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290 Cobert’s Manual of Drug Safety and Pharmacovigilance
and effectiveness submitted by a sponsor in an NDA
or BLA (Biologic License Application)
i
. Broadly speak-
ing, the process of “benefit-risk assessment” is making
a judgment as to whether the expected benefits (with
their uncertainties) of the product outweigh the poten-
tial risks (with their uncertainties and approaches to
manage risks) associated with its expected use.
Benefit-Risk Assessment, Risk Assessment, Safety
Assessment Planning, are all terms used to describe this
life-cycle process and they can be done in a variety of
ways depending on 1) the size of the company, 2) profile
of the product, and 3) differences in regional expecta-
tions and requirements. Yes, that’s right, the US proposes
“one-way”, the EU proposes “another”, the Australian
TGA “another”, and so on. However, one will find that
the primary intent and theory of this process is the same:
Acknowledge and then monitor the known risks, docu-
ment the perceived benefits, monitor for the unknown,
then assess and report on the outcome and resulting
actions to continuously protect the patient.
Finally, sponsors of new products and Marketing
Authorization Holders of approved ones, must con-
tinously prove the benefits outweigh the risks, or they
themselves with risk product refusal or withdrawal.
How is Risk Defined?
The concept of risk can be defined in many ways:
Exposure to a possibility of loss or damage. The
quantitative or qualitative possibility of loss that
considers both the probability that something will
cause harm and the consequences of that something.
The probability of an adverse event resulting from
the use of a drug in the dose and manner prescribed
or labeled, or from its use at a different dose or man-
ner, or in a patient or population for which the drug
is not approved.
The exposure to loss of money as a result of changes
in business conditions, the economy, the stock
and bond markets, interest rates, foreign currency
exchange rates, inflation, natural disasters, and war.
However, a common understanding in the health-
care domain is that risk is a combination of the prob-
ability of occurrence of harm and the severity of that
harm. We can think of risk as the harm or hazard itself.
The US (United States) Food and Drug Administration
(FDA) stated (May 1999), “Although marketed medical
products are required to be safe, safety does not mean
zero risk. A safe product is one that has reasonable
risks, given the magnitude of the benefit expected and
the alternatives available.” In other words, the bene-
fits of a medicine should outweigh its risks under the
approved conditions of use.
Under the US FDA FD&C Act, for a new drug to be
approved for marketing in the United States, the FDA
must determine that the drug is safe and effective for
use under the conditions prescribed, recommended, or
suggested in the product’s labeling.
1
The demonstration
of effectiveness under this standard requires substantial
evidence that the drug will have the effect it purports or
is represented to have.
2,3
Because all products can have
adverse effects, the demonstration of safety requires a
showing that the benefits of the drug outweigh its risks.
For many years, the pharmaceutical world (as else-
where) has been thinking about risk assessment, risk
management, and risk minimization as important,
interrelated disciplines. Several documents on risk
management have been produced by various groups.
Early documents included the US FDA draft guidances
in 2003, the ICH (International Council for Harmoni-
sation) E2E guideline finalized in 2005, and a European
Medicines Agency (EMA) risk management guidance,
also issued in 2005. The EU (European Union) guid-
ance was followed in 2012 by GVP Module V — risk
management systems, as subsequently revised (updated
1
See section 505(d) of the FD&C Act. Under section 351 of the
PHS Act (42 U.S.C. 262) licenses for biological products have been
issued only upon a showing that the products are “safe, pure, and
potent.” Potency has long been interpreted to include effectiveness
(21 CFR 600.3(s)). FDA has also generally considered “substantial
evidence” of effectiveness to be necessary to support licensure
2
See section 505(d) of the FD&C Act (21 U.S.C. 355(d)). The “sub-
stantial evidence” standard refers to both the quality and the quan-
tity of the evidence that the drug will have benefit. See the May 1998
guidance for industry Providing Clinical Evidence of Effectiveness
for Human Drug and Biological Products. The Agency has also pub-
lished a draft guidance for industry on this topic entitled Demon-
strating Substantial Evidence of Effectiveness for Human Drug and
Biological Products (December 2019). When final, this guidance
will represent the FDA’s current thinking on this topic.
