REMS program permitted FDA to approve or leave on the market certain
high-risk drugs that were needed by patients because of proven efficacy. Without the
REMS, the benefit-risk balance of these drugs might have made it impossible for them
to be approved or, in the case of previously approved drugs, impossible to leave them
on the market. For instance (see Chapter 11), the REMS has been used to try to avoid
more-stringent measures suggested by members of Congress seeking greater controls
for long-acting and extended-release opioids. One FDA official even suggested that the
clarity and control the REMS provides for these opioids might help funnel the products
to patients who could benefit from them but whose physicians otherwise might not
prescribe them because of safety concerns.36
REMS Flexibility
One important REMS characteristic is its flexibility: the manufacturer or FDA can
request changes in the REMS as the prescribing situation evolves. Every REMS is
required to undergo a formal assessment of its effectiveness at pre-specified intervals,
usually 18 months, three years and seven years after approval (see Chapter 7). This
assessment is an essential requirement for all REMS and enables FDA to quantify spe-
cific REMS actions’ effects on the benefit-risk balance and require any needed changes
to improve measures that are not functioning adequately. A REMS can be adjusted
incrementally (see Chapter 9) to increase a product’s safety, or some or all REMS con-
trols can be removed when they no longer are needed. It is easier to adjust a REMS than
to withdraw a product from the market, a factor that benefits both the manufacturer
and FDA. It has been stated:
“The adjustability of REMS—including the built-in assessment process that triggers
opportunities to reconsider the balancing act inherent in the regulatory process—is
one of its most powerful features, transforming FDA regulatory decisions from
binary (you are on the market or you are off) into more tiered, nuanced controls.”37
Figure 1-3. FDAAA-Mandated Advisory Commitee Meeting
Requires the agency, at least annually,
• to bring at least one drug with a REMS with elements to assure safe use (ETASU) to
the Drug Safety and Risk Management Advisory Committee (DSaRM)
• solicit views of DSaRM on whether the elements
assure safe use of the drug
are not unduly burdensome on patient access to the drug
to the extent practicable, minimize the burden on the healthcare delivery system