Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition 6
FDA has a specific process for evaluating the need for risk management, i.e., the
need for a REMS. When FDA is deciding whether to require a REMS for a drug prod-
uct, the reviewers go through a process (see Figure 1-2) that includes evaluating:27–29
• estimated size of the patient population for the drug
• seriousness of the disease or condition
• expected drug benefit
• expected treatment duration
• seriousness of known or potential adverse events
• whether the drug is a New Molecular Entity (NME)
Although the Food and Drug Administration Amendments Act of 2007 (FDAAA) only
applied these factors to REMS that begin at the time of a drug’s initial approval, REMS
guidance documents published since have stated that these criteria and this process also
would be used to determine the need for a REMS at any point in a drug’s lifecycle,30,31
whenever significant safety concerns arise.
In practice, the manufacturer’s perception of risk also is an important part of the
process. If there is an indication that any drug may have safety issues that could delay
approval or result in non-approval, the manufacturer should anticipate a possible
REMS. Beginning at the time of Phase 3 clinical studies, steps should be taken that
include drafting a preliminary REMS submission and discussing it at the pre-NDA
meeting with FDA.
The Concept of the REMS as a Counterbalance to Risk
The REMS program was created by FDAAA and was signed into law 27 September
2007.32 (FDAAA, in giving FDA authority to impose REMS requirements, in fact
amended the Federal Food, Drug, and Cosmetic Act (FD&C Act), inserting the REMS
narrative as “Section 505-1” in Chapter V of the act.33) High-risk products would
be required to have a REMS as part of a New Drug Application (NDA) or Biologics
License Application (BLA) beginning 25 March 2008.34 The transition period was short,
but its duration was reasonable in view of the fact many companies already had internal
procedures in place for preparing RiskMAPs (see Chapter 2),35 which could be used to
prepare REMS.
The REMS concept grew out of the RiskMAP program in response to the
high-profile adverse events associated with some major drug products in the four years
preceding FDAAA enactment. The adverse events due to Vioxx (rofecoxib, an NSAID
Figure 1-2. Basis for FDA’s Process of Determining Risk of a Drug
Estimated size of the intended patient population
Seriousness of the disease or condition
Expected benefit of the drug
Expected duration of treatment
Seriousness of the known or potential adverse events
Whether the drug is an NME
(Based on FDA’s Draft Guidance For Industry: Format and Content of Proposed Risk Evaluation and Mitigation
Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (2009))
FDA has a specific process for evaluating the need for risk management, i.e., the
need for a REMS. When FDA is deciding whether to require a REMS for a drug prod-
uct, the reviewers go through a process (see Figure 1-2) that includes evaluating:27–29
• estimated size of the patient population for the drug
• seriousness of the disease or condition
• expected drug benefit
• expected treatment duration
• seriousness of known or potential adverse events
• whether the drug is a New Molecular Entity (NME)
Although the Food and Drug Administration Amendments Act of 2007 (FDAAA) only
applied these factors to REMS that begin at the time of a drug’s initial approval, REMS
guidance documents published since have stated that these criteria and this process also
would be used to determine the need for a REMS at any point in a drug’s lifecycle,30,31
whenever significant safety concerns arise.
In practice, the manufacturer’s perception of risk also is an important part of the
process. If there is an indication that any drug may have safety issues that could delay
approval or result in non-approval, the manufacturer should anticipate a possible
REMS. Beginning at the time of Phase 3 clinical studies, steps should be taken that
include drafting a preliminary REMS submission and discussing it at the pre-NDA
meeting with FDA.
The Concept of the REMS as a Counterbalance to Risk
The REMS program was created by FDAAA and was signed into law 27 September
2007.32 (FDAAA, in giving FDA authority to impose REMS requirements, in fact
amended the Federal Food, Drug, and Cosmetic Act (FD&C Act), inserting the REMS
narrative as “Section 505-1” in Chapter V of the act.33) High-risk products would
be required to have a REMS as part of a New Drug Application (NDA) or Biologics
License Application (BLA) beginning 25 March 2008.34 The transition period was short,
but its duration was reasonable in view of the fact many companies already had internal
procedures in place for preparing RiskMAPs (see Chapter 2),35 which could be used to
prepare REMS.
The REMS concept grew out of the RiskMAP program in response to the
high-profile adverse events associated with some major drug products in the four years
preceding FDAAA enactment. The adverse events due to Vioxx (rofecoxib, an NSAID
Figure 1-2. Basis for FDA’s Process of Determining Risk of a Drug
Estimated size of the intended patient population
Seriousness of the disease or condition
Expected benefit of the drug
Expected duration of treatment
Seriousness of the known or potential adverse events
Whether the drug is an NME
(Based on FDA’s Draft Guidance For Industry: Format and Content of Proposed Risk Evaluation and Mitigation
Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (2009))