3
Biological products are subject to provisions in both the FD&C
Act as well as the PHS Act. Biologics license applications have to
meet applicable requirements in the PHS Act to ensure the contin-
ued safety, purity, and potency of the product (see section 351 of the
PHS Act; see also 21 CFR parts 600, 601, and 610).
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 291
Figure 1. Distribution of 2,645 Changes in the US Package Insert for 1,601 Approved Product
Applications, by Year After First FDA Approval (October 2002 to August 2005).
4
in 2017), along with several versions of templates for
formal risk management documents. Risk management
during the life cycle of products is now the norm and is
expected by FDA, EMA, and many other agencies. It is
also expected by patients and other stakeholders.
The FDA has looked back on labeling changes in
the United States over several years, and a striking find-
ing is that safety label changes occur years and even
decades after a drug has been approved as new safety
issues are reported. For example, changes can occur at
50 or 60 years after approval even for such a commonly
used and “well-known” drug as warfarin. Figure 1
from FDA illustrates label changes occurring after first
approval. Note that the bulk of the changes occurred in
the first 8 or 9 years but drug interactions, AEs (Adverse
events) and other important safety issues can occur up
to 60 years after approval.
4
Why Risk Management?
When a new drug first reaches the market, its safety
profile is not well characterized. Why? Relatively few
subjects have been studied in the clinical trials (espe-
cially with orphan drugs), and those who have been
4
Composition of Safety-Related Labeling for All Drug Products (changes made Oct 2002–Aug 2005, n = 2645 label changes for 1601 NDA/
BLA entries)
Source: Modified from T Mullin, CDER (Center for Drug Evaluation and Research), Office of Planning and Analysis, OTS (Office of Trans-
lational Sciences) presentation, May 2009 (http//www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/UCM205986.pdf).
studied are usually patients with no other diseases, no
or few co-medications, not too young or old, with strin-
gent inclusion and exclusion criteria, relatively short
duration of exposure, exclusion criteria and relatively
short duration of exposure. These data are further con-
strained by statistical concerns associated with looking
at multiple outcomes. Thus, “real-world” patients have
not taken the drug yet, and rare adverse drug reac-
tions (ADRs) have not been detected. It is only in the
post-marketing arena, when large numbers of patients
have taken the drug, that the safety profile is better
characterized. It is only when data on compliance, use
in patients with co-morbid conditions, and multiple
other drugs (including over-the-counter, OTC (over the
counter)), and diets are examined that the real-world
safety profile develops. In addition, data from overdose,
suicide attempts, unintended pregnancies, and lactation
will add to the profile.
Until recently, the primary way to collect such data
was from spontaneous reporting systems and periodic
aggregate reports (periodic adverse drug experience
reports (PADERs), Periodic Benefit-Risk Evaluation
Report (PBRER or PSURs), and their various predeces-
sors), and occasional post-marketing studies. Risk man-
agement was guided by regulator-approved labeling, but
292 Cobert’s Manual of Drug Safety and Pharmacovigilance
distinct risk management programs were not done in a
formal sense. However, it is now the norm to conduct
systematic risk management planning for every innova-
tive product, and some regulatory jurisdictions require
specific, detailed RMPs. Social media is now playing a
larger and larger role in safety.
Multiple drivers have come into play in pharma-
covigilance (PV) and risk management:
Multiple major safety issues and product withdraw-
als have occurred: Fen-Phen, Propulsid, Rezulin,
Vioxx, Bextra, Tysabri, Zelnorm, ranitidine (Zantac
old formulation) and others.
Rising liability costs from litigation and settlements,
particularly in the US.
The medical community was not happy with drug
marketing and drug information.
ADRs were perceived to be a major health risk,
producing death, hospitalization, and significant
morbidity. A meta-analysis noted that in 1994 more
than 2 million hospitalized patients had serious
ADRs and more than 100,000 died, making this the
fourth or fifth leading cause of death in the United
States.
5
Other publications from around the world
noted similar findings.
A public and media perception that drug companies
were villainous, greedy, and cared little for public
health and patient safety.
The Internet, bloggers, social media, and other
forums circulating stories, correct or not, on the
harm of drugs. Artificial intelligence (AI) is the
newest entry in the changes in pharmacovigilance.
A perception that drug regulators were not doing
their job because they allowed harmful drugs to
reach the market too quickly.
