3 Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition
extent of improvement five years following the IOM report could not be quantitatively
determined, but the level of medical errors remained high.11
To a great extent, the movement to require some new drugs to use a REMS
for formal risk mitigation is a manifestation of the same desire to reduce pre-
ventable risk. Although the IOM report focused on “designing the health system
at all levels to make it safer—to make it harder for people to do something
wrong and easier for them to do it right,”12 extending this approach to drug
development means assessing the safety of new drugs after they are in wide use,
analyzing the risk and, in the case of REMS, subsequently analyzing how well
the risk minimization process worked.
Although the IOM report focused on medical errors, its emphasis on the need for
healthcare systems to create a “culture of safety” became a component of many discus-
sions on health policy and drug approval. Safety, it frequently was urged, should be an
explicit organizational goal.13
The escalating discussion within both the medical community and the public at
large about preventing “never events” reached its popular culmination in the writings of
the surgeon and author, Atul Gawande. Gawande’s first two books of essays scrutinized
the potential for errors and the factors that cause them in surgery14 and other aspects
of medicine.15 In his third book, The Checklist Manifesto, he proposed a solution, using
checklists in medicine like those used by commercial aircraft pilots.16 Gawande described
formal studies that validated the ability of checklists to cut the incidence of surgical
complications by half, preventing many deaths. Some critical discussion of Gawande’s
ideas subsequently appeared in the medical literature, including others’ assertions
that a culture of safety must already be present before checklists can work effectively.
Regardless, Gawande’s crusade helped energize the discussion about risk prevention and
contributed to the atmosphere that led to the REMS concept
The Search for “Zero Risk”
In the US today, there is a relatively new societal expectation for “zero risk” in all activi-
ties and from all products. Zero risk, or nearly zero risk, is expected from every medical
treatment, even though the risks of death and infirmity are far greater from many
Figure 1-1. Evolution of Formal Risk Management Plans for Drugs With a High-Risk
Profile*
1
Assessing the
benefit-risk
balance
2
Developing
and applying
management
tools to minimize
the risk
3
Evaluating the
tools’ effectiveness,
including their
impact on the
benefit-risk balance
4
Making
adjustments to the
tools as needed
*Defined in the Risk Minimization Action Plan (RiskMAP) program, a predecessor of REMS.
(Based on FDA’s Guidance for Industry: Development and Use of Risk Minimization Action Plans (2005))
extent of improvement five years following the IOM report could not be quantitatively
determined, but the level of medical errors remained high.11
To a great extent, the movement to require some new drugs to use a REMS
for formal risk mitigation is a manifestation of the same desire to reduce pre-
ventable risk. Although the IOM report focused on “designing the health system
at all levels to make it safer—to make it harder for people to do something
wrong and easier for them to do it right,”12 extending this approach to drug
development means assessing the safety of new drugs after they are in wide use,
analyzing the risk and, in the case of REMS, subsequently analyzing how well
the risk minimization process worked.
Although the IOM report focused on medical errors, its emphasis on the need for
healthcare systems to create a “culture of safety” became a component of many discus-
sions on health policy and drug approval. Safety, it frequently was urged, should be an
explicit organizational goal.13
The escalating discussion within both the medical community and the public at
large about preventing “never events” reached its popular culmination in the writings of
the surgeon and author, Atul Gawande. Gawande’s first two books of essays scrutinized
the potential for errors and the factors that cause them in surgery14 and other aspects
of medicine.15 In his third book, The Checklist Manifesto, he proposed a solution, using
checklists in medicine like those used by commercial aircraft pilots.16 Gawande described
formal studies that validated the ability of checklists to cut the incidence of surgical
complications by half, preventing many deaths. Some critical discussion of Gawande’s
ideas subsequently appeared in the medical literature, including others’ assertions
that a culture of safety must already be present before checklists can work effectively.
Regardless, Gawande’s crusade helped energize the discussion about risk prevention and
contributed to the atmosphere that led to the REMS concept
The Search for “Zero Risk”
In the US today, there is a relatively new societal expectation for “zero risk” in all activi-
ties and from all products. Zero risk, or nearly zero risk, is expected from every medical
treatment, even though the risks of death and infirmity are far greater from many
Figure 1-1. Evolution of Formal Risk Management Plans for Drugs With a High-Risk
Profile*
1
Assessing the
benefit-risk
balance
2
Developing
and applying
management
tools to minimize
the risk
3
Evaluating the
tools’ effectiveness,
including their
impact on the
benefit-risk balance
4
Making
adjustments to the
tools as needed
*Defined in the Risk Minimization Action Plan (RiskMAP) program, a predecessor of REMS.
(Based on FDA’s Guidance for Industry: Development and Use of Risk Minimization Action Plans (2005))