v Risk Evaluation and Mitigation Strategies for US Drug Development, Second Edition
Introduction
An experienced observer of regulatory science predicted that the risk prevention pro-
gram called Risk Evaluation and Mitigation Strategy (REMS) was “likely to dominate
the development and marketing of pharmaceuticals for decades.” REMS would become
“a dominant feature in NDA reviews and post-marketing controls…[and would] force
numerous changes in the structure, organization and duties within pharma.”1
The first 10 years of the Food and Drug Administration’s (FDA) REMS program
have confirmed these predictions. REMS now are permanent features of the drug
development process for many products. The REMS concept was created by the Food
and Drug Administration Amendments Act of 2007 (FDAAA), which amended the Food,
Drug, and Cosmetic Act2 and called for REMS implementation to meet certain types of
safety concerns that otherwise might prevent FDA from approving a new drug or allow-
ing an existing drug to keep its approval. The program took effect on 28 March 2008.
As of September 2018, 74 drugs were on the market whose NDAs still had an active
REMS this number does not include those drugs FDA had released from their REMS
obligations when safety concerns were no longer an issue. A few products subsequently
have been released from the REMS requirement when FDA determined a REMS no
longer was needed (see Chapters 9 and 10).
A REMS can include one or more of the following component mechanisms to
control the risks to which FDA believes the drug exposes the patient:
• Communication Plan (Chapter 5)
• Implementation Plan (Chapter 5)
• Elements to Assure Safe Use (ETASU) (Chapter 6)
• Medication Guide, only if it is to help implement an ETASU (Chapter 4)
These components have changed slightly since the beginning of the REMS program,
particularly regarding Medication Guides (Chapter 4). In addition, FDA has moved
toward the use of the Structured Product Labeling (SPL) format for REMS, to make the
primary REMS information compatible with hospital, pharmacy and patient electronic
records (Chapter 8). Most of these changes resulted from either FDA guidance docu-
ments or FDA precedents set during various drug approvals. REMS components and
their associated requirements will undoubtedly continue to evolve over time.
This book describes the REMS program, the various ways different companies have
used it and many of the program’s indirect and unexpected effects on the regulatory
process itself. It should make it easier to predict whether a REMS will be required for a
new drug and to understand how to design a REMS, enabling regulatory strategists to
“think like an FDA reviewer” to predict whether the reviewer will require a REMS and
how stringent its components might be.
The REMS program is a tool for handling high risks that cannot be addressed by
other regulatory systems, for instance, drug labeling with black box warnings or ordinary
postmarketing surveillance. Further, the REMS allows FDA to approve products that
otherwise might be kept off the market or might undergo a delay in approval while
further studies are conducted. A senior FDA official, Robert Temple, has stated, “…
there’s a threshold [for deciding to require a REMS]. You have to conclude that labeling
directed at physicians in the usual manner, plus ordinary reporting under AERS [the
Adverse Events Reporting System] or similar systems won’t do the job.”3
Introduction
An experienced observer of regulatory science predicted that the risk prevention pro-
gram called Risk Evaluation and Mitigation Strategy (REMS) was “likely to dominate
the development and marketing of pharmaceuticals for decades.” REMS would become
“a dominant feature in NDA reviews and post-marketing controls…[and would] force
numerous changes in the structure, organization and duties within pharma.”1
The first 10 years of the Food and Drug Administration’s (FDA) REMS program
have confirmed these predictions. REMS now are permanent features of the drug
development process for many products. The REMS concept was created by the Food
and Drug Administration Amendments Act of 2007 (FDAAA), which amended the Food,
Drug, and Cosmetic Act2 and called for REMS implementation to meet certain types of
safety concerns that otherwise might prevent FDA from approving a new drug or allow-
ing an existing drug to keep its approval. The program took effect on 28 March 2008.
As of September 2018, 74 drugs were on the market whose NDAs still had an active
REMS this number does not include those drugs FDA had released from their REMS
obligations when safety concerns were no longer an issue. A few products subsequently
have been released from the REMS requirement when FDA determined a REMS no
longer was needed (see Chapters 9 and 10).
A REMS can include one or more of the following component mechanisms to
control the risks to which FDA believes the drug exposes the patient:
• Communication Plan (Chapter 5)
• Implementation Plan (Chapter 5)
• Elements to Assure Safe Use (ETASU) (Chapter 6)
• Medication Guide, only if it is to help implement an ETASU (Chapter 4)
These components have changed slightly since the beginning of the REMS program,
particularly regarding Medication Guides (Chapter 4). In addition, FDA has moved
toward the use of the Structured Product Labeling (SPL) format for REMS, to make the
primary REMS information compatible with hospital, pharmacy and patient electronic
records (Chapter 8). Most of these changes resulted from either FDA guidance docu-
ments or FDA precedents set during various drug approvals. REMS components and
their associated requirements will undoubtedly continue to evolve over time.
This book describes the REMS program, the various ways different companies have
used it and many of the program’s indirect and unexpected effects on the regulatory
process itself. It should make it easier to predict whether a REMS will be required for a
new drug and to understand how to design a REMS, enabling regulatory strategists to
“think like an FDA reviewer” to predict whether the reviewer will require a REMS and
how stringent its components might be.
The REMS program is a tool for handling high risks that cannot be addressed by
other regulatory systems, for instance, drug labeling with black box warnings or ordinary
postmarketing surveillance. Further, the REMS allows FDA to approve products that
otherwise might be kept off the market or might undergo a delay in approval while
further studies are conducted. A senior FDA official, Robert Temple, has stated, “…
there’s a threshold [for deciding to require a REMS]. You have to conclude that labeling
directed at physicians in the usual manner, plus ordinary reporting under AERS [the
Adverse Events Reporting System] or similar systems won’t do the job.”3