A perception that the agencies and industry were
too closely aligned.
Media stories highlighting gifts to physicians,
slanted continuing medical education, paid speak-
ers’ bureaus, and multiple conflicts of interest.
In addition, recent economic issues have brought
risk management of money, cars, offshore oil wells,
5
Lazarou, Pomeranz, Corey, Incidence of ADRs in hospitalized
patients, JAMA 1998; 279: 1200–1205.
pharmaceuticals, Covid and many other activities
in daily life into everyone’s mind. One result has
been that much of the world has become risk-averse
(at least for now).
A consensus developed that risk prediction, eval-
uation, management, and minimization were not well
understood and were rarely done and, when done, were
done poorly. Better procedures for risk identification
(signaling), characterization, mitigation/minimization,
tracking, and communication were needed. And this
was necessary for the entire life span of the product, not
just immediately after marketing. It was thought that
companies and health agencies (and in some cases other
organizations) needed to be proactive, collect more and
better data, put it into electronic databases that were
able to “talk to each other”, and from which data could
easily be extracted for risk evaluation. The benefit–risk
analysis (called by the pessimists the risk–benefit anal-
ysis) needed to be done in a serious, quantitative, and
reproducible manner. It was also understood that the
benefit–risk situation will change over the course of a
drug’s lifecycle and may differ from patient to patient,
group to group, indication to indication.
The goals then became the following:
Early and better detection of ADRs and characteri-
zation of the risk in various patients and settings.
Development and harmonization of data standards
and electronic transmission and storage.
Better communication of known and unknown
risks (i.e., important missing information).
Minimization of morbidity and mortality, i.e., pro-
tect patient safety and the public health.
The US FDA
The FDA first published a document on its thinking in
May 1999, entitled “Managing the Risks from Medical
Product Use and Creating a Risk Management Frame-
work”. It addressed pre- and post-marketing risk man-
agement and the FDA’s role. Further publications have
extended and elaborated the FDA’s position. However,
this topic represents a continuously evolving area of
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 293
policy and guidance, so stakeholders should review the
FDA website on a regular basis for up to date informa-
tion (www.fda.gov).
The FDA published three guidances for industry on
risk management in 2005:
1. Pre-marketing risk assessment.
2. Development and use of risk minimization action
plans (RiskMAPs).
3. Good pharmacovigilance practices and pharma-
coepidemiologic assessment.
The first guidance, on pre-marketing risk assess-
ment, focuses on measures companies might consider
throughout all stages of clinical development of prod-
ucts. For example, a section on special safety consider-
ations describes ways that risk assessment can be tailored
for those products intended for use chronically or in
children.
General recommended risk assessment strategies
include long-term controlled safety studies, enrollment
of diversified patient populations, and phase III trials
with multiple-dose levels. Some key components of the
guidance include the following:
Providing specific recommendations to industry for
improving the assessment and reporting of safety
during drug development trials.
Improving the assessment of important safety
issues during registration trials and providing best
practices for analyzing and reporting data that are
developed as a result of a careful pre-approval safety
evaluation.
Building on (but not superseding) a number of
existing FDA and International Council for Harmo-
nization guidelines related to pre-approval safety
assessments.
The other two FDA guidances have been super-
seded but are of historical interest. The RiskMAP
guidance describes how industry can address specific
risk-related goals and objectives. This guidance also
suggests various tools to minimize the risks of drug and
biologic products. This guidance has been superseded
by the 2007 FDAAA (Food and Drug Administration
Amendments Act) legislation that established REMS
(see below).
The third guidance, on the post-marketing period,
identifies recommended reporting and analytical prac-
tices to monitor the safety concerns and risks of medical
products in general use.
Concepts espoused by FDA are that all products
need full life-cycle risk management, including older and
already marketed products. This is ordinarily accom-
plished by the FDA-approved Package Insert; all prod-
ucts are subject to routine risk minimization. However,
some products (both new and old) may need specific risk
minimization tools (or REMS) above and beyond routine
post-marketing surveillance. The REMS must be tailored
to the product and its known important and unknown
risks (including missing information); it must be able
to minimize a serious risk in a measurable, quantifiable
way; and it must be modified if the risks are not min-
imized. In addition, effective communication methods
play a major role in REMS.
From the FDA perspective, each REMS must
include a goal to mitigate a specific important risk (or
risks), and the tool(s) to accomplish the goal is gen-
erally communication of focused information on the
specific serious risk(s) and the required non-routine
activities, or both. In addition to the applicant and FDA,
REMS may involve one or more stakeholders in the
healthcare delivery system (e.g., healthcare providers,
pharmacists, patients). Considered together, the REMS
goal, communications, and other non-routine activities
are intended to supplement routine risk minimization
activities and make up the safety strategy.
Each REMS is designed to focus on a specific seri-
ous safety concern, and it is important to remember
that a well-designed REMS is a means by which patients
can have access to medications with serious risks that
would otherwise not be available to them.
A key part of REMS is communication of the spe-
cific serious safety risk(s) that the REMS is intended to
mitigate. The communication tools may be directed at
healthcare providers or patients or both. Some REMS
include requirements for clinical activities that health-
care providers must perform prior to prescribing or dis-
pensing the medication to a patient.
294 Cobert’s Manual of Drug Safety and Pharmacovigilance
The FDA may require companies submitting new
drug applications (NDAs), abbreviated NDAs (ANDAs),
and biologics license applications (BLAs) to submit a
REMS if FDA “determines that such a strategy is neces-
sary to ensure that the benefits of the drug outweigh the
risks of the drug”. A company may voluntarily submit a
proposed REMS if it believes that a REMS would be nec-
essary to ensure that the benefits of the drug outweigh
the risks. New safety information on a serious risk that
arises after a product is approved may also trigger a new
requirement for a REMS. Also, applicants that had Risk-
MAPS in place continue with them, with or without
modifications, as a “deemed REMS”.
The requirement for a REMS is enforceable by
law, and if the person responsible for the drug (in the
company) fails to comply, the drug is considered mis-
branded. Penalties of up to $1 million are possible for
the first violation and may increase to $10 million for
subsequent violations.
The content of a REMS is described in the legis-
lation. There are two major sections: (1) A proposed
REMS and (2) A REMS supporting document.
The Proposed REMS from
the Applicant/Company
An applicant prepares a proposed REMS to address a
serious risk that will appear in the US Package Insert.
FDA must approve the REMS and will also assess results
of effectiveness assessments of the non-routine inter-
ventions. The contents of a proposed REMS are given
as follows:
1. Table of contents.
2. Background: The REMS should describe the
important serious risks (e.g., those seen in clin-
ical and pre-clinical studies), risks seen with
similar products or other drugs in the class,
and risks expected with the underlying medical
problem or disease (e.g., cancer seen with ulcer-
ative colitis). It should also identify subgroups
at risk (e.g., certain demographic groups such as
the elderly or newborns) and if there are risks
seen with similar products (e.g., bleeding with
non-steroidal anti-inflammatory drugs [NSAIDs]
or rhabdomyolysis with statins).
3. Goal(s): The goal(s) and objective(s) of the
REMS. The goal is a desired safety-related out-
come or understanding by patients and provid-
ers. It should be clear and absolute, and aim to
achieve maximum risk reduction. It should be
pragmatic, specific, and measurable. Following
are some examples:
Patients on Y drug should be aware of the risks
of rhabdomyolysis (measurable by the num-
ber of serious adverse events, or SAEs (Serious
adverse events), of rhabdomyolysis).
Patients on X drug should not also be prescribed
Y drug (measurable by the number of patients
receiving both drugs together).
Fetal exposures to Z drug should not occur (mea-
surable by the number of fetal exposures).
4. REMS elements: A REMS may have one or more
of the following:
Medication guide (“MedGuide”) or patient
package insert (PPI) — This will be required
if patient labeling could prevent SAEs, if the
risks relative to the benefits could affect the
patient’s decision to use or continue using
the drug, or if adherence to directions for use
is crucial for effectiveness of the drug. Some
early REMS were MedGuide only, but Med-
Guides have been de-coupled from REMS.
Some REMS continue to have MedGuides
along with other elements. Note that all
MedGuides are approved by FDA as part of
a drug’s labeling, but only a small number of
MedGuides are included as a component of a
REMS.
Communication plan to healthcare providers
— This may be variable and include letters to
healthcare providers, and information about
REMS elements to encourage implementation
or to explain certain safety requirements such
as periodic laboratory tests.
Elements to assure safe use (ETASU) — These
will be used if a medication guide and com-
munication plan are not sufficient. ETASUs
should not be confused with post-marketing
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 295
commitments or requirements (studies or
other procedures promised to FDA after NDA
approval and as a condition of the approval),
which may or may not be part of a REMS. See
Table 1 for examples of ETASU.
Implementation system — If included in
the REMS, it should describe the system for
implementing, monitoring, and evaluating the
intended goals and effects. An implemen-
tation system may include a description of
the distribution system of the drug, and the
REMS may require certification of wholesalers
and distributors to ensure they comply. Exam-
ples of implementation methods include the
maintenance of a validated database to track
certified prescribers/dispensers, and periodic
audits of pharmacies, practitioners, and others
to ensure compliance with ETASUs.
Timetable for assessments — The assessments
should be done no less frequently than at 18
months, 3 years, and 7 years after the REMS is
approved by FDA. However, the time required
to implement a REMS and for the healthcare
system to adopt it should be considered in
conducting assessments.
5. REMS assessment plan: What will be done, when
it will be done and measured to evaluate whether
the goals are achieved, and what the criteria are
for success. It is common to measure behaviors of
the various factors, which may trigger increased
or decreased REMS requirements.
6. Other relevant information.
7. Appendix: Supporting documents are included
for each section above.
Other post-marketing actions may be proposed,
such as “enhanced surveillance” (often this is ill-
defined and turns out to be just a bit more due diligence
on spontaneously reported cases), targeted safety stud-
ies, large simple safety studies (LSSS), epidemiologic
studies (e.g., comparative observational studies), and
drug utilization studies.
Table 1.
Examples of REMS Requirements that are Considered ETASU; Adapted from www.fda.gov.
ETASU Example Description
Prescribers must have
specific training, experience,
or be specially certified
Prescribers may be required to become certified and/or take training prior to prescribing the drug.
Prescribers may need to enroll in the REMS and agree to carry out certain activities for safe drug use, e.g., a
prescriber may be required to agree to counsel their patients about the particular serious risk, or agree to
enroll, and/or monitor patients throughout the treatment course.
Pharmacies, practitioners,
or healthcare settings that
dispense the drug may need
to be specially certified
Pharmacies, practitioners, or other healthcare settings that may dispense REMS medications may be
required to take the training, train staff, and oversee all processes and procedures needed to implement
the REMS requirements. For example, a pharmacy may need to put a process in place that includes
verifying that the prescriber of a REMS drug is certified, patients are enrolled, and that laboratory testing
or other certain safe use conditions have been carried out prior to dispensing the drug.
Drug may be dispensed only
in certain healthcare settings
such as hospitals
The REMS may require that the drug be dispensed or administered only in a particular setting. For
example, administration of the drug may be restricted to healthcare settings that have immediate access
to supplies or personnel trained to manage a particular adverse event.
Evidence of safe use
conditions, such as laboratory
test results, may be required
before the drug is dispensed
or administered
FDA may require that a REMS drug be dispensed only with documentation of safe use conditions. For
example, healthcare providers and patients may need to execute a signed patient–prescriber agreement
for a teratogenic drug, so they understand the risk and the need to verify a negative pregnancy test for
patients who could potentially be pregnant.
Each patient using the drug
maybe subject to monitoring
FDA may require that patients using the drug are subject to certain monitoring during and/or after
treatment. For example, patients may need periodic vision monitoring if there is a risk of vision loss.
Enrollment in a registry may
be required for each patient
using the drug
Patients may be required to be enrolled in a patient registry. The patient registry may include all patients
or a subset of all enrolled patients that experience the adverse event of concern. The purpose of a patient
registry is to follow patients during and in some cases after treatment with the drug.
296 Cobert’s Manual of Drug Safety and Pharmacovigilance
The Approved REMS
FDA must approve a REMS before implementation.
Since the REMS may be a condition of product approval,
it is advantageous for the applicant to work with FDA
on a possible REMS requirement as early as possible
after a serious risk is identified in the regulatory review
process.
Design of the REMS is important and, of course, the
non-routine tools specified in the REMS should be the
least burdensome on the healthcare delivery system,
patients, and their caregivers. With FDA’s concurrence,
the applicant is responsible for ensuring the required
assessment plan is appropriately designed, conducted,
analyzed, interpreted, and reported. The assessment
plan should be designed to assess effectiveness of the
REMS, i.e., whether the behaviors of the various factors
are consistent with achieving the goal(s) of the REMS.
Results of the assessment(s) may trigger increased or
decreased REMS requirements. If the desired behavior
is sustainable over time, the applicant may be released
from the REMS altogether.
Once approved by FDA, REMS are published on
REMS@FDA and on the applicant’s website for the prod-
uct. FDA updates REMS@FDA when an approved REMS
is revised, modified, or released. In addition, applicants
make REMS materials public on product-specific web-
sites hosted by applicants.
Roles of Key REMS
Participants
Roles of the various factors in a REMS may be similar
across programs, but the specific requirements and risk
messages of each REMS are specifically tailored to each
medication, the nature of its risks, and the likely set-
ting of the drug’s use. Regarding specific requirements
for each REMS participant, details are provided in the
REMS documents.
1. Healthcare providers: Prescribers of med-
ication (e.g., physicians, physician’s assistants,
nurse practitioners, or other healthcare provid-
ers) are important in ensuring that products with
REMS are prescribed properly and used safely.
As with patients, REMS requirements vary by
product. One of the more common tools speci-
fied in a REMS is communication(s) on serious
risks from the manufacturer(s). Providers may
have REMS enrollment obligations, training pro-
grams, documentation of patient counseling,
periodic lab testing or other monitoring, or doc-
umentation of safe use conditions, etc.
Details for each REMS are available at REMS@
FDA, in product labeling or on the manufactur-
er’s product websites.
2. Pharmacists: Practitioners who dispense med-
ications that have REMS are obligated to dispense
as specified and meet other REMS requirements,
even though they are not directly regulated by
FDA. Requirements will vary from REMS-to-
REMS, which may be related to the setting (e.g.,
inpatient pharmacy versus retail) or require-
ments for training or certification. Of course,
compliance audits for the various requirements
will ordinarily be a component. A communica-
tion plan for some REMS may include communi-
cations directly from the relevant applicant(s).
3. Details about each REMS, including the roles of
pharmacies and healthcare settings, can be found
at REMS@FDA, in product labeling or on prod-
uct-specific websites.
4. Patients and their caregivers: These roles
are important and will vary with the REMS design
and requirements. Examples include counsel-
ing (e.g., by a prescriber or pharmacist) on an
important (serious) risk, what action(s) might be
needed to mitigate an important risk, or coaching
on how to identify symptoms for consultation
with their healthcare provider. Other examples
that might be required are pre-treatment (and
during treatment) lab testing or enrollment in a
registry.
5. For some REMS, documentation must be in order
(often monitored real-time by computer) before
medication is dispensed.
6. To assist with effectiveness metrics, prescribers,
pharmacists, or patients/caregivers may be asked
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 297
to participate in various surveys. The results
may trigger modification (or elimination) of the
REMS tools.
7. Applicants (manufacturers): The role of
applicants has been codified in legislation. In
addition to drug safety obligations required by
legislation, FDA has provided various guidance
documents on expectations for REMS:
“Revised Draft Guidance for Industry on For-
mat and Content of a Risk Evaluation and Miti-
gation Strategy Document”
This describes a revised REMS document tem-
plate, designed to improve efficiency of prepar-
ing and reviewing REMS documents.
“Guidance for Industry: Use of a Drug Mas-
ter File (DMF) for Shared System REMS
Submissions”
This guidance can be helpful if a shared system
REMS is required. It permits applicants to share
a DMF, which is intended to facilitate coordina-
tion submission of shared system REMS-related
files.
“Risk Evaluation and Mitigation Strategies:
Modifications and Revisions — Guidance for
Industry”
This guidance provides definitions for “modifi-
cations” and “revisions” to approved REMS and
how they will be handled by FDA.
“FDA’s Application of Statutory Factors in
Determining When a REMS is Necessary”
This guidance outlines the process FDA uses to
comply when applying REMS authorities speci-
fied in the 2007 FDAAA legislation. These doc-
uments should be sought on the FDA website.
“Medication Guides — Distribution Require-
ments and Inclusion in Risk Evaluation and
Mitigation Strategies (REMS) Guidance for
Industry”
This guidance clarifies expectations on distribu-
tion of MedGuides under various scenarios.
“Questions and Answers on Draft Guidance for
Industry: Medication Guides — Distribution
Requirements and Inclusion in REMS”
This Q&A document provides additional clari-
fication on MedGuide requirements.
“Development of a Shared System REMS Guid-
ance for Industry” (Draft Guidance)
This document clarifies aspects of shared sys-
tem REMS development.
“Technical Conformance Guide for Shared Sys-
tem REMS Drug Master File Submissions” (the
SSR DMF Technical Conformance Guide)
This is a technical guide for using a shared DMF
as part of a shared system REMS.
“Waivers of the Single, Shared System REMS
Requirement Guidance for Industry” (Draft
Guidance)
This provides guidance on the possibility of a
waiver from a shared system REMS.
“Standardizing and Evaluating Risk Evaluation
and Mitigation Strategies” (REMS Standardiza-
tion Report)
This report outlines four priority projects to
standardize REMS, as may be appropriate, and
reduce their burden.
“REMS and Continuing Education for Health-
care Providers — FDA Feasibility Report”
This describes healthcare professional participa-
tion in educational programs that are a part of
REMS.
Comments
The goals of the REMS are to continually assess the
benefit–risk balance and to ensure that it remains pos-
itive, if not globally, for all patients treated, then for a
subset(s). This may not be clear before marketing, but,
where a REMS is required, the best effort must be put
into designing a logical and thoughtful REMS, realizing
it may change with experience gained after marketing. It
should not pose an undue burden on the healthcare sys-
tem or patients, otherwise unintended consequences,
such as diversion to less desirable products, may occur.
Careful thought by a team knowledgeable about the
disease and drug in question should work on the REMS.
298 Cobert’s Manual of Drug Safety and Pharmacovigilance
They need to evaluate the patients and disease to deter-
mine whether there are measurable early signs, symp-
toms, or markers that will allow a risk management
intervention to prevent a bad outcome or SAE. This
will require review of the data available for the drug
and similar products, and an understanding of how the
drug will be used in the “real world” and whether dif-
ferent populations from those in the clinical trials will
be exposed to the drug. Obviously, much of this may
not be known before marketing, making it necessary
to change the REMS after marketing starts. The tricky
question of off-label use (if anticipated) should be con-
sidered and possibly incorporated in the REMS.
Further details and an example of a mock REMS are
found in the FDA-revised draft guidance cited above.
Shared System REMS
Beginning in 2009, the FDA began requiring all prod-
ucts in certain classes of drugs to have REMS. The first
group in this category was for botulinum toxin prod-
ucts, which had safety issues such as muscle weakness,
loss of bladder control, and breathing problems. All such
products are mandated to have a MedGuide, communi-
cation plan, and a timetable for assessments, but there
were no other ETASUs required. Other products with
class-wide REMS include testosterone gel drugs and
extended-release (ER) oral opioid products. In addi-
tion, if a branded product (the “reference-listed drug”)
has a REMS, the generic versions of the product will
also require a REMS. See Table 2. The generic’s REMS is
the same as that of the branded product, unless other-
wise justified and negotiated with FDA. Sometimes all
the companies producing a drug may work together on
a single REMS. This is usually mandated by FDA rather
than a voluntary action by applicants.
The concept behind a shared system is that it would
“level the playing field” and reduce the burden for dif-
ferent stakeholders (e.g., applicants, the healthcare
delivery system, patients, and regulators). To accom-
plish this, there is often a single portal to access REMS
materials and other information about the program.
Efficiencies are also gained by having prescribers, phar-
macies, and healthcare settings complete certification
and other administrative requirements once rather than
for each individual drug. This decreases complexity and
bureaucracy for the healthcare system. Such programs
also have the potential for cost sharing among partici-
pating applicants.
In certain situations, it is possible to obtain a waiver
from participating in a shared system REMS. For exam-
ple, FDA granted a waiver to three ANDA (Abbreviated
New Drug Application) applicants for participation
Table 2. Example of Approved Shared System REMS in Effect, as of November 13,
2017.
Products Number of
Applicants
Number of
Products
REMS
Elements
Alosetron 2 2 ETASU
Buprenorphine transmuscosal products for opioid dependence (BTOD) 13 17 MG, ETASU, IS
Clozapine 11 13 ETASU, IS
Emtricitabine/tenofovir disoproxil fumarate 2 2 ETASU
ER and long-acting (LA) opioids 36 64 MG, ETASU
Isotretinoin iPLEDGE 6 7 MG, ETASU, IS
Mycophenolate 20 33 ETASU
Sodium oxybate
(1/3 = one reference-listed drug REMS and another waiver-granted
“comparable” REMS for three additional generic products)
1/3 4 MG, ETASU, IS
Transmucosal immediate-release fentanyl (TIRF) products 8 9 MG, ETASU, IS
Vigabatrin 2 3 ETASU, IS
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 299
in a single, shared system REMS for sodium oxybate
oral solution drug products. Serious risks associated
with these products can include central nervous sys-
tem effects. In granting a waiver to the shared system
requirement, FDA found that: (a) the burden of a single
shared system would not be easily workable and (b) the
ANDA applicants were unable to obtain a license for an
aspect of the ETASU that the innovator had patented.
Thus, FDA approved a separate shared system REMS for
the generic products that was considered “comparable”
to the innovator REMS which continued in force. Note
that FDA attached a condition that the “comparable”
waiver-granted system would be open to future appli-
cants. See Table 2.
REMS Template
As noted above, the template is available at “Proposed
Risk Evaluation and Mitigation Strategies (REMS), REMS
Assessments, and Proposed REMS Modifications”.
Comments
In theory, a REMS should be short, compact, and not
burdensome on patient access or the healthcare deliv-
ery system. In practice, many are complex and must be
designed with the European Union and other countries’
risk requirements in mind. Ideally, a company would
like to develop one risk plan for all markets, but the
practicalities and requirements for local content have
rendered this impossible. Nonetheless, REMS and risk
plans will ordinarily focus on a common goal, but the
means to achieve the goal may differ in different health-
care settings and jurisdictions. Also, plans need to be
thought about across a product’s entire life cycle by the
appropriate personnel either inside the company or
outside as consultants. Review of the publicly available
REMS should be done frequently.
There is a continuous and, for now, unresolvable
debate that many companies go through when submit-
ting a new drug/biologic application (NDA/BLA). The
question is whether one should offer up a REMS vol-
untarily or let FDA “force” one on the company. The
case for a REMS up front and voluntarily is that, if it is
good for the public health and the correct thing to do, it
should be done without having to be told to do it. It will
allow the company to prepare a thoughtful, reasonable,
low burden, cost-effective program rather than finding
out at the last moment (e.g., just before approval) that
the FDA wants a REMS and perhaps an aggressive one
that contains more than the company feels appropriate.
Negotiations and research on REMS components at the
last minute before approval in a pressured atmosphere,
where the company may feel obliged to commit to a
large program just to get the drug on the market quickly
is usually not a good idea. However, some companies
are willing to take this risk and not propose a REMS
in the hope that the FDA will not require one. This
avoids, from their point of view, unnecessary expense
and effort. Others argue that the company should pro-
pose a REMS but that it should always be minimalist
(e.g., just a MedGuide and a communication plan for
healthcare providers) to show “good faith” but not to
“overcommit”. The obvious answer to all of this is that
one should do the right thing for patients. It is also
hoped that the company’s and the Agency’s views on
what constitutes an appropriate REMS for a serious risk
will not differ too much. Unfortunately, the right thing
is not always clear, and economics and politics often
enter into the decision.
European Union RMPs
The fundamental documents establishing PV and RMP
(Risk Management Plans) concepts for the European
Union are Directive 2001/83/EC (Article 8(3)(ia)), as
amended by Directive 2004/27/EC: “The MA (Market-
ing Authorization) application shall be accompanied
by a detailed description of the pharmacovigilance and,
where appropriate, of the risk-management system
which the applicant will introduce”. In addition, Arti-
cle 9(4)(c) of Regulation EC No. 726/2004, “Requires
details of conditions and restrictions on supply or use
or with regard to safe and effective use of the medici-
nal product attached to Opinion…” Detailed require-
ments are in the EU Good PV Practices (GVP) Mod-
ule V — Risk management systems, as revised (2017).
A CHMP guideline published in 2005 was based, to a